• National Institute for Health and Clinical Excellence (NICE). Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Sep. 26 p. (Technology appraisal guidance; no. 157).

This is the current release of the guideline.

Venous thromboembolism after hip or knee replacement surgery

Assessment of Therapeutic Effectiveness
Prevention

Hematology
Internal Medicine
Orthopedic Surgery
Preventive Medicine

Advanced Practice Nurses
Nurses
Physician Assistants
Physicians

To evaluate the clinical effectiveness and cost-effectiveness of dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery

Adults undergoing hip or knee replacement surgery

Dabigatran etexilate (Pradaxa)

• Clinical effectiveness
  • Mortality
  • Incidence of deep vein thrombosis (DVT)
  • Incidence of pulmonary embolism (PE)
  • Adverse events including bleeding events
  • Post DVT complications, including post-thrombotic syndrome
  • Length of hospital stay
  • Health-related quality of life
• Cost-effectiveness

Searches of Electronic Databases

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform an assessment of the manufacturer's submission on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The assessment report for this technology appraisal was prepared by the School of Health and Related Research (ScHARR), University of Sheffield (see the "Availability of Companion Documents" field).

Critique of Manufacturer's Approach

Description of Manufacturer's Search Strategy and Comment on whether the Search Strategy Was Appropriate

The searches undertaken by the manufacturer to identify all relevant randomised controlled trials (RCTs) were conducted in February 2008. The search strategy utilises terms to identify the patient group (hip and knee replacement surgery), the intervention (dabigatran etexilate) and the type of evidence (study, trial). No language restrictions appear to have been applied. The strategy is simple and reasonably effective, but a form of methodological filter is applied (study.mp or trial.mp), even though it is clearly stated that the strategy was intended not to identify a particular study design. The filter used is not validated nor is its efficacy reported elsewhere, and given the small number of citations retrieved, these terms could have been omitted, without greatly increasing the work involved. The resulting strategy would have been more sensitive and less vulnerable to criticism.

Only five databases were searched (Medline, Medline in-process, Embase, The Cochrane Library and the manufacturer's own in-house database, BILIT/pre-BILIT); key data may therefore have been missed, particularly regarding unpublished data (no research registers, such as the National Research Register or Current Controlled Trials, were searched, other than the manufacturer's own in-house database). Key databases overlooked include the Science Citation Index (Web of Science) and BIOSIS. The searches also applied date limits, which were not justified in the manufacturer's submission (MS). The range reported to be searched for Medline in-process (1996-2008) is not congruent with the scope of the database.

No methods, other than the searching of the above electronic databases, were used to identify studies (e.g., handsearching of journals, reference and citation tracking). The use of such supplementary methods is required by the QUORUM checklist (Moher, 1999). The MS fails to report the use of such methods, or to explain why these methods were not used.

Statement of the Inclusion/Exclusion Criteria Used in the Study Selection and Comment on whether They Were Appropriate

Inclusion Criteria

• Randomised controlled trials (RCTs) evaluating dabigatran etexilate (DBG) in the prevention of thromboembolic events after total hip or knee replacement
• Observational studies evaluating DBG in the prevention of thromboembolic events after total hip or knee replace

Exclusion Criteria

• Reviews
• Comments letters/editorials containing no original data
• Abstracts presenting results of studies subsequently published in full
• Studies not using the dose of DBG proposed for use in the UK for this indication
• Studies which did not have clinical efficacy/safety as the primary objective

The inclusion/exclusion criteria appear to be appropriate, but the rationale behind the stated inclusion and exclusion criteria was not given.

What Studies Were Included in the Submission and What Were Excluded?

Of the 19 citations identified by the search of electronic databases, 16 were correctly excluded for the following reasons:

• RCT with inappropriate dose of DBG (1)
• Comment letters/editorials/reviews with no original data (3)
• Non-RCTs with clinical data potentially relevant to the decision problem (0)
• Non-RCTs without clinical data (e.g., pharmacokinetic or dose-ranging studies) (5)
• Abstracts of conference presentations of trial results subsequently published in full (7)

The remaining three studies were included. Details of the study design and patient characteristics of the included studies are summarised in Table 4 of the ERG report (see the "Availability of Companion Documents" field).

Refer to Section 4.1 of the ERG report (see the "Availability of Companion Documents" field) for additional information on search strategies.

Clinical Effectiveness

Three randomized controlled trials (RE-NOVATE, RE-MODEL and RE-MOBILIZE) were included.

Cost-Effectiveness

Three above-mentioned studies and a manufacturer's model were submitted.

Expert Consensus

Not applicable

Meta-Analysis
Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Expert Consensus

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

The manufacturer submitted an economic model assessing the impact of dabigatran etexilate for venous thromboembolic events (VTE) prevention after hip and knee replacement compared with low molecular weight heparin (LMWH) and fondaparinux. The model included an acute-phase decision-tree model to 10 weeks after surgery and a chronic-phase Markov model with a lifetime (60-year) time horizon.

Key assumptions in the economic evaluation are detailed in the manufacturer's submission. Among these, the manufacturer assumed that all LMWHs are bioequivalent, because literature on dalteparin, tinzaparin and enoxaparin and the national Institute for Health and Clinical Excellence (NICE) clinical guideline 'Venous thromboembolism' (NICE clinical guideline 46) recommendations did not distinguish between LMWHs. Furthermore, a zero cost for administration was assumed for dabigatran etexilate, whereas LMWH and fondaparinux were assumed to require resources for administration (including provision for a proportion of people who were unable or unwilling to self-inject). These administration costs were determined to be 100.00 pounds sterling and 6.00 pounds sterling for LMWH and 83.00 pounds sterling and 6.00 pounds sterling for fondaparinux after hip or knee replacement, respectively.

The base-case analysis estimated that at 220 mg dabigatran etexilate was less costly and more effective than LMWH for both hip and knee replacement surgery. At the lower dose of 150 mg, dabigatran etexilate was less costly and more effective than LMWH for hip replacement surgery, but was more costly and less effective than LMWH for knee replacement surgery. In univariate sensitivity analyses none of the parameters were associated with a significant difference in the base-case results.

The economic evaluation estimated that at both doses dabigatran etexilate is less costly but also less effective than fondaparinux after hip replacement (incremental cost-effectiveness ratios [ICERs] were in the 'southwest' quadrant of the cost-effectiveness plane). After knee replacement, dabigatran etexilate at both doses was dominated by fondaparinux (that is, it was more costly and less effective than fondaparinux). In sensitivity analysis, increasing the relative risk of VTE for fondaparinux was associated with dabigatran etexilate dominating for hip replacement and being less costly, but being less effective in knee replacement.

Probabilistic sensitivity analysis and cost-effectiveness acceptability curves suggested probabilities of dabigatran etexilate being cost effective compared with LMWH (at a willingness-to-pay threshold range of 20,000 pounds sterling per additional Quality Adjusted Life Years Saved [QALY] gained) of 99% for the 220-mg dose after hip replacement, 82% for the 220-mg dose after knee replacement, 76% for the 150-mg dose after hip replacement, and 38% for the 150-mg dose after knee replacement). The corresponding results for dabigatran compared with fondaparinux were 40% for the 220-mg dose and 32% for the 150-mg dose after hip replacement, and zero for both doses after knee replacement).

Following a request for clarification from the Evidence Review Group (ERG), the manufacturer provided cost-effectiveness analyses with inputs from meta-analysis which included data from the RE-MOBILIZE trial. The revised economic evaluation estimated that dabigatran etexilate was dominated by LMWH (that is, it was more costly and less effective than LMWH) for knee replacement at both 220-mg and 150-mg doses.

The ERG commented that the mixed-treatment comparison did not provide indirect comparisons of fondaparinux and dabigatran etexilate, making it difficult to reach conclusions about their relative efficacy and safety. The ERG also noted that the outcome assessed in the mixed-treatment comparison was deep vein thrombosis (DVT) (not the composite primary outcome of the dabigatran etexilate trials). It was also unclear how the trial data had been used to derive the mixed-treatment comparison of DVT outcome. The ERG suggested that results of the manufacturer's mixed-treatment comparison should be considered with caution.

The Committee considered the results of the economic evaluation and noted that because of the closeness of all the effectiveness and cost data, the ICERs were very sensitive to changes in assumptions. At the 220-mg once-daily dose dabigatran etexilate was less costly and more effective than LMWH for both hip and knee replacement. At the lower dose of 150 mg, dabigatran etexilate dominated LMWH for hip replacement, but was dominated by LMWH for knee replacement. It noted that results were not very sensitive to reduced drug acquisition costs reflecting the reduced purchase price available to some NHS trusts.

The Committee noted that in the base-case modelling dabigatran etexilate at either dose was less costly and less effective than fondaparinux in hip replacement and more costly and less effective than fondaparinux in knee replacement. However, the Committee was mindful of the small differences between interventions and noted the sensitivity of the model results to changes in clinical effectiveness inputs.

Furthermore, the Committee considered that the model had not attempted to incorporate the utility benefits (in the form of disutility avoided) of oral administration over injection, and that the potential benefit of greater adherence with oral as opposed to subcutaneous treatment had been modelled conservatively.

Overall, taking into account that the cost and effectiveness data of dabigatran etexilate are similar to those of LMWH and fondaparinux, and that some benefits of the availability of an oral formulation had not been captured in the modelling, the Committee concluded that dabigatran etexilate was as cost-effective a use of National Health Service (NHS) resources as LMWH or fondaparinux.

Refer to Sections 3 and 4 of the original guideline document for more information on cost-effectiveness.

External Peer Review

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

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.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate use of dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery

According to data reported in the summary of product characteristics (SPC), around one in seven people undergoing hip or knee surgery and treated with dabigatran etexilate experienced a bleeding event (13.8% of those receiving daily doses of 220 mg or 150 mg). Major bleeds were common and were experienced by 1.8% and 1.3% of people treated with 220 mg or 150 mg dabigatran etexilate, respectively. Other common adverse effects (those occurring in at least 1%, but less than 10% of patients) include gastrointestinal haemorrhage, wound secretion, anaemia, and haematoma.

For full details of side effects and contraindications, see the SPC.

• This guidance represents the view of the Institute, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. The guidance does not, however, override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
• Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.

Staying Healthy

Effectiveness
Patient-centeredness

• National Institute for Health and Clinical Excellence (NICE). Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Sep. 26 p. (Technology appraisal guidance; no. 157).

Not applicable: The guideline was not adapted from another source.

2008 Sep

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Professor David Barnett, Professor of Clinical Pharmacology, University of Leicester; Dr David W Black, Director of Public Health, Chesterfield PCT; Mr Brian Buckley, Chairman, Incontact; Dr Carol Campbell, Senior Lecturer, University of Teesside; Professor Mike Campbell, Professor of Medical Statistics, University of Sheffield; Professor David Chadwick, Professor of Neurology, University of Liverpool; Dr Christine Davey, Senior Researcher, North Yorkshire Alliance R & D Unit; Dr Mike Davies, Consultant Physician, Manchester Royal Infirmary; Mr Richard Devereaux-Phillips, Public Affairs Manager, Medtronic Ltd; Dr Rachel A Elliott, Lord Trent Professor of Medicines and Health, The University of Nottingham; Mrs Eleanor Grey, Lay member; Dr Dyfrig Hughes, Senior Research Fellow in Pharmacoeconomics, Centre for the Economics of Health and Policy in Health, University of Wales; Dr Peter Jackson, Clinical Pharmacologist, the University of Sheffield; Ms Rachel Lewis, Nurse Advisor to the Department of Health; Dr Damien Longson, Consultant in Liaison Psychiatry, North Manchester General Hospital; Professor Jonathan Michaels, Professor of Vascular Surgery, University of Sheffield; Dr Eugene Milne, Deputy Medical Director, North East Strategic Health Authority; Dr Simon Mitchell, Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester; Dr Katherine Payne, Health Economics Research Fellow, The University of Manchester; Dr Philip Rutledge, Consultant in Medicines Management, NHS Lothian; Mr Miles Scott, Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust; Dr Surinder Sethi, Consultant in Public Health Medicine, North West Specialised Services Commissioning Team; Professor Andrew Stevens, Chair of Appraisal Committee C; Dr Cathryn Thomas, Senior Lecturer, Department of Primary Care & General Practice, University of Birmingham; Dr William Turner, Consultant Urologist, Addenbrooke's Hospital

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

This is the current release of the guideline.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.