Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal

Article history

The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 07/90/01. The assessment report began editorial review in June 2008 and was accepted for publication in April 2009. See the HTA programme web site for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Declared competing interests of authors

Dr Eddie Hampton (Senior Lecturer and Honorary Consultant in Haematology, Sheffield Teaching Hospitals): none. Dr Raj Patel (Consultant Haematologist, King’s College Hospital): none. Dr Rhona Maclean (Consultant Haematologist, Sheffield Teaching Hospitals): Dr Maclean is a local investigator in a study of the use of dabigatran for the treatment of venous thromboembolism and has been approached by Boehringer Ingelheim to do an educational session/lecture in April 2008 for the employees of Boehringer Ingelheim for which she will receive payment. All other authors: none.

Copyright statement

© 2009 Queen’s Printer and Controller of HMSO. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2009 Queen’s Printer and Controller of HMSO

Summary of submitted clinical evidence

The main evidence in the submission is derived from three head-to-head, phase III, multi-arm, randomised, double-blind, controlled, noninferiority trials (RE-NOVATE, RE-MODEL and RE-MOBILIZE). These trials compared the efficacy and safety of DBG at doses of 220 mg and 150 mg once daily with that of enoxaparin [40 mg once daily in RE-NOVATE and RE-MODEL, 30 mg twice daily in RE-MOBILIZE] in patients undergoing total knee replacement (RE-MODEL and RE-MOBILIZE) or total hip replacement (RENOVATE). Follow-up was 12–14 weeks.

DBG (at both 220 mg once daily and 150 mg once daily) does not appear to be inferior to enoxaparin (40 mg once daily and 30 mg twice daily) in terms of the secondary efficacy outcome of major VTE or VTE-related events.

The meta-analysis of the primary efficacy outcome across all three trials, and across combinations of these trials, appears to show that the intervention DBG at a dose of 220 mg once daily was not inferior to the comparator enoxaparin (at either 40 mg once daily or 30 mg twice daily) in reducing levels of total VTE and all-cause mortality among patients undergoing total hip replacement and total knee replacement.

Evidence from post hoc subgroup analyses of the included trials indicates that the 150-mg once daily dose may be less effective in terms of incidence of total VTE and all-cause mortality than the 220-mg once daily dose in the special populations indicated for this lower dose and for whom the lower dose is specifically licensed. Safety outcomes were not reported for these subgroups.

The meta-analysis of the RE-MODEL and RENOVATE trials appears to show that the 150-mg once daily dose of DBG is not inferior to the comparator enoxaparin (at either 40 mg once daily or 30 mg twice daily) in reducing levels of total VTE and all-cause mortality among patients undergoing total hip replacement and total knee replacement.

The meta-analyses of the two total knee replacement trials combined (RE-MODEL and REMOBILIZE) and the three total knee replacement and total hip replacement trials combined (RENOVATE, RE-MODEL and RE-MOBILIZE) appear to show that the 150-mg once daily dose of DBG is inferior to the comparator enoxaparin (at both 40 mg once daily and 30 mg twice daily) in reducing levels of total VTE and all-cause mortality among patients undergoing total hip replacement and total knee replacement.

An MTC analysis compared the results of these trials of DBG with results for all other available interventions for patients undergoing surgery and at risk of DVT and found that DBG compared favourably with the other interventions, with the exception of extended enoxaparin and fondaparinux, which appear to be relatively more effective (level of statistical significance of difference not reported).

The adverse event profile was not significantly different in those receiving DBG compared with those receiving enoxaparin. The primary safety end point was major bleeding. Clinically relevant bleeding, any bleeding and liver function were also measured (secondary end points).

Summary of submitted cost-effectiveness evidence

The model developed by Boehringer Ingelheim has an acute phase that starts at the time of surgery and ends at 10 weeks post surgery and a chronic phase with a lifetime horizon. The model compares DBG with enoxaparin and fondaparinux in both total hip replacement and total knee replacement. The acute phase model is a decision tree which predicts the health states that patients will be in at 10 weeks based on evidence from phase III trials of DBG compared with enoxaparin and from an MTC of DBG compared with fondaparinux. At 10 weeks patients enter a chronic phase Markov model in the same health state in which they terminated the decision tree model. No further treatment effect is applied in the chronic phase model. Transition between states in the chronic phase model is dependent on VTE recurrence rates obtained from the literature.

The health states, costs, utilities and recurrence rates used within the model are considered to be appropriate for the required analysis.

The Boehringer Ingelheim model estimated that:

• at the licensed dose of 220 mg once daily DBG dominates enoxaparin in both total hip replacement and total knee replacement

• at the lower dose of 150 mg once daily DBG dominates enoxaparin in total hip replacement and enoxaparin dominates DBG in total knee replacement

• DBG is less cost-effective than fondaparinux in total hip replacement at both doses of DBG. The cost/QALY of fondaparinux versus DBG is £11,111 and £6857, respectively, for the higher and lower doses of DBG.

• In total knee replacement, both DBG doses are dominated by fondaparinux.

Table 1 presents a summary of the cost-effectiveness results. For DBG versus all comparators it should be noted that in all cases the cost-effectiveness results are based on small incremental cost and health benefits.

Strengths

The manufacturer conducted a limited, but systematic search for clinical and cost-effectiveness studies of DBG for the prevention of VTE in patients undergoing total knee replacement and total hip replacement. It appears unlikely that any additional trials would have met the inclusion criteria had the search been widened to include more free-text terms or to include other databases.

The three identified trials, which represent the main clinical efficacy evidence, were of reasonable methodological quality, with some limitations, and measured a range of outcomes that were appropriate and clinically relevant.

The meta-analyses demonstrated the noninferiority of DBG 220 mg once daily versus enoxaparin in terms of the efficacy and safety end points, and acknowledged the apparent inferiority of the 150-mg once daily dose in terms of the primary efficacy outcome.

An MTC analysis compared DBG with all other available interventions for patients undergoing surgery and at risk of DVT and found that DBG compared favourably with the other interventions, with the exception of extended low-molecularweight heparins and fondaparinux, which appear to be more effective.

The model structure is appropriate and allows sensitivity analysis to be carried out easily.

The model assumptions are reasonable.

The univariate sensitivity analysis is extensive and is performed on appropriate parameters.

The probabilistic sensitivity analysis is performed correctly.

Weaknesses

The processes undertaken by the manufacturer for screening studies, data extraction and applying quality assessment criteria to included studies were not made explicitly clear in the submission. These factors limit the robustness of the systematic review.

Quality assessment of the included studies should have been undertaken using a checklist appropriate to the types of study included (non-inferiority randomised trials).

One of the trials used in the clinical effectiveness section is published only as an abstract (REMOBILIZE); much of the key data employed are unpublished.

A simple pooled analysis of the patient level data from the two pivotal trials, as well as all three head-to-head trials, was reported. However, the methods used for this data pooling were not described; the statistical approach for combining the data appears to be inappropriate as it fails to preserve randomisation and introduces bias and confounding. The resulting pooled data should therefore be treated with caution.

Elements of the MTC reported in the manufacturer’s submission are reproduced from documents produced by organisations other than the manufacturer, rather than specifically in response to the scope. The key details of trials included in the MTC, and issues relating to heterogeneity of trials, are neither reported nor discussed. The resulting MTC should therefore be treated with caution.

The economic results for DBG compared with enoxaparin in total hip replacement and total knee replacement both rely on one trial each. These trials indicate that DBG is not inferior to enoxaparin. The small numerical difference seen in these trials is reproduced in the model in terms of both incremental costs and incremental health benefits (see Table 1). A small change in the direction of the trial results could significantly change the cost-effectiveness conclusions.

The economic results for DBG versus fondaparinux in total hip replacement are based on one study for which the manufacturer appears to have used an incorrect relative risk estimate. However, the difference is small and the impact on the results is likely to be small.

VTE recurrence rates, post-thrombotic syndrome rates and quality of life utilities used in the model are based on a literature review limited to economic studies. It is therefore possible that non-economic studies reporting these data in sources such as MEDLINE have not been identified.

Some input parameters into the modelling process are incorrect. These include using the underlying risk of DVT instead of the underlying risk of VTE for the comparison of DBG with fondaparinux, wrongly estimating the recurrence rates for VTE, wrongly estimating the probability of PE being severe, not including intensive care unit costs in PE post discharge and including the cost of informal care when it should be excluded. The ERG was unable to correct all of these mistakes and the impact on the model results is therefore unknown.

Key issues

The external validity of the evidence is limited. Only a single randomised controlled trial (RCT) using a comparator and dose applied in England and Wales has been conducted on each of the relevant total hip replacement and total knee replacement populations. The addition of evidence from any future RCTs may alter the results regarding the non-inferiority of DBG. Small changes in key parameters could markedly alter the conclusions with respect to cost and clinical effectiveness.

The results of the RE-MOBILIZE total knee replacement trial indicate that both the 220mg once daily and the 150-mg once daily dose of DBG are inferior to enoxaparin in terms of the primary efficacy outcome of total VTE and all-cause mortality. When the pivotal trials (REMODEL and RE-NOVATE) are combined with this trial in a meta-analysis the 150-mg once daily dose of DBG is found to be inferior to enoxaparin in terms of the primary efficacy outcome. The 150mg once daily dose may therefore not be suitable for use in the special populations indicated. Post hoc subgroup analyses for total VTE and all-cause mortality conducted on the special populations indicated also suggest that this dose may be less effective than the 220-mg once daily dose in terms of the primary efficacy outcome.

The economic results for DBG compared with enoxaparin in total hip replacement and total knee replacement both rely on one trial each. These trials indicate that DBG is not inferior to enoxaparin. Although at the licensed dose of 220 mg once daily DBG dominates enoxaparin, a small change in the direction of the trial results could significantly alter the cost-effectiveness conclusions.

The cost-effectiveness analysis based on a metaanalysis of the RE-MODEL plus the RE-MOBILIZE trials reverses the direction of the results, that is, DBG is now dominated by enoxaparin for both doses. However, it is the manufacturer’s opinion that the RE-MOBILIZE study is not generalisable to the England and Wales setting. This is also the opinion of the clinical advisors to the ERG.

Areas of uncertainty

There is uncertainty around the clinical effectiveness and cost-effectiveness of DBG compared with other relevant treatments included in the scope, especially fondaparinux and standard and extended low-molecular-weight heparins other than enoxaparin, especially with respect to the 150mg once daily dose. The 150-mg once daily dose may be less effective than the 220-mg once daily dose for the special populations for whom this lower dose is licensed.

The economic results for DBG compared with enoxaparin in total hip replacement and total knee replacement both rely on one trial each. The small numerical difference seen in these trials is reproduced in the model in terms of both incremental costs and incremental health benefits. The conclusions of the cost-effectiveness analysis could be significantly changed with only a small change in the direction of the trial results.

Disclaimers

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.