Dabigatran etexilate for the prevention of venous thromboembolism ...

DOI: 10.3310/hta13suppl2/08Health Technology Assessment 2009; Vol. 13: Suppl. 2Dabigatran etexilate for the prevention of venousthromboembolism in patients undergoing electivehip and knee surgery: a single technology appraisalM Holmes,* C Carroll and D PapaioannouSchool of Health and Related Research (ScHARR), University of Sheffield, UK*Corresponding authorDeclared competing interests of authors: Dr Eddie Hampton (Senior Lecturer and HonoraryConsultant in Haematology, Sheffield Teaching Hospitals): none. Dr Raj Patel (Consultant Haematologist,King’s College Hospital): none. Dr Rhona Maclean (Consultant Haematologist, Sheffield TeachingHospitals): Dr Maclean is a local investigator in a study of the use of dabigatran for the treatment ofvenous thromboembolism and has been approached by Boehringer Ingelheim to do an educationalsession/lecture in April 2008 for the employees of Boehringer Ingelheim for which she will receivepayment. All other authors: none.AbstractThis paper presents a summary of the evidencereview group (ERG) report into the clinicaleffectiveness and cost-effectiveness of dabigatranetexilate (DBG) for the prevention of venousthromboembolism (VTE) in patients undergoingelective hip and knee surgery based upon areview of the manufacturer’s submission to theNICE as part of the single technology appraisal(STA) process. The submission’s evidence camefrom three reasonable-quality trials comparingDBG with enoxaparin, and a comparison ofDBG with fondaparinux based on the relativeefficacy and safety as derived from a mixedtreatment comparison (MTC) meta-analysis. DBG(220 mg and 150 mg once daily) is not inferior toenoxaparin (40 mg once daily and 30 mg twicedaily) in terms of major VTE or VTE-related events(secondary outcome). Meta-analysis shows that220 mg DBG is not inferior to enoxaparin (40 mgonce daily or 30 mg twice daily) in reducing totalVTE and all-cause mortality (primary outcome)in total hip or knee replacement, whereas thereis uncertainty around the clinical effectivenessof 150 mg DBG for this outcome. In the MTCanalysis DBG compared favourably with the otherinterventions, with the exception of extendedenoxaparin and fondaparinux. The adverse eventprofile was not significantly different in thosereceiving DBG and those receiving enoxaparin.© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.HTA 07/90/01Date of ERG submission:May 2008TAR Centre(s):School of Health and Related Research (ScHARR)List of authors:M Holmes, C Carroll and D PapaioannouContact details:Michael Holmes, Research Fellow, ScHARR, Universityof Sheffield, Regents Court, 30 Regent Street, SheffieldS1 4DA, UKE-mail: m.w.holmes@shef.ac.uk.The research reported in this article of the journalsupplement was commissioned and funded by theHTA programme on behalf of NICE as project number07/90/01. The assessment report began editorial reviewin June 2008 and was accepted for publication in April2009. See the HTA programme web site for furtherproject information (www.hta.ac.uk). This summaryof the ERG report was compiled after the AppraisalCommittee’s review.The views and opinions expressed therein are those ofthe authors and do not necessarily reflect those of theDepartment of Health.Discussion of ERG reports is invited. Visit the HTAwebsite correspondence forum (www.hta.ac.uk/correspond).55

Dabigatran etexilate for the prevention of venous thromboembolismThe submitted two-phase economic modelcompares DBG with enoxaparin and fondaparinuxin total hip and knee replacement. The modelstructure is appropriate and the model assumptionsare reasonable. The health states, costs, utilitiesand recurrence rates used are considered to beappropriate for the required analysis. The modelestimated that at the licensed dose of 220 mg oncedaily DBG dominates enoxaparin in both totalhip replacement and total knee replacement andthat at the lower dose of 150 mg once daily DBGdominates enoxaparin in total hip replacementand enoxaparin dominates DBG in total kneereplacement. DBG is less cost-effective thanfondaparinux in total hip replacement at bothdoses; the cost per quality-adjusted life-year offondaparinux versus DBG is £11,111 and £6857for the higher and lower doses of DBG respectively.In total knee replacement, both DBG doses aredominated by fondaparinux. For DBG versus allcomparators in all cases the cost-effectivenessresults are based on small incremental cost andhealth benefits. Weaknesses of the submittedevidence include that methods used for screeningstudies, data extraction and applying qualityassessment criteria to included studies, as well askey details of trials included in the MTC, werenot adequately described. In addition, someinput parameters into the modelling process areincorrect. The ERG was unable to correct all ofthese mistakes and the impact on the model resultsis therefore unknown. The National Institute forHealth and Clinical Excellence guidance issued as aresult of the STA states that DBG is recommendedas an option for the primary prevention of VTEevents in adults who have undergone elective totalhip or knee replacement surgery.IntroductionThe National Institute for Health and ClinicalExcellence (NICE) is an independent organisationwithin the NHS that is responsible for providingnational guidance on the treatment and care ofpeople using the NHS in England and Wales.One of the responsibilities of NICE is to provideguidance to the NHS on the use of selected newand established health technologies, based on anappraisal of those technologies.NICE’s single technology appraisal (STA) processis specifically designed for the appraisal of a singleproduct, device or other technology, with a singleindication, for which most of the relevant evidencelies with one manufacturer or sponsor. 1 Typically,it is used for new pharmaceutical products closeto launch. The principal evidence for an STA isderived from a submission by the manufacturer/sponsor of the technology. In addition, a reportreviewing the evidence submission is submittedby the evidence review group (ERG), an externalorganisation independent of NICE. This paperpresents a summary of the ERG report for the STAof dabigatran etexilate for the prevention of venousthromboembolism in patients undergoing electivehip and knee surgery. 2Description of theunderlying health problemVenous thromboembolism (VTE) is the formationof a blood clot (thrombus) in a vein, whichmay dislodge from its site of origin to cause anembolism. Most thrombi occur in the deep veins ofthe legs; this is called deep vein thrombosis (DVT).Dislodged thrombi may travel to the lungs; thisis called a pulmonary embolism (PE) and can befatal. Thrombi can also cause long-term morbiditydue to venous insufficiency and post-thromboticsyndrome, potentially leading to venous ulceration.Recurrence of DVT is common. Studies have shownthat up to 30% of patients who have experiencedan acute DVT will experience one or morerecurrences over the following 10–15 years. 3–5Total hip or knee replacement surgery is astrong risk factor for VTE. In the absence ofthromboprophylaxis the risk of developing a DVTafter a primary total hip replacement and after aprimary total knee replacement is 50% and 60%respectively. 6Mortality due to VTE is significant. Long-termfollow-up of patients who have experienced anepisode of VTE (usually acute DVT) has shown thatthere is a high mortality rate over the subsequent10–15 years. 3,5,7,8PE has a high mortality rate with 13% proving fatalin elderly patients 1 month after onset 9 and 17.5%within 3 months. 10The National Joint Registry for England and Walesrecorded 61,456 hip replacement procedures, ofwhich 10% were revisions or reoperations, and60,986 knee replacement procedures, of which 8%were revisions or reoperations, undertaken between1 January and 31 December 2006. 1156

Dabigatran etexilate for the prevention of venous thromboembolism58once daily dose in the special populations indicatedfor this lower dose and for whom the lower doseis specifically licensed. Safety outcomes were notreported for these subgroups.The meta-analysis of the RE-MODEL and RE-NOVATE trials appears to show that the 150-mgonce daily dose of DBG is not inferior to thecomparator enoxaparin (at either 40 mg once dailyor 30 mg twice daily) in reducing levels of total VTEand all-cause mortality among patients undergoingtotal hip replacement and total knee replacement.The meta-analyses of the two total kneereplacement trials combined (RE-MODEL and RE-MOBILIZE) and the three total knee replacementand total hip replacement trials combined (RE-NOVATE, RE-MODEL and RE-MOBILIZE) appearto show that the 150-mg once daily dose of DBGis inferior to the comparator enoxaparin (at both40 mg once daily and 30 mg twice daily) in reducinglevels of total VTE and all-cause mortality amongpatients undergoing total hip replacement andtotal knee replacement.An MTC analysis compared the results of thesetrials of DBG with results for all other availableinterventions for patients undergoing surgery andat risk of DVT and found that DBG comparedfavourably with the other interventions, withthe exception of extended enoxaparin andfondaparinux, which appear to be relativelymore effective (level of statistical significance ofdifference not reported).The adverse event profile was not significantlydifferent in those receiving DBG compared withthose receiving enoxaparin. The primary safetyend point was major bleeding. Clinically relevantbleeding, any bleeding and liver function were alsomeasured (secondary end points).Summary of submitted costeffectivenessevidenceThe model developed by Boehringer Ingelheimhas an acute phase that starts at the time of surgeryand ends at 10 weeks post surgery and a chronicphase with a lifetime horizon. The model comparesDBG with enoxaparin and fondaparinux in bothtotal hip replacement and total knee replacement.The acute phase model is a decision tree whichpredicts the health states that patients will be in at10 weeks based on evidence from phase III trials ofDBG compared with enoxaparin and from an MTCof DBG compared with fondaparinux. At 10 weekspatients enter a chronic phase Markov model inthe same health state in which they terminated thedecision tree model. No further treatment effectis applied in the chronic phase model. Transitionbetween states in the chronic phase model isdependent on VTE recurrence rates obtained fromthe literature.The health states, costs, utilities and recurrencerates used within the model are considered to beappropriate for the required analysis.The Boehringer Ingelheim model estimated that:• at the licensed dose of 220 mg once dailyDBG dominates enoxaparin in both total hipreplacement and total knee replacement• at the lower dose of 150 mg once daily DBGdominates enoxaparin in total hip replacementand enoxaparin dominates DBG in total kneereplacement• DBG is less cost-effective than fondaparinuxin total hip replacement at both doses of DBG.The cost/QALY of fondaparinux versus DBG is£11,111 and £6857, respectively, for the higherand lower doses of DBG.• In total knee replacement, both DBG doses aredominated by fondaparinux.Table 1 presents a summary of the cost-effectivenessresults. For DBG versus all comparators it shouldbe noted that in all cases the cost-effectivenessresults are based on small incremental cost andhealth benefits.Commentary onthe robustness ofsubmitted evidenceStrengthsThe manufacturer conducted a limited, butsystematic search for clinical and cost-effectivenessstudies of DBG for the prevention of VTE inpatients undergoing total knee replacement andtotal hip replacement. It appears unlikely thatany additional trials would have met the inclusioncriteria had the search been widened to includemore free-text terms or to include other databases.The three identified trials, which represent themain clinical efficacy evidence, were of reasonablemethodological quality, with some limitations,and measured a range of outcomes that wereappropriate and clinically relevant.

Health Technology Assessment 2009; Vol. 13: Suppl. 2TABLE 1 Summary of deterministic and probabilistic sensitivity analysis resultsProbability cost-effective atthreshold:Deterministic £20,000/QALY £30,000/QALYDBG compared with enoxaparin in THR patientsDBG 220 mgIncremental cost –£99 99% 98%Incremental QALYs 0.010ICERDBG dominantDBG 150 mgIncremental cost –£83 76% 71%Incremental QALYs 0.001ICERDBG dominantDBG compared with enoxaparin in TKR patientsDBG 220 mgIncremental cost –£18 82% 82%Incremental QALYs 0.011ICERDBG dominantDBG 150 mgIncremental cost £20 38% 39%Incremental QALYs –0.002ICERDBG dominatedDBG compared with fondaparinux in THR patientsDBG 220mgIncremental cost –£200 40% 35%Incremental QALYs –0.018ICER£11,111 aDBG 150mgIncremental cost –£192 32% 27%Incremental QALYs –0.028ICER£6857 aDBG compared with fondaparinux in TKR patientsDBG 220 mgIncremental cost £16 0% 0%Incremental QALYs –0.016ICERDBG dominatedDBG 150 mgIncremental cost £25 0% 0%Incremental QALYs –0.019ICERDBG dominatedDBG, dabigatran etexilate; ICER, incremental cost-effectiveness ratio; QALY(s), quality-adjusted life-year(s); THR, total hipreplacement; TKR, total knee replacement.a Note that this ICER is in the ‘south/west’ quadrant of the cost-effectiveness plane.59© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.

Dabigatran etexilate for the prevention of venous thromboembolism60The meta-analyses demonstrated the noninferiorityof DBG 220 mg once daily versusenoxaparin in terms of the efficacy and safety endpoints, and acknowledged the apparent inferiorityof the 150-mg once daily dose in terms of theprimary efficacy outcome.An MTC analysis compared DBG with all otheravailable interventions for patients undergoingsurgery and at risk of DVT and found that DBGcompared favourably with the other interventions,with the exception of extended low-molecularweightheparins and fondaparinux, which appearto be more effective.The model structure is appropriate and allowssensitivity analysis to be carried out easily.The model assumptions are reasonable.The univariate sensitivity analysis is extensive andis performed on appropriate parameters.The probabilistic sensitivity analysis is performedcorrectly.WeaknessesThe processes undertaken by the manufacturer forscreening studies, data extraction and applyingquality assessment criteria to included studies werenot made explicitly clear in the submission. Thesefactors limit the robustness of the systematic review.Quality assessment of the included studies shouldhave been undertaken using a checklist appropriateto the types of study included (non-inferiorityrandomised trials).One of the trials used in the clinical effectivenesssection is published only as an abstract (RE-MOBILIZE); much of the key data employed areunpublished.A simple pooled analysis of the patient level datafrom the two pivotal trials, as well as all threehead-to-head trials, was reported. However, themethods used for this data pooling were notdescribed; the statistical approach for combiningthe data appears to be inappropriate as it fails topreserve randomisation and introduces bias andconfounding. The resulting pooled data shouldtherefore be treated with caution.Elements of the MTC reported in themanufacturer’s submission are reproduced fromdocuments produced by organisations otherthan the manufacturer, rather than specificallyin response to the scope. The key details of trialsincluded in the MTC, and issues relating toheterogeneity of trials, are neither reported nordiscussed. The resulting MTC should therefore betreated with caution.The economic results for DBG compared withenoxaparin in total hip replacement and totalknee replacement both rely on one trial each.These trials indicate that DBG is not inferiorto enoxaparin. The small numerical differenceseen in these trials is reproduced in the model interms of both incremental costs and incrementalhealth benefits (see Table 1). A small change inthe direction of the trial results could significantlychange the cost-effectiveness conclusions.The economic results for DBG versus fondaparinuxin total hip replacement are based on one studyfor which the manufacturer appears to have usedan incorrect relative risk estimate. However, thedifference is small and the impact on the results islikely to be small.VTE recurrence rates, post-thrombotic syndromerates and quality of life utilities used in the modelare based on a literature review limited to economicstudies. It is therefore possible that non-economicstudies reporting these data in sources such asMEDLINE have not been identified.Some input parameters into the modelling processare incorrect. These include using the underlyingrisk of DVT instead of the underlying risk of VTEfor the comparison of DBG with fondaparinux,wrongly estimating the recurrence rates for VTE,wrongly estimating the probability of PE beingsevere, not including intensive care unit costs in PEpost discharge and including the cost of informalcare when it should be excluded. The ERG wasunable to correct all of these mistakes and theimpact on the model results is therefore unknown.ConclusionsKey issuesThe external validity of the evidence is limited.Only a single randomised controlled trial(RCT) using a comparator and dose applied inEngland and Wales has been conducted on eachof the relevant total hip replacement and totalknee replacement populations. The addition ofevidence from any future RCTs may alter theresults regarding the non-inferiority of DBG. Smallchanges in key parameters could markedly alter

Health Technology Assessment 2009; Vol. 13: Suppl. 2the conclusions with respect to cost and clinicaleffectiveness.The results of the RE-MOBILIZE total kneereplacement trial indicate that both the 220-mg once daily and the 150-mg once daily doseof DBG are inferior to enoxaparin in terms ofthe primary efficacy outcome of total VTE andall-cause mortality. When the pivotal trials (RE-MODEL and RE-NOVATE) are combined with thistrial in a meta-analysis the 150-mg once daily doseof DBG is found to be inferior to enoxaparin interms of the primary efficacy outcome. The 150-mg once daily dose may therefore not be suitablefor use in the special populations indicated. Posthoc subgroup analyses for total VTE and all-causemortality conducted on the special populationsindicated also suggest that this dose may be lesseffective than the 220-mg once daily dose in termsof the primary efficacy outcome.The economic results for DBG compared withenoxaparin in total hip replacement and totalknee replacement both rely on one trial each.These trials indicate that DBG is not inferior toenoxaparin. Although at the licensed dose of220 mg once daily DBG dominates enoxaparin,a small change in the direction of the trial resultscould significantly alter the cost-effectivenessconclusions.The cost-effectiveness analysis based on a metaanalysisof the RE-MODEL plus the RE-MOBILIZEtrials reverses the direction of the results, that is,DBG is now dominated by enoxaparin for bothdoses. However, it is the manufacturer’s opinionthat the RE-MOBILIZE study is not generalisableto the England and Wales setting. This is also theopinion of the clinical advisors to the ERG.Areas of uncertaintyThere is uncertainty around the clinicaleffectiveness and cost-effectiveness of DBGcompared with other relevant treatments includedin the scope, especially fondaparinux and standardand extended low-molecular-weight heparins otherthan enoxaparin, especially with respect to the 150-mg once daily dose. The 150-mg once daily dosemay be less effective than the 220-mg once dailydose for the special populations for whom thislower dose is licensed.The economic results for DBG compared withenoxaparin in total hip replacement and totalknee replacement both rely on one trial each.The small numerical difference seen in these© 2009 Queen’s Printer and Controller of HMSO. All rights reserved.trials is reproduced in the model in terms of bothincremental costs and incremental health benefits.The conclusions of the cost-effectiveness analysiscould be significantly changed with only a smallchange in the direction of the trial results.Summary of NICE guidanceissued as a result of the STAAt the time of writing, the final appraisaldetermination issued by NICE on 21 July 2008states that:Dabigatran etexilate, within its marketingauthorisation, is recommended as an option forthe primary prevention of venous thromboembolicevents in adults who have undergone elective totalhip replacement surgery or elective total kneereplacement surgery.Key references1. National Institute for Health and ClinicalExcellence. Guide to the single technology (STA) process.19 September 2006. URL: www.nice.org.uk/page.aspx?o=STAprocessguide.2. Holmes M, Carroll C, Papaioannou D. Dabigatranetexilate for the prevention of venous thromboembolismin patients undergoing elective hip and knee surgery: asingle technology appraisal. NICE Guidance 2008;157.3. Bergqvist D, Jendteg S, Johansen L, Persson U,Odegaard K. Cost of long-term complications ofdeep venous thrombosis of the lower extremities: ananalysis of a defined patient population in Sweden.Ann Intern Med 1997;126:454–7.4. Janssen MC, Haenen JH, van Asten WN,Wollersheim H, Heijstraten FM, de Rooij MJ, etal. Clinical and haemodynamic sequelae of deepvenous thrombosis: retrospective evaluation after7–13 years. Clin Sci (Lond) 1997;93:7–12.5. Schulman S, Lindmarker P, Holmstrom M, LarfarsG, Carlsson A, Nicol P, et al. Post-thromboticsyndrome, recurrence, and death 10 years after thefirst episode of venous thromboembolism treatedwith warfarin for 6 weeks or 6 months. J ThrombHaemost 2006;4:734–42.6. Faroug R, Konnuru S, Min S, Hussain F, Ampat G.Venous thromboembolism prevention post neckof femur fractures – does it make a difference?Thrombosis J 2008;6:87. Eichlisberger R, Widmer MT, Frauchiger B, WidmerLK, Jager K. [The incidence of post-thrombotic61

Dabigatran etexilate for the prevention of venous thromboembolismsyndrome] [German]. Wien Med Wochenschr1994;144:192–5.8. Murray DW, Britton AR, Bulstrode CJ.Thromboprophylaxis and death after total hipreplacement. J Bone Joint Surg Br 1996;78:863–70.9. Siddique RM, Siddique MI, Connors AF, Jr,Rimm AA. Thirty-day case-fatality rates forpulmonary embolism in the elderly. Arch Intern Med1996;156:2343–7.10. Goldhaber SZ, Visani L, De Rosa M. Acutepulmonary embolism: clinical outcomes in theInternational Cooperative Pulmonary EmbolismRegistry (ICOPER). Lancet 1999;353:1386–9.11. National Joint Registry for England and Wales4th Annual Report. URL: www.rcseng.ac.uk/surgical_research_units/docs/National%20Joint%20Registry%20Report%202007.pdf.12. Eriksson BI, Dahl OE, Rosencher N, Kurth AA,van Dijk CN, Frostick SP, et al; RE-NOVATE StudyGroup. Dabigatran etexilate versus enoxaparin forprevention of venous thromboembolism after totalhip replacement: a randomised, double-blind, noninferioritytrial. Lancet 2007;370:949–56.13. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, vanDijk CN, Frostick SP, et al. Oral dabigatran etexilatevs. subcutaneous enoxaparin for the preventionof venous thromboembolism after total kneereplacement: the RE-MODEL randomized trial. JThromb Haemost 2007;5:2178–85.14. Friedman RJ, Caprini JA, Comp PC, DavidsonBL, Francis CW, Ginsberg J, et al. Dabigatranetexilate versus enoxaparin in preventing venousthromboembolism following total knee arthroplasty.J Thromb Haemost 2007;5(Suppl. 2):W-051.62