Dabigatran etexilate for the prevention of venous thromboembolism ...

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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
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