Dabigatran etexilate for the prevention of venous thromboembolism ...

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