4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dabigatran etexilate for the prevention of VTE after elective total hip or knee replacement surgery in adults having considered evidence on the nature of the condition and the value placed on the benefits of dabigatran by people with experience of VTE, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.2 The Committee discussed the decision problem and agreed that this appraisal would focus on choice among pharmacological agents for VTE prevention. The Committee discussed the NICE clinical guideline 'Venous thromboembolism' (NICE clinical guideline 46 [Replaced by NICE clinical guideline 92]). It noted the recommendation that in addition to mechanical prophylaxis, people at increased risk of VTE and people undergoing orthopaedic surgery should be offered LMWH, and that fondaparinux, within its marketing authorisation, may be used as an alternative to LMWH. It also heard representations that drugs for the prevention of VTE are not used by all orthopaedic surgeons because some surgeons are concerned that they may increase the incidence, or worsen the consequences, of deep infection in the site of the orthopaedic surgery. The Committee was mindful of these concerns, but concluded that any recommendations made would be limited to situations where drugs for the prevention of VTE were already recommended in 'Venous thromboembolism' (NICE clinical guideline 46 [Replaced by NICE clinical guideline 92]).
4.3 The Committee discussed the clinical effectiveness of dabigatran etexilate compared with LMWH and fondaparinux in people undergoing elective hip or knee surgery, as well as the relative acceptability and ease of management conferred by oral as opposed to subcutaneous administration. It noted that LMWH is the key comparator for dabigatran etexilate because fondaparinux is used much less extensively, but concluded that both should be considered in this appraisal. It also noted that the available direct evidence was limited to a comparison of dabigatran etexilate and enoxaparin and that the manufacturer assumed that all LMWHs were bioequivalent. The Committee agreed that LMWH types may be considered to have equivalent clinical effectiveness, as stated in the NICE clinical guideline 'Venous thromboembolism' (NICE clinical guideline 46).
4.4 The Committee first considered evidence on the clinical effectiveness of dabigatran etexilate compared with enoxaparin. It discussed the applicability of the trials to UK clinical practice, understanding that there is variation in prevention strategies. The Committee agreed that data from the RE-NOVATE and RE-MODEL RCTs, in which the patients in the control arm received 40 mg LMWH once daily, were applicable to UK clinical practice. It agreed that the RE-MOBILIZE study, which used an alternative dosing regimen of 30 mg LMWH twice daily, did not reflect the UK clinical setting, but agreed that it usefully contributes to the overall evidence base and that the results of RE-MOBILIZE were relevant for consideration.
4.5 The Committee discussed the outcome data from these trials. It heard from one clinical specialist that a major component of the composite primary outcome of the studies (DVT detected by venogram) was a surrogate outcome that was not universally recognised as a valid predictor of clinically relevant outcomes. However, the Committee considered that this outcome was objectively assessed and allowed comparison between prevention strategies. It noted that the Guideline Development Group for 'Venous thromboembolism' (NICE clinical guideline 46 [Replaced by NICE clinical guideline 92]) had accepted these outcomes after careful consideration.
4.6 The Committee discussed the results of the RE-NOVATE, RE-MODEL and RE-MOBILIZE studies. The Committee considered that the results of the trials overall indicated that dabigatran etexilate was not inferior to LMWH in preventing VTE despite some concerns about the statistical power of the studies and the RE-MOBILIZE study indicating that dabigatran was inferior to 30 mg LMWH twice daily. The Committee considered adverse events such as bleeding, noting that no statistically significant differences were observed between dabigatran etexilate and LMWH. The Committee was mindful of the absence of an antidote for dabigatran etexilate, and noted that antidotes were available for LMWH and warfarin. Overall the Committee concluded that dabigatran etexilate could, on the evidence available, be considered broadly comparable to LMWH in preventing VTE events and in terms of short-term adverse effects.
4.7 The Committee considered evidence on the clinical effectiveness of dabigatran etexilate at the reduced 150-mg dose for special patient populations (see section 2.2). The Committee noted that the 150-mg dose for special populations was specified in the marketing authorisation. The Committee was mindful of the results of meta-analysis that indicated that 150 mg may be less effective in terms of the primary outcome than 220 mg, but that few differences were observed in safety outcomes. It also considered that in those special populations, 150 mg might have a similar pharmacokinetic profile to 220 mg, but there were no subgroup analyses from which this could be determined. It heard from clinical specialists and patient experts how important it was to balance the potential advantages of prevention of VTE with the potential consequences of adverse effects, especially for people for whom the lower dose is specified in the market authorisation.
4.8 The Committee considered evidence on the clinical effectiveness of dabigatran etexilate compared with fondaparinux. The Committee was aware of indirect evidence suggesting that fondaparinux was more effective at reducing VTE, but that it may be more likely to be associated with treatment-related bleeds than dabigatran etexilate. However, it agreed with the ERG that it was not possible to clearly determine from the mixed-treatment comparison whether fondaparinux was significantly more or less effective than dabigatran etexilate, or no different due to limitations of the data included in the analysis. It was mindful of the need to balance prevention of VTE with possible adverse effects.
4.9 The Committee discussed the use of oral compared with subcutaneous treatments. The Committee heard from clinical specialists and the patient expert about their experience of administration of LMWH and their opinions on an oral alternative such as dabigatran etexilate. The Committee discussed the implications of providing an option for oral administration for adherence to treatment and thus effectiveness of prevention of VTE after hospital discharge. The Committee heard that adherence might be improved because people may find oral medication more acceptable. The once-daily dosing regimen of dabigatran etexilate might also encourage adherence. However, it also heard that people who are offered treatment for the prevention of thromboembolism may consider injected medications important (that is, clinically efficacious and necessary to adhere to). Therefore they may be highly motivated towards adhering to the treatment.
4.10 The Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of dabigatran etexilate for the prevention of VTE in people undergoing hip or knee replacement, the ERG's critique of the manufacturer's submission, and the manufacturer's response to the clarification requested by the ERG.
4.11 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.
4.12 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.
4.13 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.
4.14 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 NHS resources as LMWH or fondaparinux.
4.15 The Committee concluded that although there was uncertainty in the evidence base, dabigatran etexilate was likely to be of equivalent clinical and cost effectiveness to LMWH or fondaparinux in the prevention of VTE. The Committee acknowledged that oral administration of dabigatran etexilate, without the need for monitoring, would reduce administration costs and may support adherence to treatment. The Committee therefore concluded that dabigatran etexilate should be recommended as an option in the circumstances in which LMWH (or fondaparinux as an alternative) may be offered.