4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban 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 rivaroxaban 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 framework and in particular the major outcomes that were considered. The Committee was concerned that joint outcomes had not been included in the decision problem. It noted, however, that the main trials for total hip and total knee replacement did not evaluate joint outcomes. The Committee also noted that fondaparinux was not included in the manufacturer's decision problem, although the NICE clinical guideline 'Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery' (NICE clinical guideline 46 [Replaced by NICE clinical guideline 92]) recommended that in addition to mechanical prophylaxis, people at increased risk of VTE and people undergoing orthopaedic surgery should be offered LMWH. The guideline also recommended that fondaparinux, within its licensed indications, may be used as an alternative to LMWH. The Committee noted that the manufacturer had not included fondaparinux as a comparator because it was used in less than 2% of patients in current UK clinical practice. The Committee noted comments from clinical specialists that drugs for the prevention of VTE are not routinely used by all orthopaedic surgeons because of concerns that they may increase the incidence, or worsen the consequences, of wound haemorrhage in the site of the orthopaedic surgery.
4.3 The Committee discussed the clinical effectiveness of rivaroxaban compared with enoxaparin and dabigatran in people having elective hip or knee surgery. It noted the direct RCT evidence of a comparison of rivaroxaban and enoxaparin, and the indirect comparison of rivaroxaban versus dabigatran. The Committee agreed that the methodology used in the indirect comparison was plausible and therefore it was reasonable to consider the results of this comparison.
4.4 The Committee considered evidence on the clinical effectiveness of rivaroxaban compared with enoxaparin. It discussed the applicability of the trials to UK clinical practice, noting that there is variation in prevention strategies. The Committee discussed the relevance of the RECORD 1, 2 and 3 trials, in which the patients in the control arm received 40 mg enoxaparin once daily, and agreed that the data from these trials were applicable to UK clinical practice. The Committee noted that the RECORD 4 study used an alternative dosing regimen of 30 mg enoxaparin twice daily that did not reflect the UK clinical setting, but agreed that the results of this study contributed to the overall evidence base and so were relevant for consideration. The Committee discussed the outcome data from these trials and was concerned about the use of surrogate outcomes as valid predictors of clinically relevant outcomes. Clinical specialists indicated that a major component of the composite primary outcome of the studies (DVT detected by venogram) was a surrogate outcome that was objectively assessed and allowed comparison between prevention strategies. Furthermore, the clinical specialists indicated that there was a direct relationship between venographically assessed outcomes and symptomatic outcomes. The Committee noted that the Guideline Development Group of NICE clinical guideline 46 had accepted venographically determined outcomes after careful consideration.
4.5 The Committee discussed the results of the RECORD studies and concluded that rivaroxaban was at least as effective as enoxaparin in preventing VTE. The Committee considered adverse events such as bleeding, noting that the relative risk of major bleeding numerically favoured enoxaparin. The Committee noted that the chosen dose of rivaroxaban appeared to increase efficacy in prevention of VTE after surgery, with a small increase in risk of major bleeding when compared with enoxaparin. It concluded that rivaroxaban at its licensed dosage of 10 mg daily might be more efficacious than enoxaparin in preventing VTE but this was accompanied by a small increased risk of major bleeding. The Committee was persuaded by testimony from the clinical specialists that there was a 'trade off' to be made between increasing anticoagulant efficacy and the risk of adverse effects, including major bleeding.
4.6 The Committee considered evidence on the clinical effectiveness of rivaroxaban compared indirectly with dabigatran that showed that rivaroxaban significantly reduced the relative risk of the major primary endpoints. However, the Committee noted that in this analysis the relative risk of major bleeding favoured dabigatranalthough this difference was not statistically significant. It agreed that on balance, rivaroxaban and dabigatran had broadly similar efficacy profiles, and noted the need to balance prevention of VTE with possible adverse effects, particularly the incidence of major bleeding events.
4.7 The Committee discussed the benefits to patients of treatments given orally compared with subcutaneous injection. The Committee heard from the clinical specialists and patient experts that in general, oral dosing was preferred to subcutaneous injection. It discussed the implications of providing an option for oral administration in adherence to treatment. The Committee discussed whether a recommendation for an oral treatment rather than a subcutaneous injection would give rise to any issues related to equalities and diversity legislation. The Committee concluded that there were no issues related to equality of access to treatment that it would need to take into account when considering positively recommending rivaroxaban. The Committee also agreed that the option of oral treatment would be preferred by some patients and their clinicians.
4.8 The Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of rivaroxaban for the prevention of VTE in people having total hip or total knee replacement, the ERG's critique of the manufacturer's submission, and the manufacturer's response to the clarification requested by the ERG. The base-case analysis in the manufacturer's submission showed that rivaroxaban dominated enoxaparin and dabigatran in both total hip and total knee replacement. The Committee noted that this base-case analysis depended on the exclusion of the numerically increased adverse events for rivaroxaban compared with enoxaparin on the basis that they were not statistically significant. The Committee was concerned that this might not be in line with normal economic modelling procedures and took into account the ERG's preference for using observed data in the analysis. The Committee noted that the main variables that affected the output of the model were the rate of fatal PE and whether the model used observed values from the trials when there were insignificant differences in outcomes.
4.9 The ERG's exploratory analysis showed that rivaroxaban did not always dominate enoxaparin and dabigatran in total knee replacement when the observed values from the trials were used. The Committee also noted the ERG's comments that the model did not incorporate the effect of fatal PE but concluded that there were very small differences in the costs and QALYs in any of the analyses presented.
4.10 The Committee noted that although the primary clinical outcome data indicated that rivaroxaban was superior to enoxaparin and dabigatran, several of the point estimates in the economic analysis favoured enoxaparin. It also noted that the relative risk for major bleeding was in favour of enoxaparin and dabigatran. The Committee was mindful that the differences in the effectiveness and cost data were very small and therefore the ICERs were very sensitive to minor changes in assumptions. The Committee acknowledged that oral administration of rivaroxaban without the need for haematological monitoring would reduce administration costs and may support adherence to treatment.
4.11 The Committee concluded that, on balance, rivaroxaban, enoxaparin and dabigatran had very similar costs and benefits in the prevention of VTE. Therefore, the Committee agreed that the use of rivaroxaban for the prevention of VTE is an appropriate use of NHS resources and that rivaroxaban should be recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery.