Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism

Clinical effectiveness

4.4 The Committee discussed the company's decision problem. It noted that the company had not compared apixaban with fondaparinux because fondaparinux is rarely used in UK clinical practice. The Committee considered this appropriate. The Committee noted that the company had included dabigatran etexilate as an additional comparator to those listed in the final scope issued by NICE. It was aware that NICE technology appraisal guidance for dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism has only recently been published and so clinical experience with dabigatran etexilate may be limited. The Committee agreed that warfarin was the most established treatment for DVT and PE and that clinical experience with rivaroxaban is increasing. It concluded that the company's decision problem was appropriate for its decision making.

4.5 The Committee considered the evidence presented by the company on the clinical effectiveness of apixaban. It noted that the main source of evidence was from 2 trials: AMPLIFY and AMPLIFY‑EXT. It noted that the average age of people in both trials was lower than the average age of people being treated for VTE in clinical practice in England. It was aware that both the risk of bleeding and VTE increases with age and a younger trial population would be expected to have a lower risk of these events. However, it accepted that the average age of the population in the AMPLIFY and AMPLIFY‑EXT trials was similar to that in other trials of anticoagulants for the treatment and secondary prevention of VTE. The Committee also noted that AMPLIFY included people in whom a minimum of 6 months treatment with an anticoagulant was considered appropriate and that people who were likely to need only 3 months of anticoagulation, such as those with a provoked VTE without risk factors for a further VTE, were excluded from the study. The Committee further noted that AMPLIFY‑EXT included only people who were considered to be at clinical equipoise (there was uncertainty about the balance of risks and benefits of continued anticoagulation). It understood that because AMPLIFY‑EXT was a placebo‑controlled trial, people who were in definite need of continued anticoagulation were not included in the trial. It further understood that people who had a recurrent VTE while having 6–12 months of anticoagulation for their initial VTE were also excluded from AMPLIFY‑EXT. The Committee accepted that there were limited data for people who needed less than 6 months' treatment and for people still at high risk of recurrent VTE after 6 months of treatment. The Committee concluded that despite these limitations, the AMPLIFY trials had informed the marketing authorisation for apixaban, and as such were appropriate to make a recommendation for the whole population covered by the marketing authorisation.

4.6 The Committee discussed whether apixaban could be considered clinically effective with an acceptable safety profile for treating and preventing recurrent VTE. It noted that in AMPLIFY apixaban had been demonstrated to be similarly effective to enoxaparin/warfarin, and that although bleeding is a risk with all anticoagulants the risk of bleeding was lower with apixaban than with enoxaparin/warfarin. The Committee noted that the marketing authorisation for apixaban states that a lower dose of 2.5 mg rather than 5 mg twice daily should be used for secondary prevention beyond 6 months following an initial VTE. The Committee noted that in the AMPLIFY‑EXT trial, both doses of apixaban had similar efficacy in reducing the rate of recurrent VTE compared with placebo, but the 2.5 mg twice‑daily dose had a lower rate of bleeds than the 5 mg twice‑daily dose. No statistically significant difference in the incidence of bleeds was seen between the 2.5 mg twice‑daily apixaban dose and placebo. The Committee concluded that apixaban had been demonstrated to be effective in treating VTE and was associated with fewer bleeds than warfarin. It also concluded that over the long term the lower dose was as effective as the higher dose in preventing VTE, with a lower risk of bleeding.

4.7 The Committee discussed the network meta‑analyses which were done in the absence of head‑to‑head trials to evaluate the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE. The Committee noted that the ERG considered the combination of data from the trials in the 6‑month treatment meta‑analysis (NMA 1) to be appropriate because the trials had similar characteristics, but that the trials included in the secondary prevention meta‑analysis (NMA 2) were too different for appropriate combination of the results since the time spent on treatment and follow‑up periods were different. The Committee noted that the results of both meta‑analyses suggested that apixaban, rivaroxaban and dabigatran etexilate were similarly effective in terms of reducing recurrent VTE and that apixaban had lower rates of bleeding. The Committee commented that indirect comparisons of any outcome will be subject to more uncertainty than from a direct comparison and the uncertainty will be greater for outcomes which have a low incidence (that is, are uncommon) such as bleeding or VTE. The Committee agreed with the ERG that the estimates from the secondary prevention treatment meta‑analysis were subject to additional uncertainty, because the trials included in the network had very different follow‑up periods (and the longer people remain in a trial the more likely a bleed or VTE would be observed). The Committee noted that the ERG's alternative modelling assumptions, which attempted to account for the potential bias from different trial lengths, resulted in point estimates in which the relative risks of major bleeding were more similar between the apixaban, rivaroxaban and dabigatran etexilate than in the company's analysis, and had wider credible intervals which crossed 1. The Committee concluded that the meta‑analysis results should be interpreted with some caution in light of these uncertainties. It agreed that no evidence had been shown of a difference in the effectiveness of apixaban, rivaroxaban and dabigatran etexilate. The Committee concluded that although it was reasonable to conclude that there was a difference in bleeding between apixaban and warfarin as had been demonstrated in AMPLIFY, the estimates from the network meta‑analyses were not sufficiently robust to differentiate between apixaban, rivaroxaban and dabigatran etexilate in terms of bleeding.

4.8 The Committee considered the effectiveness and safety of apixaban in people with active cancer. It was aware that in clinical practice in England, people with cancer who have a VTE have at least 6 months' treatment with LMWH. It was aware that AMPLIFY and AMPLIFY‑EXT included very few people who had active cancer and that there were no head‑to‑head data available comparing apixaban with LMWH for treating VTE in people who have cancer. The Committee concluded that there were insufficient data to assess the effectiveness and safety of apixaban in people with active cancer who had DVT or PE, and that it was not possible to make a specific recommendation for this group of people.

Cost effectiveness

4.9 The Committee discussed the company's economic model, noting that it had presented base‑case results for 2 treatment durations: 6‑month treatment and lifelong treatment. The Committee noted the ERG's concerns that when the company modelled lifelong treatment, it had assumed that the risks of bleeding and recurrent VTE would be the same as in AMPLIFY for the first 6 months and the same as AMPLIFY‑EXT for the following 12 months, even though the trial populations differed. The Committee agreed that because AMPLIFY‑EXT excluded people who had a recurrent VTE during treatment for their initial VTE and people who had a higher risk of VTE, the populations upon which the risk estimates were based were different. The Committee heard from the ERG that 2 distinct models should have been developed, 1 for short‑term use of apixaban and another for long‑term use. It also noted its earlier concerns (see section 4.5) about the generalisability of the population in AMPLIFY‑EXT to clinical practice in England. The Committee heard from the clinical experts that people do not typically switch anticoagulants once they have started treatment, and during a risk‑benefit assessment for continued anticoagulation the decision is whether to continue treatment rather than whether to switch anticoagulants. It therefore considered that modelling treatment in secondary prevention separately would not be appropriate. The Committee concluded that the company's model structure and approach to modelling lifelong treatment was appropriate, but it was aware of the limitations in the data used to inform the model from the network meta‑analyses.

4.10 The Committee discussed the assumptions used in the company's model and whether they were similar to assumptions used in previous appraisals of oral anticoagulants. It noted that some assumptions in the company's model, such as those surrounding INR monitoring costs, were similar to those it had accepted as reasonable in its appraisals of rivaroxaban and dabigatran etexilate. The Committee further noted that although the utility value decrements assumed for taking warfarin and for clinically relevant non‑major bleeds presented by the company were not the same as in all of the previous appraisals of the anticoagulants that it had seen, they were within the range presented in previous appraisals. The Committee also heard from the ERG that the choice of utility decrement used in the company's base case did not have a large effect on the incremental cost‑effectiveness ratio (ICER). The Committee concluded that agreed values have not been established for INR monitoring costs and utility decrements associated with anticoagulation, and the assumptions used in the company's model were within the range of those used in previous appraisals of apixaban, rivaroxaban and dabigatran etexilate.

4.11 The Committee discussed the company's base‑case analyses. It noted that for 6 months' treatment the ICER for apixaban compared with enoxaparin/warfarin was £2400 per quality adjusted life year (QALY) gained, and that apixaban dominated (that is, was more effective and less costly than) rivaroxaban and dabigatran etexilate. For lifelong treatment, the ICER for apixaban compared with enoxaparin/warfarin was £16,700 per QALY gained and rivaroxaban was dominated by enoxaparin/warfarin, and extendedly dominated by enoxaparin/warfarin and apixaban (a treatment is 'extendedly dominated' when its ICER is higher than that of the next, more effective, option when compared with a common baseline). The sensitivity analyses done by the company and the ERG showed that changing the estimate for the relative risk of bleeding derived from the network meta‑analyses had the greatest effect on the ICER; the more similar the bleeding risk between treatments, the higher the ICER became. The Committee was aware that although a difference had been demonstrated in the rate of bleeds between apixaban and warfarin, it was unclear what the relative risk of bleeding with apixaban would be compared with the other newer oral anticoagulants. The Committee noted that in most of the company and ERG sensitivity analyses, the ICER was less than £20,000 per QALY gained for either treatment duration. The Committee concluded that apixaban could be considered a clinically and cost effective use of NHS resources and could be recommended as an option for the treatment and secondary prevention of DVT and PE.

Summary of Appraisal Committee's key conclusions