4 Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of apixaban, having considered evidence on the nature of venous thromboembolism and the value placed on the benefits of apixaban by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

4.1 The Committee discussed the options for treating and preventing deep vein thrombosis (DVT) and pulmonary embolism (PE). It was aware that the NICE guideline on venous thromboembolic diseases and the role of thrombophilia testing recommends that DVT and PE are treated with immediate parenteral anticoagulation, most commonly with low molecular weight heparin (LMWH) delivered by subcutaneous injection together with an oral vitamin K antagonist such as warfarin. Both treatments are continued for at least 5 days or until the person's international normalised ratio (INR) has been within the therapeutic range for at least 24 hours, whichever is longer, at which point the LMWH is stopped. The Committee was further aware that following publication of NICE technology appraisal guidance on rivaroxaban for the treatment of deep vein thrombosis and pulmonary embolism, rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism and dabigatran etexilate for the treatment of secondary prevention of deep vein thrombosis and/or pulmonary embolism that rivaroxaban and dabigatran etexilate are also recommended as options for treating and preventing recurrent venous thromboembolism (VTE). The Committee heard from clinical and patient experts that there are regional differences in the uptake of newer oral anticoagulants to treat VTE. The experts explained that this variation is in part because of local protocols and also related to whether treatments can be prescribed in primary or secondary care. The patient experts emphasised that differences in access to newer anticoagulants is of great concern to patients.

4.2 The Committee considered how long patients would remain on anticoagulants. It noted that the NICE guideline on venous thromboembolic diseases recommends that the risks and benefits of continuing anticoagulation following a DVT or PE should be assessed at 3 months. The Committee heard from the clinical experts that treatment for provoked VTE usually lasted for 3 months and treatment for an unprovoked VTE was often longer, and could be lifelong. It heard that although the risk‑benefit assessment was increasingly being done at 3 months as recommended, it was also common for people to have a risk‑benefit assessment only after completing a 6‑month course of treatment following an unprovoked VTE. The clinical experts explained that the risk‑benefit assessment considered the relative risks of a further VTE and the person's risk of having a bleed. They stated that there is no validated standardised algorithm for determining the risks and benefits of continued anticoagulation following VTE, but factors that are considered include type of initial event, time since initial event, experience on anticoagulant, a person's age (because risk of VTE and risk of bleeding increase with age) and frailty. The Committee concluded that there is variation in the length of treatment with anticoagulants, and the decision to continue was dependent on an assessment and discussion of the risks and benefits for the individual.

4.3 The Committee heard from the patient experts about the experience of taking the currently available treatments for VTE. They noted that treatment with warfarin requires attendance at clinics for monitoring and dose adjustments which can affect a person's lifestyle. Some people self‑monitor their INR, but only a few would make the dose adjustments needed without contact with a health professional. The clinical experts stated that apixaban, rivaroxaban and dabigatran etexilate have the advantage of not needing monitoring or individual dose adjustments. They also stated that these anticoagulants have a shorter half‑life than warfarin, meaning that the effect of the drug wears off in a short time. This can be an advantage if the person has a bleed, but may be a disadvantage if the person misses a dose because the anticoagulant effect will wear off more quickly. The patient experts stated that even though there are fewer opportunities to check that people are taking these anticoagulants appropriately compared with warfarin, having a VTE has a major emotional and psychological effect on people so they are very likely to take their medication to avoid a recurrent event. The Committee noted that apixaban and dabigatran etexilate are taken twice a day and rivaroxaban is taken once a day after an initial 3‑week period. The clinical experts stated that taking a drug once a day may be considered more convenient by some patients, but a twice‑daily drug has the advantage that if a dose is missed patients have inadequate anticoagulation for a shorter time before they take their next tablet. The Committee noted that apixaban is the only anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. The clinical experts stated that patients and doctors may welcome the option of an anticoagulant which can be used at a lower dose for secondary prevention when considering the risk and benefits of continued treatment, and this may result in a higher chance that a person would take apixaban long term. The Committee heard that studies were currently underway to assess whether lower long‑term dosage may also be appropriate for other anticoagulants. The patient experts stated that it is essential patients have the opportunity to discuss the anticoagulation options available to them and be involved in the decision about which anticoagulant is best suited for them. The Committee concluded that there are advantages and disadvantages associated with all anticoagulants used to treat VTE and patients should have the opportunity for an informed discussion to decide the best treatment option for them.

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

TA341

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

Section

Key conclusion

Apixaban is recommended, within its marketing authorisation, as an option for treating and preventing deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults.

The Committee noted that in most of the company and ERG sensitivity analyses, the ICER was less than £20,000 per QALY gained and 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.

1.1, 4.11

Current practice

Clinical need of patients, including the availability of alternative treatments

Currently available treatments for treating and preventing DVT and PE include vitamin K antagonists such as warfarin, low molecular weight heparin, rivaroxaban and dabigatran etexilate. These treatment options differ with regards to whether monitoring of anticoagulation or initial treatment with low molecular weight heparin is needed, number of doses taken per day and dose reductions over time. The Committee concluded that there are advantages and disadvantages associated with all anticoagulants used to treat VTE and patients should have the opportunity for an informed discussion to decide the best treatment option for them. The patient experts emphasised that differences in access to newer oral anticoagulants is of great concern to patients.

4.1, 4.3

The technology

Proposed benefits of the technology

How innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?

The Committee noted that apixaban is the only novel oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. The clinical experts stated that patients and doctors may welcome the option of an anticoagulant which can be used at a lower dose for secondary prevention when considering the risk and benefits of continued treatment, and which may result in a higher chance that a person would take apixaban long term.

Apixaban has been demonstrated to be effective in treating VTE and was associated with fewer bleeds than warfarin.

4.2, 4.6

What is the position of the treatment in the pathway of care for the condition?

Apixaban is taken at the same position in the treatment pathway as warfarin, rivaroxaban, and dabigatran etexilate.

4.1

Adverse reactions

Apixaban was associated with fewer bleeds than warfarin. The estimates from the network meta‑analyses were not sufficiently robust to differentiate between apixaban, rivaroxaban and dabigatran etexilate in terms of bleeding.

4.6, 4.7

Evidence for clinical effectiveness

Availability, nature and quality of evidence

The Committee noted that the main source of evidence was from 2 trials: AMPLIFY and AMPLIFY‑EXT. 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 were the pivotal trials which informed the marketing authorisation for apixaban, and as such were appropriate to make a recommendation for the whole population covered by the marketing authorisation.

4.5

Relevance to general clinical practice in the NHS

The average age of people in both trials (of apixaban) was lower than the average age of people being treated for VTE in clinical practice in England. However, it accepted that the average age of the population in the trials was similar to that in other trials of anticoagulants for the treatment and secondary prevention of VTE.

4.5

Uncertainties generated by the evidence

There were no head‑to‑head trials to evaluate the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE. The company performed 2 meta‑analyses to indirectly compare apixaban with warfarin, rivaroxaban and dabigatran etexilate for treating VTE and for the secondary prevention of recurrent VTE. 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 are less common such as bleeding or VTE. The Committee agreed 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 concluded that the meta‑analysis results should be interpreted with some caution in light of these uncertainties.

4.7

Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?

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.

4.8

Estimate of the size of the clinical effectiveness including strength of supporting evidence

Apixaban has been demonstrated to be effective in treating VTE and was associated with fewer bleeds than warfarin.

There was no evidence of a difference in the effectiveness of apixaban, rivaroxaban and dabigatran etexilate. The estimates from the network meta‑analyses were not sufficiently robust to differentiate between apixaban, rivaroxaban and dabigatran etexilate in terms of bleeding.

4.6, 4.7

Evidence for cost effectiveness

Availability and nature of evidence

The company had presented base‑case results for 2 treatment durations: 6‑month treatment and lifelong treatment. 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.

4.7, 4.9

Uncertainties around and plausibility of assumptions and inputs in the economic model

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.

4.10

Incorporation of health‑related quality‑of‑life benefits and utility values

Have any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?

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 novel oral anticoagulants that it had seen, they were within the range presented in previous appraisals.

4.10

Are there specific groups of people for whom the technology is particularly cost effective?

Not applicable.

What are the key drivers of cost effectiveness?

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 novel oral anticoagulants.

4.11

Most likely cost‑effectiveness estimate (given as an ICER)

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 (6 months or lifelong).

4.11

Additional factors taken into account

Patient access schemes (PPRS)

None.

End‑of‑life considerations

Not applicable.

Equalities considerations and social value judgements

No equalities issues were raised in this appraisal.