4 Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of edoxaban, having considered evidence on the nature of venous thromboembolism (VTE) and the value placed on the benefits of edoxaban 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 considered the experience of people with VTE. It noted submissions from clinical and patient experts which stated that the impact of a deep vein thrombosis (DVT) or pulmonary embolism (PE) can be devastating, with patients often hospitalised, restricted in movement and unable to continue with previous activities. When recovering from VTE, patients may need further treatment and monitoring. It heard from the patient and clinical experts that the need for International Normalised Ratio (INR) checks when taking warfarin represents a major disadvantage, and the most important issue for patients is to have an effective treatment which minimises disruption to their day‑to‑day lives. The Committee was aware that various models of provision of INR monitoring are in use in England. It heard from the patient experts that some people taking warfarin monitor their own INR levels, but in some areas in the UK this was being made more difficult or phased out. The Committee heard that patients value newer oral anticoagulants such as edoxaban which do not need routine monitoring. In addition, the Committee noted that warfarin has many drug and food interactions which is not the case for the newer agents. The Committee heard from the patient and clinical experts that in the absence of regular monitoring, compliance with the newer anticoagulants would not be regularly checked, and good patient information was vital to help encourage compliance. However, they noted that this was not an issue for most patients, who were well aware of the importance of anticoagulation treatment. The Committee noted that edoxaban has a simple once‑daily dosage, and would usually only need 1 annual monitoring visit to check renal function. The Committee concluded that patients value newer oral anticoagulants such as edoxaban, which cause less disruption to their lives than warfarin.

4.2 The Committee considered the current treatment for people with VTE. It heard from the patient experts that there was variation in practice in the UK. Patients were sometimes not informed about the range of anticoagulants available, and prescription of newer oral anticoagulants depended on local clinical leadership and policies. One expert stated that some clinicians consider it easier to reverse the effects of warfarin than the newer oral anticoagulants, and in some instances warned their patients about the lack of reversibility of newer agents. However, this concern was not necessarily justified because most of the newer anticoagulants can be reversed with prothrombin complex concentrates, and more specific reversing agents are awaiting marketing authorisation. The clinical and patient experts also stated that some hospitals restrict the choice of anticoagulants to minimise prescribing errors, and that rivaroxaban was currently the most widely used of the new oral anticoagulants. The clinical expert noted that there had been a recent drive to increase outpatient treatment for VTE and agents that do not need heparin to be given for a few days at the beginning of treatment would be preferable for the 30% to 40% of patients treated for VTE as an outpatient. However, the clinical expert noted that a large proportion of treatment for VTE is still started as an inpatient, when patients typically have parenteral heparin for several days. In this situation a drug such as edoxaban may be useful because of its simple dosing schedule. The Committee also heard from the clinical expert that having the option to use a lower dose of edoxaban was of value, and the availability of a range of anticoagulant agents was necessary because patients may be allergic to 1 or more agents. The Committee concluded that the choice of anticoagulant treatment would largely depend on the healthcare setting and local policies.

Clinical effectiveness

4.3 The Committee considered the Hokusai‑VTE trial. It noted that it had an unconventional design in a number of ways; for example, patients could change dosage during the trial, there was a flexible treatment duration, and the primary efficacy outcome was measured at 12 months irrespective of the time when treatment stopped (which could have been as early as 3 months). The Committee noted that the trial therefore differed from VTE trials for other anticoagulants. The clinical expert agreed that it was unusual that the primary outcome was measured in patients who had potentially been untreated for up to 9 months (although the Committee noted that 60% of patients in the trial had treatment for at least 6 months). However, the company stated that this approach accurately reflected real‑world clinical practice, and led to a more conservative estimate of efficacy, with which the clinical expert agreed. The Committee was aware that the design of the trial was not strictly comparable with other recent trials for newer anticoagulants, and that the value of assessing efficacy several months after some patients had stopped treatment was questionable. However, the trial did allow a choice of dosage, and did not predetermine the length of treatment at the start, both of which mirrored clinical practice. The Committee concluded that Hokusai‑VTE was well designed and suitable for evaluating the clinical effectiveness of edoxaban.

4.4 The Committee considered the baseline characteristics of the patients in the trial. It noted the ERG's concerns about generalisability (section 3.14). However, it heard from the clinical and patient experts that they had no concerns about the generalisability of the trial, including the age of participants, with 1 expert explaining that people can experience VTE at any age. The Committee also noted that the patient population was comparable to that in other trials for newer anticoagulants. The Committee concluded that the results of the clinical trial were generalisable to people with VTE in the NHS and were appropriate for decision making on the clinical effectiveness of edoxaban.

4.5 The Committee discussed the clinical efficacy results from Hokusai‑VTE. It noted that the trial had shown a higher rate of VTE recurrence in the edoxaban group compared with warfarin in the first 30 days, but agreed that caution was needed in interpreting this difference because the numbers were small and the difference was not statistically significant. The Committee concluded that overall the trial had demonstrated that edoxaban was statistically non‑inferior to warfarin for VTE recurrence.

4.6 The Committee considered the network meta‑analysis presented by the company. The Committee noted the wide credible intervals and the non‑inferiority design of the trials in the network. It further noted that the unconventional design of Hokusai‑VTE compared with the other trials in the network had led to heterogeneity. The Committee concluded that no clear differences between treatments for any outcome had been demonstrated, but that the comparative evidence was weak (because of the lack of direct evidence comparing the newer anticoagulants, and the issues noted with the network meta‑analysis) and therefore the results needed to be interpreted with caution.

4.7 The Committee noted that a small number of people with cancer had been included in the trial but that no subgroup analysis results had been presented for these patients. The Committee heard from the clinical expert that the standard treatment for VTE in people with cancer is low‑molecular‑weight heparin. Hokusai‑VTE did not include this as a comparator group, so there was no comparison of edoxaban with the current standard of care for these patients. The Committee concluded that the trial did not provide relevant data for people with cancer who experienced VTE, and it was unable to make any specific recommendation for this subgroup of patients.

4.8 The Committee discussed the adverse events associated with edoxaban. It noted that there were 18 primary intracranial haemorrhages in the warfarin group (of which 6 were fatal) and 5 in the edoxaban group, none of which were fatal (section 3.9). The Committee was aware that intracranial haemorrhage is considered to be the single most serious complication of anticoagulation treatment. It heard from the clinical expert that the reduced risk of intracranial haemorrhage is recognised as a benefit of newer oral anticoagulants in general and there is also the suggestion that, when intracranial haemorrhage does occur, the bleed may be less extensive than with warfarin. However, this benefit needs to be balanced against an increased risk of gastrointestinal bleeding as suggested in the trial; there were 9 more gastrointestinal bleeds in the edoxaban group than in the warfarin group (section 3.9). The Committee heard concerns from the ERG that although Hokusai‑VTE demonstrated a statistically significant reduction in bleeding (major and clinically relevant non‑major bleeding), the reduction for major bleeding alone was not statistically significant. The Committee concluded that there was no statistically significant difference for major bleeding for edoxaban compared with warfarin, but that a reduction in intracranial haemorrhage with edoxaban was a potential substantial benefit.

Cost effectiveness

4.9 The Committee considered the structure of the company's health economic model and the assumptions used. The ERG had raised a number of parameter and structural concerns about the model. The Committee generally agreed with these concerns, particularly:

  • The assumption that some adverse events such as chronic thromboembolic pulmonary hypertension and post‑thrombotic syndrome were treatment‑related rather than disease‑related.

  • The exclusion of treatment‑switching after VTE recurrence (the Committee heard from the clinical expert that returning to a treatment that had failed to prevent recurrence was not clinically plausible).

  • The inclusion of both ischaemic and haemorrhagic stroke within the stroke health state. Ischaemic stroke is not treatment‑related whereas intracranial haemorrhage is; putting them together was an oversimplification and not clinically plausible. It also resulted in potential double‑counting of intracranial haemorrhage because this was also included in the major bleeding health state.

    Despite these and other concerns about the reliability of the model, the Committee heard from the ERG that flaws in the model, although important methodologically, did not have a substantial impact on the cost‑effectiveness results, because they affected both arms equally, or because the probabilities of the associated adverse events were low. The Committee concluded that some of the assumptions in the model and model structure lacked clinical plausibility but, taking into account the ERG's comments and analyses, these flaws were not key drivers of cost‑effectiveness.

4.10 The Committee considered the clinical‑effectiveness estimates that had been used in the company's economic model, noting that the estimates were from a network meta‑analysis which had limited capacity to demonstrate statistically significant differences between treatments. The Committee concluded that the efficacy data from the network meta‑analysis contributed to uncertainty in the cost effectiveness results.

4.11 The Committee considered the warfarin monitoring‑cost assumptions used in the company model. The Committee noted that the company had assumed an annual cost of warfarin monitoring of approximately £630. The Committee discussed whether this cost was reasonable. It heard from the ERG that according to their clinical experts the company had overestimated the costs of monitoring – the frequency was too high, and the monitoring would usually be done by a nurse rather than a consultant as assumed in the company base case. After reducing the frequency of visits and assuming monitoring would be nurse‑led, the ERG had used a monitoring cost of £342 in the first year and £190 after that. The Committee heard from the company that it had access to unpublished preliminary registry data suggesting that monitoring costs in clinical practice were substantially higher than the estimates used by the ERG. The Committee was aware that there is considerable variation in how warfarin monitoring is provided in the NHS, which would affect the costs, and that there is also individual variation (some patients have INR levels which are more unstable than others and need more frequent monitoring). The exact frequency and cost of warfarin monitoring is therefore unknown. The Committee referred to previous appraisals in its consideration of the very different estimates from the company and ERG. It noted that the cost assumed by the company was substantially higher than the range considered plausible in previous appraisals for VTE (£304 to £379). The Committee concluded that the company estimates were higher than had previously been accepted as plausible and the ERG estimates for the first year were closer to those previously accepted. However, the precise costs of warfarin monitoring remained uncertain.

4.12 The Committee considered the cost‑effectiveness estimates generated by the company and ERG. It noted that the warfarin monitoring cost was the main driver of the cost‑effectiveness estimates. The Committee agreed that the cost of monitoring in the first year in the ERG base case was more consistent with previous appraisals than the company's estimate. Therefore, it considered that the ICER relative to warfarin was likely to be closer to the ERG estimate of £26,000 per QALY gained than the company estimate of approximately £2500 per QALY gained. Nevertheless, it considered that both ICERs were subject to high levels of uncertainty because of the previously discussed flaws in the company model on which they were based, and the lack of definitive warfarin monitoring costs in the NHS. Noting these uncertainties, the Committee further considered the cost effectiveness of edoxaban compared with other anticoagulants that had been considered in previous appraisals for the treatment of VTE. The Committee accepted that the clinical effectiveness of edoxaban had been adequately demonstrated by the clinical trial. It also noted that the price of edoxaban was similar to one of the other agents, rivaroxaban. Taking into account the lack of any clear trial evidence that edoxaban was substantially different from the other newer oral anticoagulants, and the testimony of the experts, the Committee concluded that the most plausible ICER was likely to be in line with that of the other oral anticoagulants already recommended in previous NICE guidance for the treatment of VTE. The Committee therefore concluded that edoxaban could be recommended as a cost‑effective use of NHS resources.

4.13 The Committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism, when appraising edoxaban. The Committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of edoxaban. It therefore concluded that the PPRS Payment Mechanism was not relevant for its consideration of the cost effectiveness of edoxaban.

Summary of Appraisal Committee's key conclusions

TA354

Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism

Section

Key conclusion

Edoxaban is recommended, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults.

Taking into account the similar price of edoxaban to rivaroxaban, the lack of any clear trial evidence that edoxaban was substantially different from the other newer oral anticoagulants, and the testimony of the experts, the Committee concluded that the most plausible ICER was likely to be in line with that of the other oral anticoagulants already recommended in previous NICE guidance for the treatment of VTE. The Committee therefore concluded that edoxaban could be recommended as a cost‑effective use of NHS resources.

1.1, 4.12

Current practice

Clinical need of patients, including the availability of alternative treatments

The Committee noted that the impact of a DVT or PE can be devastating, with patients often hospitalised, restricted in movement and unable to continue with previous activities. It heard from the patient and clinical experts that the need for International Normalised Ratio (INR) checks when taking warfarin represents a major disadvantage. The Committee noted that edoxaban has a simple once‑daily dosage, and would usually only need 1 annual monitoring visit to check renal function. The Committee concluded that patients value newer oral anticoagulants such as edoxaban, which cause less disruption to their lives than warfarin.

4.1

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 edoxaban has a simple once‑daily dosage, and would usually only need 1 annual monitoring visit to check renal function.

4.1

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

The Committee heard from the clinical and patient experts that some hospital protocols limit the choice of anticoagulants to minimise prescribing errors. It heard from the clinical expert that agents that do not need heparin would be preferable for the 30% to 40% of patients treated for VTE as an outpatient. However, those treated for VTE as an inpatient typically have parenteral heparin for several days, and in this situation a drug such as edoxaban may be preferable, because of its simple dosing schedule. A range of anticoagulant agents is necessary because patients may be allergic to 1 or more agents. The Committee concluded that the choice of anticoagulant treatment would largely depend on the healthcare setting and local policies.

4.2

Adverse reactions

The Committee noted that there were fewer primary intracranial haemorrhages in the edoxaban group of the trial compared with the warfarin group. It heard from the clinical expert that this was recognised as a benefit of newer oral anticoagulants in general, but that this benefit needs to be balanced against an increased risk of gastrointestinal bleeding with the newer oral anticoagulants.

The Committee concluded that there was no statistically significant difference for major bleeding for edoxaban compared with warfarin, but that a reduction in intracranial haemorrhage with edoxaban was a potential substantial benefit.

4.8

Evidence for clinical effectiveness

Availability, nature and quality of evidence

The Committee noted that the Hokusai‑VTE trial had an unconventional design; for example, the primary efficacy outcome was measured at 12 months irrespective of the time when treatment stopped. The Committee noted that the design of the trial was not strictly comparable with other recent trials for newer anticoagulants, and that the value of assessing efficacy several months after some patients had stopped treatment was questionable. However, the trial did allow a choice of dosage, and did not predetermine the length of treatment at the start of treatment, both of which mirrored clinical practice. The Committee concluded that Hokusai‑VTE was well designed and suitable for decision making on the clinical effectiveness of edoxaban.

4.3

Relevance to general clinical practice in the NHS

The Committee noted the ERG's concerns about the generalisability of Hokusai‑VTE to the UK population. However, it heard from the clinical and patient experts that they had no concerns about the generalisability of the trial. The Committee also noted that the patient population was comparable to that in other trials for newer anticoagulants. The Committee concluded that the results of the trial were generalisable to people with VTE in the NHS and were appropriate for decision making on the clinical effectiveness of edoxaban.

3.14, 4.4

Uncertainties generated by the evidence

The Committee noted the wide credible intervals and the non‑inferiority design of the trials in the network meta‑analysis. It further noted that the unconventional design of Hokusai‑VTE had led to heterogeneity. The Committee concluded that no clear differences between treatments for any outcome had been demonstrated, but that the comparative evidence was weak (because of the lack of direct evidence comparing the newer anticoagulants, and the issues noted with the network meta‑analysis) and therefore the results needed to be interpreted with caution.

4.6

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

The Committee noted that a small number of people with cancer had been included in the trial but that no subgroup analysis results had been presented for these patients. It heard from the clinical expert that the standard treatment for VTE in people with cancer is low‑molecular‑weight heparin. Hokusai‑VTE did not include this as a comparator arm, so there was no comparison of edoxaban with the current standard of care for these patients. The Committee concluded that the trial did not provide relevant data for people with cancer who experienced VTE.

4.7

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

The Committee concluded that the trial was well designed, appropriately powered, and had demonstrated that edoxaban was statistically non‑inferior to warfarin for VTE recurrence.

4.3, 4.5

Evidence for cost effectiveness

Availability and nature of evidence

The company developed a new economic model that compared edoxaban with warfarin, rivaroxaban and dabigatran etexilate for the treatment and secondary prevention of an acute VTE event. The model included 12 states representing treatment status (on‑treatment or off‑treatment health states), adverse events, and death. The model had a lifetime time horizon (maximum 50 years) and each model cycle was 2‑weeks long.

3.21–3.22

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

The Committee noted that the modelled clinical‑effectiveness estimates were from a network meta‑analysis which had limited capacity to demonstrate statistically significant differences between treatments. The Committee concluded that there was uncertainty about the cost‑effectiveness results.

The Committee noted and agreed with the parameter and structural concerns about the model noted by the ERG, particularly: the assumption that some adverse events were treatment‑related rather than disease‑related; the exclusion of treatment‑switching after VTE recurrence; and the inclusion of both ischaemic and haemorrhagic stroke within the stroke health state. The Committee concluded that some of the assumptions in the model and the model structure lacked clinical plausibility but, taking into account the ERG comments and analyses, these flaws were not key drivers of cost‑effectiveness.

The Committee agreed that the cost‑effectiveness results were largely driven by the estimates of warfarin monitoring costs, and noted that the costs of monitoring assumed by the company were substantially higher than the range considered plausible in previous appraisals for VTE (£304 to £379). The Committee concluded that the ERG estimates for the first year were closer to those previously accepted as plausible. However, the precise costs of warfarin monitoring remained uncertain.

4.9–4.11

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?

At entry into the model, for the first cycle only, all patients had a utility value that reflected the disutility of the initial VTE (derived from Hokusai‑VTE data). For all subsequent cycles, all patients in all treatment groups were assigned age‑dependent baseline utility values from the general population without illness. When patients experienced adverse events in the model, the company applied a health‑state‑related utility decrement that was deducted from the baseline utility value (derived from its systematic literature review).

3.25

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

The Committee concluded that the trial did not provide relevant data for people with cancer who experienced VTE, and it was unable to make any specific recommendation for this subgroup of patients.

4.7

What are the key drivers of cost effectiveness?

The Committee agreed that the cost‑effectiveness results were largely driven by the estimates of warfarin monitoring costs.

4.9, 4.12

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

The Committee agreed that the ICER was likely to be closer to the ERG estimate of £26,000 per QALY gained than the company estimate of approximately £2500 per QALY gained. Nevertheless, it considered that both ICERs were subject to high levels of uncertainty because of parameter and structural uncertainties in the model.

4.11, 4.12

Additional factors taken into account

Patient access schemes (PPRS)

N/A

End‑of‑life considerations

N/A

Equalities considerations and social value judgements

N/A

  • National Institute for Health and Care Excellence (NICE)