The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban, having considered evidence on the nature of venous thromboembolism and the value placed on the benefits of rivaroxaban by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee heard from the clinical specialists that currently venous thromboembolism is initially treated with a LMWH (such as enoxaparin, dalteparin or tinzaparin) for rapid anticoagulation, overlapped with warfarin until an effective INR is achieved. The Committee also heard that treatment duration is based on an assessment of the benefit of continued anticoagulation compared with the risk of bleeding. The clinical specialists stated that treatment is often started with an expected duration of therapy, but that increasingly, a clinical re-evaluation is carried out at 3 or 6 months and a decision is made whether or not to continue therapy. The clinical specialists stated that in current UK practice, most people receive anticoagulation treatment for 6 months, which corresponds to the largest group in the EINSTEIN-DVT trial. However, the Committee heard that a NICE guideline in development on venous thromboembolic diseases is expected to recommend anticoagulation for 3 months in people with transient risk factors for deep vein thrombosis, and to recommend longer-term treatment in people with permanent risk factors and unprovoked deep vein thrombosis, taking into account individual risk factors such as risk of bleeding. The Committee concluded that although 6 months is currently the commonest duration of treatment in UK practice, this could change in light of the NICE guideline on venous thromboembolic diseases.
The Committee noted the written evidence from patient experts, which stated that many people find taking warfarin to be stressful, because of the necessary regular monitoring with blood tests, dosing adjustments, and because people must be careful about their diet because of warfarin's interaction with certain foods. The Committee heard from clinical specialists who agreed that warfarin is associated with a wide range of important and potentially dangerous drug interactions, and that warfarin can also negatively impact people's quality of life by preventing travel and other freedoms because of the need for regular monitoring. The Committee also heard from the patient experts that rivaroxaban may improve the quality of life of people who currently take warfarin by removing the need for constant monitoring, frequent blood tests and visits to an anticoagulation clinic. It also heard that rivaroxaban is likely to benefit people who are needle phobic or who want to resume normal patterns of life without having to worry about the disruption associated with attending clinics. The use of rivaroxaban would also relieve the concern that people may have about not being on the correct warfarin dose to keep their INR well controlled. Additional advantages of rivaroxaban are the lack of need for INR monitoring, which could reduce the need for support services, and its oral formulation compared with LMWH, which is injected.
The Committee discussed the clinical-effectiveness data from the EINSTEIN-DVT trial, which compared rivaroxaban with enoxaparin and a vitamin K antagonist in people with venous thromboembolism. The Committee heard from the clinical specialists that enoxaparin and a vitamin K antagonist is the key comparator. The Committee discussed whether the dosage of enoxaparin used in the EINSTEIN-DVT trial is relevant to UK clinical practice. The Committee heard from the clinical specialists that the dosage used in the UK (1.5 mg/kg once daily) and the dosage used in the EINSTEIN-DVT trial (1 mg/kg twice daily) are similar in efficacy and the difference is not expected to have affected the results of the trial. The Committee concluded that the difference in dosage did not appear to be clinically significant and was satisfied that the comparators used in the trial represented routine and best practice in the NHS.
The Committee considered the time in therapeutic range in the warfarin arm of the trial. It noted that the mean time in therapeutic range was 58%, which is lower than might be expected in routine UK clinical practice. However, the Committee heard from the clinical experts that control of INR is more difficult when warfarin is first started and before stabilisation on longer-term treatment. The Committee therefore concluded that for this patient population, the data from the warfarin arm in the trial was applicable to routine UK practice.
The Committee considered the trial design and results of EINSTEIN-DVT. The Committee noted that EINSTEIN-DVT was a non-inferiority trial that compared rivaroxaban with enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol). The Committee heard that patients recruited into the trial were allocated to 3-, 6- and 12-month treatment durations by the treating physician, based on individual patient risk factors, before randomisation. The Committee noted that, for the whole trial population, rivaroxaban was at least as effective as the enoxaparin and a vitamin K antagonist regimen with respect to the primary efficacy endpoint of symptomatic recurrent venous thromboembolism and to the primary safety endpoint of clinically relevant bleeding. The Committee concluded that rivaroxaban was as effective as enoxaparin followed by a vitamin K antagonist for preventing recurrent venous thromboembolism, and did not have the disadvantages of an injected treatment followed by an oral treatment with the need for regular monitoring with blood tests.
The Committee considered the baseline characteristics of the EINSTEIN-DVT trial population and the results of the pre-specified subgroup analyses presented by the manufacturer. The Committee noted that rivaroxaban appeared to be more effective in people with a previous episode of deep vein thrombosis or pulmonary embolism, and that the effect of rivaroxaban varied between the subgroups allocated to the 3 different intended treatment durations. The Committee noted that the subgroup analysis by intended treatment duration suggested that rivaroxaban might be less effective than enoxaparin and warfarin in patients for whom 3 months of treatment was intended. The Committee noted the heterogeneity of the trial population in terms of underlying risk factors for deep vein thrombosis, and noted that no individually identifiable clinical group was included in only 1 treatment duration subgroup. The Committee also heard from the manufacturer that there were no specific clinical criteria or algorithms used to allocate people into the different intended treatment duration groups, and that there was no apparent biological or clinical plausibility for the differential effectiveness of rivaroxaban across the intended treatment duration subgroups. A similar view was taken by the clinical specialists, who noted that they were not aware of any clinical reasons why rivaroxaban would be less effective than LMWH and a vitamin K antagonist in people who received 3 months of treatment, while being more effective in the 6- and 12-months groups. The Committee also heard from the ERG that the lower efficacy in the patient group treated for 3 months only was based on a small number of events in both arms and the majority of events occurred in the 6- and 12-month groups. The Committee accepted that there is insufficient evidence to demonstrate that rivaroxaban had a substantially different effectiveness across treatment durations, and was not aware of any biological reason to expect a differential effect in the first 3 months. The Committee therefore concluded that evidence of treatment effect should be based on the whole trial population of EINSTEIN-DVT.
The Committee questioned whether the pre-specified intended treatment duration used in the EINSTEIN-DVT trial reflects clinical practice. It noted that the clinical advisers to the ERG estimated that approximately 20% of people with deep vein thrombosis may need treatment for longer than 12 months. The Committee heard from the clinical specialists that the average duration of treatment is currently 6 months, at which time further treatment, including life-long treatment, would be considered if the person's risk of a recurrence remained high. However, the Committee noted that the summary of product characteristics for rivaroxaban states that experience with rivaroxaban in this indication for more than 12 months is limited. The manufacturer informed the Committee that there is a risk management plan agreed with the European Medicines Agency that involves the non-interventional XALIA study. The study will recruit people with a diagnosis of acute deep vein thrombosis and aims to estimate the recurrence of venous thromboembolism, incidence of major bleeding and mortality over the longer term. The Committee concluded that it may not be realistic to assume that people stop treatment once the pre-specified treatment period has ended and some people with ongoing risk factors for recurrence would need ongoing treatment, possibly for many years or lifelong.
The Committee discussed the results from the EINSTEIN-Ext trial. It noted that the trial inclusion criteria included people defined to be in 'clinical equipoise'. The manufacturer defined this as people for whom the decision to treat with anticoagulants was finely balanced. However, the Committee heard from the clinical specialists that in UK practice people who are to be treated for up to 12 months, as in the EINSTEIN-Ext trial, would generally not fall under this definition because they would have a strong clinical reason for further anticoagulation. It therefore agreed that the population in the EINSTEIN-DVT trial was more relevant for appraising rivaroxaban in venous thromboembolism for up to 12 months of treatment.
The Committee considered the adverse events reported in the EINSTEIN-DVT and EINSTEIN-Ext trials. The Committee noted that patients treated with rivaroxaban experienced a comparable number of clinically relevant bleeding episodes to those treated with enoxaparin and a vitamin K antagonist in EINSTEIN-DVT. The Committee noted that patients treated with rivaroxaban in the extension study experienced a higher rate of clinically relevant non-major bleeding but that the comparator was placebo and not active control. The Committee concluded that treatment with rivaroxaban had an acceptable adverse event profile compared with the combination of LMWH and warfarin.
The Committee considered the cost effectiveness of rivaroxaban for up to 12 months of treatment. The Committee noted that the economic model used clinical-effectiveness data from the EINSTEIN-DVT trial and that the results were presented by treatment duration. It noted that rivaroxaban dominated treatment with enoxaparin and a vitamin K antagonist in the manufacturer's deterministic analysis, that is, rivaroxaban was less costly and more effective across all 3 treatment durations (3, 6 and 12 months). The manufacturer's model assumed a first-year INR monitoring cost of £656, and £540 in subsequent years. The Committee was mindful of the QALY increment for people treated with rivaroxaban but considered that the estimate of INR costs was too high and was not likely to reflect the actual cost in UK clinical practice. The Committee could therefore not accept the results of the manufacturer's base-case analysis as the estimate of cost effectiveness.
The Committee discussed the estimate of the cost of INR monitoring. The Committee acknowledged the multiple models of provision for INR monitoring across the UK and the uncertainty about the costs. It noted that estimates of INR monitoring costs varied greatly, and some community-based monitoring programmes appeared to be much cheaper than the manufacturer's estimate. The Committee considered the ERG's critique of the base-case economic model for up to 12 months of treatment. The ERG assumed a less intensive INR monitoring programme of 6 visits in the first 3 months followed by 3 visits every 3 months thereafter, and assumed different provisions for INR monitoring than did the manufacturer. The ERG's estimate of the cost of INR monitoring was £320 in the first year and £248 thereafter. It noted that the ERG estimate appeared to be in the region of the estimated INR costs used in NICE's technology appraisal guidance on dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. The Committee heard from the clinical specialists that the population eligible for treatment with rivaroxaban is not likely to need significantly more frequent INR monitoring than people being started on anticoagulation therapy for other indications. Comments from consultees also indicated that the manufacturer's estimate of INR monitoring costs was higher than was plausible for UK practice. The Committee therefore concluded that the ERG's alternative assumptions and estimate of £320 for INR monitoring in the first year of treatment were reasonable and relevant for this appraisal.
The Committee considered the results of the ERG's economic evaluation of rivaroxaban treatment for up to 12 months. The ERG's estimate used clinical-effectiveness data from the whole trial population of EINSTEIN-DVT and the ERG's lower estimate for INR monitoring. The results indicated that rivaroxaban dominated therapy with LMWH and a vitamin K antagonist in the 3-month treatment duration group. The ICER for rivaroxaban was £3,200 per QALY gained for the 6-month treatment duration and £14,900 per QALY gained for the 12-month treatment duration. The Committee agreed that these cost-effectiveness results for up to 12 months of treatment using the ERG estimate for the cost of INR monitoring were more plausible than those provided by the manufacturer. The Committee concluded that treatment with rivaroxaban represented a clinical and cost-effective option in people in whom treatment for up to 12 months is indicated.
The Committee then discussed the manufacturer's submission for rivaroxaban in those who need long-term anticoagulation; that is, beyond 12 months of treatment. It noted that the manufacturer's economic model included a decrement in utility of 0.012 for people on warfarin only, which was taken from a small study by Marchetti et al. The Committee heard from the patient experts that warfarin has an impact on quality of life (see section 4.3). The Committee considered that although treatment with rivaroxaban could be associated with a small disutility, it was satisfied that treatment with warfarin was associated with a higher disutility than treatment with rivaroxaban, and the relative difference in disutility could be even higher than 0.012 for people who may have to take it for many years or lifelong. The Committee concluded that although it was not convinced that the utility decrement used by the manufacturer was supported by strong evidence, it was of the opinion that the relative difference in disutility was at least as great as the value used by the manufacturer in its long-term model.
The Committee discussed the discontinuation rates in the economic evaluation of rivaroxaban in those who need ongoing anticoagulation. It noted that the manufacturer had used a discontinuation rate of 3.6% for every 3-month period for both treatments, which was taken from a study on long-term statin therapy. The Committee acknowledged the lack of evidence for the long-term adherence of people treated with rivaroxaban in venous thromboembolism, but noted there was no strong evidence to suggest that the people treated with rivaroxaban should have different rates of discontinuation compared with warfarin. The Committee concluded that it was satisfied that equal or near-equal discontinuation rates should be applied to both treatment arms.
The Committee then considered the results of the cost-effectiveness analysis of rivaroxaban for long-term anticoagulation. It noted the results from the manufacturer's long-term model which incorporated INR monitoring costs of £656 and a disutility of 0.012 applied to warfarin only, resulting in an ICER of £6,000 per QALY gained for rivaroxaban compared with enoxaparin and a vitamin K antagonist. The Committee noted that the equivalent ICER, when a less intensive INR monitoring cost of £413 was assumed, was £15,800 per QALY. The Committee also noted the ERG's exploratory analysis, which provided a range of estimates of the ICERs for ongoing anticoagulation under the scenarios outlined in 3.27. This gave ICERs ranging from £19,400 to £38,800 per QALY gained. The Committee noted that the INR monitoring costs assumed by the manufacturer were higher than are considered to be reasonable and therefore considered the ERG's analysis to be more appropriate. The Committee was satisfied that the differential disutility for warfarin compared with rivaroxaban, although uncertain, was at least 0.012 when long-term or lifelong treatment is needed Assuming an equal discontinuation rate, a differential disutility of more than 0.012 would bring the ICER down to below £19,400 per QALY gained. The Committee also explored the scenario incorporating a discontinuation rate for rivaroxaban of just over half the warfarin discontinuation rate which, if a differential disutility of 0.012 was applied, gave an ICER of £25,100 per QALY gained. However, the Committee was not convinced that the discontinuation rate would be different, and felt that the ICER estimate of £25,100 was too high (see section 4.17). The Committee therefore concluded that £19,400 per QALY gained was a plausible estimate, and that rivaroxaban was a cost-effective treatment option for people who need anticoagulation treatment for longer than 12 months.
The Committee discussed the effectiveness of rivaroxaban in people with cancer. It considered the manufacturer's mixed-treatment analyses, and found the manufacturer's secondary analysis 2 (see section 3.7) to be the most relevant because it used data from the cancer subgroup. It noted that this analysis indicated that rivaroxaban was less effective than dalteparin at preventing venous thromboembolism recurrence but induced fewer major bleeding events. It also noted that the credible intervals around these estimates were wide. The Committee acknowledged that the ERG did not find the cancer subgroup analyses to be robust and had concerns with the limited evidence and with how the mixed-treatment comparison was conducted and implemented. The Committee heard from the clinical specialists that the current standard care in treating venous thromboembolism in people with cancer is LMWH alone, which the evidence suggests provides benefits greater than warfarin. This seems to be a cancer-specific effect. The clinical specialists further stated that there is no direct trial evidence demonstrating that rivaroxaban is superior to a LMWH in people with cancer, and so would not expect the availability of rivaroxaban to change UK clinical practice in this population. The Committee heard from the patient experts that people with cancer would welcome a non-invasive treatment option such as rivaroxaban, particularly people receiving palliative care, as long as the treatment is safe and does not interact with the cancer treatment. Given the lack of clinical evidence for this group, the Committee was unable to make specific recommendations on the use of rivaroxaban in people with cancer but recognised the disadvantages of the currently available treatment, which involves regular injections, and which some people might choose to decline. The Committee concluded that rivaroxaban should not be excluded as a treatment option for preventing venous thromboembolism in people with cancer.