1     Appraisal Committee’s preliminary recommendations

1.1  The Committee is minded not to recommend rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism after an acute deep vein thrombosis in adults.

1.2  The Committee requests further information about the clinical and cost effectiveness of rivaroxaban. The manufacturer should provide the following for the second Appraisal Committee meeting:

• Comments on the differences between the populations that were assigned treatment durations of 3, 6 and 12 months, and further details of any clinical criteria or algorithm used by the treating physician for assigning patients to the three groups.
• Consideration of the cost effectiveness of rivaroxaban compared with low molecular weight heparin (LMWH) and a vitamin K antagonist in patients in whom long-term anticoagulation is intended. Ideally this should be supported by a cost-effectiveness analysis of rivaroxaban as a lifelong treatment after the index event. This analysis should use data from the whole population of the EINSTEIN-DVT trial for estimating clinical effectiveness and should include sensitivity analyses that assume a less intensive INR monitoring program of 6 visits in the first 3 months, followed by 2 or 3 visits every 3 months thereafter in the comparator arm.

2  The technology

2.1  Rivaroxaban (Xarelto, Bayer) is indicated for the ‘treatment of deep vein thrombosis (DVT), and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults’. For the initial treatment of acute deep vein thrombosis, the recommended dose of rivaroxaban is 15 mg twice daily for the first 21 days followed by 20 mg once daily for continued treatment and prevention of recurrence.

2.2 The duration of treatment recommended in the summary of product characteristics depends on bleeding risk and other clinical criteria: short-term treatment (3 months) is recommended for those with transient risk factors such as recent surgery and trauma, and longer treatment for permanent risk factors or idiopathic (unprovoked) deep vein thrombosis. A reduced dose of 15 mg twice daily for 21 days followed by 15 mg once daily should be used in people with moderate (creatinine clearance 30–49 ml/min) or severe (creatinine clearance 15–29 ml/min) renal impairment. The summary of product characteristics states that about 24% of the patients exposed to at least one dose of rivaroxaban experienced adverse events related to the treatment. In patients prescribed doses for preventing recurrent deep vein thrombosis and pulmonary embolism, bleeding events occurred in approximately 22.7% and anaemia occurred in approximately 1.8% of patients. Experience with rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism for longer than 12 months is limited. For full details of side effects and contraindications, see the summary of product characteristics.

2.3   Rivaroxaban costs £2.10 per 15 mg or 20 mg tablet. The cost of treatment is estimated to be £235.86, £427.61 and £811.13 for 3, 6 and 12 months of treatment respectively. Costs may vary in

3  The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1   The key clinical evidence in the manufacturer’s submission came from two trials (EINSTEIN-DVT and EINSTEIN-Ext). EINSTEIN-DVT was an open-label non-inferiority study that compared rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for 3, 6 or 12 months) with enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) in patients with acute symptomatic deep vein thrombosis without any symptoms of pulmonary embolism, and for the prevention of recurrent venous thromboembolism. Enoxaparin was given until a vitamin K antagonist had brought the INR into the target range, and was then discontinued. Based on individual patient risk factors, patients were either assigned to 3, 6 or 12 months of treatment as determined by the treating physician. EINSTEIN-Ext was a randomised placebo-controlled superiority trial that compared rivaroxaban (20 mg once daily; n = 602) with placebo once daily (n = 594) in patients with confirmed symptomatic deep vein thrombosis or pulmonary embolism that had been treated for 6 or 12 months with a vitamin K antagonist (warfarin or acenocoumarol) or rivaroxaban up to the moment of randomisation. Patients were recruited based on physician assessment of likely risk.

3.2  The manufacturer’s submission noted that about 60% of patients recruited into EINSTEIN-Ext were assigned to 6 months of treatment, 53% had participated in EINSTEIN-DVT and 28% had previously used rivaroxaban. The manufacturer also noted that some people were excluded from the EINSTEIN-DVT and EINSTEIN-Ext trials, such as those with a creatinine clearance of less than 30 ml/min, clinically significant liver disease, high blood pressure (systolic more than 180 mmHg or diastolic more than 110 mmHg), active bleeding or at high risk of bleeding.

3.3  The primary efficacy endpoint was a composite of deep vein thrombosis or pulmonary embolism (symptomatic, recurrent venous thromboembolism). Pulmonary embolism included both fatal and non-fatal pulmonary embolism. The primary safety endpoint was a composite of major bleeding and other clinically relevant non-major bleeding (‘clinically relevant bleeding’) for EINSTEIN-DVT and major bleeding for EINSTEIN-Ext. A range of secondary composite endpoints were also included.

3.4  In EINSTEIN-DVT, the primary efficacy endpoint of symptomatic recurrent venous thromboembolism occurred in 2.1% (n = 36) of patients in the rivaroxaban group compared with 3.0% (n = 51) in the enoxaparin and vitamin K antagonist group (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.44 to 1.04, p < 0.001 for non-inferiority and p = 0.076 for superiority). The overall HR for rivaroxaban was 0.97 (95% CI 0.76 to 1.22, p = 0.77) for the primary safety endpoint of clinically relevant bleeding and 0.67 (95% CI 0.44 to 1.02, p =0.06) for death from all causes. Recurrent deep vein thrombosis occurred less frequently in patients treated with rivaroxaban than with enoxaparin and a vitamin K antagonist (14 compared with 28). Pulmonary embolisms (fatal and non-fatal) did not differ between treatment groups.

3.5 The manufacturer reported a time in therapeutic range for the comparator enoxaparin and a vitamin K antagonist of 57.7% across all centres and 59.7% in western European centres. The manufacturer highlighted that guidelines from the National Patient Safety Agency and the Scottish Executive Health Department recommend a time in therapeutic range of at least 60%. It also noted there was no statistical interaction observed in EINSTEIN-DVT between time in therapeutic range and treatment effect.

3.6 In EINSTEIN-Ext, patients taking rivaroxaban experienced fewer recurrences of venous thromboembolism (1.3%) than patients taking placebo (7.1%) (HR 0.18, 95% CI 0.09 to 0.39, p < 0.0001). The numbers of clinically relevant non-major bleeding events were significantly higher in the rivaroxaban arm than in the placebo arm (32 patients compared with 7 patients, p < 0.001). There were more major bleeding events in patients taking rivaroxaban (4 patients compared with 0 patients), although this did not reach statistical significance.

3.7 The manufacturer reported a mixed treatment comparison to compare the relative effectiveness of rivaroxaban compared with dual low molecular weight heparin (LMWH) and a vitamin K antagonist, long-term LMWH compared with LMWH and a vitamin K antagonist, and rivaroxaban compared with long-term LMWH. The manufacturer provided two separate analyses. The primary analysis used data from a systematic review of long-term anticoagulation in patients with cancer reported by Akl et a. (2011) and from the whole EINSTEIN-DVT trial. The secondary analysis used data from a trial by Lee et al. (2003) evaluating the LMWH dalteparin for the prevention of recurrent venous thromboembolism in patients with cancer and the data from the cancer subgroup of EINSTEIN-DVT.

3.8 Results from the primary analysis indicated that for patients with active cancer, the venous thromboembolism recurrence hazard ratio for rivaroxaban compared with long-term LMWH was 1.44 (95% CI 0.07 to 31.4). The manufacturer noted that the mixed treatment comparison had wide margins of uncertainty for the efficacy and safety of rivaroxaban compared with long-term LMWH. Following a request from the ERG, the manufacturer also presented an additional analysis for the subgroup of patients with active cancer. This showed that rivaroxaban was less effective than LMWH at preventing venous thromboembolism recurrence (HR 1.32, 95% credible intervals 0.06 to 32.3) but induced fewer major bleeding events (odds ratio 0.24, 95% credible intervals 0.00 to 9.44).

39  The manufacturer reported adverse events from EINSTEIN-DVT and EINSTEIN-Ext that were experienced in at least 4% of any treatment group. The most common adverse events across both EINSTEIN trials were headache, pain in extremity, nasopharyngitis and nosebleed. The reported incidences of post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension were low in both arms of EINSTEIN-DVT and EINSTEIN-Ext.

3.10 The manufacturer’s submission used a Markov-based model for the economic evaluation of rivaroxaban within its licensed indication for the treatment of deep vein thrombosis and prevention of recurrence of venous thromboembolism. Two analyses were presented: a primary analysis comparing rivaroxaban with LMWH and vitamin K antagonist over 3, 6 and 12 months, and a cost-minimisation analysis for patients with active cancer, which used dalteparin as the comparator.

3.11  The Markov model comprised 11 health and treatment states and patients entered the model following a diagnosis of deep vein thrombosis. The model relied on the whole trial population of EINSTEIN-DVT to derive baseline risk events, treatment effects, probabilities for bleeding events and discontinuation rates. Probabilities for long-term complications and risk of mortality were taken from both EINSTEIN-DVT and literature reviews. Drug and resource costs were derived from relevant UK sources (British national formulary, NHS Reference Costs 2010-11 and Personal Social Services Research Unit [PSSRU], 2010) and generally reflected UK clinical practice. The model did not include monitoring for patients treated with rivaroxaban or LMWH. It assumed nine visits in the first 3 months, followed by five visits thereafter (every 3 months) for patients treated with a vitamin K antagonist. It also assumed that 66% of visits for INR monitoring would take place in primary care and 34% in secondary care. For primary care, the manufacturer assumed INR monitoring would be delivered equally by a GP and a nurse (50/50 split). The estimated annual cost of INR monitoring was £656, including transport costs.

3.12  A validated preference-based measure of quality of life was not used in the EINSTEIN-DVT trial, so the economic model submitted by the manufacturer used utility values sourced from literature reviews and expert opinion. The manufacturer assigned a baseline utility value of 0.825 to all patients with deep vein thrombosis entering the model, which was taken from a survey of the UK general population using a visual analogue scale rating (Kind et al. 1998) and adjusted with disutility values for deep vein thrombosis, pulmonary embolism, extracranial bleed, intracranial bleed and post-thrombotic syndrome.

3.13  The base-case results included all the drug acquisition costs, resources associated with monitoring, and costs associated with adverse events (that is, bleeding events) and were presented by intended treatment durations (3, 6 and 12 months). Treatment with rivaroxaban dominated treatment with LMWH and a vitamin K antagonist across all treatment durations, that is, rivaroxaban was less costly and more effective compared with LMWH and a vitamin K antagonist (0.02 incremental QALYs for all treatment durations and cost savings of £163 at 3 months, £124 at 6 months and £33 at 12 months).

3.14  The manufacturer undertook a series of univariate and multivariate deterministic sensitivity analyses to test the robustness of the results by varying most of the parameters used in the economic evaluation. The results were generally sensitive to cost of monitoring and the hazard ratio for venous thromboembolism. The manufacturer also provided probabilistic sensitivity analyses. These showed that there was a 94.2–98.9% probability of rivaroxaban being cost effective at £20,000 per QALY gained for all treatment durations. The treatment duration of 3 months produced the most cost savings and increased incremental QALYs. The probability of rivaroxaban being the dominant treatment option (that is, less costly and more effective than LMWH and a vitamin K antagonist) was 97.1% in patients having 3 months of anticoagulation, 83.9% in those having 6 months and 53.0% in those having 12 months.

3.15  The manufacturer conducted a subgroup analysis evaluating the benefits of rivaroxaban in patients with active cancer. Patients with cancer were assumed to be treated for 6 months. At 6 months, rivaroxaban was reported to be cost saving relative to dalteparin (dalteparin £8.47 per day for 1 month and £7.06 per day for 5 months). The cost for rivaroxaban was £4.20 per day for the first 21 days (two tablets daily), followed by £2.10 per day (one tablet daily).

3.16  The ERG raised concerns with the applicability of the EINSTEIN trials to UK clinical practice; the trials did not fully reflect the UK population with deep vein thrombosis because a number of important patient groups were excluded from EINSTEIN-DVT and EINSTEIN-Ext. These included patients with high risk of bleeding, creatinine clearance less than 30 ml/min (but not less than 15 ml/min), clinically significant liver disease, high blood pressure (systolic more than 180 mmHg or diastolic more than 110 mmHg) and non-proximal deep vein thrombosis. Specifically, the ERG noted that there are no data to inform decisions about patients with increased risk of bleeding. The ERG also noted that the EINSTEIN trials did not include patients for whom vitamin K antagonists are not appropriate, other than patients with cancer. It noted the population recruited into the EINSTEIN trials excluded a number of important groups relevant to the decision problem.

3.17 The ERG and its clinical advisers considered the comparator (enoxaparin) used by the manufacturer to be appropriate, although  the dose used in the EINSTEIN trials (1 mg/kg twice daily) was not in line with UK clinical practice (1.5 mg/kg once daily). Using the twice-daily dose may have been unfavourable to rivaroxaban.

3.18  The manufacturer assumed a maximum treatment duration of 12 months for idiopathic deep vein thrombosis or in the presence of permanent risk factors. However, the clinical advisers to the ERG questioned this assumption and stated that it is now common for treatment to extend beyond 12 months, depending on patient characteristics and risk factors. The ERG’s clinical advisers estimated that around 20% of people with deep vein thrombosis would have long-term treatment because recurrence of venous thromboembolism indicated ongoing risk.

3.19  The ERG raised concerns about the population and interpretation of ‘clinical equipoise’ (when the arguments for and against continuing treatment were finely balanced) in the EINSTEIN-Ext trial, and the inclusion criteria used to assess clinical benefit. It was unclear to the ERG which patients would have been included in the EINSTEIN-Ext trial.

3.20 The ERG raised concerns about the robustness of the mixed treatment comparison and the way the evidence was synthesised. The ERG noted that the included trials varied in the length of follow-up, and choice and dosage of LMWH also varied across studies. The ERG concluded that the mixed treatment comparison did not provide good estimates of the uncertainty associated with the true treatment effect, but found the point estimate to be reasonable.

3.21  The ERG noted that composite endpoints would be valid only if the incidence of deep vein thrombosis and pulmonary embolism were expected to be affected equally by the treatment. However, it noted that there could be differential impacts on mortality, costs and quality of life for these two events. Therefore the validity of the composite endpoints was uncertain.

3.22  The ERG also noted that anticoagulation with rivaroxaban could increase access to treatment for people of certain religions or beliefs (because LMWH is made of heparinfrom pigs) and for patients with poor dexterity or needle phobia. The ERG also noted that reversal of rivaroxaban is a potential issue because this has not yet been standardised.

3.23  The ERG presented exploratory analyses that took into account duration-specific effectiveness data and also corrected certain errors in the model. Compared with LMWH and a vitamin K antagonist, the results indicated that rivaroxaban was associated with an incremental QALY of -0.02 and cost saving of £182 for the 3 month duration (ICER of £11,792 saved per QALY lost, that is, less costly but also less effective). However rivaroxaban dominated (that is, was less costly and more effective) for the 6 and 12 month treatment durations (0.01 incremental QALYs and cost saving of £104 for 6 months; 0.04 incremental QALYs and cost saving of £10 for 12 months). The ERG noted that when adopting a less intensive INR monitoring strategy, rivaroxaban was associated with an ICER of £8341 per QALY gained for the 6 month treatment duration and £8089 per QALY gained for 12 month duration, but an ICER of £6358 saved per QALY lost for the 3 month treatment duration.

3.24 The ERG revised the manufacturer’s analysis in cancer patients to take into account what it considered to be a more plausible – and smaller – distribution of between-study standard deviations (as opposed to the alternative distributions used by the manufacturer). This found rivaroxaban to be less effective than LMWH at preventing venous thromboembolism recurrence, but to induce fewer major bleeding events and to be less costly. The ERG concluded that any reliance on the results of the network meta-analyses may lead to inaccurate estimates of mean ICERs because they are based on inflated expected values.

3.25 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 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.

4.2  The Committee heard from the clinical specialists and patient experts that current management of venous thromboembolism is initiated with a LMWH (such as enoxaparin, which is most commonly used in the UK) for rapid anticoagulation, overlapped with warfarin until an effective INR is achieved. The Committee also heard that duration of treatment is based on an assessment of the benefit of 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 most commonly used duration of treatment in current practice is 6 months, which corresponds with that used in the largest group in the trial. 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 patient experts expressed the view that rivaroxaban may improve the quality of life of people who currently take with warfarin by removing the need for constant monitoring, frequent blood tests and visits to an anticoagulation clinic.

 Clinical effectiveness

4.3  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 noted that unfractionated heparin was a comparator for rivaroxaban, but heard from the clinical specialists that unfractionated heparin is only used in people with renal failure, who represent a small proportion of people eligible for anticoagulation and in whom rivaroxaban would not be used. The Committee was therefore satisfied that the comparators used in the trial represented routine and best practice in the NHS.

4.4   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.

4.5  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 noted 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.

4.6  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 more effective than enoxaparin followed by a vitamin K antagonist for preventing recurrent venous thromboembolism.

4.7  The Committee considered the results from subgroup analyses presented by the manufacturer. Based on pre-specified subgroups defined in the EINSTEIN-DVT trial, 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 three different intended treatment durations. The Committee noted that the latter subgroup analysis suggested that rivaroxaban might be less effective than enoxaparin and warfarin in patients for whom 3 months of treatment was pre-specified. The Committee heard from the clinical specialists that they were not aware of any clinical reasons why rivaroxaban would be less effective in patients who received 3 months treatment. The Committee heard from the ERG that the lower efficacy in the patient group treated for 3 months 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 concluded that there was uncertainty as to whether the relative clinical effectiveness of rivaroxaban in the patients who were assigned 3 months of treatment differed from that seen in the whole trial.

4.8  The Committee noted that in the EINSTEIN-DVT trial, patients were treated for the pre-specified duration, after which treatment was stopped. The Committee questioned whether this reflects clinical practice and noted that clinical advisers to the ERG estimated that approximately 20% of people with deep vein thrombosis may need treatment for longer than 12 months. The clinical specialists estimated the average duration of treatment to be 6 months, after which the person’s risk factors would be reassessed and further treatment would be considered if the person’s risk of a recurrence remained high. 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 patients with ongoing risk factors for recurrence would need ongoing treatment, possibly for many years. However, evidence relating to the relative clinical effectiveness of rivaroxaban versus warfarin used according to this practice had not been presented by the manufacturer.

4.9  The Committee heard from clinical specialists that the advantages of rivaroxaban are its oral formulation, and the lack of need for monitoring (therefore a reduced need for support services). It also heard that rivaroxaban is likely to benefit people who are needle phobic or who want to resume normal patterns of daily life without having to find time to attend clinics. The patient experts highlighted that rivaroxaban is not associated with dietary restrictions and has the potential to increase quality of life for people currently treated with a vitamin K antagonist.

4.10  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 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 noted 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.

Cost effectiveness

4.11  The Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of rivaroxaban for deep vein thrombosis and the prevention of recurrent venous thromboembolism, the ERG’s critique of the manufacturer’s submission, and the manufacturer’s response to the clarification requested by the ERG.

4.12  The Committee considered the base-case results of the economic evaluation presented by the manufacturer. The Committee noted that the economic model used effectiveness data from the whole trial population of EINSTEIN-DVT and that the results were presented by intended 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 three treatment durations (3, 6 and 12 months). The base-case results were based on the manufacturer’s assumption of an annual INR monitoring cost of £656. The Committee concluded that rivaroxaban appeared to be a cost-effective option compared with enoxaparin and a vitamin K antagonist in the analysis for symptomatic recurrent venous thromboembolism.

4.13 The Committee went on to consider the key uncertainties around the cost-effectiveness analyses. It considered the ERG’s critique of the economic model. The Committee noted that the ERG presented an additional analysis in which estimates of relative treatment effects were based on the subgroup analysis by intended treatment duration rather than the whole trial population. This analysis showed that rivaroxaban remained dominant over LMWH and a vitamin K antagonist for the 6 and 12 month treatment durations, but the 3 month treatment duration was associated with an ICER of £11,800 saved per QALY lost (that is rivaroxaban was less effective and less costly than LMWH and a vitamin K antagonist). The Committee noted that the estimate of relative effectiveness for the 3 month group was based on relatively few events and was therefore uncertain (see section 4.7). Although the Committee agreed that this analysis should be treated cautiously, it nevertheless considered that any differences between the groups that could explain a differential effect should be explored further.

4.14   The Committee noted that the ERG had presented further analyses that assumed a less intensive INR monitoring program of 6 visits in the first 3 months, followed by 2 or 3 visits every 3 months thereafter. The Committee acknowledged that there are variations in INR monitoring within UK clinical practice, and concluded that the ERG’s alternative assumptions were reasonable and relevant for this appraisal. The Committee noted that this exploratory analysis was based on effectiveness data specific to treatment duration (see 4.13), and indicated that rivaroxaban was associated with an ICER of £6400 saved per QALY lost for the 3 month intended treatment duration (that is, less costly and less effective). The ICER for the group treated for 6 months was £8300 per QALY gained and £8100 per QALY gained for the group treated for 12 months. The Committeeconcluded that the ICERs for 6 and 12 months were within the range that is normally considered a cost-effective use of NHS resources, but it was mindful that the incremental costs and QALYs were small and sensitive to assumptions.

4.15 The Committee discussed the economic model and its relevance to people who need ongoing anticoagulation treatment. The Committee noted that the model assumed that patients were not treated for longer than the intended treatment duration and the manufacturer did not provide an analysis in which patients were treated with rivaroxaban beyond 12 months. The Committee heard from the clinical specialists that some people would need long-term, possibly lifetime treatment because of ongoing risk factors for recurrence. The Committee noted that people who experience a recurrent thromboembolic event in the model discontinued assigned therapy and were treated with 6 months of LMWH and a vitamin K antagonist. The Committee also noted that the model did not include the option for patients to be treated with rivaroxaban for subsequent thromboembolic events, which it deemed to be a plausible scenario for this group of patients. The Committee concluded that the main limitation in the manufacturer’s model was that it did not account for a scenario where people need long-term anticoagulation.

4.16  The Committee considered the uncertainties in the manufacturer’s submission. The Committee noted that the ERG had requested analyses based on subgroup-specific effectiveness data. However, the Committee viewed the differences between subgroups with caution and wished to explore further the biological plausibility for any differential effectiveness in the subgroups of people receiving different durations of treatment. The Committee also acknowledged a clinically relevant scenario in which people need long-term, possibly lifetime, anticoagulation because of their ongoing risk of recurrence. Further, the Committee acknowledged that an analysis considering this scenario would inform their decision on the clinical and cost effectiveness of rivaroxaban. Taken together, the Committee was unable to deliberate further and decide about the clinical and cost effectiveness of rivaroxaban for this indication. The Committee requested that the manufacturer of rivaroxaban should provide the following for the second Appraisal Committee meeting:

• Comments on the differences between the populations that were assigned treatment durations of 3, 6 and 12 months, and further details of any clinical criteria or algorithm used by the treating physician for assigning patients to the three groups.
• Consideration of the cost effectiveness of rivaroxaban compared with low molecular weight heparin (LMWH) and a vitamin K antagonist in patients in whom long-term anticoagulation is intended. Ideally this should be supported by a cost-effectiveness analysis of rivaroxaban as a lifelong treatment after the index event. This analysis should use data from the whole population of the EINSTEIN-DVT trial for estimating clinical effectiveness and should include sensitivity analyses that assume a less intensive INR monitoring program of 6 visits in the first 3 months, followed by 2 or 3 visits every 3 months thereafter in the comparator arm.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism		Section
Key conclusion
The Committee is minded not to recommend the use of rivaroxaban for deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism following an acute deep vein thrombosis in adults. The Committee requested that the manufacturer provide further information for the second Appraisal Committee. These analyses are: ·       Commetns on the differences between the populations that were assigned treatment durations of 3, 6 and 12 months, and further details of any clinical criteria or algorithm used by the treating physician for assigning patients to the the three groups. ·       Consideration of the cost effectiveness of rivaroxaban compared with low molecular weight heparin (LMWH) and a vitamin K antagonist in patients in whom long-term anticoagulation is intended. Ideally this should be supportd by a cost-effectiveness analysis of rivaroxaban as a lifelong treatment after the index event. This analysis should use data from the whole population of the EINSTEIN-DVT trial for estimating clinical effectiveness and should include sensitivity analyses that assume a less intensive INR monitoring program of 6 visits in the first 3 months, followed by 2 or 3 visits every 3  months thereafter in the comparator arm.			1.1 1.2
Current practice
Clinical need of patients, including the availability of alternative treatments		Current management of venous thromboembolism is initiated with an LMWH (such as enoxaparin, which is commonly used in the UK) for rapid anticoagulation, and overlapped with warfarin until an effective dose is achieved. Continued treatment is based on the benefit of anticoagulation compared with the risk of bleeding. The main concern with long-term anticoagulation with warfarin is the impact on people’s lifestyle and resource use associated regular INR monitoring.	4.2
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?		Clinical and patient experts note that warfarin is associated with a number of contraindications, including diet restrictions that impact a patient’s quality of life. Patient experts stated that rivaroxaban may improve the quality of life of patients who are currently treated with warfarin by removing the need for constant monitoring, frequent blood tests and visits to an anticoagulation clinic. The Committee acknowledged the limitations of warfarin therapy, and recognised the potential benefits of rivaroxaban oral therapy and its ability to increase access to people of certain relgions or beliefs.	3.22 4.2 4.9
What is the position of the treatment in the pathway of care for the condition?		Rivaroxaban is licensed for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism after an acute deep vein thrombosis in adults.	2.1
Adverse effects		The Committee noted that rivaroxaban had comparable rates of clinically relevant bleeding when compared with enoxaparin and a vitamin K antagonist but was associated with higher bleeding events when compared with placebo in the extension study.	4.10
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The EINSTEIN-DVT and EINSTEIN-Ext trials are the key trials supporting the clinical effectiveness of rivaroxaban in the manufacturer’s submission.	3.1 3.6
Relevance to general clinical practice in the NHS		The Committee considered the trials to reflect UK clinical practice.	4.3
Uncertainties generated by the evidence		The Committee viewed the differences between subgroups with caution and wished to explore further the biological plausibility for any differential effectiveness in the subgroups of people receiving different length of treatment. The Committee highlighted that evidence relating to the clinical effectiveness of rivaroxaban beyond 12 months had not been presented by the manufacturer.	4.16 4.15
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee considered the subgroup results presented by the manufacturer, which showed that  rivaroxaban appeared to be less effective in certain groups of patients, including those for whom 3 months of treatment was clinically indicated. The Committee concluded there was uncertainty about the relative clinical effectiveness of rivaroxaban in the patients who were assigned 3 months treatment because of the low number of events in this group.	4.7
Estimate of the size of the clinical effectiveness including strength of supporting evidence		Compared with enoxaparin and a vitamin K antagonist, rivaroxaban was associated with a hazard ratio of 0.68 for prevention of venous thromboembolism. The Committee concluded that rivaroxaban was more effective than enoxaparin followed by a vitamin K antagonist in preventing venous thromboembolism recurrences.	3.4 4.6
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer presented a Markov model using effectiveness data from the whole trial population of EINSTEIN-DVT.	3.11
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted that the model did not consider a scenario in which patients were treated with rivaroxaban beyond 12 months. The Committee heard from clinical specialists that some patients would need long-term or lifetime treatment because of ongoing risk factors for recurrence. The Committee concluded that the main limitation of the model was that it did not account for a scenario where people need ongoing anticoagulation.	4.15
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?		The manufacturer’s economic model used utility values sourced from literature reviews, expert opinion and vignettes because a validated preference based measure of quality of life was not used in the EINSTEIN-DVT trial.	3.12
Are there specific groups of people for whom the technology is particularly cost effective?		The Committee noted the ERG’s opinion and additional analyses which showed that the cost effectiveness of rivaroxaban varied by intended treatment duration. The Committee viewed the differences between subgroups with caution and wished to explore further the biological plausibility for any differential effectiveness in the subgroups of people receiving different length of treatment.	4.13 4.16
What are the key drivers of cost effectiveness?		INR monitoring costs, duration of treatment.	3.23
Most likely cost-effectiveness estimate (given as an ICER)		The Committee was unable to decide on the most likely cost-effectiveness estimate given the limitations outlined in 4.7, 4.8 and 4.16.	1.2
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable.
End-of-life considerations		End-of-life considerations were not discussed.
Equalities considerations and social value judgements		Rivaroxaban could improve access to treatment of people of certain religions or beliefs, and for people who find taking warfarin difficult because of the associated regular monitoring and diet restrictions.	3.22, 4.2

5 Implementation

5.1  The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2  NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6  Related NICE guidance

Published

• Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE clinical guideline 92 (2010). Available from cg92
• Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. NICE technology appraisal guidance 245 (2012). Available from ta245
• Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. NICE technology appraisal guidance 170 (2009). Available from ta170
• Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008). Available from ta157

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. NICE clinical guideline. Publication expected June 2012.
• Dabigatran etexilate for the treatment of acute venous thromboembolic events. NICE technology appraisal. Publication date to be confirmed.

7  Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive 2015. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Jane Adam
Chair, Appraisal Committee A
March 2012

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Jane Adam (Chair)
Department of Diagnostic Radiology, St George’s Hospital

Professor A E Ades
Professor of Public Health Science, Department of Community Based Medicine, University of Bristol

Dr Jeremy Braybrooke
Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust

Mr Christopher Earl
Surgical Care Practitioner, Renal Transplant Unit, Manchester Royal Infirmary

Ms Eleanor Grey
Lay Member

Dr Sharon Saint Lamont
Head of Quality and Innovation, North East Strategic Health Authority

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

Dr Anne McCune
onsultant Hepatologist, University Hospitals Bristol NHS Foundation Trust

Professor John McMurray
Professor of Medical Cardiology, University of Glasgow

Ms Pamela Rees
Lay Member

Dr Ann Richardson
Lay Member

Ms Ellen Rule
Programme Director, NHS Bristol

Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit

Dr Peter Sims
General Practitioner, Devon

Mr Cliff Snelling
Lay Member

Ms Amelia Stecher
Associate Director of Individual Funding Requests and Clinical Effectiveness, NHS Kent and Medway

Mr David Thomson
Lay Member

Dr Anthony S Wierzbicki
Consultant in Metabolic Medicine / Chemical Pathology, Guy’s and St Thomas’ Hospitals NHS Trust

Dr Olivia Wu
Reader in Health Economics, University of Glasgow

B Guideline representatives

The following individual, representing the Guideline Development Group responsible for developing NICE’s clinical guideline related to this topic, were invited to attend the meeting to observe and to contribute as advisers to the Committee.

• Mr Scott Harrison - Lead Pharmacist – Anticoagulation, John Radcliffe Hospital

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Kumar Perampaladas
Technical Lead

Pall Jonsson
Technical Adviser

Bijal Joshi
Project Manager

  Appendix B: Sources of evidence considered by the Committee

A   The Evidence Review Group (ERG) report for this appraisal was prepared by the School of Health and Related Research (ScHARR):

• Harnan S, Rafia R, Poku E, et al. Rivaroxaban for the treatment of deep vein thrombosis and secondary prevention of venous thromboembolism: A Single Technology Appraisal. ScHARR, The University of Sheffield (2012)

B  The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I   Manufacturer/sponsor:

• Bayer

II  Professional/specialist and patient/carer groups:

• Anticoagulation Europe (ACE)
• British Society for Haematology
• Lifeblood: The Thrombosis Charity
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• UK Clinical Pharmacy Association

III  Other consultees:

• Department of Health
• Haringey Primary Care Trust
• Northumberland Care Trust
• Welsh Government

IV  Commentator organisations (did not provide written evidence and without the right of appeal):

• Boehringer Ingelheim
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Health Care Improvement Scotland
• Leo Pharma
• Medicines and Healthcare products Regulatory Agency
• National Clinical Guidelines Centre
• National Institute for Health Research Health Technology Assessment Programme
• Pfizer
• Sanofi- Aventis
• School of Health & Related Research Sheffield (ScHARR)

C  The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on rivaroxaban by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Roopen Arya, Consultant Haematologist and Director, King’s Thrombosis Centre, nominated by Bayer – clinical specialist
• Dr David Bevan, Consultant Haematologist and Clinical Lead for Haemostasis & Thrombosis, nominated by Royal College of Pathologists – clinical specialist
• Ms Diane Eaton, nominated by Anticoagulation Europe – patient expert
• Mrs Annya Stephens-Boal, nominated by Lifeblood: The Thrombosis Charity – patient expert

D         

E  Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Bayer