Rivaroxaban for the treatment of deep vein thrombosis and ...

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The ERG notes that whilst these guidelines point to uncertainty about the benefits of long term treatment, they do not recommend that treatment should cease at 12 months, or give any other suggestions for a maximum treatment duration. In the absence of guidelines recommending against ongoing treatment, and with clinical advice to the ERG indicating that treatment is long term in patients with certain risk factors, amounting to approximately 20% of the DVT population (Personal Communication from Dr Patel and Dr Hampton, December 2011), the ERG remains of the opinion that treatment beyond 12 months in some patients is current practice in England and Wales. Whether Superseded – this will change in light of the new guidelines is unclear, as the guidelines are not specific on this point. Furthermore, whether clinicians would use rivaroxaban in the same way as current anticoagulant treatment is also unclear, given the lack of evidence beyond 12 months, as stated in the Summary of Product Characteristics (SmPCs) See Erratum 19,20 which recommend “The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT. Experience with Xarelto in this indication for more than 12 months is limited.” Additionally, the EINSTEIN-Ext trial includes patients who are being treated for between 12 months and 2 years. This trial design would appear to contradict the manufacturer’s statements about treatment durations, and could be seen to lend weight to the view that ongoing treatment does occur in a proportion of patients. Given that there is considerable uncertainty on this point, it would have been prudent for analyses assuming treatment >12 months to have been undertaken by the manufacturer. A further unrelated point is that, on Page 21 of the MS, the manufacturer states “rivaroxaban will be initiated during a secondary care outpatient consultation”. The ERG feel that there will be some variation in this and that in some cases, rivaroxaban would be initiated during inpatient care. 15 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
3 Critique of manufacturer’s definition of decision problem The MS contains a summary of the decision problem defined by NICE in the final scope, compared to the decision problem as addressed in the MS (reproduced here as Table 2). A rationale is provided where the MS decision problem differs from the NICE final scope. The main areas of disparity highlighted in the MS are to do with the comparator used and the subgroups considered. The ERG has additional comments to make relating to the PICO definition of the decision problem and the evidence submitted in the MS. These are outlined in sections 3.1 to 3.5. 3.1 Population As shown in Table 2, the terminology used by the manufacturer to define the patient population differs slightly from the definition provided in the NICE scope. The clinical advisors to the ERG are happy with the differences in terminology, and do not feel that this represents a significant difference in patient populations. The clinical evidence submitted by the manufacturer consists of two main trials both reported in one journal publication, 21 and within the MS. 1 One (EINSTEIN-DVT) is a pivotal, phase III equivalence (non-inferiority) clinical trial, whilst the other (EINSTEIN-Ext) is a phase III extension trial. Both trials have safety and efficacy outcomes. The patient population recruited into each trial differs, and neither completely covers the whole of the confirmed symptomatic DVT population defined in the NICE scope. 16 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
Page 1 and 2: Rivaroxaban for the treatment of de
Page 3 and 4: TABLE OF CONTENTS List of Abbreviat
Page 5 and 6: Table 12 Time to therapeutic INR (I
Page 7 and 8: identified in the model). Table 40
Page 9 and 10: Figures Figure 1 Flow diagram for i
Page 11 and 12: Figure 23 Exploratory analysis in c
Page 13 and 14: MS Manufacturer’s submission NE S
Page 15 and 16: The dose of LMWH used reflects Amer
Page 17 and 18: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Page 19 and 20: The exploratory analysis in cancer
Page 21 and 22: intended treatment duration of 12 m
Page 23 and 24: VTE therefore has a substantial bur
Page 25: indefinite treatment. VTE LMWH, low
Page 29 and 30: Subgroups to be considered Special
Page 31 and 32: contraindications for the drug (as
Page 33 and 34: 3.1.3 MTC populations The populatio
Page 35 and 36: 3.2.2 Length of treatment As discus
Page 37 and 38: “No preventative therapy” is th
Page 39 and 40: It could be argued that poor TTR ma
Page 41 and 42: 3.4.2 Outcomes recommended by EMA r
Page 43 and 44: 4 CLINICAL EFFECTIVENESS 4.1 Critiq
Page 45 and 46: competitor products were excluded f
Page 47 and 48: Figure 1 Flow diagram for identifyi
Page 49 and 50: Table 7: Table showing list of rele
Page 51 and 52: The approach taken to quality asses
Page 53 and 54: o EINSTEIN-DVT dose-ranging study 3
Page 55 and 56: Trial name References, study type E
Page 57 and 58: 4.2.1 Critique of pivotal EINSTEIN-
Page 59 and 60: However, the study design did not i
Page 61 and 62: Table 10: Summary of outcomes for E
Page 63 and 64: Chi-square analyses were undertaken
Page 65 and 66: clarification on this matter, the m
Page 67 and 68: Both of these factors are likely to
Page 69 and 70: It remains unclear why these patien
Page 71 and 72: leeding may be less suited to longe
Page 73 and 74: may account for the apparent differ
Page 75 and 76: Table 13: Criteria used to define a
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DVT and/or PE xxxxxxxxx xxxxxxxxxxx
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There is some doubt about the appro
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Subgroup analyses - EINSTEIN-Ext Su
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o It is clear that bleed events wer
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is likely to be small as the outcom
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depends on the specific parameteris
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4.4.3 Between study standard deviat
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Table 19.2: VTE recurrence (dichoto
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Table 22 Uncertainties in clinical
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The ERG are of the understanding th
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For the primary analysis, the rates
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In the economic model, the manufact
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Finally, in cancer patients, the ma
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Our experts believed that patients
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Similarly, the manufacturer used da
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Table 25: baseline risk of events f
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y intended treatment duration given
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eflect the current long term risk o
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survival of 70% in the 148 non-surg
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Monitoring xxxxxxxxxxxxxxxxxxxxxxxx
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The ERG acknowledges that the monit
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For patients managed in the inpatie
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The searches identified 2,811 poten
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The health state utility value for
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xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxx
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few occasions for both VTEs and ble
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2) the values used in the PSA for t
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5.2.1 Results included in the manuf
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Figure 8: Tornado plot - Net Moneta
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5.2.2.1.2. Results for patients for
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Figure 12: Cost-effectiveness plane
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Figure 14: Tornado plot - Net Monet
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5.2.2.2 Subgroup analysis - cancer
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Figure 17: Tornado plot - Net Monet
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5.2.3 Comment on validity of result
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Table 36: Summary of uncertainties
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Summary of uncertainties Has the im
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Superseded - See Erratum 6. ADDITIO
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Superseded - See Erratum Table 37 S
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Superseded - See Erratum Table 38:
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Page 163 and 164:
Superseded - See Erratum Figure 21:
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Page 167 and 168:
Superseded - See Erratum 6.3. Proba
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Page 171 and 172:
Page 173 and 174:
6.5. Exploratory analysis in cancer
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Figure 23: Exploratory analysis in
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Table 60: Deterministic base case a
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The ERG also examined the impact of
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days after stopping treatment.(Bull
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Both Phase II studies performed ana
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Appendix 2 Correction of Tables 29
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Appendix 3 Definition of `sufficien
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A bullet on page 42 states that `53
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Both numbers refer to the placebo a
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9. REFERENCES 1. Bayer PLC. Rivarox
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http://www.dh.gov.uk/en/Publication
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51. Department of Health. NHS Refer
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77. NICE Guidance. Atrial fibrillat
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