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

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6.4 6.5 analyses conducted by the ERG. Cost-minimisation analysis, assuming the same treatment effect between rivaroxaban and LMWH/VKA Exploratory analysis in cancer patients – examining different HR 7 Overall conclusions 167 8 Appendices 169 9 References 182 Tables Table 1 Summary of international guidelines and recommendations (reproduction of Table 3, page 19 of MS) Table 2 Statement of the decision problem, reproduced from the MS, page 27 17 Table 3 Summary of patient population of studies included in mixed treatment comparison of LMWH treatment versus VKA treatment in DVT patients with cancer Table 4 Rivaroxaban characteristics. Compiled by the ERG using information given on pages 11 to 13, and in Table 2, page 15 of MS. Table 5 Summary of outcomes as defined in the NICE scope, as recommended by the EMA Research Guidelines, and as outlined in Table 14 and 15 of the MS. Table 6 Eligibility criteria used in search strategy (reproduction of Table 4, page 30, in MS) Table 7 Table showing list of relevant RCTs (reproduced from Table 6 in MS, p.32) Table 8 Quality assessment of EINSTEIN-DVT and EINSTEIN-Ext as reported in MS (Table 17, page 53). Table 9 Summary of key characteristics of the clinical effectiveness studies identified in the MS. Data drawn from tables 5, 6, 10, 11 and 14 of the MS Table 10 Summary of outcomes for EINSTEIN-DVT, taken from table 18 and 29, data on page 56, 58, 65, 96 of MS 1 and Bauersachs et al. 2011 Table 11 Additional interaction test statistics for the primary analysis of time to VTE recurrence. Reproduction of Table 1, page 8, manufacturer’s clarifications Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved. 160 162 13 22 23 29 34 38 41 43 50 55
Table 12 Time to therapeutic INR (INR>=2.0) in days from randomisation among patients with/without parenteral anticoagulation prior to randomisation (safety population) (reproduction of Table 11, page 24 of manufacturer’s clarifications). Table 13 Criteria used to define a suspected DVT event, and the criteria used to confirm the event. Compiled from the manufacturer’s clarifications, and the EMA research guidelines Table 14 Summary of outcomes for EINSTEIN-Ext, taken from Tables 18 and 29, data on page 59 of MS 1 and data from the Manufacturer’s clarification document Table 15 Summary of characteristics of trials included in the MTC 71 Table 16 Relative effectiveness of long-term LMWH vs LMWH/VKA dual therapy in VTE patients with cancer. Reproduction of Table 24, page 74 of MS Table 17 Reproduction of quality assessment reported in Akl 2011, selecting only trials of relevance to this assessment Table 18.1 VTE recurrence (time to event, hazard ratio) - U(0,5) 79 Table 18.2 VTE recurrence (time to event, hazard ratio) - U(0,2) 79 Table 18.3 VTE recurrence (time to event, hazard ratio) - U(0, 0.6) 79 Table 19.1 VTE recurrence (dichotomous, odds ratio) - U(0,5) 79 Table 19.2 VTE recurrence (dichotomous, odds ratio) - U(0,2) 80 Table 19.3 VTE recurrence (dichotomous, odds ratio) - U(0,0.6) 80 Table 20.1 Major bleeding - U(0,5) 80 Table 20.2 Major bleeding - U(0,2) 80 Table 20.3 Major bleeding - U(0,0.6) 80 Table 21.1 Non-major bleeding - U(0,5) 81 Table 21.2 Non-major bleeding - U(0,2) 81 Table 21.3 Non-major bleeding - U(0,0.6) 81 Table 22 Uncertainties in clinical data and direction of effect 82 Table 23 Weighted average daily drug acquisition cost of LMWH treatments 89 Table 24 Probabilities of VTEs and bleeding events for patients treated with dual therapy LMWH/VKA (reproduction of Table 36, p. 112, MS, November 2011) Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved. 61 64 69 72 73 93
Page 1 and 2: Rivaroxaban for the treatment of de
Page 3: TABLE OF CONTENTS List of Abbreviat
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
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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 and 26: indefinite treatment. VTE LMWH, low
Page 27 and 28: 3 Critique of manufacturer’s defi
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
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Trial name References, study type E
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4.2.1 Critique of pivotal EINSTEIN-
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However, the study design did not i
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Table 10: Summary of outcomes for E
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Chi-square analyses were undertaken
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clarification on this matter, the m
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Both of these factors are likely to
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It remains unclear why these patien
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leeding may be less suited to longe
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may account for the apparent differ
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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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Superseded - See Erratum Figure 21:
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Superseded - See Erratum 6.3. Proba
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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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