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

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Table 51 Probabilistic base case analysis (in patients treated for 12 months) using the manufacturer’s assumptions (after amendment of errors identified in the model). Table 52 Probabilistic base case analysis (in patients treated for 12 months) after amendment of errors identified in the model, assuming less intensive INR monitoring (same split DVTs/PEs between arms). Table 53 Probabilistic base case analysis (in patients treated for 12 months) using the manufacturer’s assumptions on INR monitoring (after amendment of errors identified in the model) and assuming a different split DVTs/PEs between treatment arms. Table 54 Probabilistic base case analysis (in patients treated for 12 months) after amendment of errors identified in the model assuming less intensive INR monitoring and assuming a different split DVTs/PEs between treatment arms. Table 55 Drug and monitoring costs by intended treatment duration and treatment arm (using MS assumption’s on monitoring) Table 56 Drug and monitoring costs by intended treatment duration and treatment arm (using a less intensive monitoring than assumed by the manufacturer) Table 57 Summation of ERG exploratory analyses in cancer patients Table 58 Deterministic base case analysis (in cancer patients) using the manufacturer’s assumptions (before amendment of errors identified in the model). Table 59 Deterministic base case analysis (in cancer patients) using the manufacturer’s assumptions after amendment of errors identified in the model. Table 60 Deterministic base case analysis (in cancer patients) using the manufacturer’s assumptions after amendment of errors identified in the model, using the mean HR assuming U(0,5) Table 61 Deterministic base case analysis (in cancer patients) using the manufacturer’s assumptions after amendment of errors identified in the model, using the mean HR assuming U(0,2) Table 62 Deterministic base case analysis (in cancer patients) using the manufacturer’s assumptions after amendment of errors identified in the model, using the mean HR assuming U(0,0.6) Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved. 157 158 158 160 160 161 163 165 165 166 166 167
Figures Figure 1 Flow diagram for identifying RCTs (reproduced from Figure 2 ‘Study flow diagram for the identification of references relating to RCTs’ in the MS, page 31) Figure 2 Kaplan-Meier plot for VTE recurrence (primary efficacy outcome) in EINSTEIN-DVT (reproduction of Figure 7, Page 55 of MS) Figure 3 Analysis of VTE recurrence (primary efficacy outcome) across the pre-specified subgroups in EINSTEIN-DVT (reproduction of Figure 8, Page 56 in MS) Figure 4 Analysis of clinically relevant bleeding (primary safety outcome) across the pre-specified subgroups in EINSTEIN-DVT. Reproduction of Figure 12, page 61 of MS xxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 59 Figure 6 Analysis of VTE recurrence (primary efficacy outcome) across the pre-specified subgroups in EINSTEIN-Ext (reproduction of Figure 10, page 58 of MS) Figure 7 Structure of the manufacturers’s economic model (reproduction of Figure 16, p. 106, MS, 1 November 2011) Figure 8 Tornado plot - Net Monetary Benefit of rivaroxaban vs. LMWH/VKA, 3 months of treatment, lifetime horizon, duration specific inputs (reproduction of Figure 3, p. 31, Clarification letter December 2011) Figure 9 Cost-effectiveness plane, rivaroxaban vs. LMWH/VKA, 3 months of anticoagulation treatment, lifetime horizon, duration specific inputs (reproduction of Figure 4, p. 32, Clarification letter 17 December 2011) Figure 10 CEAC, rivaroxaban vs. LMWH/VKA, 3 months of anticoagulation treatment, lifetime horizon, duration specific inputs (reproduction of Figure 5, p. 32, Clarification letter December 2011) Figure 11 Tornado plot - Net Monetary Benefit of rivaroxaban vs. LMWH/VKA, 6 months of treatment, lifetime horizon, duration specific inputs (reproduction of Figure 6, p. 34, Clarification letter December 2011) Figure 12 Cost-effectiveness plane, rivaroxaban vs. LMWH/VKA, 6 months of anticoagulation treatment, lifetime horizon, duration specific inputs Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved. 36 52 53 56 70 91 122 123 123 125 126
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: identified in the model). Table 40
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 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
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-
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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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