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

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Table 11: Additional interaction test statistics for the primary analysis of time to VTE recurrence. Reproduction of Table 1, page 8, manufacturer’s clarifications. 17 Hazard ratio (95% CI) Tests for interaction Wald Gail- Simon 147 Previous episode of DVT/PE xxxxx xxxx Yes xxxx xxxxxxxxxxxxx No xxxx xxxxxxxxxxxxx Intended duration of xxxxx xxxx anticoagulation 3 months xxxx xxxxxxxxxxxxx 6 months xxxx xxxxxxxxxxxxx 12 months xxxx xxxxxxxxxxxxx Age group xxxxx xxx 75 years xxxx xxxxxxxxxxxxx Renal function: creatinine clearance xxxxx xx >= 80 mL/min xxxx xxxxxxxxxxxxx 50 -
Both of these factors are likely to increase the plasma levels of rivaroxaban, which may account for the increase in bleeding events. The dose ranging studies 35,36 indicate that bleeding is much more sensitive to dose than VTE recurrence. The SmPC advises a lower dose of rivaroxaban for patients with renal impairment, which is discussed elsewhere in this report. No advice to tailor doses according to weight is made, and the fixed dose nature of rivaroxaban is cited as one of its advantages. (MS, page 15, section 1.13) Figure 4: Analysis of clinically relevant bleeding (primary safety outcome) across the prespecified subgroups in EINSTEIN-DVT. Reproduction of Figure 12, page 61 of MS. 1 Adverse events and mortality data – EINSTEIN-DVT An interpretation of non-inferiority of rivaroxaban for adverse events and mortality is supported by the results and analyses of this study. Upon request from the ERG, the manufacturer provided a clarification of Tables 29 and 30 of the MS, 1 where a transposition error had occurred. These are provided in Appendix 2. The events entitled “specific adverse events” in the tables were not thought by the clinical advisors to the ERG to have a significant impact on HRQoL, and were mostly well balanced across treatment arms. Health related quality of life – EINSTEIN-DVT The HRQoL measures used in the study were the Anit-Clot Treatment Scale (ACTS) and Treatment satisfaction questionnaire (TSQM). As already discussed in section 3.4, neither of these measures has been mapped to the EQ-5D or other preference based measures. (MS, page 64). 1 In addition, the 56 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
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Rivaroxaban for the treatment of de
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TABLE OF CONTENTS List of Abbreviat
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Table 12 Time to therapeutic INR (I
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identified in the model). Table 40
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Figures Figure 1 Flow diagram for i
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Figure 23 Exploratory analysis in c
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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
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: clarification on this matter, the m
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
Page 77 and 78: DVT and/or PE xxxxxxxxx xxxxxxxxxxx
Page 79 and 80: There is some doubt about the appro
Page 81 and 82: Subgroup analyses - EINSTEIN-Ext Su
Page 83 and 84: o It is clear that bleed events wer
Page 85 and 86: is likely to be small as the outcom
Page 87 and 88: depends on the specific parameteris
Page 89 and 90: 4.4.3 Between study standard deviat
Page 91 and 92: Table 19.2: VTE recurrence (dichoto
Page 93 and 94: Table 22 Uncertainties in clinical
Page 95 and 96: The ERG are of the understanding th
Page 97 and 98: For the primary analysis, the rates
Page 99 and 100: In the economic model, the manufact
Page 101 and 102: Finally, in cancer patients, the ma
Page 103 and 104: Our experts believed that patients
Page 105 and 106: Similarly, the manufacturer used da
Page 107 and 108: Table 25: baseline risk of events f
Page 109 and 110: y intended treatment duration given
Page 111 and 112: eflect the current long term risk o
Page 113 and 114: survival of 70% in the 148 non-surg
Page 115 and 116: 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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