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

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Table 2. Relative and absolute risk differences (%) for the most common adverse events in EINSTEIN-DVT and EINSTEIN-Ext (to replace Table 30 of the MS, 1 page 82, provided in the manufacturer’s clarification letter, as Table 34, page 64) Treatment-emergent adverse events EINSTEIN-DVT EINSTEIN-Ext Risk ratio ARD (%) Risk ratio ARD (%) (95% CI) (95% CI) (95% CI) (95% CI) Drug-related xxx xxx xxx xxx xxx xxx xxx xxx Serious 0.86 (0.72 to -1.9 (-4.1 to xxx xxx xxx xxx 1.02) 0.3) Drug-related and serious xxx xxx xxx xxx xxx xxx xxx xxx Any 0.99 (0.94 to -0.4 (-3.6 to xxx xxx xxx xxx Specific adverse events 1.05) 2.8) Nasopharyngitis xxx xxx xxx xxx xxx xxx xxx xxx Epistaxis xxx xxx xxx xxx xxx xxx xxx xxx Headache xxx xxx xxx xxx xxx xxx xxx xxx Pain in extremity xxx xxx xxx xxx xxx xxx xxx xxx Cough xxx xxx xxx xxx xxx xxx xxx xxx Contusion xxx xxx xxx xxx xxx xxx xxx xxx Notes: The AEs listed are those which were experienced in at least 4% of patients in any treatment group. CIs for risk ratios were calculated as per Equation 4.24 of Armitage, Berry and Matthews (see MS for reference). CIs for the ARDs were calculated using a Normal approximation to the Binomial. ARD: absolute risk difference. 175 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
Appendix 3 Definition of `sufficient compliance’ A subject on rivaroxaban was to be considered valid for per protocol analysis if xxxxxxxxxxxx xxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxx xxxxxxxxxxxxx xxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxx. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxx. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx 176 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
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The dose of LMWH used reflects Amer
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The exploratory analysis in cancer
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intended treatment duration of 12 m
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VTE therefore has a substantial bur
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indefinite treatment. VTE LMWH, low
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3 Critique of manufacturer’s defi
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Subgroups to be considered Special
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contraindications for the drug (as
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3.1.3 MTC populations The populatio
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3.2.2 Length of treatment As discus
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“No preventative therapy” is th
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It could be argued that poor TTR ma
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3.4.2 Outcomes recommended by EMA r
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4 CLINICAL EFFECTIVENESS 4.1 Critiq
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competitor products were excluded f
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Figure 1 Flow diagram for identifyi
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Table 7: Table showing list of rele
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The approach taken to quality asses
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o EINSTEIN-DVT dose-ranging study 3
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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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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
Page 135 and 136: 5.2.2.1.2. Results for patients for
Page 137 and 138: Figure 12: Cost-effectiveness plane
Page 139 and 140: Figure 14: Tornado plot - Net Monet
Page 141 and 142: 5.2.2.2 Subgroup analysis - cancer
Page 143 and 144: Figure 17: Tornado plot - Net Monet
Page 145 and 146: 5.2.3 Comment on validity of result
Page 147 and 148: Table 36: Summary of uncertainties
Page 149 and 150: Summary of uncertainties Has the im
Page 155 and 156: Superseded - See Erratum 6. ADDITIO
Page 157 and 158: Superseded - See Erratum Table 37 S
Page 159 and 160: Superseded - See Erratum Table 38:
Page 163 and 164: Superseded - See Erratum Figure 21:
Page 167 and 168: Superseded - See Erratum 6.3. Proba
Page 173 and 174: 6.5. Exploratory analysis in cancer
Page 175 and 176: Figure 23: Exploratory analysis in
Page 177 and 178: Table 60: Deterministic base case a
Page 179 and 180: The ERG also examined the impact of
Page 181 and 182: days after stopping treatment.(Bull
Page 183 and 184: Both Phase II studies performed ana
Page 185: Appendix 2 Correction of Tables 29
Page 189 and 190: A bullet on page 42 states that `53
Page 191 and 192: Both numbers refer to the placebo a
Page 193 and 194: 9. REFERENCES 1. Bayer PLC. Rivarox
Page 195 and 196: http://www.dh.gov.uk/en/Publication
Page 197 and 198: 51. Department of Health. NHS Refer
Page 199: 77. NICE Guidance. Atrial fibrillat
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