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

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Secondary efficacy outcomes Symptomatic recurrent VTE 12.1) 11.3) 12.6) 2.6 3.6 1.7 6.9 Symptomatic recurrent VTE or 6.1 5.4 6.6 9.9 deterioration of thrombotic burden Major bleeding and Clinically relevant non-major bleeding 5.9 6.0 2.2 8.8 (2.6 -11.3) (2.6 – 11.4) (0.5 – 6.3) (4.6 -14.8) Major bleeding 0.7 1.5 0.0 1.5 *Clinically bleeds relevant non-major 5.2 4.5 2.2 7.3 *Premature treatment discontinuation of 13.0 14.0 9.0 11.0 *Adverse events 7.0 5.0 4.0 4.0 *Death (any cause) 3.0 6.0 1.5 3.6 *Death (due to bleeding) 0.0 0.0 0.0 0.7 Abbreviation: bd-twice daily; od-once daily: LMWH-low molecular weight heparin; VKAvitamin K antagonist Values shown are proportion of patients experiencing the specified outcome with the stated 95% confidence interval. *These outcomes were not reported in the MS but were obtained by the ERG from the published reports of the studies. (Agnelli, 2007 and Buller, 2008) 171 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
Both Phase II studies performed analyses if the primary efficacy outcome in the per-protocol (PP) population, that is patients who complied with the trial protocol. PP analysis is a method of demonstrating the best potential of the treatment under investigation, provided the rate of non-compliance and other protocol deviations are minimal. The introduction of bias in this type of analysis may be investigated by a supporting ITT analysis. It was reported in the EINSTEIN-DVT dose-ranging study 36 , that observed estimates of efficacy were similar in the PP and modified ITT analyses, though the exact composition of the modified ITT population remains unclear. Comparing the two Phase II studies, the manufacturer concluded that both studies showed similar efficacy for the twice-daily and once-daily rivaroxaban dosing regimens although the studies were concerned with different primary efficacy outcomes. The ERG notes that this type of comparison may lead to misinterpretation of some of the efficacy- related findings in the described studies. The MS further asserts that with regards to safety, ‘all rivaroxaban regimens were numerically better than heparin/VKA’(page 35, in the MS) with once-daily schedules being better than twice-daily dosing. Whilst the ERG assumes that this statement is with reference to the primary safety outcomes of the two studies, available evidence (not included in the MS) from the published reports showed that minor bleeding occurred in 3.4 – 9.9% of patients on twice daily rivaroxaban regimens compared to 6.3% of patients in the Enoxaparin/VKA arm. Furthermore, frequency of events such as premature discontinuation of medication, adverse events and death differed between patients on once daily dosing of rivaroxaban and patients on LMWH/VKA with some patients in the intervention group having more episodes of some of these outcomes. (See Table 1 of this Appendix). To investigate the apparent differential effect of rivaroxaban on PEs compared to DVTs seen in the EINSTEIN-DVT trial, the ERG considered the PE and DVT events in these two trials as reported in the journal articles. 35,36 The results are presented in Tables 2 and 3 of this Appendix. 172 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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Page 141 and 142: 5.2.2.2 Subgroup analysis - cancer
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Page 145 and 146: 5.2.3 Comment on validity of result
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Page 149 and 150: Summary of uncertainties Has the im
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Page 157 and 158: Superseded - See Erratum Table 37 S
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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: days after stopping treatment.(Bull
Page 185 and 186: Appendix 2 Correction of Tables 29
Page 187 and 188: Appendix 3 Definition of `sufficien
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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