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

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Table 2 Incidence of Recurrent DVT, PE, or VTE-Related Death up to Day 84 (+14): Intention-to-Treat Population (n=543). Reproduced from Agnelli et al. 2007 35 Rivaroxaban 10 mg BID 20 mg BID 30 mg BID 40 mg OD Enoxaparin/VKA (n=106) OD indicates once daily. Values are n (%). (n=100) (n=111) (n=114) (n=112) Any event 2 (1.9) 2 (2.0) 2 (1.8) 3 (2.6) 1 (0.9) Death (VTErelated) 1 (0.9) 0 (0.0) 0 (0.0) 1 (0.9) 0 (0.0) PE, nonfatal 0 (0.0) 1 (1.0) 1 (0.9) 1 (0.9) 0 (0.0) Recurrent DVT 1 (0.9) 1 (1.0) 1 (0.9) 1 (0.9) 1 (0.9) Table 3 Efficacy outcomes in the per protocol population (n = 449). Reproduced from Buller et al. 2008. 36 20 mg, n = 115 173 Rivaroxaban 30 mg, n = 112 40 mg, n = 121 LMWH/VKA n = 101 Primary efficacy outcome n (%) 7 (6.1) 6 (5.4) 8 (6.6) 10 (9.9) 95% CI * 2.5%- 12.1% 2.0%- 11.3% 2.9%- 12.6% 4.9-17.5% Symptomatic events, n (%) 3 (2.6) 4 (3.6) 2 (1.7) 7 (6.9) Death (VTE-related) 0 (0.0) 2 (1.8) 1 (0.8) 0 (0.0) PE, nonfatal 1 (0.9) 1 (0.9) 0 (0.0) 1 (1.0) Recurrent DVT 2 (1.7) 1 (0.9) 1 (0.8) 7 (6.9) † Asymptomatic deterioration on ultrasound 4 (3.5) and/or perfusion lung scanning, n (%) 2 (1.8) 6 (5.0) 3 (3.0) Agnelli et al. 35 report 1 PE or VTE related death in the 10mg bid rivaroxaban arm, versus 0 in the comparator arm. DVT rates are the same in both; 1 event. Buller et al 36 report 1 PE or VTE related death in the rivaroxaban arm versus 1 in the comparator arm. However, DVTs follow a similar pattern to that seen in the EINSTEIN-DVT trial, with 2 events in the rivaroxaban arm, and 7 in the comparator arm. In other words, rivaroxaban appears to reduce the number of DVTs, but not the number of PEs. However, the ERG felt that this evidence was too weak to be presented, given the above criticisms and the small number of events observed. Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
Appendix 2 Correction of Tables 29 and 30 from the MS. Table 1. Most common adverse events in EINSTEIN-DVT and EINSTEIN-Ext (to replace Table 29 of the MS, page 81, provided in the manufacturer’s clarification letter as Table 33, page 63) EINSTEIN-DVT EINSTEIN-Ext Rivaroxaban LMWH/VKA Rivaroxaban Placebo (N=1718) (N=1711) (N=598) (N=590) n (%) n (%) n (%) n (%) Treatment-emergent adverse events Drug-related xxx xxx xxx xxx xxx xxx xxx xxx Serious 201 (12.0) 233 (13.6) xxx xxx xxx xxx Drug-related and serious xxx Xxxx xxx xxx xxx xxx xxx xxx Any Specific adverse events 1078 (62.7) 1080 (63.1) xxx xxx xxx xxx 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 Note: The AEs listed are those which were experienced in at least 4% of patients in any treatment group. 174 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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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
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: Both Phase II studies performed ana
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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