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

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4.2.1.3 Results and interpretation – EINSTEIN-DVT Table 10 summarises the key outcome data reported in the MS for EINSTEIN-DVT. Efficacy outcomes – EINSTEIN-DVT In the EINSTEIN-DVT Superseded trial, the manufacturer states that – upper limit of the two sided 95% confidence interval (CI) for the (HR) ratio was below the pre- See Erratum “rivaroxaban would be considered statistically significantly non-inferior to comparator therapy if the defined non-inferiority margin of 2.0. This margin corresponds to maintenance of at least 50% of the proven efficacy of standard therapy and was derived based on a comprehensive meta-analysis of historical trials in this indication” (MS, page 47 to 48). 1 EINSTEIN-DVT reports an overall hazard ratio of xxxxxxxxxxxxxxxxx for the primary efficacy outcome, VTE recurrence, when compared to Enoxaparin/VKA, which suggests rivaroxaban is non- inferior to the comparator (p
Table 10: Summary of outcomes for EINSTEIN-DVT, taken from table 18 and 29, data on page 56, 58, 65, 96 of MS 1 and Bauersachs et al. 2011 21 Trial name Einstein-DVT References Bauersachs et al 2010 21 Manufacturer’s submission Group Rivaroxaban Superseded – See Primary outcome VTE recurrence Erratum ITT population: Safety population: PP population: N, (%) 1731 1718 1525 ITT population: 36 (2.1) PP population: NR Secondary outcomes (ITT population) 50 LMWH/Enoxaparin N, (%) 1718 1711 1571 51 (3.0) NR Fatal PE 1 (0.1) 0 (0) NR PE cannot be ruled out 3 (0.2) 6 (0.3) NR Nonfatal PE 20 (1.2) 18 (1.0) NR Recurrent DVT plus PE 1 (0.1) 0 (0) NR Recurrent DVT 14 (0.8) 28 (1.6) NR (safety population) Hazard ratio (95% CI, p value) NA xxxxxxx xxxxxxxx Clinically relevant 139 (8.1) 138 (8.1) 0.97 (0.76 to 1.22, bleeding p=0.77) Major bleeding 14 (0.8) 20 (1.2) 0.65 (0.33 to 1.30, p=0.21) Clinically relevant nonmajor bleeding Vascular events 126 (7.3) 119 (7.0) NR On treatment 12 (0.7) 14 (0.8) 0.79 (0.36 to 1.71, Off treatment (30 day follow-up) 1 (
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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
Page 9 and 10: Figures Figure 1 Flow diagram for i
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-
Page 59: However, the study design did not i
Page 63 and 64: Chi-square analyses were undertaken
Page 65 and 66: clarification on this matter, the m
Page 67 and 68: Both of these factors are likely to
Page 69 and 70: It remains unclear why these patien
Page 71 and 72: leeding may be less suited to longe
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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
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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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