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

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Figure 3: Analysis of VTE recurrence (primary efficacy outcome) across the pre-specified subgroups in EINSTEIN-DVT (reproduction of Figure 8, Page 56 in MS) 1 As would be expected, generally the subgroup analyses shows that smaller patient numbers increased the uncertainty around point estimates, although there was generally a lack of power to make definitive conclusions. In addition, the following observations were made; Age: there is a point estimate trend towards increasing efficacy with increasing age. Weight: there is a point estimate trend towards decreasing efficacy with increasing weight. Intended duration of anticoagulation. There is a numerical trend towards greater efficacy with increasing intended treatment duration. VTE recurrence HR point estimate is >1 (i.e. favours enoxaparin) in the 3 month intended treatment duration group, but with large uncertainty. The 12 month intended treatment duration group appears to experience greater efficacy in terms of VTE recurrence, with rivaroxaban being favoured in this group. In response to the ERG’s request for 53 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
clarification on this matter, the manufacturer argues that the number of events are small and statistical power is lacking 17 for the subgroup analyses, and whilst the ERG agree that powering may be a problem and the difference seen may be due to chance alone, it would still seem that a conclusion of inferiority cannot be rejected in the 3 months subgroup for the outcome VTE recurrence as the upper limit of the 95% CI for the Hazard Ratio exceeds the predefined non-inferiority limit of 2.0, and the point estimate is >1. To investigate this apparent difference in efficacy according to intended treatment duration, the ERG requested an interaction test on this subgroup analysis, which was provided and is presented in Table 11. Because interaction tests in subgroup analyses are often underpowered, it is usual to interpret these at the p=0.1 significance level, rather than the more usual p=0.05. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. Parenteral anticoagulation before randomisation. The point estimate for those who did not receive parenteral anticoagulation before randomisation is lower than for those who did. This may indicate an advantage to parenteral anticoagulation, or may indicate bias introduced by confounding factors, for example, later administration of treatment (post randomisation), or selection of more severe patients for immediate treatment, or may be due to chance alone. Previous episodes of DVT/PE. The point estimates suggest patients who have already had a VTE obtain greater relative benefit from rivaroxaban in comparison to Enoxaparin/VKA treatment than those who have not. Those who have already had a VTE are more likely to be on 12 month treatment, so these two factors are likely to be confounded.xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx x xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx.xxxxxx. Location of index DVT. Patients with non-extensive DVT have a trend towards gaining more benefit than extensive patients, based on the point estimate. Malignancy at randomisation. Active cancer does not appear to affect the point estimate, but there is increased uncertainty in the active cancer group, likely due to the small number in this group. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxx. 54 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
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 and 60: However, the study design did not i
Page 61 and 62: Table 10: Summary of outcomes for E
Page 63: Chi-square analyses were undertaken
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
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
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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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