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

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Table 21.1: Non-major bleeding - U(0,5) node mean sd 2.5% median 97.5% OR[1,2] 463.7 76420.0 0.09107 1.327 18.21 OR[1,3] 29.5 2465.0 0.1009 1.058 11.65 OR[2,3] 1.139 12.79 0.2463 0.8023 2.813 SD 0.8535 0.7552 0.0646 0.6345 3.09 1, rivaroxaban; 2, long term LMWH; 3, dual heparin/VKA; SD, standard deviation; OR, odds ratio. Table 21.2: Non-major bleeding - U(0,2) node mean sd 2.5% median 97.5% OR[1,2] 2.468 29.52 0.1769 1.331 9.499 OR[1,3] 1.67 8.863 0.1844 1.06 6.119 OR[2,3] 0.9006 0.5284 0.3215 0.8019 2.086 SD 0.6817 0.441 0.05926 0.5892 1.765 1, rivaroxaban; 2, long term LMWH; 3, dual heparin/VKA; SD, standard deviation; OR, odds ratio. Table 21.3: Non-major bleeding - U(0,0.6) Node mean sd 2.5% median 97.5% OR[1,2] 1.497 0.8066 0.4813 1.346 3.525 OR[1,3] 1.149 0.5095 0.457 1.06 2.438 OR[2,3] 0.826 0.2335 0.471 0.7913 1.389 SD 0.3425 0.1591 0.02811 0.3566 0.5869 1, rivaroxaban; 2, long term LMWH; 3, dual heparin/VKA; SD, standard deviation; OR, odds ratio. 4.5.2 Update of Akl et al. 31 The ERG undertook additional searches to update the Akl et al. 31 systematic review. The searches followed the same search strategy as reported in Akl et al., 31 covering the years 2010 and 2011. The searches were sifted by title, abstract and full text. No further relevant RCT studies were found. 4.6 Conclusions of the clinical effectiveness section Table 22 summarises remaining uncertainties for the clinical data. The methods of the review of direct evidence were sometime unclear, though the ERG does not suspect that any studies have been missed, and rate the systematic review as reliable. The evidence from EINSTEIN-DVT, a non-inferiority, open label, randomised trial upon which the MS focuses, is generally a well conducted study which is highly relevant to the decision problem. However, the study fails to provide information on some important subgroups of patients, such as those with high risk of bleeding, and creatinine clearance
Table 22 Uncertainties in clinical data and direction of effect. Issue Is the current assumption favourable or unfavourable to rivaroxaban? Ongoing treatment option not represented Unknown Use of Enoxaparin to represent LMWHs Probably no effect Enoxaparin dose Possibly unfavourable to rivaroxaban Wrong comparator (cancer) Favourable to rivaroxaban (in whole cohort) HRQoL measurements Unknown Potentially rare adverse events which occur as a Potentially favourable to rivaroxaban consequence of not being able to reverse rivaroxaban anticoagulation, being missed in this trial All cause mortality HR is shown to be significant Unfavourable to rivaroxaban, but may be dependent on intended treatment duration Lack of allocation concealment Unknown Under or over-diagnosis of patients into the wrong treatment Unknown duration group Subgroup by those with and without a previous VTE Favourable to rivaroxaban for those without previous VTE Unfavourable to rivaroxaban for those with previous VTE Inclusion of patients who did not fulfil the selection criteria Unknown from the study. Patients with distal DVT appear also to have been excluded, even though the SmPC 19,20 does not exclude them from treatment. A small number of patients (with PE and/or creatinine clearance
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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
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
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Page 59 and 60: However, the study design did not i
Page 61 and 62: Table 10: Summary of outcomes for E
Page 63 and 64: Chi-square analyses were undertaken
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Page 67 and 68: Both of these factors are likely to
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Page 77 and 78: DVT and/or PE xxxxxxxxx xxxxxxxxxxx
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Page 81 and 82: Subgroup analyses - EINSTEIN-Ext Su
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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: Table 19.2: VTE recurrence (dichoto
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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Page 113 and 114: survival of 70% in the 148 non-surg
Page 115 and 116: Monitoring xxxxxxxxxxxxxxxxxxxxxxxx
Page 117 and 118: The ERG acknowledges that the monit
Page 119 and 120: For patients managed in the inpatie
Page 121 and 122: The searches identified 2,811 poten
Page 123 and 124: The health state utility value for
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Page 127 and 128: few occasions for both VTEs and ble
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Page 131 and 132: 5.2.1 Results included in the manuf
Page 133 and 134: 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
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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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