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

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Table 26: Treatment effect (rivaroxaban vs. dual therapy LMWH/VKA), by treatment duration (reproduction of Table 13, p. 30, Clarification letter, 17 December 2011) Outcome and patient group Point estimate Lower Upper Incidence of recurrent VTE (hazard ratio) Table 27: Proportion of VTEs that are DVTs – proportion (number of DVTs / number of VTEs) 3 months xxx xxxx xxx 6 months xxx xxx xxx 12 months xxx xxx xxx Incidence of major bleed (hazard ratio) 3 months xxx xxx xxx 6 months xxx xxx xxx 12 months xxx xxx xxx Incidence of CRNM bleeds (risk ratio) 3 months xxx xxx xxx 6 months xxx xxx xxx 12 months xxx xxx xxx Rivaroxaban Dual therapy LMWH/VKA All 3 months xxx xxx xxx xxx 6 months xxx xxx xxx 12 months xxx xxx xxx xxx All xxx xxx xxx The data suggests that using data by the initial treatment received xxx of VTEs were PEs in the rivaroxaban arm versus xxx in the dual therapy arm. The ERG also undertaken a chi-square test, and found that the differences xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. Because PEs are associated with greater cost implications and reduction in QoL compared with DVTs, the ERG explored a scenario using specific data by treatment arms. Results of this analysis are presented in section 5.2.1 of the ERG report. Note that we did not examine the impact of using data 97 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
y intended treatment duration given the small sample size when splitting patients by treatment arms and intended treatment duration. The manufacturer assumed that the probability that a major bleeding event is an IC bleeding event (conditional on one occurring) was the same between the two treatment arms in the economic model (12.5%). It is unclear why the manufacturer assumed this to be the same irrespective of the treatment arm (and intended treatment duration). No data was presented to support or reject this assumption. The split between intracranial/extracranial (IC/EC) bleeds is likely to affect the ICER as IC bleeds are associated with greater cost implication and reduction in QoL compared with EC bleeds. The impact of this assumption in the model has not been formally examined in the economic model by the ERG in the absence of data by treatment arm. This remains an area of uncertainty in the model. If the proportion of major bleeding events that are IC bleeds is higher in the rivaroxaban arm, this assumption will favour rivaroxaban. If the proportion is higher in the dual therapy LMWH/VKA arm, this assumption will favour the dual therapy arm. Discontinuation rate The discontinuation rate whilst on treatment was taken from the EINSTEIN-DVT trial, 50 and was assumed to be the same irrespective of the initial treatment received and intended treatment duration. 1 The manufacturer included the following reasons for discontinuation: non compliant with study medication, protocol violation, patient convenience, switch to commercial drug, insufficient therapeutic effect and bleeding adverse events. The manufacturer reported the total discontinuation for those reasons: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. This equated to an overall 3 month probability of xxxxxxxxx. The model additionally assumes that all patients with IC bleeds, xxx of patients with major EC bleeds and xxx of patients with CRNM bleeds discontinue treatment, based on xxxxxxxxxxxxxxxxxxxxxxxxxxxx. The MS stated that assuming the same discontinuation rate irrespective of the initial treatment was a conservative assumption; 1 however the ERG disagrees with this xxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. There is also double counting as the manufacturer included bleeding events to calculate the discontinuation rate whilst this was already included in the economic model. The discontinuation rate was calculated from the whole trial population, rather than specifically by intended treatment duration. There was also a mismatch between the economic model and the report, as the manufacturer 98 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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xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
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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
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 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
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: Table 25: baseline risk of events f
Page 111 and 112: eflect the current long term risk o
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
Page 125 and 126: xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxx
Page 127 and 128: few occasions for both VTEs and ble
Page 129 and 130: 2) the values used in the PSA for t
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
Page 143 and 144: Figure 17: Tornado plot - Net Monet
Page 145 and 146: 5.2.3 Comment on validity of result
Page 147 and 148: Table 36: Summary of uncertainties
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
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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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