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

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5.2.1.13. Model validation The manufacturer stated that the economic model has been assured through internal and external validation. The manufacturer stated that the internal validity was ensured by quality control of the model by the model developers, as well as a model audit performed by an external health economist. The MS also reported that an extensive external validation was undertaken in consultation with experts in DVT treatment, and comparing outputs of the model with the EINSTEIN-DVT trial and other sources. Despite the validation and model checking conducted by the manufacturer, the ERG identified some errors/inconsistencies in the economic model. These are described below: - In the reporting of outputs, the number of bleeding events was inverted between the two arms (error in xxxxxxxxxxxxxxxxxxx). This had no impact on the results. - The risk ratio for CRNM bleeding events was used as a hazard ratio in the economic model xxxxxxxxxxxxxxxxxxxx), but this had almost no impact on the ICER after correction by the ERG. - There was a discrepancy between the economic model and the report, as the manufacturer stated that xxx of patients discontinued treatment after an EC bleed, but used xxx in the economic model. - There was a discrepancy between the economic model and the report, as the manufacturer stated that 8.55% of patients treated in clinic required transportation, but used 7.5% in the economic model. - There was a discrepancy for the cost of CTEPH between the economic model and the report. - There was an error in Sheet “xxxxxxxxxxx. The cell was linked to the wrong cell. - An error was also identified by the ERG, in that the probability of PE recurrences after the first year was incorrectly divided by 4 (xxxxxxxxxxxxx. - there were also inconsistencies in the economic model, with the sum of the transition probabilities over 1 over few iterations in the PSA, due to the absence of constraints and correlation. This lead to negative values for the LMWH arm in 2.4% of iteration in the subgroup analysis. None of the errors identified had a significant impact on the results. 119 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
5.2.1 Results included in the manufacturer’s submission The MS included two analyses: - the primary analysis conducted in the whole trial population, by intended treatment duration, - a cost-minimisation analysis and an exploratory cost-effectiveness analysis in a subgroup of patients with cancer. This section of the report summarise the results presented by the manufacturer. Limitations of these analyses are discussed in Section 5.2. The additional analyses undertaken by the ERG is described in Section 6. 5.2.2.1 Primary analysis – whole trial population In its original submission to NICE, the manufacturer provided separate cost-effectiveness analyses for patients treated with rivaroxaban against dual therapy LMWH/VKA for the three intended treatment duration (3, 6 or 12 months) using effectiveness data from the whole trial population, irrespective of the intended treatment duration (Section 5.1). 1 In addition to those, the ERG requested analyses to be conducted using data specific to the intended treatment duration and using different time horizons. 5.2.2.1.1. Results for patients for whom three months of anticoagulation treatment is appropriate Using a lifetime horizon, the manufacturer reported that rivaroxaban was dominant (i.e. provided more QALYs at a lower cost) compared with dual therapy LMWH/VKA in patients treated for three months, using data by intended treatment duration, or estimated from the whole trial population (Table 31). Using data by intended treatment duration, the rivaroxaban strategy was less costly (savings of £218.05) but also provided more QALYs (0.0015) compared with dual therapy LMWH/VKA. Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx Table 31: Cost-effectiveness results for patients for whom three months of anticoagulation is appropriate (reproduction of Table 14, p. 30, Clarification letter 17 December 2011) Time horizon Treatment Total costs (£) Total QALYs Inc costs (£) Inc QALYs ICER (£) Duration specific 3 months RIV xxx xxx xxx xxx xxx LMWH/VKA xxx xxx xxx xxx xxx 1 year RIV xxx xxx xxx xxx xxx LMWH/VKA xxx xxx xxx xxx xxx Lifetime RIV 1,138.08 13.3373 - - - LMWH/VKA 1,356.13 13.3358 -218.05 0.0015 Dominated* 120 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
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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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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 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
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
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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
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
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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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