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

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All outcomes identified by NICE were reported, with the exception of health related quality of life data. Whilst a measure of quality of life was used, this was not in line with the NICE reference case, and was not a preference-based measure or a validated tool. The validity of the use of the composite outcome (VTE) depends on the assumption that similar reductions in hazard ratios will occur for all components of the outcome, i.e. PE and DVT, in response to treatment. The study appears relatively free of bias in its conduct. The results indicate that rivaroxaban is non- inferior to enoxaparin/VKA treatment for VTE recurrence and rates of clinically significant bleeding, on average, when considering the selected group of patients all together. However, subgroup analyses indicate that rivaroxaban may be less effective in certain groups of patients, including those who are clinically indicated to receive 3 months of treatment. The ERG feels that the data relating to VTE recurrences in this group does not definitively prove non-inferiority. Patients whose index event was a recurrence of a previous DVT or PE appear to obtain more relative benefit from rivaroxaban than those whose index event was their first DVT. Xxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. However, it should be noted that major bleeding events in the intended treatment groups do not appear different, and as such the balance between risk and benefit is unknown. No subgroup analysis was provided for bleeding events in the subgroups “previous episode of DVT/PE”. Bleeding events, adverse events and mortality results support the non-inferiority of rivaroxaban to enoxaparin/VKA treatment. Subgroup analyses indicate there may be increased bleeding rates for those who are ≤70kg and those with poor renal function in those taking rivaroxaban. Rivaroxaban patients scored more favourably on the quality of life measure used than those in the comparator group. Only one subgroup analysis included in the NICE scope was provided, mainly because there were no data available from the trial for patients in the other subgroups mentioned by NICE as these patients were excluded. The subgroup analysis provided was for patients with cancer, and involved an MTC to allow a comparison between rivaroxaban and LMWH, which is standard anticoagulant treatment for patients with cancer. The ERG felt that the results generated by the MTC were limited by the available evidence and also by the way the analysis was conducted. The results of the MTC using a uniform prior distribution on the range (0,0.6) shows that rivaroxaban is less effective than LMWH at preventing VTE recurrence, but induces fewer major bleeding events. The credible intervals are wide, and the ERG has concerns about the accuracy of the point estimates and credible intervals. 83 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
The ERG are of the understanding that antiocoagulation is used long term in approximately 20% of patients with a DVT. The EINSTEIN-DVT trial provided no data on longer term treatment with rivaroxaban, and data from the EINSTEIN-Ext provided data versus placebo, rather than an active treatment in a poorly defined population of patients. This trial showed that rivaroxaban is effective at decreasing recurrence of VTE in patients with an index DVT, but with some increase in clinically relevant non-major bleeding rates, and a non-significant increase in major bleeding. The effects of long term treatment with rivaroxaban in comparison with long term treatment with LMWH/VKA, whether this be in patients indicated for long term treatment or those in an equivocal state, is unknown. In conclusion, the decision problem has been fairly well addressed by the evidence provided. Gaps in the population include those at high risk of bleeding, those with a non-proximal DVT and those with renal impairment. There is no information relating to how rivaroxaban compares to treatment with unfractionated heparin and LMWH in patients who would normally be treated with these. The data relating to the cancer subgroup of patients is not considered robust by the ERG. The ERG also has concerns about the efficacy of rivaroxaban in patients who fall into the 3 month intended treatment duration, and there is no evidence relating to long term treatment with rivaroxaban compared to other active treatments. However, for patients in a poorly defined class of “clinical equipoise”, ongoing treatment appears better than no preventative therapy, and in the majority of patients treated for one year or less for proximal DVT in England and Wales, rivaroxaban appears to be non-inferior to treatment with Enoxaparin/VKA. 84 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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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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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 and 64: Chi-square analyses were undertaken
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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
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: Table 22 Uncertainties in clinical
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
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
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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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