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

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The Heparin/VKA combination used and dosing schedule used. A mixture of anticoagulants, in combination or on their own, are included in this set of studies, and it is unclear to what extent they are comparable. The manufacturer did not discuss this point, nor did they report seeking clinical opinion on the matter. Populations included. As discussed in section 3, the MTC trials included patients with PE or DVT, and one study included patients of DVT alone. The proportion of DVT and PE patients in each study are not reported in the MS, thought the clinical advisors to the ERG do not feel that the ratio of PE:DVT patients is likely to have vastly affected outcomes. However, the manufacturer did not discuss this point, nor did they report seeking clinical opinion on the matter. Quality assessment of MTC studies The MS submission reproduced the quality assessment provided in the Cochrane review. However, this included studies not relevant to this appraisal, and no discussion of the quality of the evidence relating only to the data that was used was provided. The ERG has reproduced the quality assessment selecting only the studies of relevance in Table 17. Table 17: Reproduction of quality assessment reported in Akl 2011, 31 selecting only trials of relevance to this assessment. Random sequence generation Allocation concealment Blinding of participants Blinding of providers Hull 2006 42 Y U N N N Y N Y Y Y Y Lee 2003 43 Y Y N N U Y Y Y Y Y Y Meyer 2002 44 Y Y N N N N Y Y Y Y Y Deitcher 2006 41 Y U N N N N N Y Y Y N Romera 2009 45 Y N N N Y N Y Y Y Y Y Y, yes; N, no; U, unclear; ITT, intention to treat. Studies involved in the primary analysis of VTE recurrence were Hull 2006 42 Lee 2003, 43 and Meyer 2002. 44 Blinding of participants and providers appears to be poor. The impact of this in terms of bias 73 Blinding of data collectors Blinding of data analysts Blinding of outcome adjudicators Incomplete data outcome reported Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved. Free of selective reporting Free of other bias ITT analysis
is likely to be small as the outcomes are objectively determined, except in the case of the Hull 42 study, where the outcome adjudicators were not blinded. All of the studies except Romera 45 were involved in the analyses of bleeding rates. Deitcher 2006 41 has similar limitations as the study by Hull et al 42 and in addition does not provide an ITT analysis. Otherwise, the studies generally appear well conducted. 4.4 Critique of the indirect comparison and/or multiple treatment comparison In general, the ERG has concerns with the way the (network) meta-analysis has been implemented and the impact that the prior information has had on the results. The ERG has outlined a number of problems with the conduct of the MTC above, and would like to highlight the following points of interest: Overall, there is a lack of clarity about where data has come from, and a lack of depth in the analysis of study characteristics in relation to one another. Additional searches were not conducted to update the Akl et al 31 . The ERG has conducted update searches following the Akl et al. search strategy. The results were sifted, but no further eligible RCT studies were identified. The MS states the study by Romera Villegas et al 45 is an RCT, however it appears from the online abstract to be a systematic review. This is also reported as an RCT in the citing Cochrane review, Akl et al. 31 On Pg 71 of the MS 1 it is stated that “the treatment interaction term for presence of active cancer was xxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx. Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxx. Indeed the use of data that does not come from the cancer group in this MTC seems to negate the point of the comparison, which is to study the effects in cancer patients. Therefore, the ERG feels the “secondary analysis 2” presented by the MS is more 74 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
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 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
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Page 73 and 74: may account for the apparent differ
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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 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
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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
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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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