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

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The ERG considers that the data extraction strategy outlined in Appendix 9.2.7 (page 233, in the MS) appears mostly adequate and comprehensible. The manufacturer states that data extraction was performed independently by two reviewers, although it was not stated exactly how disagreements between the two were addressed, e.g. through discussion, or involvement of a third party. In addition, there are some discrepancies between the methods stated, and the data presented, which may be a series of omissions in writing up, or may indicate a more general failure to follow the review protocol in a systematic way. According to the MS, items for which data were retrieved included the following (page 233 to 234, in the MS): Study characteristics: Author, title, year, country, study design, duration. Details of participants: number of patients in each treatment arm, age, gender, initial diagnosis, time from onset of symptoms, cause of DVT or PE, known thrombophilic condition, previous VTE. Details of intervention and comparators: drugs used, duration and intensity. Details of primary and secondary outcomes: recurrent VTE, bleeding (severity & location), all-cause mortality, treatment satisfaction (EINSTEIN-DVT only), pulmonary hypertension (to include CTEPH), PTS and other adverse events. Data extracted was used to populate Tables 9 to 16 (page 39 to 48, in the MS). 1 From the data presented, it is evident that some fields were populated, but not listed in appendix 9.2.7 in the MS as data extraction fields. These include: information relating to quality assessment (Table 9, page 39 ) inclusion criteria, exclusion criteria (Table 10, page 40) body mass, creatinine clearance (Table 11, page 41) risk factors, previous use of rivaroxaban (Tables 12 & 13, page 43) and information on statistic analysis methods used (Table 16, page 47). Of note also is a lack of formal data extraction, tabulation and presentation of compliance rates, though these are available elsewhere in the report (page 96 of the MS), 1 and also of time in target range (presented on page 88 of the MS). 1 For all these data, it is unclear if the data extraction methods of double data extraction and checking were applied. There is a risk that these data are more prone to error and potentially bias. However, the ERG does not feel that the risk is significant in this report, or that these omissions should detract from the data presented as the report appears generally of high quality. 4.1.4 Quality assessment 39 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
The approach taken to quality assessment by the MS conforms to the requirements of NICE. The summary table of quality assessment provided in the MS is reproduced in Table 8. However, the ERG has two concerns. 4.1.4.1 Concealment Superseded of treatment allocation – The question “was the concealment of treatment allocation adequate” was answered as “N/A” by the manufacturer. This may be because the trial is open label. However, this question relates to the concealment of allocation up to the point of randomisation, where the important factor is whether See Erratum study personnel can predict which group a patient will be allocated to before allocation takes place. This can result in selection bias. It is the opinion of the ERG that this should have been attempted, and that a NA answer is not appropriate. However, the trial arms xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx, so it is unlikely that selection bias has affected the results. 4.1.4.2 xxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx: “xxxxxxxxxxxxxxxxxxxxxxxxxxxxx: o xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxx. o xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx. o xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxx. o xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxx The ERG agrees, given the manufacturer’s response, that the scoring is acceptable. 4.1.4.3 Blinding of outcome assessors In addition, in light of responses received by the ERG, 17 the ERG have some concerns relating to the blinding of outcome assessors. This is discussed elsewhere in the report (section 4.2.1.3, “Difference between suspected and confirmed events”). 40 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
Page 1 and 2: Rivaroxaban for the treatment of de
Page 3 and 4: TABLE OF CONTENTS List of Abbreviat
Page 5 and 6: Table 12 Time to therapeutic INR (I
Page 7 and 8: identified in the model). Table 40
Page 9 and 10: Figures Figure 1 Flow diagram for i
Page 11 and 12: Figure 23 Exploratory analysis in c
Page 13 and 14: MS Manufacturer’s submission NE S
Page 15 and 16: The dose of LMWH used reflects Amer
Page 17 and 18: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Page 19 and 20: The exploratory analysis in cancer
Page 21 and 22: intended treatment duration of 12 m
Page 23 and 24: VTE therefore has a substantial bur
Page 25 and 26: indefinite treatment. VTE LMWH, low
Page 27 and 28: 3 Critique of manufacturer’s defi
Page 29 and 30: Subgroups to be considered Special
Page 31 and 32: 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: Table 7: Table showing list of rele
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
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
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Our experts believed that patients
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Similarly, the manufacturer used da
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Table 25: baseline risk of events f
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y intended treatment duration given
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eflect the current long term risk o
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survival of 70% in the 148 non-surg
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Monitoring xxxxxxxxxxxxxxxxxxxxxxxx
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The ERG acknowledges that the monit
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For patients managed in the inpatie
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The searches identified 2,811 poten
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The health state utility value for
Page 125 and 126:
xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxx
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few occasions for both VTEs and ble
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2) the values used in the PSA for t
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5.2.1 Results included in the manuf
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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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Page 153 and 154:
Page 155 and 156:
Superseded - See Erratum 6. ADDITIO
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Superseded - See Erratum Table 37 S
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Superseded - See Erratum Table 38:
Page 161 and 162:
Page 163 and 164:
Superseded - See Erratum Figure 21:
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Page 167 and 168:
Superseded - See Erratum 6.3. Proba
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Page 171 and 172:
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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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