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

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Records excluded were described in the flow diagram. This stated ‘Most were duplicates, review articles, editorials, non-English language publications related to included RCTs or concerning orthopaedic or non-VTE indications.’ This reporting lacks clarity, in that the numbers of articles excluded for each category are not given. For most categories, this is not of great importance. However, where English language is used as a selection criterion, it is usual to list how many potentially includable studies with potentially relevant data were excluded on this basis, to give some indication of the risk of language bias affecting the results. Overall, the above points are thought unlikely by the ERG to introduce any significant bias to the review. In relation to study selection, the presentation of two unpublished studies in the “Overview of rivaroxaban trials” (presented in Table 5, section 5.2.3 of the MS), 1 namely the CYP cohort and EINSTEIN-PE study, was not necessary, as these studies do not fall within the NICE scope or the inclusion/exclusion criteria. However, the manufacturer’s provision of information related to them is appreciated by the ERG, by way of explanation of their exclusion. The MS presented a list of four RCTs comprising two Phase II studies and two Phase III studies 21,35,36 (Table 6 in MS, page 32, reproduced here as Table 7) comparing the intervention with other therapies in the population group as defined by the selection criteria, which is reproduced in Table 6. Of the listed RCTs, the MS highlighted two Phase III randomised controlled trials as the main sources of clinical evidence for rivaroxaban treatment in patients with DVT and the prophylaxis of recurrent DVT and PE. The studies were the EINSTEIN-DVT study 21 and the EINSTEIN-Ext study 21 . The Phase II studies, the Oral Direct Factor Xa Inhibitor BAY-59-7939 in Patients with Acute Symptomatic Deep-Vein Thrombosis (ODIXa-DVT) study 35 and EINSTEIN dose-ranging Phase II 36 study did not directly contribute data for the review of clinical effectiveness. However, the manufacturer stated that these were included as they informed the selection of rivaroxaban doses and also served as supportive evidence on the efficacy and safety of rivaroxaban. These studies are summarised in Appendix 1. 37 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
Table 7: Table showing list of relevant RCTs (reproduced from Table 6 in MS, page 32) 1 Study reference Agnelli et al 2007 35 Buller et al 2008 36 Bauersachs et al 2010 21 Bauersachs et al 2010 21 Trial name/Study OXIDa-DVT Phase II study EINSTEIN doseranging Phase II study EINSTEIN DVT Phase III study EINSTEIN- Extension Phase III study Population Intervention Comparator Symptomatic proximal DVT without PE Acute symptomatic DVT without PE Acute symptomatic DVT without any symptoms of PE Objectively confirmed symptomatic DVT or PE that had been treated for 6 to 12 months with warfarin, acenocoumarol or rivaroxaban in patients with clinical equipoise for continued anticoagulation 38 Rivaroxaban 10mg, 20mg, or 30mg twice daily or 40mg once daily Rivaroxaban 20, 30 or 40mg once daily Rivaroxaban 15mg twice daily for 3 weeks then 20mg once daily for 3,6 or 12 months Rivaroxaban 20mg once daily Enoxaparin (1mg/kg) twice daily overlapping with and followed by VKA Enoxaparin, tinzaparin or UH overlapping with and followed by VKA Enoxaparin (body weight adjusted) followed by VKA*, for 3, 6 or 12 months Placebo DVT, Deep vein thrombosis; EINSTEIN- OXIDa, Oral Direct Factor Xa Inhibitor; PE, pulmonary embolism; UH, unfractionated heparin; VKA, vitamin K antagonist. *The dose of VKA was adjusted to maintain a therapeutic INR of 2.5 (range 2.0-3.0). 4.1.3 Critique of data extraction – direct evidence review 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
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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
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Page 27 and 28: 3 Critique of manufacturer’s defi
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Page 33 and 34: 3.1.3 MTC populations The populatio
Page 35 and 36: 3.2.2 Length of treatment As discus
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Page 93 and 94: Table 22 Uncertainties in clinical
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In the economic model, the manufact
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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
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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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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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