Apixaban for the prevention of venous thromboembolism in people ...

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The incidence of reported adverse events and severe adverse events was similar between two groups. The available evidence from both trials for each outcome mentioned in the NICE scope is summarised in Table 4.5. 4.2.2 Describe and critique the manufacturer’s approach to validity assessment for each relevant trial. Formal appraisals of the validity of the trials ADVANCE 1, 2 & 3 were clearly presented in the MS (MS, table 12, page 54; appendix 3, page 36-38). All the criteria listed under Section 5.4.1 (MS page 54 – as specified in the NICE STA Specification for manufacturer/sponsor submission of evidence) were addressed in the quality assessment findings. These findings are reproduced in table 4.6 alongside a validity assessment provided by the ERG for the APROPOS trial. The APROPOS was reported to be a dose finding study and subsequently excluded in the main submission. However, as it fulfils all inclusion criteria, the ERG group thinks that this study should be included alongside the ADVANCE 1, 2 & 3 studies for validity assessment. The ERG checked the quality assessment findings against the provided trial data and original study publications and any additional points are discussed within this section. Overall the ERG was in agreement with the MS quality assessment findings. It was not clear if any of the procedures for searching, screening, assessing validity, extraction and synthesis were undertaken by a single reviewer and independently checked by a second reviewer or using a consensus of multiple reviewers. Table 4.6: Quality assessment results for RCTs Trial no. (acronym) ADVANCE 1 ADVANCE 2 ADVANCE 3 APROPOS* Was randomisation carried out appropriately? Was the concealment of treatment allocation adequate? Were the groups similar at the outset of the study in terms of prognostic factors? Were the care providers, participants and outcome assessors blind to treatment allocation? Were there any unexpected imbalances in drop-outs between groups? Is there any evidence to suggest that the authors measured more outcomes than they reported? Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes Yes 24 Yes Yes Yes Yes Yes No No No No No No No No Copyright 2011 Queen’s Printer and Controller of HMSO. All rights reserved.
Trial no. (acronym) ADVANCE 1 ADVANCE 2 ADVANCE 3 APROPOS* Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data? The primary efficacy analysis dataset included all randomised subjects who had; an adjudicated and evaluable bilateral venogram; or had an adjudicated VTE; or died due to any cause. The key secondary efficacy analysis data sets included all randomised subjects if asymptomatic events were not part of the endpoint or all randomised subjects with either an adjudicated event that was part of the endpoint or an adjudicated evaluable bilateral venogram (MS, Table 11, page 48). This was deemed clinically appropriate since asymptomatic DVT can only be detected with an evaluable venogram. The ITT analysis assumes that no readable venogram represents no event, therefore potentially underestimating the number of VTE events occurring within the ITT population. The remaining efficacy and safety outcome analyses were conducted on the ITT population. There is debate around the use of venographically confirmed VTE as the primary endpoint. It can be argued that symptomatic VTE and VTE-related mortality is a more clinically relevant outcome. However the problems associated with the use of this endpoint are well documented (i.e. the rarity of the event) and the primary endpoint adheres with the EMEA guideline for study development in this therapeutic area (reference 72 in the main submission. 33 In addition, two previous STAs on rivaroxaban 34 and dabigatran 35 also used this outcome and described it as appropriate. Nevertheless, the large amount of missing data is problematic. The most appropriate way to assess whether missing data are likely to have an effect on the results is by performing a sensitive analysis in which all missing data are treated as negative events. However, with one-third of respondents having missing data there is no possibility to do any kind of sensitivity analysis. 4.2.3 Describe and critique the statistical approach used within each relevant trial. The statistical analysis in the ADVANCE 1, 2& 3 trials are described in the MS on pages 48-50 and in table 11 (MS, page 48) and copied into Table 4.7 below. The analyses for the APROPOS trial were copied from the trial data. The statistical analyses in the trials seemed appropriate. 25 Copyright 2011 Queen’s Printer and Controller of HMSO. All rights reserved.
Page 1 and 2: in collaboration with: Apixaban for
Page 3 and 4: Abbreviations AAOS American Academy
Page 5 and 6: 1. SUMMARY ........................
Page 7 and 8: 1. SUMMARY 1.1 Scope of the manufac
Page 9 and 10: The three identified trials, which
Page 11 and 12: Table 2.1. Summary of Annual TKR an
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ISPOR 11th Annual European Congress
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Appendix 1A: ERG Search Strategies
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85 84 not 83 (88613) 86 1 or 2 or 3
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76 Comment/ (451657) 77 Letter/ (72
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68 Motion Therapy, Continuous Passi
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23 pentasaccharide*.mp. (2192) 24 e
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Appendix 1B: Review of search strat
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Question(s) Appendix 2: Phillips et
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Has the source for all costs been d
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