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

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Table 5: Summary of outcomes as defined in the NICE scope, 3 as recommended by the EMA Research Guidelines, 23 and as outlined in Table 14 and 15 of the MS. 1 Efficacy outcomes NICE scope 3 Recurrent VTE EMA guidelines 23 EINSTEIN-DVT 1 EINSTEIN-Ext 1 Recurrent, symptomatic VTE non-fatal DVT and/or nonfatal PE. Non-inferiority trials: The combined incidence of recurrent DVT/PE and VTE-related deaths, with secondary analyses for each individual component separately. Superiority trials: The combined incidence of recurrent DVT/PE and all deaths, with secondary analyses for each individual component separately. 29 Symptomatic, recurrent VTE Symptomatic, recurrent VTE Secondary outcome 1: composite of DVT, nonfatal PE and all-cause mortality Mortality Mortality All cause mortality Not listed in Table 14, but reported PTS and NR Not listed in Table Not listed in Table 14, CTEPH 14, but reported but reported Safety Adverse Bleeding episodes* Clinically relevant Major bleeding outcomes events bleeding including bleeding events Vascular events Additional HRQoL NR Anti-clot treatment outcomes scale Treatment Satisfaction Questionnaire Discontinuation rates Discontinuation rates ands reasons Time in Target range and reasons Secondary NA NA Net clinical benefit; Secondary outcome 2: outcomes not a composite of composite of DVT, non- required by recurrent VTE and fatal PE, fatal PE, all- EMA or NICE major bleeding cause mortality and vascular events Secondary outcome 3: net clinical benefit; a composite of recurrent VTE and major bleeding Post hoc: risk-benefit NICE, National Institute for Health and Clinical Excellence; EMA, European Medicines Agency; DVT, Deep vein thrombosis; VTE, Venous thromboembolism; PE, pulmonary embolism; HRQoL, health related quality of life; PTS, post thrombotic syndrome; CTEPH, Chronic Thromboembolic Pulmonary Hypertension. * Bleeding episodes are defined as major or minor. Major bleeding is defined as: fatal bleeding; clinically overt bleeding causing a fall in Hb level of 20g/L or more, or leading to transfusion of two or more units of whole blood or red cells; bleeding in areas of special concern, such as retroperitoneal, intracranial, intraspinal or intraocular bleeding; bleeding causing permanent treatment cessation. Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
3.4.2 Outcomes recommended by EMA research guidelines 23 Whilst all the outcomes specified by NICE were reported (with the exception of HRQoL), some of the outcomes specified in the EMA document were not reported. The EMA guidelines recommend composite primary outcomes: Non-inferiority trials: The combined incidence of recurrent DVT/PE and VTE-related deaths, with secondary analyses for each individual component separately. Superiority trials: The combined incidence of recurrent DVT/PE and all deaths, with secondary analyses for each individual component separately. The EMA primary outcomes were not reported in the corresponding EINSTEIN trials. However, all the individual of these composite primary outcomes were reported. In addition, the composite primary outcomes specified by the EMA were not specified in the NICE scope, and the ERG does not feel that their omission is problematic; composite outcomes are generally not used in economic analyses as Superseded – there are differential impacts on both costs and utility for the constituent events, and whilst composite outcomes may seem to have simplicity on their side, they can be criticised for obscuring important differences in outcomes. 29 3.4.3 Composite See primary endpoint Erratum This last point is of further interest as the primary outcome defined by NICE is itself a composite outcome. VTE recurrence includes both DVT and PE. PEs are generally caused by parts of a DVT clot breaking off and getting lodged in the arteries of the lungs. Whilst these two events are manifestations of the same underlying condition, the clinical implications of each are different, with PE being more associated with death and CTEPH. There are also different costs associated with each. The use of a composite outcome might be argued to be valid if the constituent events are not thought to differ in their response to treatment, i.e. they have similar reductions in relative risk. 29 If there is reason to believe that the two events may behave differently, then the composite outcome may not be appropriate. 3.4.4 The diagnosis of primary outcomes The diagnosis of DVT and PE, for both index events and recurrence, described in the MS are largely consistent with those recommended by the European Medicines Agency (EMA) Committee for Proprietary Medical Products (CPMP) 23 guidelines for the evaluation of new technologies for managing VTE. Exceptions are discussed later in the report in section 4.2.1.3, “difference between expected and confirmed events”. 30 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
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Table 19.2: VTE recurrence (dichoto
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Table 22 Uncertainties in clinical
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The ERG are of the understanding th
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For the primary analysis, the rates
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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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