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

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SUMMARY 1.1 Critique of the decision problem in the manufacturer’s submission The ERG noted the following about the manufacturer’s definition of the decision problem. Population: the population selected was not fully representative of the deep vein thrombosis (DVT) population. Patients excluded from EINSTEIN-DVT include: Most patients with high risk of bleeding Patients with creatinine clearance 180 mmHG or diastolic >110 mmHg). Patients with distal DVT In addition to the above, the EINSTEIN-Ext trial: Only included patients in an inadequately defined group of patients “in clinical equipoise”. Included patients with both DVT and pulmonary embolism (PE) index events. The ERG requested data from DVT patients only, which was provided by the manufacturer. Intervention: the intervention matches the intervention described in the final scope except in that: Patients with creatinine clearance
The dose of LMWH used reflects American practice (1mg/kg bid), whereas the UK dose is 1.5mg/kg od. Evidence suggests these doses are largely equivalent, though a Cochrane review does not rule out the possibility that the once daily dose may be less effective for VTE recurrence. Using the twice daily dose may have been unfavourable to rivaroxaban. Cancer patients should have been treated with LMWH throughout according to international guidelines. Inclusion of these patients in the trial with the wrong (less effective/safe) treatment could have been favourable to rivaroxaban. No preventative therapy, as defined by NICE in the scope, was only included as a comparator in the EINSTEIN-Ext trial, which had an appropriately limited patient population. Patients indicated for treatment with unfractionated heparin are not represented in the trial, and no data for these patients and this comparator are available. Patients for whom VKA is not considered appropriate are only represented by cancer patients in the trial, as other groups of patients for whom VKA is not considered appropriate were not included. No data for these patients with an appropriate comparator is available. Time in treatment range for VKA was poor, but not outside UK norms. Outcomes: Most of the outcomes listed in the NICE scope were included in the submission. Points noted by the ERG include: Health related quality of life was not measured using a validated or preference based measure. VTE is a composite primary endpoint. The constituent parts, DVT and PE, have very different impacts on mortality, quality of life and costs. Composite outcomes are valid where the constituent events are not thought to differ in their response to treatment. Other relevant factors: Rivaroxaban could potentially increase access to anticoagulation for those of some religious denominations, as warfarin is made of porcine heparin Rivaroxaban could potentially increase access for patients who have problems injecting for dexterity or phobia reasons. Reversal of rivaroxaban anticoagulation (for example where an emergency surgical intervention is required) is a potential issue as this has not yet been standardised. 4 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: 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
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 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
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clarification on this matter, the m
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Both of these factors are likely to
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It remains unclear why these patien
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leeding may be less suited to longe
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may account for the apparent differ
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Table 13: Criteria used to define a
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DVT and/or PE xxxxxxxxx xxxxxxxxxxx
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There is some doubt about the appro
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Subgroup analyses - EINSTEIN-Ext Su
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o It is clear that bleed events wer
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is likely to be small as the outcom
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depends on the specific parameteris
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4.4.3 Between study standard deviat
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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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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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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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