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

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Compliance in the enoxaparin/VKA arm was judged sufficient if the enoxaparin treatment period xxxxxxxxxxxx or more, and xxxxxxxx INR visits were completed during the VKA treatment period. Parenteral anticoagulation. The ERG also asked for clarification of why some patients did not receive parenteral anticoagulation before randomisation, as implied in the subgroup analyses in Figure 8, page 56 of the MS (reproduced as Figure 3 above). The manufacturer was unable to provide data on this as the trial did not specifically record this data. However, they were able to show that the time to therapeutic INR was not different between the groups (Table 12, reproduced from manufacturer’s clarifications), 17 and as such the ERG feels that this factor is unlikely to have a large effect on estimates of efficacy. Table 12: Time to therapeutic INR (INR>=2.0) in days from randomisation among patients with/without parenteral anticoagulation prior to randomisation (safety population) (reproduction of Table 11, page 24 of manufacturer’s clarifications). 17 Parenteral anticoagulation prior to randomisation Xxx xx Number of patients Xxxx xxx Mean Xxxx Xxx SD Xxxx Xxx 25 th percentile X X Median X X 75 th percentile x Xx Difference between suspected and confirmed events. DVT events were captured within the trial in a two stage process. Patients presenting with suspected VTE were subject to diagnostic tests to confirm the event, and the events were confirmed by an external, blinded committee. A higher proportion of suspected events presenting in the enoxaparin/VKA arm (52/214 (24.3%)) were confirmed to be DVT events by the committee than in the rivaroxaban arm (36/229 (15.7%) (p=0.06). The ERG requested clarification of the criteria used to define a suspected DVT event, and the criteria used to confirm the event (Table 13). These mostly matched with EMA research recommendations, but there are some exceptions, which are discussed here, along with a number of potential explanations for this apparent difference; Explanation 1 - Suspected events relied on patients self-presenting, based on a booklet detailing symptoms (though these criteria were not included in the manufacturer’s response). 17 As such, the open label nature of this trial may have lead to patients being more likely to present with suspected VTEs in the rivaroxaban arm, if for example, patients were less trusting of the newer intervention, this 61 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
may account for the apparent difference in proportions of suspected events becoming confirmed events between the two arms. Explanation 2 - Whilst the committee were blinded, the clinicians completing the case notes do not appear to have been blinded, as this was an open label trial. This is a possible source of bias for some of the diagnostic tests used. For example, the EMA states “Compression ultrasonography (US) has been documented to have adequate sensitivity and specificity for symptomatic, proximal DVT, but is less adequate for distal DVT. The findings can be interpreted by the observer only, who should be well trained and carefully selected by the study co-ordinator” As such, the US tests may have been subject to the potential for bias. The likelihood of this bias affecting results is not thought by the ERG to be large because this was a multi-centre trial, and it would seem unlikely that differential interpretations due to expectation bias would have affected all operators. Explanation 3 - The final criteria listed by the manufacturer is xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx “Diagnosis on clinical signs is discouraged. The number of such episodes, especially if leading to changed or renewed therapy, must, however, be noted and accommodated for in the analyses.” And further state “Sensitivity analyses should be performed to assess the robustness of the conclusions of the study to the decisions of the clinical events committee regardless of unconfirmed cases of VTE.” Both of these analyses should have been performed by the manufacturer, but were not presented in the submission. 1 62 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
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Rivaroxaban for the treatment of de
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TABLE OF CONTENTS List of Abbreviat
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Table 12 Time to therapeutic INR (I
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identified in the model). Table 40
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Figures Figure 1 Flow diagram for i
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Figure 23 Exploratory analysis in c
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MS Manufacturer’s submission NE S
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The dose of LMWH used reflects Amer
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xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
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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
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: leeding may be less suited to longe
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
Page 103 and 104: Our experts believed that patients
Page 105 and 106: Similarly, the manufacturer used da
Page 107 and 108: Table 25: baseline risk of events f
Page 109 and 110: y intended treatment duration given
Page 111 and 112: eflect the current long term risk o
Page 113 and 114: survival of 70% in the 148 non-surg
Page 115 and 116: Monitoring xxxxxxxxxxxxxxxxxxxxxxxx
Page 117 and 118: The ERG acknowledges that the monit
Page 119 and 120: For patients managed in the inpatie
Page 121 and 122: 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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