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

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Table 4: Rivaroxaban characteristics. Compiled by the ERG using information given on pages 11 to 13, and in Table 2, page 15 of MS. 1 Brand name Xarelto Approved name Rivaroxaban Therapeutic class Oral anticoagulant Anticipated indication (confirmed in December 2011) 19,20 Treatment of deep vein thrombosis (DVT), and Superseded prevention of recurrent DVT and pulmonary – embolism (PE), follow an acute DVT in adults. Factor Xa interrupts the intrinsic and extrinsic See Erratum pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not Mode of action Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of Pharmaceutical formulation inhibit thrombin (activated Factor II) and no effects on platelets have been demonstrated. 15 mg and 20 mg film-coated tablets are relevant to this appraisal Acquisition cost (excluding VAT) Xxxxxxxxxxxxxxxxxxxxxxxx) Method of administration Oral Doses 15 mg and 20 mg Dosing frequency 15 mg twice daily for 21 days, then 20 mg once daily 19,20 Average length of a course of 3-12 months according to assessment of individual treatment risk-benefits, according to the MS 1 .* Average cost of a course of treatment xxxxxxxxxxxxxxxxxxxxxxxxxxxxx Anticipated average interval between Not applicable courses of treatments Anticipated number of repeat courses Not applicable of treatments Dose adjustments The SmPC advises a reduced dose in patients with moderate or severe renal impairment (i.e. creatinine clearance < 50 ml/min). The reduced dose would be 15 mg twice daily for 21 days, then 15 mg once daily. 19,20 * The ERG disagrees with the manufacturer’s understanding of length of treatment, and do not know how the assumptions made by the manufacturer on this point will affect average length of a course of treatment. Marketing authorisation was gained for rivaroxaban during the course of this assessment and the SmPCs have been published. 19,20 23 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
3.2.2 Length of treatment As discussed in section 2.2, the clinical advisors to the ERG do not recognise 12 months as a clinical cut off point for anticoagulation treatment, but agree that 3 months and 6 months treatment periods are often used. The clinical advisors to the ERG estimate approximately 20% of DVT patients would currently proceed to long term (ongoing) treatment, mainly because recurrence of VTE would indicate ongoing risk. As already outlined in section 2.2, this point was raised with the manufacturer, and a number of pieces of evidence were presented by the manufacturer. 17 However, the manufacturer was unable to provide any direct or robust evidence that contradicted the ERG’s view that ongoing treatment is a current treatment option, and it does not appear that they have obtained guidance from clinical experts on this point. Given that there is considerable uncertainty on this point, The ERG feels that it would have been prudent for analyses assuming treatment >12 months to have been undertaken by the manufacturer. 3.3 Comparators The comparator in the pivotal EINSTEIN-DVT trial is a combination of Enoxaparin, a LMWH in common use in the UK, followed by ongoing treatment with a VKA (warfarin or acenocoumarol). 3.3.1 Enoxaparin vs. other LMWHs – EINSTEIN-DVT Enoxaparin is not the only LMWH used in the UK for this indication. The manufacturer has not addressed the representativeness of enoxaparin in terms of clinical effectiveness (though some discussion is made in relation to cost effectiveness), nor have they declared that they have sought advice from a clinical panel regarding this. The ERG have found that current UK guidelines 25 state that there is still debate about whether LMWH drugs should be treated as a generic class of drug, or whether each drug should be regarded as a separate entity. The guidelines conclude that whilst there is little head to head evidence, the published data indicated that any differences in efficacy or safety were likely to be very small for those LMWHs that have similar action and physiochemical structures. In addition, the clinical advisors to the ERG agree that enoxaparin is an acceptable comparator, with high relevance to UK practice. As such, it is the opinion of the ERG that enoxaparin is an acceptable comparator for the purpose of this assessment. 24 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
Page 15 and 16: The dose of LMWH used reflects Amer
Page 17 and 18: xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
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: 3.1.3 MTC populations The populatio
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 and 72: leeding may be less suited to longe
Page 73 and 74: may account for the apparent differ
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
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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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