Rivaroxaban for the Treatment of Deep Vein Thrombosis and Secondary Prevention of Venous Thromboembolism
Total Page：16
File Type：pdf, Size：1020Kb
Rivaroxaban for the treatment of deep vein thrombosis and secondary prevention of venous thromboembolism. Produced by School of Health and Related Research (ScHARR), The University of Sheffield Authors Sue Harnan, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA Rachid Rafia, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA Edith Poku, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA John Stevens, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA Matt Stevenson, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA Ruth Wong - ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA Correspondence to Sue Harnan, Research Fellow, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA Date completed 18th January 2012 Source of funding: This report was commissioned by the NIHR HTA Programme as project number 108501. Rider on responsibility for report: The views expressed in this report are those of the authors and not necessarily those of the NIHR HTA Programme. Any errors are the responsibility of the authors. This report should be referenced as follows: Harnan, S, Rafia, R, Poku, E, Stevens, J W, Stevenson, M, Wong, R. Rivaroxaban for the treatment of deep vein thrombosis and secondary prevention of venous thromboembolism: A Single Technology Appraisal. ScHARR, The University of Sheffield, 2012. Contributions of authors The review of the clinical evidence was undertaken by Sue Harnan and Edith Poku. The review of the cost-effectiveness evidence was undertaken by Rachid Rafia and Matt Stevenson. John Stevens undertook the review of the mixed treatment comparison meta-analysis. Ruth Wong re-ran the searches included in the manufacturer’s submission. Matt Stevenson advised the project. Acknowledgements Dr Raj Patel (Consultant Haematologist, Kings Thrombosis Centre) and Dr Eddie Hampton (Senior Lecturer in Haematology, University of Sheffield) provided advice during the project. Matt Stevenson (Technical Director, ScHARR Technology Assessment Group) and Kumar Perampaladas (Technical Lead, NICE) commented on a draft version of the report. The authors wish to thank all of the above. We would also like to thank Gill Rooney, Project Administrator, ScHARR, for her help in preparing and formatting the report. Declared competing interests of the authors: Dr Raj Patel declared no competing interests. Dr Eddie Hampton declared no competing interests. TABLE OF CONTENTS List of Abbreviations 1 1 SUMMARY 3 2 BACKGROUND 11 3 Critique of manufacturer’s definition of decision problem 16 3.1 Population 16 3.2 Intervention 22 3.3 Comparators 24 3.4 Outcomes 28 3.5 Other relevant factors 31 4 CLINICAL EFFECTIVENESS 32 4.1 Critique of the methods of review(s) 32 4.2 Critique of trials of the technology of interest, their analysis and 41 interpretation (and any standard meta-analyses of these) 4.3 Critique of trials identified and included in the indirect comparison 70 and/or multiple treatment comparison 4.4 Critique of the indirect comparison and/or multiple treatment 74 comparison 4.5 Additional work on clinical effectiveness undertaken by the ERG 79 4.6 Conclusions of the clinical effectiveness section 81 5 COST EFFECTIVENESS 85 5.1 Review of the cost-effectiveness evidence 85 5.2 Summary and critique of the manufacturer’s submitted economic 85 evaluation 6 ADDITIONAL WORK UNDERTAKEN BY THE ERG 144 6.1 145 Probabilistic cost-effectiveness results in patients for whom 3 months of anticoagulation treatment is appropriate – exploratory analyses conducted by the ERG. 6.2 151 Probabilistic cost-effectiveness results in patients for whom 6 months of anticoagulation treatment is appropriate – exploratory analyses conducted by the ERG. 6.3 156 Probabilistic cost-effectiveness results in patients for whom 12 months of anticoagulation treatment is appropriate – exploratory analyses conducted by the ERG. 6.4 160 Cost-minimisation analysis, assuming the same treatment effect between rivaroxaban and LMWH/VKA 6.5 162 Exploratory analysis in cancer patients – examining different HR 7 Overall conclusions 167 8 Appendices 169 9 References 182 Tables Table 1 Summary of international guidelines and recommendations 13 (reproduction of Table 3, page 19 of MS) Table 2 Statement of the decision problem, reproduced from the MS, page 27 17 Table 3 Summary of patient population of studies included in mixed 22 treatment comparison of LMWH treatment versus VKA treatment in DVT patients with cancer Table 4 Rivaroxaban characteristics. Compiled by the ERG using information 23 given on pages 11 to 13, and in Table 2, page 15 of MS. Table 5 Summary of outcomes as defined in the NICE scope, as 29 recommended by the EMA Research Guidelines, and as outlined in Table 14 and 15 of the MS. Table 6 Eligibility criteria used in search strategy (reproduction of Table 4, 34 page 30, in MS) Table 7 Table showing list of relevant RCTs (reproduced from Table 6 in 38 MS, p.32) Table 8 Quality assessment of EINSTEIN-DVT and EINSTEIN-Ext as 41 reported in MS (Table 17, page 53). Table 9 Summary of key characteristics of the clinical effectiveness studies 43 identified in the MS. Data drawn from tables 5, 6, 10, 11 and 14 of the MS Table 10 Summary of outcomes for EINSTEIN-DVT, taken from table 18 and 50 29, data on page 56, 58, 65, 96 of MS1 and Bauersachs et al. 2011 Table 11 Additional interaction test statistics for the primary analysis of time 55 to VTE recurrence. Reproduction of Table 1, page 8, manufacturer’s clarifications Table 12 Time to therapeutic INR (INR>=2.0) in days from randomisation 61 among patients with/without parenteral anticoagulation prior to randomisation (safety population) (reproduction of Table 11, page 24 of manufacturer’s clarifications). Table 13 Criteria used to define a suspected DVT event, and the criteria used 64 to confirm the event. Compiled from the manufacturer’s clarifications, and the EMA research guidelines Table 14 Summary of outcomes for EINSTEIN-Ext, taken from Tables 18 and 69 29, data on page 59 of MS1 and data from the Manufacturer’s clarification document Table 15 Summary of characteristics of trials included in the MTC 71 Table 16 Relative effectiveness of long-term LMWH vs LMWH/VKA dual 72 therapy in VTE patients with cancer. Reproduction of Table 24, page 74 of MS Table 17 Reproduction of quality assessment reported in Akl 2011, selecting 73 only trials of relevance to this assessment Table 18.1 VTE recurrence (time to event, hazard ratio) - U(0,5) 79 Table 18.2 VTE recurrence (time to event, hazard ratio) - U(0,2) 79 Table 18.3 VTE recurrence (time to event, hazard ratio) - U(0, 0.6) 79 Table 19.1 VTE recurrence (dichotomous, odds ratio) - U(0,5) 79 Table 19.2 VTE recurrence (dichotomous, odds ratio) - U(0,2) 80 Table 19.3 VTE recurrence (dichotomous, odds ratio) - U(0,0.6) 80 Table 20.1 Major bleeding - U(0,5) 80 Table 20.2 Major bleeding - U(0,2) 80 Table 20.3 Major bleeding - U(0,0.6) 80 Table 21.1 Non-major bleeding - U(0,5) 81 Table 21.2 Non-major bleeding - U(0,2) 81 Table 21.3 Non-major bleeding - U(0,0.6) 81 Table 22 Uncertainties in clinical data and direction of effect 82 Table 23 Weighted average daily drug acquisition cost of LMWH treatments 89 Table 24 Probabilities of VTEs and bleeding events for patients treated with 93 dual therapy LMWH/VKA (reproduction of Table 36, p. 112, MS, November 2011) Table 25 baseline risk of events for patients treated with dual therapy 96 LMWH/VKA, by intended treatment duration (reproduction of Table 12, p. 29, Clarification letter, December 2011) Table 26 Treatment effect (rivaroxaban vs. dual therapy LMWH/VKA), by 97 treatment duration (reproduction of Table 13, p. 30, Clarification letter, December 2011) Table 27 Proportion of VTEs that are DVTs – proportion (number of DVTs / 97 number of VTEs) Table 28 Management costs for the different health states (reproduction of 107 Table 52, p. 155, MS, November 2011) Table 29 Health state utility values used in the cost-effectiveness evaluation 111 (Adaptation from Table 46, p. 134, MS,1 November 2011) Table 30 multivariate SA conducted by the manufacturer (reproduction of 118 Table 53, p. 158, MS, November 2011) Table 31 Cost-effectiveness results for patients for whom three months of 120 anticoagulation is appropriate (reproduction of Table 14, p. 30, Clarification letter December 2011) Table 32 Cost-effectiveness results for patients for whom six months of 124 anticoagulation is appropriate (reproduction of Table 15, p. 33, Clarification letter December 2011) Table 33 Cost-effectiveness results for patients for whom 12 months of 127 anticoagulation treatment is appropriate (reproduction of Table 16, p. 36, Clarification letter December 2011) Table 34 Cost minimisation of rivaroxaban vs. LMWH in the cancer subgroup 130 (reproduction of Table 79, p. 209, MS1 November 2011) Table 35 indicative cost-effectiveness results for cancer patients for whom six 131 months of anticoagulation treatment is appropriate (reproduction of Table 21, p. 42, Clarification letter December 2011) Table 36 Summary of uncertainties 136 Table 37 Summation of ERG exploratory analyses in patients for whom 3 146 months of anticoagulation treatment is appropriate. Table 38 148 Probabilistic base case analysis (in patients treated for 3 months) using the manufacturer’s assumptions (before amendment of errors identified in the model). Table 39 Probabilistic base case analysis (in patients treated for 3 months) 148 using the manufacturer’s assumptions (after amendment of errors identified in the model). Table 40 Probabilistic base case analysis (in patients treated for 3 months) after 149 amendment of errors identified in the model, assuming less intensive INR monitoring (same split DVTs/PEs between arms).