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

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The medians of the posterior distributions are less affected because medians tend not to be influenced by extreme values. This was examined by the ERG in a scenario analysis presented in Section 6. The ERG showed using the mean, rivaroxaban was no longer associated with a gain in QALYs. 3) There are also concerns with the approach used by the manufacturer to characterise the uncertainty in the economic model for patients with cancer. Indeed, the manufacturer sampled the treatment effect (HR/RR) using an arbitrary lognormal distribution, assuming no correlation with the baseline risk of events, instead of using the correlated samples from the joint posterior distribution. For information, the ERG compared the mean treatment effect taken from the MTC (calculated by the ERG) with the mean treatment effect calculated in the economic model (over 5,000 iterations in the PSA). The analysis showed that there were some inconsistencies. The mean OR for major bleedings was estimated to be 928.1 using results from the MTC assuming a between study variability of U(0,5) as used by the manufacturer. The mean OR calculated in the economic model over 5,000 iterations was 5.2. 4) The manufacturer used rivaroxaban for the baseline risk of events and applied a HR/OR to estimate the risk of events in cancer patients treated with LMWH. Whilst this may be reasonable approach, the ERG has some concerns that results are biased toward the rivaroxaban arm given the concerns regarding the outputs of the MTC, and the approach used by the manufacturer to sample the treatment effect (use of arbitrary lognormal) described above. In the economic model, the HR/ORs were sampled within extreme values (for example between 0.01 and 378.85 for VTEs and between 0.0004 and 406.08 for major bleedings, calculated over 5,000 iterations). However, because rivaroxaban was used for the baseline risk of events, large gains in QALYs (rivaroxaban vs. LMWH) can be expected when the treatment effect is varied at the lower 95% CI (i.e. increase in risk of events for patients treated with LMWH). On the contrary, only small gains are possible for LMWH when the treatment effect is varied at the upper 95% CI (i.e. reduction in the risk of events in patients treated with LMWH). For illustration, let’s assume that the baseline risk of events in the rivaroxaban arm is 5%. Using a HR of 0.1 (rivaroxaban vs. LMWH), the risk of events for patients treated with LMWH will be about 40.13% (i.e. an absolute increase of 35.13% compared with rivaroxaban). If the HR for rivaroxaban against LMWH is 10 (i.e. rivaroxaban is associated with poorer outcomes compared with LMWH), the risk of events for the LMWH arm will be about 0.51% (i.e. an absolute reduction of 4.49% compared with rivaroxaban). 5) There were also inconsistencies in the economic model, with the sum of the transition probabilities over 1 possible in the PSA. This is due to the absence of correlation in the model, issues with the MTC, the arbitrary lognormal distribution and the absence of constraints in the current model structure. This led to negative values in the LMWH arm in 115 Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.
few occasions for both VTEs and bleedings (For example 2.4% over 5,000 iterations for VTEs). 6) There was also an error in Sheet “xxxxxxxxxxxxx. The cell was linked to the wrong cell. This was not in favour of rivaroxaban, as part of the administration costs for LMWH were missed. 7) The analysis in the subgroup of cancer patients relies on several assumptions. Data not specific to cancer patients were used for the risk of events once treatment cease; it is unclear if this is appropriate. The ERG did not conduct a systematic review of the literature, but found a study showing that the probability of readmission for VTEs within 6 months was almost four times higher among Medicare patients with cancer than among Medicare patients without malignancy. 76 8) The manufacturer assumed a median life expectancy of 5 years; however it is unclear if this reflects the life expectancy of patients with a DVT. 9) It is also unclear what the risk of events in cancer patients is. The manufacturer re-used results from the main analysis and adjusted the risk for the increased risk in cancer vs. non cancer patients. It is unclear whether the estimate from the manufacturer reflect the baseline risk of events. 10) The manufacturer also assumed the same baseline utility value and impact on Qol in the general population and patients with cancer. It is likely that the baseline utility value is different between cancer vs. non cancer patients. VTEs might also affect differently cancer patients. Overall, the ERG has some concerns with the accuracy of the exploratory analysis conducted by the manufacturer in cancer patients. Whilst the ERG acknowledges that this is an exploratory analysis, the ERG does not believe results of this analysis to be robust. 5.2.1.11. Sensitivity analysis The manufacturer conducted a series of one-way deterministic sensitivity analyses. The probabilities of clinical events on dual LMWH/VKA therapy and treatment effects in relation to efficacy and safety variables for rivaroxaban vs. dual LMWH/VKA therapy were varied by using the upper and lower 95% CI values. Utility values were set at upper and lower 95% CI values or, where these were not available, the interquartile (IQR). Resource usages were also varied in SA. Unit costs were varied by ±30% and discounting ranged between 0% to 6%. The time horizon was also varied from lifetime to 5 years. Assumptions about the monitoring were also explored varying the setting of care (primary/secondary/hybrid). The MS also varied the mean baseline age from 46 years to 66 years. 116 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
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intended treatment duration of 12 m
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VTE therefore has a substantial bur
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indefinite treatment. VTE LMWH, low
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3 Critique of manufacturer’s defi
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Subgroups to be considered Special
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contraindications for the drug (as
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3.1.3 MTC populations The populatio
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3.2.2 Length of treatment As discus
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“No preventative therapy” is th
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It could be argued that poor TTR ma
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3.4.2 Outcomes recommended by EMA r
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4 CLINICAL EFFECTIVENESS 4.1 Critiq
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competitor products were excluded f
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Figure 1 Flow diagram for identifyi
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Table 7: Table showing list of rele
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The approach taken to quality asses
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o EINSTEIN-DVT dose-ranging study 3
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Trial name References, study type E
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4.2.1 Critique of pivotal EINSTEIN-
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However, the study design did not i
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Table 10: Summary of outcomes for E
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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
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
Page 123 and 124: The health state utility value for
Page 125: xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxx
Page 129 and 130: 2) the values used in the PSA for t
Page 131 and 132: 5.2.1 Results included in the manuf
Page 133 and 134: Figure 8: Tornado plot - Net Moneta
Page 135 and 136: 5.2.2.1.2. Results for patients for
Page 137 and 138: Figure 12: Cost-effectiveness plane
Page 139 and 140: Figure 14: Tornado plot - Net Monet
Page 141 and 142: 5.2.2.2 Subgroup analysis - cancer
Page 143 and 144: Figure 17: Tornado plot - Net Monet
Page 145 and 146: 5.2.3 Comment on validity of result
Page 147 and 148: Table 36: Summary of uncertainties
Page 149 and 150: Summary of uncertainties Has the im
Page 155 and 156: Superseded - See Erratum 6. ADDITIO
Page 157 and 158: Superseded - See Erratum Table 37 S
Page 159 and 160: Superseded - See Erratum Table 38:
Page 163 and 164: Superseded - See Erratum Figure 21:
Page 167 and 168: Superseded - See Erratum 6.3. Proba
Page 173 and 174: 6.5. Exploratory analysis in cancer
Page 175 and 176: 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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