NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE ® Apixaban (Eliquis ) for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation Submitted by Bristol-Myers Squibb and Pfizer Single technology appraisal (STA) 17th August 2012 Contents List of Tables ............................................................................................................... 4 List of Figures .............................................................................................................. 9 Abbreviations ............................................................................................................. 11 Executive summary .................................................................................................... 13 Section A – Decision problem .................................................................................... 16 1 Description of technology under assessment ................................................... 16 2 Context ............................................................................................................ 19 3 Equity and equality .......................................................................................... 29 3.1 Identification of equity and equalities issues .................................................... 29 4 Innovation ........................................................................................................ 30 5 Statement of the decision problem................................................................... 32 Section B – Clinical and cost effectiveness ................................................................ 34 6 Clinical evidence .............................................................................................. 34 6.1 Identification of studies .................................................................................... 35 6.2 Study selection ................................................................................................ 35 6.3 Summary of methodology of relevant RCTs .................................................... 39 6.4 Critical appraisal of relevant RCTs .................................................................. 52 6.5 Results of the relevant RCTs ........................................................................... 53 6.6 Meta-analysis .................................................................................................. 63 6.7 Indirect and mixed treatment comparisons ...................................................... 64 6.8 Non-RCT evidence .......................................................................................... 80 6.9 Adverse events ............................................................................................... 81 6.10 Interpretation of clinical evidence .................................................................... 93 7 Cost-effectiveness ......................................................................................... 100 7.1 Published cost-effectiveness evaluations ...................................................... 100 7.2 De novo analysis ........................................................................................... 103 7.3 Clinical parameters and variables.................................................................. 110 7.4 Measurement and valuation of health effects ................................................ 128 7.5 Resource identification, measurement and valuation..................................... 132 7.6 Sensitivity analysis ........................................................................................ 141 7.7 Results .......................................................................................................... 144 7.8 Validation ...................................................................................................... 164 7.9 Subgroup analysis ......................................................................................... 165 7.10 Interpretation of economic evidence .............................................................. 171 Section C – Implementation ..................................................................................... 174 Apixaban – BMS and Pfizer 2 8 Assessment of factors relevant to the NHS and other parties ........................ 174 9 References .................................................................................................... 181 10 Appendices .................................................................................................... 194 10.1 Appendix 1 .................................................................................................... 194 10.2 Appendix 2: Search strategy and flow diagram for Section 6.1 and 6.2 ......... 195 10.3 Appendix 3: Quality assessment of RCT(s) ................................................... 207 10.4 Appendix 4: Search strategy for Section 6.7 .................................................. 209 10.5 Appendix 5: Quality assessment of comparator RCT(s) in Section 6.7 .......... 210 10.6 Appendix 6: Search strategy and flow diagram for Section 6.2 and 6.8 ......... 213 10.7 Appendix 7: Quality assessment of non-RCT(s) in Section 6.8 ...................... 218 10.8 Appendix 8: Search strategy for Section 6.9 .................................................. 218 10.9 Appendix 9: Quality assessment of adverse event data in Section 6.9 .......... 218 10.10 Appendix 10: Search strategy for Section 7.1 – cost-effectiveness................ 219 10.11 Appendix 11: Quality assessment of cost-effectiveness studies .................... 233 10.12 Appendix 12: Search strategy for Section 7.4 ................................................ 235 10.13 Appendix 13: Search strategy for Section 7.5 ................................................ 245 10.14 Appendix 14: Network meta-analysis ............................................................ 246 10.15 Appendix 15: AVERROES safety ITT population ........................................... 269 10.16 Appendix 16: Literature search for background AF mortality ......................... 273 10.17 Appendix 17: Testing Fits for UK Lifetime Mortality Data for Men and Women 274 10.18 Appendix 18: One-way sensitivity analysis variables ..................................... 278 10.19 Appendix 19: PSA variables .......................................................................... 291 10.20 Appendix 20: Markov traces .......................................................................... 306 10.21 Appendix 21: Number of Events (Total Population) ....................................... 318 10.22 Appendix 22: Output from tornado diagrams ................................................. 330 11 Related procedures for evidence submission ................................................ 354 11.1 Cost-effectiveness models ............................................................................ 354 11.2 Disclosure of information ............................................................................... 354 11.3 Equity and equality ........................................................................................ 356 Apixaban – BMS and Pfizer 3 List of Tables Table 1: Unit costs of technology being appraised ........................................................ 17 Table 2: Morbidity and mortality (AF-associated stroke) ................................................ 19 Table 3: Estimated number of patients with AF in England and Wales, 2013-2017 ....... 20 Table 4: Estimated number of patients eligible for apixaban in England and Wales, 2013- 2017 .............................................................................................................................. 20 Table 5: Eligibility criteria applied to search results of RCT evidence systematic review (SR) .............................................................................................................................. 36 Table 6: Eligibility criteria used in search strategy for non-RCT evidence ...................... 36 Table 7: List of relevant RCTs ....................................................................................... 38 Table 8: Comparative summary of methodology of the RCTs ........................................ 39 Table 9: Eligibility criteria of the RCTs ........................................................................... 40 Table 10: Characteristics of participants in ARISTOTLE across randomised groups ..... 42 Table 11: Characteristics of participants in AVERROES across randomised groups ..... 43 Table 12: Reasons for unsuitability of VKA therapy† ...................................................... 44 Table 13: Primary and secondary outcomes of the RCTs .............................................. 45 Table 14: Summary of statistical analyses in RCTs ....................................................... 47 Table 15: Subgroups assessed for primary efficacy and safety endpoints ..................... 49 Table 16: Quality assessment results for RCTs ............................................................. 52 Table 17: Summary of primary efficacy outcome – randomised subjects ....................... 54 Table 18: Summary of secondary efficacy outcomes – randomised subjects ................ 55 Table 19: Relative risks of stroke or SE with apixaban compared with warfarin, according to TTR subgroup ........................................................................................................... 58 Table 20: Summary of primary efficacy outcome – randomised subjects ....................... 60 Table 21: Summary of secondary efficacy outcomes – randomised subjects ................ 61 Table 22: Summary of the trials used to conduct the NMAs .......................................... 66 Table 23: NMA 1 and NMA 2 outcomes and additional data sources ............................ 70 Table 24: NMA 1 (warfarin suitable population) base case analysis .............................. 74 Table 25: NMA 2 (warfarin suitable and unsuitable population) base case analysis ...... 76 Table 26: Centre-TTR quartile sub-groups across the three trials in NMA1 ................... 77 Table 27: Bleeding outcomes and net clinical outcomes – treated patients ................... 82 Table 28: Relative risks of major bleeding with apixaban compared with warfarin, according to cTTR subgroup ......................................................................................... 85 Table 29: Summary of adverse events – treated subjects ............................................. 85 Table 30: Summary of hepatic safety – treated patients ................................................ 86 Table 31: Summary of bleeding outcomes – treated subjects ........................................ 87 Table 32: Summary of adverse events – treated subjects ............................................. 90 Apixaban – BMS and Pfizer 4 Table 33: Summary of serious adverse events (>2% in either treatment arm) – treated subjects ......................................................................................................................... 90 Table 34: Summary of liver function test abnormalities – treated subjects ..................... 91 Table 35: Baseline characteristics of the apixaban trials compared with a recent GPRD study of patients in UK clinical practice .......................................................................... 98 Table 36: Patient characteristics used in base case analysis ...................................... 104 Table 37: Health states ............................................................................................... 107 Table 38: Key features of analysis ............................................................................... 109 Table 39: Intervention and comparator ........................................................................ 110 Table 40: Stroke risk by CHADS for apixaban (per 100 PY) ....................................... 112 2 Table 41: Clinical event hazard ratios (versus apixaban) ............................................. 112 Table 42: Distribution of stroke severity ....................................................................... 114 Table 43: Risk adjustment factor (per decade) ............................................................ 114 Table 44: Baseline risks for non-stroke events (per 100PY) ........................................ 115 Table 45: Distribution of ICH type ................................................................................ 115 Table 46: Distribution of haemorrhagic stroke severity ................................................ 117 Table 47: Distribution of other major bleeds ................................................................ 117 Table 48: Bleeding fatality rates (VKA suitable and unsuitable populations) ................ 118 Table 49: Anticoagulant treatment choice post event .................................................. 118 Table 50: Absolute event risk in 2nd line therapy options (per 100 PY) ......................... 120 Table 51: Distribution of stroke severity in 2nd line therapy options .............................. 120 Table 52: Absolute risk of trial based other cause mortality ......................................... 121 Table 53: Trial based other cause mortality hazard ratio versus apixaban ................... 121 Table 54: Gompertz regression parameters for background mortality ......................... 122 Table 55: Additional mortality risk adjustment hazard ratios ........................................ 122 Table 56: Risks of Stroke, ICH, CRNM, and Other Major Bleed by cTTR Ranges ....... 123 Table 57: Hazard ratios for ischaemic stroke, ICH, Other major bleed and CRNM bleed by cTTR group ............................................................................................................ 125 Table 58: Baseline risks (per 100 PY) ......................................................................... 125 Table 59: Risk of Stroke (Excluding Hemorrhagic Strokes) by CHADS Score (Rate per 2 100 Person Years) ...................................................................................................... 126 Table 60: Assumptions used in the model ................................................................... 127 Table 61: Summary of quality of life values for cost-effectiveness analysis ................. 130 Table 62: Intervention costs ........................................................................................ 133 Table 63: Stroke acute costs (per episode) ................................................................. 134 Table 64: Stroke event long-term costs (per month) .................................................... 135 Table 65: Costs of SE ................................................................................................. 135 Table 66: MI acute costs ............................................................................................. 135 Table 67: Additional MI costs ...................................................................................... 136 Apixaban – BMS and Pfizer 5 Table 68: Long-term costs of pharmaco-management of MI ........................................ 136 Table 69: Cost per other ICH event ............................................................................. 137 Table 70: Cost of GI bleeds ......................................................................................... 137 Table 71: Cost of non-ICH and non-GI related major bleeds ....................................... 138 Table 72: Cost of CRNM bleeds .................................................................................. 138 Table 73: Cost of Other CV hospitalisation .................................................................. 138 Table 74: Pharmacological therapies in management of dyspepsia ............................ 139 Table 75: Summary of costs ........................................................................................ 140 Table 76: Deterministic scenario analysis .................................................................... 141 Table 77: Model results compared with clinical data in VKA suitable population .......... 144 Table 78: Model results compared with clinical data in VKA unsuitable population ...... 145 Table 79: Base-case results – VKA suitable population ............................................... 146 Table 80: Base-case results – VKA unsuitable population ........................................... 146 Table 81: Probability of cost-effectiveness at different WTP thresholds in VKA suitable population ................................................................................................................... 157 Table 82: Probability of cost-effectiveness at different WTP thresholds in VKA unsuitable population ................................................................................................................... 158 Table 83: Results of scenario analysis ........................................................................ 161 Table 84: cTTR subgroups considered by the analysis ............................................... 165 Table 85: cTTR < 52.38% – VKA suitable population .................................................. 166 Table 86: 52.38% ≤ cTTR < 66.02% – VKA suitable population .................................. 167 Table 87: 66.02% ≤ cTTR < 76.51% – VKA suitable population .................................. 167 Table 88: cTTR ≥ 76.51% – VKA suitable population .................................................. 167 Table 89: CHADS score of 1 – VKA suitable population ............................................. 168 2 Table 90: CHADS score of 1 – VKA unsuitable population ......................................... 169 2 Table 91: CHADS score of 2 – VKA suitable population ............................................. 169 2 Table 92: CHADS score of 2 – VKA unsuitable population ......................................... 169 2 Table 93: CHADS score of 3-6 – VKA suitable population ......................................... 170 2 Table 94: CHADS score of 3-6 – VKA unsuitable population ...................................... 170 2 Table 95: Estimation of patients eligible for treatment ................................................. 175 Table 96: Market share with and without apixaban ...................................................... 176 Table 97: Annual event costs per patient by treatment ................................................ 176 Table 98: Acute event and adverse event costs with and without apixaban ................. 177 Table 99: Annual follow-up and management costs per patient by treatment .............. 177 Table 100: Follow-up and management costs with and without apixaban .................... 178 Table 101: Costs of INR monitoring with and without apixaban ................................... 179 Table 102: Unit costs assumed in budget impact calculations ..................................... 179 Table 103: Treatment costs with and without apixaban ............................................... 179 Apixaban – BMS and Pfizer 6 Table 104: Budget impact ............................................................................................ 180 Table 105: Quality assessment of ARISTOTLE ........................................................... 207 Table 106: Quality assessment of AVERROES ........................................................... 208 Table 107: Summary of identified cost-effectiveness studies and conference abstracts .................................................................................................................................... 223 Table 108: Summary of relevant cost-utility studies ..................................................... 230 Table 109: Studies reporting utility values for health states used in the economic model .................................................................................................................................... 241 Table 110: Data used in the base case NMAs ............................................................. 248 Table 111: Trial data used in NMA sensitivity analyses (RE-LY 2010, ROCKET on- treatment and AVERROES ITT data) .......................................................................... 251 Table 112: NMA 1 sensitivity analysis 1 (RELY 2010 and ROCKET ITT data) ............ 253 Table 113: NMA 1 sensitivity analysis 2 (RELY 2009 and ROCKET OT data) ............. 254 Table 114: NMA 2 sensitivity analysis 1 (RELY 2010 and ROCKET ITT data) ............ 255 Table 115: NMA 2 sensitivity analysis 2 (RELY 2009 and ROCKET OT data) ............. 255 Table 116: NMA 1 base case results: rivaroxaban versus comparators ....................... 257 Table 117: NMA 1 base case results: dabigatran 150 mg versus comparators ............ 257 Table 118: NMA 1 base case results: dabigatran 110 mg versus comparators ............ 258 Table 119: NMA 2 base case results: rivaroxaban versus comparators ....................... 259 Table 120: NMA 2 base case results: dabigatran 150 mg versus comparators ............ 260 Table 121: NMA 2 base case results: dabigatran 110 mg versus comparators ............ 261 Table 122: Data used in the analysis of stroke/SE and major bleed for subgroups based on CHADS score ........................................................................................................ 264 2 Table 123: Data used in the analysis of stroke/SE and major bleed for subgroups based on TTR ........................................................................................................................ 265 Table 124: NMA 1 (warfarin suitable population) subgroup analyses based on CHADS 2 score and TTR ............................................................................................................ 266 Table 125: NMA 2 (warfarin unsuitable population) subgroup analyses based on CHADS score and TTR .............................................................................................. 267 2 Table 126: Summary of bleeding outcomes – randomised subjects ............................ 269 Table 127: Summary of serious adverse events (>2% in either treatment arm) – randomised subjects ................................................................................................... 272 Table 128: Summary of liver function test abnormalities – randomised subjects ......... 272 Table 129: Predicted curves and fits with each distribution .......................................... 275 Table 130: One-way sensitivity analysis variables ....................................................... 278 Table 131: PSA variables ............................................................................................ 291 Table 132: Markov trace, apixaban, VKA suitable ....................................................... 306 Table 133: Markov trace, warfarin, VKA suitable ......................................................... 306 Table 134: Markov trace, dabigatran 110mg & 150mg, VKA suitable .......................... 307 Table 135: Markov trace, dabigatran 110mg, VKA suitable ......................................... 307 Apixaban – BMS and Pfizer 7 Table 136: Markov trace, rivaroxaban, VKA suitable ................................................... 308 Table 137: Markov trace, apixaban, VKA unsuitable ................................................... 308 Table 138: Markov trace, aspirin, VKA unsuitable ....................................................... 308 Table 139: Markov trace, dabigatran 110mg & 150mg, VKA unsuitable ...................... 309 Table 140: Markov trace, dabigatran 110mg, VKA unsuitable ..................................... 309 Table 141: Markov trace, rivaroxaban, VKA unsuitable ............................................... 310 Table 142: Markov trace, apixaban, VKA suitable discounted QALYs ......................... 311 Table 143: Markov trace, warfarin, VKA suitable discounted QALYs ........................... 311 Table 144: Markov trace, dabigatran 110mg & 150mg, VKA suitable discounted QALYs .................................................................................................................................... 312 Table 145: Markov trace, dabigatran 110 mg, VKA suitable discounted QALYs .......... 313 Table 146: Markov trace, rivaroxaban, VKA suitable discounted QALYs ..................... 313 Table 147: Markov trace, apixaban, VKA unsuitable discounted QALYs ..................... 314 Table 148: Markov trace, aspirin, VKA unsuitable discounted QALYs ......................... 315 Table 149: Markov trace, dabigatran 110 mg & 150 mg, VKA unsuitable discounted QALYs ......................................................................................................................... 315 Table 150: Markov trace, dabigatran 110 mg, VKA unsuitable discounted QALYs ...... 316 Table 151: Markov trace, rivaroxaban, VKA unsuitable discounted QALYs ................. 317 Table 152: Summary of QALY gain by health state in VKA suitable population ........... 318 Table 153: Summary of QALY gain by health state in VKA unsuitable population ....... 319 Table 154: Number of Events (Total Population) VKA suitable population ................... 320 Table 155: Number of Events (Total Population) VKA unsuitable population ............... 322 Table 156: Summary of costs by health state for VKA suitable population .................. 326 Table 157: Summary of costs by health state for VKA unsuitable population............... 328 Table 158: Output from tornado diagrams in VKa suitable population, variables ranked by size of effect on ICER ............................................................................................. 330 Table 159: Output from tornado diagrams in VKA unsuitable population, variables ranked by size of effect on ICER ............................................................................................. 342 Apixaban – BMS and Pfizer 8 List of Figures Figure 1: Stroke risk stratification algorithm ................................................................... 22 Figure 2: Treatment with warfarin or aspirin in different age groups .............................. 26 Figure 3: Participant flow – ARISTOTLE ....................................................................... 51 Figure 4: Participant flow – AVERROES ....................................................................... 51 Figure 5: Kaplan-Meier curve for stroke or SE – randomised subjects........................... 54 Figure 6: Relative risks of stroke and systemic embolism according to major pre- specified subgroups ...................................................................................................... 57 Figure 7: Cumulative hazard rates for stroke or SE according to treatment group ......... 60 Figure 8: Relative risks of stroke or SE with apixaban compared with aspirin, according to subgroup ................................................................................................................... 62 Figure 9: Network diagram for warfarin-suitable population (NMA 1) ............................. 68 Figure 10: Network diagram for patients unsuitable for warfarin (NMA 2) ...................... 69 Figure 11: Kaplan-Meier curve for major bleeding – treated subjects ............................ 82 Figure 12: Relative risks of major bleeding according to major pre-specified subgroups 84 Figure 13: Cumulative hazard rates for major bleeding, according to treatment group – treated subjects ............................................................................................................. 88 Figure 14: Subgroup analyses for major bleeding – treated subjects ............................. 89 Figure 15: Markov state diagram – NVAF .................................................................... 105 Figure 16: Markov state diagram – NVAF without original anticoagulant ..................... 106 Figure 17: Tornado diagram demonstrating the effect on the ICER for apixaban vs. warfarin of varying parameter inputs in the VKA suitable population ........................... 148 Figure 18: Tornado diagram demonstrating effect on ICER vs aspirin of varying parameter inputs in VKA unsuitable population ........................................................... 149 Figure 19: Tornado diagram demonstrating effect on ICER vs dabigatran (110mg & 150mg) of varying parameter inputs in VKA suitable population .................................. 150 Figure 20: Tornado diagram demonstrating effect on ICER vs dabigatran (110mg) of varying parameter inputs in VKA suitable population ................................................... 150 Figure 21: Tornado diagram demonstrating effect on ICER vs rivaroxaban of varying parameter inputs in VKA suitable population ............................................................... 151 Figure 22: Tornado diagram demonstrating effect on ICER vs dabigatran (110mg & 150mg) of varying parameter inputs in VKA unsuitable population .............................. 151 Figure 23: Tornado diagram demonstrating effect on ICER vs dabigatran (110mg) of varying parameter inputs in VKA unsuitable population ............................................... 152 Figure 24: Tornado diagram demonstrating effect on ICER vs rivaroxaban of varying parameter inputs in VKA unsuitable population ........................................................... 152 Figure 25: Scatter plot results of PSA in VKA suitable population, apixaban vs warfarin .................................................................................................................................... 153 Figure 26: Scatter plot results of PSA in VKA suitable population, apixaban vs rivaroxaban ................................................................................................................. 153 Apixaban – BMS and Pfizer 9 Figure 27: Scatter plot results of PSA in VKA suitable population, apixaban vs dabigatran 150mg/110mg ............................................................................................................. 154 Figure 28: Scatter plot results of PSA in VKA suitable population, apixaban vs dabigatran 110mg ......................................................................................................................... 154 Figure 29: Scatter plot results of PSA in VKA unsuitable population, apixaban vs aspirin .................................................................................................................................... 155 Figure 30: Scatter plot results of PSA in VKA unsuitable population, apixaban vs rivaroxaban ................................................................................................................. 155 Figure 31: Scatter plot results of PSA in VKA unsuitable population, apixaban vs dabigatran 150mg/110mg............................................................................................ 156 Figure 32: Scatter plot results of PSA in VKA unsuitable population, apixaban vs dabigatran 110mg ....................................................................................................... 156 Figure 33: Cost-effectiveness acceptability curves in VKA suitable population ............ 157 Figure 34: Cost-effectiveness acceptability curves in VKA unsuitable population ........ 158 Figure 35: Schematic for the systematic review of clinical evidence ............................ 206 Figure 36: Schematic for the systematic review of non-RCT evidence for apixaban .... 216 Figure 37: Schematic for the systematic review of cost-effectiveness evidence .......... 222 Figure 38: Schematic for the systematic review of HRQL evidence ............................. 238 Figure 39: Cumulative hazard rates for major bleeding, according to treatment group – randomised subjects ................................................................................................... 270 Figure 40: Relative risks of major bleeding with apixaban compared with aspirin, according to subgroup ................................................................................................. 271 Figure 41: Males Observed and Predicted Distributions .............................................. 276 Figure 42: Females Observed and Predicted Distributions .......................................... 277 Apixaban – BMS and Pfizer 10