Supplementary Data

Electronic supplementary material to Kongnakorn T., Lanitis T., Annemans L., Thijs V., Goethals M., Marbaix S., Wautrecht J. “Stroke Prevention in Patients with Atrial Fibrillation in Belgium: Comparative cost-effectiveness of new oral anticoagulants and warfarin—Technical Model Documentation ”

objective

The objective of this appendix is to provide additional technical documentation surrounding the uncertainty analysis conducted in the manuscript entitled “Stroke Prevention in Patients with Atrial Fibrillation in Belgium: Comparative cost-effectiveness of new oral anticoagulants and warfarin”.

1.1  Inputs for univariate Sensitivity Analysis

Table 1 presents the range and source of variation for the univariate sensitivity analysis. In addition to parameter uncertainty the univariate analysis evaluated changes in discount rates for costs and health outcomes, assumptions around treatment discontinuation rates and the anticoagulant dependence of stroke and bleed severity. Results from the sensitivity analysis not presented in the manuscript are available in section 2 of this appendix.

Table 1 Range of Variation for Univariate Sensitivity Analysis

Description / Base Case Value / Lower Value / Upper Value / Source of Variation /
Gender (% Male) / 0.65 / 0.63 / 0.66 / Patient numbers –Beta distribution
Mean age for males / 70.00 / 63.00 / 77.00 / 95% CI intervals from source
Mean age for females / 70.00 / 63.00 / 77.00 / 95% CI intervals from source
Risk of ischemic and unspecified stroke for apixaban (Rate/100 PYs) / 0.98 / 0.30 / 0.81 / Assumed 25% SE of the mean –Gamma Distribution
Risk of ischemic and unspecified stroke for warfarin (Rate/100 PYs) / 1.08 / 0.43 / 0.68 / 95% CI on HR from source multiplied by apixaban base case rate
Stroke Hazard ratio versus apixaban for dabigatran 110mg / 1.17 / 0.85 / 1.62 / 95% CI intervals from source
Stroke Hazard ratio versus apixaban for dabigatran 150mg / 0.79 / 0.55 / 1.10 / 95% CI intervals from source
Stroke Hazard ratio versus apixaban for rivaroxaban / 1.02 / 0.76 / 1.37 / 95% CI intervals from source
Risk adjustment factor for stroke per decade / 1.46 / 0.80 / 2.16 / 95% CI intervals from source
Risk of intracranial hemorrhage for apixaban (Rate/100 PYs) / 0.33 / 0.19 / 0.51 / Assumed 25% SE of the mean –Gamma Distribution
Risk of intracranial hemorrhage for Warfarin (Rate/100 PYs) / 0.80 / 0.36 / 1.97 / 95% CI on HR from source multiplied by apixaban base case rate
Intracranial hemorrhage hazard ratio versus apixaban for dabigatran 110mg / 0.73 / 0.42 / 1.24 / 95% CI intervals from source
Intracranial hemorrhage hazard ratio versus apixaban for dabigatran 150mg / 1.02 / 0.61 / 1.68 / 95% CI intervals from source
Intracranial hemorrhage hazard ratio versus apixaban for rivaroxaban / 1.73 / 1.08 / 2.79 / 95% CI intervals from source
Risk adjustment factor for intracranial hemorrhage per decade / 1.97 / 1.79 / 2.16 / 95% CI intervals from source
Risk of clinically relevant non major bleeds for apixaban (Rate/100PYs) / 2.08 / 1.19 / 3.22 / Assumed 25% SE of the mean –Gamma Distribution
Risk of clinically relevant non major bleeds for warfarin (Rate/100PYs) / 3.00 / 2.62 / 3.56 / 95% CI on HR from source multiplied by apixaban base case rate
Clinically relevant non major bleeds hazard ratio versus apixaban for dabigatran 110mg / 1.00 / 0.90 / 1.10 / 95% CI intervals from source
Clinically relevant non major bleeds hazard ratio versus apixaban for dabigatran 150mg / 1.00 / 0.90 / 1.10 / 95% CI intervals from source
Clinically relevant non major bleeds hazard ratio versus apixaban for rivaroxaban / 1.52 / 1.28 / 1.80 / 95% CI intervals from source
Risk adjustment factor for clinically relevant non major bleeds per decade / 1.97 / 1.79 / 2.16 / 95% CI intervals from source
Risk of other major bleeds for apixaban (Rate/100PYs) / 1.79 / 1.02 / 2.77 / Assumed 25% SE of the mean –Gamma Distribution
Risk of other major bleeds for warfarin (Rate/100PYs) / 2.27 / 1.30 / 3.51 / 95% CI on HR from source multiplied by apixaban base case rate
Other major bleeds hazard ratio versus apixaban for dabigatran 110mg / 1.21 / 0.96 / 1.51 / 95% CI intervals from source
Other major bleeds hazard ratio versus apixaban for dabigatran 150mg / 1.38 / 1.10 / 1.73 / 95% CI intervals from source
Other major bleeds hazard ratio versus apixaban for rivaroxaban / 1.43 / 1.15 / 1.79 / 95% CI intervals from source
Risk adjustment factor for other major bleeds per decade / 1.97 / 1.79 / 2.16 / 95% CI intervals from source
Risk of myocardial infarction for apixaban (Rate/100PYs) / 0.53 / 0.30 / 0.82 / Assumed 25% SE of the mean –Gamma Distribution
Risk of myocardial infarction for Warfarin (Rate/100PYs) / 0.61 / 0.46 / 0.81 / 95% CI on HR from source multiplied by apixaban base case rate
Myocardial infarction hazard ratio versus apixaban for dabigatran 110mg / 1.46 / 0.97 / 2.23 / 95% CI intervals from source
Myocardial infarction hazard ratio versus apixaban for dabigatran 150mg / 1.45 / 0.96 / 2.18 / 95% CI intervals from source
Myocardial infarction hazard ratio versus apixaban for rivaroxaban / 0.93 / 0.63 / 1.38 / 95% CI intervals from source
Risk of cardiovascular hospitalization for apixaban (Rate/100 PYs) / 10.46 / 5.98 / 16.17 / Assumed 25% SE of the mean –Gamma Distribution
Risk of cardiovascular hospitalization for warfarin (Rate/100 PYs) / 10.46 / 5.98 / 16.17 / Assumed 25% SE of the mean –Gamma Distribution
Cardiovascular hospitalization hazard ratio versus apixaban for dabigatran 110mg / 1.00 / 0.90 / 1.10 / Assumption
Cardiovascular hospitalization hazard ratio versus apixaban for dabigatran 150mg / 1.00 / 0.90 / 1.10 / Assumption
Cardiovascular hospitalization hazard ratio versus apixaban for rivaroxaban / 1.00 / 0.90 / 1.10 / Assumption
Risk of other treatment discontinuations for apixaban (Rate/100 PYs) / 13.18 / 7.53 / 20.38 / Assumed 25% SE of the mean –Gamma Distribution
Risk of other treatment discontinuations for warfarin (Rate/100 PYs) / 14.41 / 8.23 / 22.27 / 95% CI on HR from source multiplied by apixaban base case rate
Other treatment discontinuation hazard ratio versus apixaban for dabigatran 110mg / 1.45 / 1.31 / 1.61 / 95% CI intervals from source
Other treatment discontinuation hazard ratio versus apixaban for dabigatran 150mg / 1.51 / 1.36 / 1.67 / 95% CI intervals from source
Other treatment discontinuation hazard ratio versus apixaban for rivaroxaban / 1.18 / 1.08 / 1.29 / 95% CI intervals from source
Risk of ischemic and unspecified strokes for aspirin 2nd line (Rate/100 PYs) / 3.45 / 1.97 / 5.34 / Assumed 25% SE of the mean –Gamma Distribution
Risk of intracranial haemorrhage for aspirin 2nd line (Rate/100 PYs) / 0.32 / 0.18 / 0.50 / Assumed 25% SE of the mean –Gamma Distribution
Risk of other major bleeds for aspirin 2nd line (Rate/100 PYs) / 0.89 / 0.51 / 1.37 / Assumed 25% SE of the mean –Gamma Distribution
Risk of CRNMB for aspirin 2nd line (Rate/100 PYs) / 2.94 / 1.68 / 4.54 / Assumed 25% SE of the mean –Gamma Distribution
Risk of MI for aspirin 2nd line (Rate/100 PYs) / 1.11 / 0.63 / 1.72 / Assumed 25% SE of the mean –Gamma Distribution
Risk of cardiovascular hospitalization for aspirin 2nd line (Rate/100 PYs) / 13.57 / 7.76 / 20.98 / Assumed 25% SE of the mean –Gamma Distribution
Utility atrial fibrillation / 0.73 / 0.71 / 0.75 / 95% CI intervals calculated from source
Utility ischemic stroke mild / 0.62 / 0.56 / 0.67 / 95% CI intervals calculated from source
Utility ischemic stroke moderate / 0.56 / 0.51 / 0.62 / 95% CI intervals calculated from source
Utility ischemic stroke severe / 0.51 / 0.46 / 0.57 / 95% CI intervals calculated from source
Utility hemorrhagic stroke mild / 0.62 / 0.56 / 0.67 / 95% CI intervals calculated from source
Utility hemorrhagic stroke moderate / 0.56 / 0.51 / 0.62 / 95% CI intervals calculated from source
Utility hemorrhagic stroke severe / 0.51 / 0.46 / 0.57 / 95% CI intervals calculated from source
Utility decrement: intracranial haemorrhage / 0.15 / 0.08 / 0.24 / 95% CI intervals calculated from source
Utility decrement: other major bleed / 0.15 / 0.08 / 0.24 / 95% CI intervals from source
Utility decrement: clinically relevant non-major bleed / 0.06 / 0.03 / 0.10 / 95% CI intervals from source
Utility decrement: myocardial infarction / 0.61 / 0.57 / 0.65 / 95% CI intervals from source
Utility decrement: Other cardiovascular hospitalization / 0.13 / 0.08 / 0.18 / 95% CI intervals from source
Utility decrement: warfarin / 0.01 / 0.00 / 0.08 / 95% CI intervals from source
Hazard Ratio for long-term mortality post ischemic & unspecified stroke mild / 3.18 / 1.42 / 4.94 / Assumed 25% SE of the mean –Gamma Distribution
Hazard Ratio for long-term mortality post ischemic & unspecified stroke moderate / 5.84 / 4.08 / 7.60 / Assumed 25% SE of the mean –Gamma Distribution
Hazard Ratio for long-term mortality post ischemic & unspecified stroke severe / 15.75 / 13.99 / 17.51 / Assumed 25% SE of the mean –Gamma Distribution
Hazard Ratio for long-term mortality post hemorrhagic stroke mild / 3.18 / 1.82 / 4.92 / Assumed 25% SE of the mean –Gamma Distribution
Hazard Ratio for long-term mortality post hemorrhagic stroke moderate / 5.84 / 3.34 / 9.03 / Assumed 25% SE of the mean –Gamma Distribution
Hazard Ratio for long-term mortality post hemorrhagic stroke severe / 15.75 / 9.00 / 24.35 / Assumed 25% SE of the mean –Gamma Distribution
Monitoring visit cost (annual) / 34.73 / 27.95 / 40.88 / 95% CI intervals from source
Routine care cost (annual) / 22.80 / 16.78 / 23.32 / 95% CI intervals from source
Acute care ischemic stroke costs mild / 3,731.81 / 977.23 / 7,200.96 / 95% CI intervals from source
Acute care ischemic stroke costs moderate / 6,430.73 / 1,621.61 / 17,703.55 / 95% CI intervals from source
Acute care ischemic stroke costs severe / 12,538.39 / 2,068.39 / 33,265.10 / 95% CI intervals from source
Acute care hemorrhagic stroke costs mild / 161.27 / 120.90 / 169.94 / 95% CI intervals from source
Acute care hemorrhagic stroke costs moderate / 268.84 / 220.61 / 310.09 / 95% CI intervals from source
Acute care hemorrhagic stroke costs severe / 517.70 / 425.56 / 598.17 / 95% CI intervals from source
Long-term follow-up ischemic stroke costs mild / 4,296.04 / 681.20 / 11,467.09 / 95% CI intervals from source
Long-term follow-up ischemic stroke costs moderate / 6,920.70 / 731.85 / 19,097.44 / 95% CI intervals from source
Long-term follow-up ischemic stroke costs severe / 10,689.56 / 1,020.17 / 30,162.73 / 95% CI intervals from source
Long-term follow-up hemorrhagic stroke costs mild / 161.27 / 120.90 / 169.94 / 95% CI intervals from source
Long-term follow-up hemorrhagic stroke costs moderate / 268.84 / 220.61 / 310.09 / 95% CI intervals from source
Long-term follow-up hemorrhagic stroke costs severe / 517.70 / 425.56 / 598.17 / 95% CI intervals from source
Other intracranial haemorrhage cost / 8,740.22 / 757.24 / 27,568.01 / 95% CI intervals calculated from source
Cost of other major bleeds / 2,273.51 / 2,055.16 / 2,352.45 / 95% CI intervals calculated from source
Clinically relevant non-major bleeds cost / 18.45 / 15.17 / 21.32 / 95% CI intervals calculated from source
Myocardial infarction Acute care cost / 4,814.07 / 733.35 / 12,281.37 / 95% CI intervals calculated from source
Myocardial infarction long-term follow-up cost / 202.00 / 115.46 / 312.35 / 95% CI intervals calculated from source
Cardiovascular hospitalization cost / 4,644.13 / 1,045.55 / 11,243.70 / 95% CI intervals calculated from source
Risk of recurrent ischemic stroke / 4.10 / 3.41 / 4.91 / 95% CI intervals calculated from source
Risk of recurrent hemorrhagic stroke / 3.00 / 2.02 / 4.46 / Assumed 25% SE of the mean –Gamma Distribution
Risk of systemic embolism for apixaban (Rate/100PYs) / 0.09 / 0.05 / 0.14 / Assumed 25% SE of the mean –Gamma Distribution
Risk of systemic embolism for Warfarin (Rate/100PYs) / 0.10 / 0.06 / 0.15 / 95% CI intervals from source
Systemic embolism hazard ratio versus apixaban for dabigatran 110mg / 0.79 / 0.29 / 2.07 / Assumption
Systemic embolism hazard ratio versus apixaban for dabigatran 150mg / 0.72 / 0.26 / 1.95 / Assumption
Systemic embolism hazard ratio versus apixaban for rivaroxaban / 0.84 / 0.34 / 2.07 / Assumption
Utility systemic embolism / 0.63 / 0.59 / 0.66 / 95% CI intervals calculated from source
Hazard Ratio for long-term mortality post systemic embolism / 1.34 / 1.20 / 3.18 / Assumption based on HR for AF
Hazard Ratio for long-term mortality post MI females / 4.16 / 3.44 / 5.03 / Upper bound based on highest RR observed in publication over 15 year period
Hazard Ratio for long-term mortality post MI males / 2.56 / 2.27 / 2.88 / Upper bound based on highest RR observed in publication over 15 year period
Hazard Ratio for long-term mortality post atrial fibrillation / 1.34 / 1.20 / 1.53 / Assumed upper and lower bound based on GPRD studies1, 2
Acute care systemic embolism costs / 6,267.40 / 1,594.37 / 12,281.37 / 95% CI intervals from source
Long-term follow-up systemic embolism costs / 0.00 / 0.00 / 169.90 / 95% CI intervals from source
Discount rates for health and outcomes / 3.0% for costs/ 1.5% for outcomes / 0% / 5% / Guideline recommendation
Treatment discontinuation rates / From ITC, clinical trias / Set to 0 after 1.9 years (trial period) / Set equal amongst all comparators after 1.9 years (trial period)
Risk of stroke (CHADS2) / Average CHADS2: 2.1 / CHADS2: 3-6
Stroke and bleed severity / Anticoagulant dependent / Anticoagulant independent
Long-term maintenance costs per month for stroke, and myocardial infarction / Annemans et al. 20033
Mild ischemic and hemorrhagic stroke: €161.27
Moderate ischemic and hemorrhagic stroke: €268.84
Severe ischemic and hemorrhagic stroke: €517.7
Myocardial infarction: €517.7 / Kleintjens et al. 2013:4
Mild ischemic and hemorrhagic stroke: €81
Moderate ischemic and hemorrhagic stroke: €81
Severe ischemic and hemorrhagic stroke: €739
Myocardial infarction: €0
Relative efficacy estimates / Network meta analysis5 / Simple pairwise indirect comparison6

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