Background
Methods
Model structure
State name
|
Description
|
---|---|
On Tx | Patients who have just experienced an acute VTE, and are receiving one of the acute treatments being evaluated (either 3, 6 or 12 months or lifetime treatment with rivaroxaban or dual LMWH/VKA therapy) |
rVTE – DVT | Patients who have just experienced a recurrent DVT. Assigned therapy was discontinued and all patients assumed to receive 6 months of dual LMWH/VKA. The duration of utility impact was assumed to be 1 month in the base case. DVT events were not associated with excess mortality |
rVTE – PE | Patients who have just experienced a recurrent PE (± DVT). Patients with coincident DVT transit to a post-DVT state to capture PTS risk. Assigned therapy was discontinued and all patients assumed to receive 6 months of dual LMWH/VKA. The duration of utility impact was assumed to be 1 month in the base case. PE events were associated with excess mortality |
Major bleed – IC | Patients on assigned therapy who have just experienced an IC bleeding event. Therapy was temporarily withheld during the cycle in which the IC bleeding event took place. IC bleeding events were associated with excess mortality |
Major bleed – EC | Patients on assigned therapy who have just experienced a major EC bleeding event (e.g. gastrointestinal bleeding). Therapy was temporarily withheld for 1 month during the cycle in which the bleeding event took place. The duration of utility impact was assumed to be 1 month in the base case |
NMCR bleed | Patients on assigned therapy who have just experienced a NMCR bleeding event. Defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of a study drug, or discomfort or impairment of activities of daily life. Therapy was temporarily withheld for 1 month during the cycle in which the bleeding event took place. An example of this would be spontaneous bleeding from gums which requires acute medical intervention. NMCR bleeding was assumed not to impact on utility |
Post-IC bleed | Patients who previously experienced an IC bleeding event. Any assigned therapy is assumed to stop. IC bleeding events are associated with major risks of residual disability stemming from their impact on the central nervous system. The health-related quality of life and costs associated with this are included |
Off Tx-post index PE* | Patients currently off treatment after index PE. These patients are not at ongoing risk of PTS |
Off Tx-post DVT | Patients who have experienced an incident DVT within the time frame of the model and who are currently off treatment. These patients are at risk of PTS |
On Tx-post DVT | This state is only applicable to analyses of lifelong treatment duration. Patients who have experienced an incident DVT within the time frame of the model and who are currently on treatment. These patients are at risk of PTS |
PE post DVT* | Patients with recurrent PE and a history of DVT within the model. Survivors return to relevant post-DVT states so as to continue exposure to a risk of PTS conferred by their DVT history |
CTEPH | Patients diagnosed with CTEPH who are exposed to management costs, health-related quality of life loss and excess mortality |
Long-term CTEPH | State to which patients with CTEPH transition in the long term |
Death | Terminal state. Patients could die because of either events captured in the model, such as PE or IC bleed, or from other causes |
Patient population and treatment
Model input data
Clinical parameters and variables
Probability, mean (SE)
|
EINSTEIN DVT
|
EINSTEIN PE
|
---|---|---|
Recurrent VTE (LMWH/VKA)
| ||
3-month population
| ||
0–3 months | 0.015 (0.008) | 0.016 (0.011) |
6-month population
| ||
0–3 months | 0.024 (0.005) | 0.016 (0.003) |
3–6 months | 0.003 (0.002) | 0.002 (0.001) |
12-month population
| ||
0–3 months | 0.035 (0.009) | 0.015 (0.004) |
3–6 months | 0.008 (0.004) | 0.003 (0.002) |
6–12 months | 0.003 (0.003) | 0.001 (0.001) |
Lifelong population [61] | ||
>12 months | 0.700 (0.107) | 0.700 (0.107) |
Major bleeding (LMWH/VKA)
| ||
3-month population
| ||
0–3 months | 0.020 (0.010) | 0.041 (0.018) |
6-month population
| ||
0–3 months | 0.009 (0.003) | 0.010 (0.003) |
3–6 months | 0.004 (0.002) | 0.008 (0.003) |
12-month population
| ||
0–3 months | 0.002 (0.002) | 0.013 (0.004) |
3–6 months | – (0.002) | 0.004 (0.002) |
6–12 months | – (0.002) | 0.006 (0.003) |
Lifelong population [61] | ||
>12 months | 1.600 (0.245) | 1.600 (0.245) |
NMCR bleeding (LMWH/VKA)
| ||
3-month population
| ||
0–3 months | 0.060 (0.017) | 0.066 (0.022) |
6-month population
| ||
0–3 months | 0.047 (0.006) | 0.067 (0.007) |
3–6 months | 0.013 (0.004) | 0.022 (0.004) |
12-month population
| ||
0–3 months | 0.049 (0.01) | 0.062 (0.008) |
3–6 months | 0.024 (0.008) | 0.029 (0.006) |
6–12 months | 0.038 (0.01) | 0.030 (0.006) |
Lifelong population
| ||
>12 months | 0.014 (0.002) | 0.022 (0.002) |
Probability, mean (SE)
|
DVT patients
|
PE patients
|
Source
|
---|---|---|---|
Event/outcome
| |||
Incidence of recurrent VTE (HR) | 0.68 (0.218) | 1.123 (0.207) | * |
Incidence of major bleeding (HR) | 0.646 (0.242) | 0.493 (0.24) | * |
Incidence of NMCR bleeding (RR) | 1.055 (0.123) | 1.001 (0.088) | * |
Probability that a recurrent VTE is a DVT | 0.483 (0.054) | 0.372 (0.050) | * |
Probability that a major bleeding event is a (major) IC bleed | 0.125 (0.058) | 0.143 (0.076) | * |
Discontinuation
| |||
Patients with IC bleeding events | 1.00 (0.0) | 1.00 (0.0) | * |
Patients with major EC bleeding events | 0.400 (0.089) | 0.164 (0.045) | * |
Patients with NMCR bleeding events | 0.110 (0.020) | 0.054 (0.010) | * |
For any other reason (additional) 3–12 months | 0.019 (0.001) | 0.021 (0.001) | * |
For any other reason (additional) >12 months | 0.036 (0.013) | 0.036 (0.013) | Boggon 2011 [62] |
DVT and PE patients
| |||
Risks of subsequent morbidities
| |||
Recurrent VTE (per 3-month time step) | 0.013 (0.074) | Prandoni 2007 [41] | |
Progression to CTEPH after a PE | 0.013 (0.002) | Miniati 2006 [38] | |
Cumulative incidence of severe PTS (to 1 year) | 0.027 (0.007) | Prandoni 1997 [40] | |
Cumulative incidence of severe PTS (to 5 years) | 0.081 (0.012) | Prandoni 1997 [40] | |
Mortality associated with another model event
| |||
PE (during acute treatment phase) | 0.250 (0.041) | * | |
PE (after acute treatment phase) | 0.331 (0.041) | Prandoni 1997 [40] | |
Major IC bleeding | 0.436 (0.036) | Linkins 2010 [42] | |
Major EC bleeding | 0.039 (0.007) | * | |
CTEPH (per 3-month cycle) | 0.025 (0.020) | Condliffe 2008 [43] |
Utility values
Model state
|
Mean
|
Sensitivity analyses
|
Source
| |
---|---|---|---|---|
Lower
|
Upper
| |||
Population norm | 0.825 | 0.819 | 0.831 | Kind 1998 [48] |
Post-IC bleeding | 0.71 | 0.70 | 0.72 | Rivero-Arias 2010 [44] |
CTEPH | 0.56 | 0.53 | 0.59 | Meads 2008 [45] |
Adjustments to utility norm due to modelled events
| ||||
DVT | 0.84 | 0.64 | 0.98 | Locadia 2004 [46] |
PE | 0.63 | 0.36 | 0.86 | Locadia 2004 [46] |
EC bleeding (gastrointestinal bleeding was the disease state valued) | 0.65 | 0.49 | 0.86 | Locadia 2004 [46] |
IC bleeding (haemorrhagic stroke was the disease state valued) | 0.33 | 0.14 | 0.53 | Locadia 2004 [46] |
PTS (serious PTS was the disease state valued) | 0.93 | 0.91 | 1.00 | Lenert 1997 [47] |
Cost and resource input data
EINSTEIN DVT
|
EINSTEIN PE
| |||||
---|---|---|---|---|---|---|
Rivaroxaban
|
Dual LMWH/VKA therapy
|
Incremental
|
Rivaroxaban
|
Dual LMWH/VKA therapy
|
Incremental
| |
Patients appropriate for 3 months of anticoagulation
| ||||||
Drug acquisition cost (£) | 220 | 98 | 122 | 217 | 99 | 118 |
Other costs (£) | 1592 | 1964 | −372 | 4295 | 4808 | −513 |
Total costs (£) | 1812 | 2063 | −251 | 4511 | 4907 | −396 |
QALYs | 13.286 | 13.264 | 0.022 | 11.940 | 11.912 | 0.027 |
ICER (£) | Rivaroxaban dominates | Rivaroxaban dominates | ||||
Patients appropriate for 6 months of anticoagulation
| ||||||
Drug acquisition cost (£) | 398 | 104 | 295 | 393 | 105 | 288 |
Other costs (£) | 1561 | 2040 | −479 | 4153 | 4654 | −501 |
Total costs (£) | 1959 | 2143 | −184 | 4546 | 4759 | −213 |
QALYs | 13.294 | 13.268 | 0.026 | 11.992 | 11.979 | 0.013 |
ICER (£) | Rivaroxaban dominates | Rivaroxaban dominates | ||||
Patients appropriate for 12 months of anticoagulation
| ||||||
Drug acquisition cost (£) | 731 | 114 | 617 | 728 | 115 | 613 |
Other costs (£) | 1512 | 2186 | −673 | 4154 | 4900 | −746 |
Total costs (£) | 2243 | 2299 | −56 | 4881 | 5015 | −133 |
QALYs | 13.308 | 13.274 | 0.034 | 12.035 | 12.015 | 0.020 |
ICER (£) | Rivaroxaban dominates | Rivaroxaban dominates | ||||
Patients appropriate for lifelong anticoagulation
| ||||||
Drug acquisition cost (£) | 6566 | 288 | 6278 | 6025 | 284 | 5740 |
Other costs (£) | 2084 | 6835 | −4751 | 4532 | 9209 | −4677 |
Total costs (£) | 8649 | 7122 | 1527 | 10,557 | 9493 | 1064 |
QALYs | 13.507 | 13.331 | 0.176 | 12.526 | 12.375 | 0.150 |
ICER (£) | 8677 | 7072 |
Resource item
|
Mean
|
Sensitivity analyses
|
Rationale
| ||
---|---|---|---|---|---|
Lower
|
Upper
|
Distribution
| |||
Acute treatment
| |||||
Number of days of acute treatment (i.e. LMWH) required by a DVT patient | 9.6 | 6 | 10 | Dirichlet | EINSTEIN DVT [25] |
SIGN guidelines [15] | |||||
Number of days of acute treatment (i.e. LMWH) required by a PE patient | 9.7 | 7 | 13 | Dirichlet | Mean duration from EINSTEIN PE [26] |
Proportion of patients who self-inject LMWH (%) | 92 | 64.40 | 100 | Beta | The point estimate is taken from the assumptions in NICE CG92 [56]. The sensitivity range is an assumption |
Proportion of remaining patients who require nurse assistance at home (%) | 80 | 60 | 100% | Beta | These values are assumptions based on inputs determined for the NICE CG92 model |
INR monitoring while on LMWH/VKA
| |||||
Visits in first 3 months | 9 | 5 | 15 | Gamma | |
Visits each 3 months thereafter | 5 | 2.5 | 10 | Gamma | |
Recurrent VTE: proportion treated as outpatients rather than inpatients
| |||||
Recurrent DVT patients (%) | 69 | 50 | 100 | Beta | SIGN guidelines [15] |
Incident PE patients (%) | 17 | 0 | 30 | Beta | Survey data |
Other
| |||||
Proportion of patients requiring NHS-funded transportation (%) | 8.55 | 6 | 11 | Beta | Survey data |
Proportion of CTEPH patients who require PEA (%) | 68.40 | 64.20 | 72.60 | Beta | 321 of 469 patients from Condliffe 2008 [43] |
Length of admission post DVT, days | van Bellen 2014 [52] | ||||
LMWH/VKA | 8* | 4 | 10 | ||
Rivaroxaban | 5* | 3 | 9 | ||
Length of admission post PE, days | van Bellen 2014 [52] | ||||
LMWH/VKA | 7* | 5 | 10 | ||
Rivaroxaban | 6* | 4 | 9 |