A decision-analytic model (Fig. 1 ) was developed to estimate the cost-effectiveness of caspofungin (70 mg on day one and 50 mg once daily thereafter) vs. L-Amb (3 mg/kg per day for an average patient weighing 77 kg (based on data for UK patients).
Patients were differentiated according to the presence (branches P1–P6) or absence of baseline infection (branches P7–P12). A baseline infection was defined as the presence of a proven or probable infection on the first or second day of the antifungal treatment (11 (link)). Patients dying prior to 7 d on initial therapy were collapsed into two branches (P6 and P12), irrespective of premature discontinuation of therapy or clinical failure. This was conducted to reduce model complexity and since cause of death could not be ascertained. However, nephrotoxicity being a cost driver was estimated within patients that died. Therefore, our costing process took into consideration the incidence of nehprotoxicity amongst patients that died on initial therapy (P6 and P12). A patient that survived initial therapy (branches P1–P5 and P7–P11) could either continue their initial therapy (P1–P3 and P7–P9) or discontinue due to drug-related toxicity. Nephrotoxicity (P4 and P10) being a significant cost-driver was differentiated from other drug-related adverse events (P5 and P11).
A patient categorised as successful in branch P1 was defined as having complete resolution of baseline fungal infection, including resolution of their fever during the neutropenic period, no premature discontinuation of therapy due to drug-related toxicity, and survival for 7 d after completion of therapy. A patient categorised as successful in group P7 (those without a baseline infection) had resolution of fever during the neutropenic period and no breakthrough fungal infection (defined as absence of infection from day 3 onward) during therapy or within 7 d after the completion of therapy, no premature discontinuation of therapy due to drug-related toxicity, and survival for 7 d after completion of therapy. These definitions of success are in accordance with the five-component end point used in clinical trials on empirical antifungal treatments (6 (link), 8 (link), 9 (link), 12 (link), 13 (link)).
For pragmatic reasons, we assumed that a patient does not discontinue due to lack of efficacy, as most of these patients have been accounted for in other branches related to adverse clinical outcomes (P3, P6, P9, P12). An additional analysis of the trial by Walsh et al. (2004) supports this assumption (8 (link)). If a patient discontinued initial therapy due to toxicity, a switch to a second line antifungal drug took place (from caspofungin to L-Amb or vice versa). Mortality and costs of these second line antifungal drugs were also included in the model.
The following data were estimated to use within our model:
(1) Probability that the patient has a successful outcome, or dies on initial treatment. The conditional probabilities of efficacy, survival and discontinuation of initial therapy (Table 1 ) were based on additional analyses of the RCT which assessed the efficacy and safety of caspofungin compared with L-Amb in empirical therapy (8 (link)).
(2) Life years lost: the expected life years lost per treatment arm were calculated by multiplying the probability of death on first line treatment (P6/P12) and the mortality observed on second line treatment (P4–P5 and P10–P11) with the life expectancy based on the underlying condition of patients enrolled in the study.
The estimate for life years lost was based on the life expectancy of the underlying diagnoses. In the study by Walsh et al. (2004), 74% of the patients suffered from acute leukaemia, 11% from non-Hodgkin's lymphoma and 15% from other cancers. We used 1- and 5-yr UK survival data from 1998–2001 (National Statistics, Survival data England 1998–2001) to calculate life expectancy for each of these conditions (14 ). Survival probability for a patient with acute leukaemia was defined in the model according to figures reported within the acute myelogenous leukaemia (AML) trials of the Medical Research Council. Overall, this resulted in an average discounted life expectancy of 12.9 yr. For second line treatment, the probability of dying was assumed to be 24% (15–33%) based on the study by Maertens et al. (15 (link)) who evaluated patients with fungal infections who were intolerant or refractory to their first line antifungal agent.
(3) Quality adjusted life years (QALYs) lost: this was determined by multiplying life years lost in each treatment arm by the utility (or quality of life score) based on the underlying condition. QALY estimates were discounted at 3.5% per year according to UK requirements.
Each life year lost was valued with a weighted quality of life multiplier of 0.72 (0.50–0.94) in order to calculate the QALYs lost upon death. This utility value for the defined underlying conditions was based on the catalogue of preference scores 1997–2000 from the CEA Registry from the Harvard School of Public Health (http://www.hsph.harvard.edu ). QALYs saved were determined as the difference between QALYs lost with caspofungin and L-Amb.
(4) The cost evaluation included: expected antifungal drug costs (first line and second line), other direct costs (hospitalisation costs + drug costs related to adverse events) and overall costs. Costs were expressed in 2005 British Pounds (1 pound = 1.80 US dollar).
Patients were differentiated according to the presence (branches P1–P6) or absence of baseline infection (branches P7–P12). A baseline infection was defined as the presence of a proven or probable infection on the first or second day of the antifungal treatment (11 (link)). Patients dying prior to 7 d on initial therapy were collapsed into two branches (P6 and P12), irrespective of premature discontinuation of therapy or clinical failure. This was conducted to reduce model complexity and since cause of death could not be ascertained. However, nephrotoxicity being a cost driver was estimated within patients that died. Therefore, our costing process took into consideration the incidence of nehprotoxicity amongst patients that died on initial therapy (P6 and P12). A patient that survived initial therapy (branches P1–P5 and P7–P11) could either continue their initial therapy (P1–P3 and P7–P9) or discontinue due to drug-related toxicity. Nephrotoxicity (P4 and P10) being a significant cost-driver was differentiated from other drug-related adverse events (P5 and P11).
A patient categorised as successful in branch P1 was defined as having complete resolution of baseline fungal infection, including resolution of their fever during the neutropenic period, no premature discontinuation of therapy due to drug-related toxicity, and survival for 7 d after completion of therapy. A patient categorised as successful in group P7 (those without a baseline infection) had resolution of fever during the neutropenic period and no breakthrough fungal infection (defined as absence of infection from day 3 onward) during therapy or within 7 d after the completion of therapy, no premature discontinuation of therapy due to drug-related toxicity, and survival for 7 d after completion of therapy. These definitions of success are in accordance with the five-component end point used in clinical trials on empirical antifungal treatments (6 (link), 8 (link), 9 (link), 12 (link), 13 (link)).
For pragmatic reasons, we assumed that a patient does not discontinue due to lack of efficacy, as most of these patients have been accounted for in other branches related to adverse clinical outcomes (P3, P6, P9, P12). An additional analysis of the trial by Walsh et al. (2004) supports this assumption (8 (link)). If a patient discontinued initial therapy due to toxicity, a switch to a second line antifungal drug took place (from caspofungin to L-Amb or vice versa). Mortality and costs of these second line antifungal drugs were also included in the model.
The following data were estimated to use within our model:
(1) Probability that the patient has a successful outcome, or dies on initial treatment. The conditional probabilities of efficacy, survival and discontinuation of initial therapy (
(2) Life years lost: the expected life years lost per treatment arm were calculated by multiplying the probability of death on first line treatment (P6/P12) and the mortality observed on second line treatment (P4–P5 and P10–P11) with the life expectancy based on the underlying condition of patients enrolled in the study.
The estimate for life years lost was based on the life expectancy of the underlying diagnoses. In the study by Walsh et al. (2004), 74% of the patients suffered from acute leukaemia, 11% from non-Hodgkin's lymphoma and 15% from other cancers. We used 1- and 5-yr UK survival data from 1998–2001 (National Statistics, Survival data England 1998–2001) to calculate life expectancy for each of these conditions (14 ). Survival probability for a patient with acute leukaemia was defined in the model according to figures reported within the acute myelogenous leukaemia (AML) trials of the Medical Research Council. Overall, this resulted in an average discounted life expectancy of 12.9 yr. For second line treatment, the probability of dying was assumed to be 24% (15–33%) based on the study by Maertens et al. (15 (link)) who evaluated patients with fungal infections who were intolerant or refractory to their first line antifungal agent.
(3) Quality adjusted life years (QALYs) lost: this was determined by multiplying life years lost in each treatment arm by the utility (or quality of life score) based on the underlying condition. QALY estimates were discounted at 3.5% per year according to UK requirements.
Each life year lost was valued with a weighted quality of life multiplier of 0.72 (0.50–0.94) in order to calculate the QALYs lost upon death. This utility value for the defined underlying conditions was based on the catalogue of preference scores 1997–2000 from the CEA Registry from the Harvard School of Public Health (
(4) The cost evaluation included: expected antifungal drug costs (first line and second line), other direct costs (hospitalisation costs + drug costs related to adverse events) and overall costs. Costs were expressed in 2005 British Pounds (1 pound = 1.80 US dollar).
