Cost-effectiveness of posaconazole versusfluconazole or itraconazole in the prevention of invasive fungal infections among high-risk neutropenic patients in Spain

Using Microsoft Excel 2003 for Windows^®, an interactive economic evaluation model was developed to assess the clinical benefits obtained with each therapeutic option, and to estimate the associated health costs of patients receiving prophylaxis with posaconazole or SAT for the prevention of IFI. The costs associated with the prevention or treatment of the IFI that may arise in each of the treatment groups were calculated.

The model consists of two integrated parts. The first part is a decision tree (Figure 1) that reproduces, in the 100 days post-treatment, the clinical outcomes for the patients treated with posaconazole or with SAT in a clinical trial comparing both strategies [10]. The decision tree starts with a decision node that describes the prophylaxis selection for IFI, either posaconazole or SAT. After prophylaxis initiation, the patient can develop IFI according to the probabilities described in the clinical trial (Table 1). The model also takes into account the probability of survival or death once the IFI occurrs. The model takes into account not only the patients who do not develop IFI but also those who survive the IFI, as well as the probability of death from other causes not related to the IFI during the initial 100 days of prophylaxis.

The second part of the model consists of an additional Markov model [30], which extrapolates the results of the clinical trial and simulates the progression of the disease over the long-term course of the patients' life, i.e. beyond the first 100 days of prophylaxis. The patients who survive the initial 100 days enter into this Markov model which, following the monthly cycles, projects the risk of death from the underlying disease (AML or MDS) or from whatever cause, independently of whether or not the patients had had an IFI [31]. In this case, the relative survival values obtained from the literature were 0.21 for AML [32] and 0.08 for MDS [33] or other causes (Table 1).

Clinical efficacy data used in the analyses were collected from a clinical trial that compared posaconazole versus fluconazole or itraconazole in the prevention of IFI in high-risk patients with neutropenia [10]. This was a prospective, randomised, multicenter study in which 304 patients were assigned to receive posaconazole and 298 patients SAT (fluconazole in 81% and itraconazole in 19% of patients). The patients received 200 mg posaconazole in oral suspension three times a day (total daily dose: 600 mg), 400 mg fluconazole in oral suspension once a day (total daily dose: 400 mg) or 200 mg itraconazole in oral solution twice a day (total daily dose: 400 mg). Prophylaxis was administered with each chemotherapy cycle, and was continued until recovery from neutropenia and complete remission, or until occurrence of an IFI, or for up to 12 weeks post-randomisation, whichever came first. Patients were followed-up for 100 days post-randomisation, and for 30 days after the last dose of the study drug administered during the last chemotherapy cycle. Proven or probable IFI occurred during the treatment phase in 7 of the 304 patients (2%) in the posaconazole group and in 25 of the 298 patients (8%) in the SAT group; absolute reduction in the posaconazole group of -6% (95%CI: -9.7 to -2.5%; p < 0.001). During the 100-days of the post-randomisation period, 14 of 304 patients (4.6%) in the posaconazole group had a proven or probable fungal infection, compared to 33 of the 298 patients (11%) in the SAT group (p = 0.003) (Table 1). Two patients (1%) in the posaconazole group had invasive aspergillosis versus 20 (7%) in the SAT group (p < 0.001). The mean (± SD) time to IFI was 41 ± 26 days in the posaconazole group and 25 ± 26 days in the SAT group. Survival was significantly longer among patients treated with posaconazole than among patients in the SAT group. Of the 304 patients in the posaconazole group, 49 (16%) died during the study period, as did 67 of 298 patients (22%) in the SAT group (p = 0.048). The incidence of adverse events was similar among both treatment groups, 52% in the posaconazole group vs 59% in the SAT group [10]. Kaplan-Meier analysis of the all-cause time-to-death at the end of the 100-day period post-randomisation showed a significant survival benefit in favour of posaconazole over fluconazole or itraconazole (p = 0.04). The data on efficacy of both therapeutic options are summarised in Table 1.

The economic evaluation was performed in patients with neutropenia resulting from chemotherapy for AML or MDS and who were at high risk of developing an IFI. The patient population studied correspond to the patients at baseline in the study by Cornely et al [10].

To determine the costs and benefits of the treatments under comparison, the perspective used was that of the Spanish NHS and, as such, only the following direct health costs were considered (Table 2).

The model did not include the cost of the adverse events nor the cost of management of the underlying disease (AML or MDS) since these costs would be common and similar to both treatment groups. All the costs are expressed in terms of euros at November 2009 values.

The time horizon of the study was 100 days, and lifetime of the patient. Hence, for each prophylactic alternative we calculated the number of IFI avoided in 100 days, and the number of LYS over the long-term of the patient's life. Similarly, we obtained the total cost for each treatment group including the costs of the prophylaxis (drug, preparation and administration) and of the treatment of the IFI that may arise. From these results we calculated the incremental cost per IFI avoided, and the incremental costs for each LYS with the more effective treatment (in the present case posaconazole), compared to the less effective SAT (fluconazole or itraconazole).

If the result of the modelling indicated that one of the therapeutic options was more efficacious (less IFI or greater number of LYS) and, in turn, had a lower total cost compared to the other option, this would establish therapeutic dominance. If, as well, a saving is produced relative to the alternative option, then it would be unnecessary to calculate the incremental cost-effectiveness ratio [37]. If, on the other hand, one of the options evaluated was more efficacious but more costly than the alternative, the incremental cost-effective ratio is calculated relative to the less costly alternative. In the analysis we considered that one of the strategies is efficient if the cost per LYS is less than the threshold of efficiency currently accepted in Spain, and which has been established at < €30,000 euros per LYS [38].

We performed a deterministic univariate sensitivity analysis with the objective of assessing the robustness of the model, and the consistency of the assumptions used in the model. The parameters modified were those that were most relevant in the model or those with the greatest uncertainty. These were the efficacy of prophylaxis, the risk of death from IFI, and the cost of treatment of the IFI with a value of 75% or 125% of the value used in the base case estimations, except for the probability of experiencing an IFI that a wider range was considered (Tables 1 and 2). Further, a sensitivity analysis was performed applying a discount rate of 0% and 5% to the costs and the outcomes [29].

A multivariate probabilistic sensitivity analysis (PSA) was also performed using 1,000 second-order Monte Carlo simulations. The assumptions of the model were randomly modified based on probability functions described in Tables 1 and 2.

In the base case over the 100 first days of prophylaxis, the IFI per patient in the SAT group was 0.11 versus 0.05 in the posaconazole group (Table 3), i.e. posaconazole avoided a mean of 0.06 IFI per patient.

In the projection of progression of the disease over the life-term of the patient, the treatment with posaconazole achieved better clinical results, increasing the life expectancy of the patients by 2.52 years, compared to a mean increase of 2.43 years in the SAT group. As such, posaconazole produces an increase of 0.09 in LYS (Table 3).

The total costs of treatment in the SAT group was €7,928 per patient (Table 3), €450 related to the prophylactic drug used in avoiding IFI (drug costs, administration and monitoring) and €7,478 associated with the costs of treatment of FI in the patients with neutropenia. In the group of patients treated with posaconazole, the average cost per patient was €6,121, of which €3,007 was due to the anti-fungal treatment and €3,114 for the management of IFI. The final result was a saving of €1,807 per patient treated with posaconazole compared to the patients who received SAT prophylaxis with fluconazole or itraconazole.

Table 3 summarises the costs and the benefits (IFI avoided and LYS) obtained for each treatment group. The prophylaxis with posaconazole is the dominant strategy compared to prophylaxis with SAT i.e. the clinical outcomes were better and with lower overall cost.

The results of the univariate deterministic sensitivity analysis are summarised in Table 4. All the outcomes are consistent with the base case, i.e. for all the variations of the parameters introduced into the model; posaconazole is the dominant strategy over that of SAT.

The results of the PSA show that there is a probability of 85% that posaconazole is a cost-saving strategy, compared to SAT (Figure 2) and a probability of 97% that the incremental cost-effectiveness ratio for posaconazole versus SAT is below the estimated €30,000 per LYS threshold currently accepted in Spain (Figure 3).

A final sensitivity analysis was performed, to find at what values results changed. Only when the probability of experiencing an IFI was identical in both groups, SAT was dominant over posaconazole treatment due to lower treatment costs. The treatment with posaconazole would not be more cost-effective if the incremental benefit over SAT was reduced from 6% to 2%, as the ICER would be higher than €30,000.