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

Patients with neutropenia as a result of chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) are at high risk of developing invasive fungal infection (IFI) [1–7]. Early diagnosis and treatment of IFI are difficult and, as such, are associated with high mortality rates in neutropenic patients. Hence, prophylaxis of IFI has become a commonly used strategy to reduce overall morbidity-mortality rates in patients with haematologic malignancies [8].

Posaconazole is a new-generation oral azole [9] that has been demonstrated to be superior to standard azole therapy (SAT; fluconazole or itraconazole) in preventing IFI and reducing overall mortality in high-risk neutropenic patients [10]. In a recent study, posaconazol was shown not only to be as efficacious as fluconazole in the prevention of IFI but also superior to fluconazole in the prevention of invasive aspergilosis (proven or probable) in haematopoietic stem cell transplant patients with graft-versus-host disease (GHVD) [11]. As such, posaconazole is recommended in major clinical guidelines [12–15] as prophylaxis for neutropenic patients with AML or MDS (category 1/A-I).

From the National Health Service (NHS) point of view, the financial sustainability of new health interventions is a fundamental priority due to the limitation of the financial resources [16]. Consequently, the authorities responsible for health-care provision require that new therapeutic or preventative alternatives bear information regarding their efficacy, safety, therapeutic usefulness and efficiency (cost-effectiveness) [17]. In this sense, the financial burden of IFI is consistently high, essentially in high-risk neutropenic patients and those who require a protracted stay in the intensive care unit [18–23]. The economic impact of diagnosis and treatment of IFI is related to the cost of the acquisition of the anti-fungal agent, the extra costs of hospitalisation, the cost of diagnostic tests, laboratory analyses and complementary tests, the diagnosis and treatment of the adverse effects of the treatment, the management of the therapeutic failures, and relapses that require the administration of second-line anti-fungal agents [24, 25]. Disease burden and high mortality rates oblige health authorities to be aware of efficient anti-fungal prophylaxis in patients at high risk of suffering IFI such as, for example, patients with neutropenia following intensive chemotherapy. However, despite several studies having shown efficacy in specific groups of neutropenic patients at high risk of IFI [26–28], there is a relative dearth of economic evaluations of prophylactic anti-fungal agents.

Posaconazole has been shown to be more efficacious than SAT for the prophylaxis of AML or MDS among high-risk neutropenic patients. However, the cost of the drug is higher than fluconazole and itraconazole. Therefore, the objective of this study was to evaluate the cost-effectiveness of posaconazole compared to SAT for the prevention of IFI in patients with AML or MDS who are at high risk of developing an IFI as a result of chemotherapy-induced neutropenia. The perspective was the Spanish NHS, which is a system of universal health-care provision for 45 million citizens. The data for the present analyses were based on the randomised phase III trial conducted by Cornely et al [10]. The outcomes of the analyses would be useful not only from the Spanish perspective but also for those European countries with a similar health service to that in Spain.

A decision analytic model was constructed to evaluate the cost-effectiveness of posaconazole versus SAT in preventing IFI in high-risk neutropenic patients. Evidence of clinical effectiveness of both alternatives was based on a randomised study [10] that compared the efficacy and safety of posaconazole with that of SAT as prophylaxis for patients with protracted neutropenia. The trial was conducted following good clinical practice guidelines and the Declaration of Helsinki of the World Medical Association. It was published on clinicaltrials.gov (NCT00044486) and it was approved by the institutional review board or ethics committee at each participating center. The numbers of IFI avoided and the number of life years saved (LYS) with each of the alternative therapies were used to measure the economical benefits. Similarly, we assessed the total cost of treatment including the costs of the prophylactic anti-fungal drug, preparation and administration of posaconazole or SAT, and the treatment of the IFI cases in each group. Based on this information we calculated the incremental cost-effectiveness ratio of the most effective strategy versus the least effective, i.e. the incremental cost for each IFI avoided and the cost for each LYS with posaconazole compared to fluconazole or itraconazole. Model assumptions and parameters of resource use were decided in consultation with an advisory group. The perspective adopted was that of the Spanish NHS, with costs and benefits discounted at an annual rate of 3% after the 1^st year of treatment [29].

Decision-analytical model

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.

Sensitivity analysis
	Base-case estimate		Deterministic		Probabilistic
		Reference		Reference	Distribution	SD
Within first 100 days of prophylaxis
Probability of an invasive fungal infection (IFI)
Posaconazole	0.05	Cornely[10]	0.0344 -0.0573	Assumption	Beta	0.0120
SAT	0.11	Cornely[10]	0.0825 -0.1375	Assumption	Beta	0.0181
Probability of an IFI-related death
Posaconazole	0.36	Cornely[10]	0.2678 -0.4464	Assumption	Beta	0.1247
SAT	0.48	Cornely[10]	0.3636-0.6060	Assumption	Beta	0.0857
Probability of death from other causes (non IFI-related)
Posaconazole	0.16	Cornely[10]	0.1185-0.1975	Assumption	Beta	0.0148
SAT	0.16	Cornely[10]	0.1185-0.1975	Assumption	Beta	0.0148
After first 100 days of prophylaxis
Relative survival associated with acute myelogenous leukaemia (AML)
IFI	0.21	NCI[32]	0.16-0.26	Assumption	Gamma	0.000
No IFI	0.21	NCI[32]	0.16-0.26	Assumption	Gamma	0.000
Relative survival associated with myelodysplastic syndrome (MDS)
IFI	0.08	Kantarjian[33]	0.06-0.10	Assumption	Gamma	0.000
No IFI	0.08	Kantarjian[33]	0.06-0.10	Assumption	Gamma	0.000

SAT standard azole treatment (fluconazole 81% patients or itraconazole 19% patients) SD standard deviation

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).

The findings from this study show that, from the perspective of the Spanish NHS, posaconazole is more effective than standard azoles (in the present case fluconazole or itraconazole) in preventing proven or probable IFI. The outcome is a reduction in overall mortality and a longer IFI-free survival among high-risk neutropenic patients with AML or MDS. Under most conditions in the model, posaconazole is the dominant strategy compared to SAT, i.e. patients who are treated with posaconazole have avoided a greater number of IFI with a higher survival rate while, at the same time, have lower total costs compared to patients receiving SAT. Deterministic sensitivity analyses showed that the modification of key parameters of the model had very little impact on the cost-effectiveness of posaconazole and, as such, the model is considered consistent in all the established assumptions.

Some limitations of the study need to be taken into account when interpreting these results. Firstly, the data on efficacy of the two therapeutic alternatives evaluated were obtained from a single clinical trial [10] so the differences in frequency and distribution of fungal species in real clinical setting could affect the efficacy results reported. Also, the data on resource use in the IFI were estimated from the published literature and, in a retrospective manner, by a panel of experts (authors of this manuscript). However, a probabilistic sensitivity analysis was conducted to evaluate the level of uncertainty associated with the inputs and assumptions of the model and, as well, to determine the interactions between the variables analysed. This analysis showed that there is an 85% probability that posaconazole is a cost-saving strategy compared to SAT and that the probability that the incremental cost-effectiveness ratio for posaconazole versus SAT is below the accepted threshold in Spain (currently €30,000 per LYS) is 98%. However, with regards to external validity required by decision makers, it would be of considerable interest to evaluate whether these results are transferable to other settings. There may be further doubts regarding the benefits encountered in the clinical trial (the data from which were used in the present model) and whether these outcomes would apply to patients treated in routine clinical practice. On the other hand, the quality-of-life related to health in the outcomes of the patients treated with posaconazole or SAT was not taken into account, nor was the cost of the management of adverse events. However, in the referenced clinical trial [10], the incidence of adverse events was similar in both treatment groups. Similarly, the costs of management of the underlying diseases were not incorporated in the model since these were considered to be equal in the two alternative treatments and, consequently, would not have an impact on the final outcomes of the analyses.

Although our results are only valid for the Spanish National Health Care System due to the local nature of costs, our findings are in line with previous cost-effectiveness analyses of posaconazole in the prevention of IFI among high-risk neutropenic patients with AML or MDS, based on Cornely study [10], conducted in other European countries and in the USA. All the cost-effectivenes analyses followed similar methodology and show that the incremental cost per LYS of posaconazole versus SAT is below the threshold commonly accepted in each of the countries as ceiling threshold for determining society's willingness to pay for a treatment, even when it is a dominant strategy (cost-saving) [28, 39–43].

Our results suggest that prophylactic posaconazole in neutropenic patients with acute myelogenous leukaemia or myelodysplastic syndromes could potentially increase patient life expectancy and reduce the overall health-care budget.