Economic Evaluation of Voriconazole versus Caspofungin for the Treatment of Invasive Aspergillosis in Spain

Alfonso Domínguez-Gil; Isabel Martín; Mercedes García Vargas; Almudena Del Castillo; Silvia Díaz; Cristina Sánchez


Clin Drug Invest. 2007;27(3):197-205. 

In This Article

Materials and Methods

Estimation of Efficacy and Tolerability

The efficacy and safety of both caspofungin (Cancidas®, Merck Sharp & Dohme, Madrid, Spain)* and voriconazole (Vfend®, Pfizer, Alcobendas, Spain) were estimated from a systematic review of the clinical trials and revisions published on both compounds up to the time of the study (2005). Clinical experience with these two new antifungal agents is still limited, and no head-to-head trials comparing their efficacy are yet available. The studies published to date with caspofungin and voriconazole for the treatment of aspergillosis are studies of the two drugs as isolated therapies,[18,20] either in patients refractory to or intolerant of standard antifungal therapy or in comparative trials versus amphotericin B as the primary therapy in patients with severe aspergillosis. The results of these trials (see table I , where the percentages of clinical response in the most relevant studies are indicated) show that caspofungin and voriconazole have similar efficacy, defined as clinical response (percentage of patients cured or improved) in the treatment of invasive aspergillosis.[17] Although this conclusion must be considered in light of the limitation implied by the fact that the populations included in the different clinical trials are not comparable, these are the only efficacy data currently available for these two drugs.

The most common adverse reactions observed in clinical trials and published revisions that were possibly related to the treatment and therefore evaluated in this study were: clinically significant alterations in liver function tests (voriconazole 13.97% and caspofungin 10.45%) and thrombophlebitis/infusion vein complications (voriconazole 0.1–0.1% and caspofungin 16%). The mean percentage of these adverse reactions was calculated as the mean of the results obtained in the approved prescribing information for each product, together with two product reviews in the case of voriconazole[21,22] and one review of caspofungin.[23]

Description of Economic Evaluation

As comparative clinical trials with both antifungal agents in severe aspergillosis are not currently available, there is no reason to assume that the two drugs have statistically different efficacy profiles, even though their efficacy was demonstrated in different populations. Because of this, a cost-minimisa-tion economic analysis was performed for which both compounds were assumed to have the same efficacy. The model was constructed following the general recommendations for pharmacoeconomic analyses[24,25] and taking into account previously published Spanish pharmacoeconomic analyses on the treatment of severe fungal infections.[15]

Perspective and Timeframe of the Analysis

The economic evaluation was performed from the perspective of the National Health System (hospital level), calculating only the direct healthcare costs, expressed in 2006 Euros. Other costs, such as direct nonhealthcare costs, intangible costs or indirect costs caused by days lost from work as a result of prolongation of hospital stay due to the disease, were not calculated.

The timeframe of the model was adjusted to the duration of treatment of a systemic fungal infection caused by Aspergillus spp., according to the values estimated in the Fungcost study.[19] This study was conducted during 2000 and 2001 in 17 tertiary hospitals in the Spanish National Health System. A retrospective review was conducted of the clinical histories of 399 episodes of hospitalisation that included a diagnosis of systemic mycosis and reported the duration and costs of the hospital stay, the costs of antifungal treatments divided into three groups (intravenous treatment on admission, oral treatment during hospitalisation and treatment prescribed on discharge), and the cost of some related diagnostic and therapeutic tests, as well as the factors associated with these costs. According to the study, treatment with an antifungal agent of an episode of invasive aspergillosis in the hospital had an approximate mean duration of 20.94 days (14.30 days of intravenous therapy and 6.64 days of oral therapy). For this reason, it was not necessary to apply any discount rate.

Estimation of Costs

Table II lists the acquisition and administration costs for the two therapies, as well as the cost of the adverse effects that were subsequently weighted, for an average patient with invasive aspergillosis treated with voriconazole or caspofungin. This analysis does not take into account supplementary or laboratory tests for the diagnosis of aspergillosis, since they should be the same in both groups, as should the laboratory tests performed over the course of treatment. Mean costs were estimated according to the results of the Fungcost study[19] for an average adult (68.6kg) with invasive aspergillosis who received hospital treatment with caspofungin or voriconazole plus oral continuation therapy. For both treatment groups, oral treatment of aspergillosis was with voriconazole, excluding itraconazole in the case of caspofungin, according to the approved indications in prescribing information for this drug (treatment of invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, among others). Only the direct costs of an episode of systemic fungal infection for the hospital were included. A mean cost was established for treatment with voriconazole and caspofungin at the laboratory selling prices, which is the price invoiced in hospitals, based on the mean doses and recommended dosing regimens in the prescribing information for each drug. The acquisition costs of the medicines were obtained from Royal Decree 2402/2004 of 30 December 2004,[26] which remains constant to 2006, with the corresponding price reduction. The costs of intravenous administration (material necessary for reconstitution of the vial plus cost of the material required for injection) were taken account for those aspects in which the two treatments were different, and therefore the cost of the time employed by healthcare personnel in preparation and subsequent administration to the patient were not calculated. These costs were obtained from a national database of healthcare costs.[27] Oral administration does not have associated costs. The costs of distribution from the pharmacy department to the hospital wards were not taken into account, as they are very similar for the two therapeutic options evaluated.

Mean weight and total duration of intravenous and oral treatment were obtained from the Fungcost study.[19] The costs of the other healthcare resources were estimated from Spanish databases of health-care costs.[27] The costs associated with treatment and follow-up of adverse effects occurring with both compounds were calculated by estimating the probability of occurrence of the different reactions reported with each treatment. Most of these reactions are mild-to-moderate and the cost of treatment per patient will be insignificant in relation to the total cost. However, adverse reactions that do have associated costs, such as hepatotoxicity and venous alterations, were recorded and considered in the analysis. With regard to hepatotoxicity, follow-up of patients by hepatic monitoring was considered necessary, which included a complete blood count and general biochemistry tests. Treatment of thrombo-phlebitis/infusion vein complications included: changing the intravenous (IV) line (10mL disposable syringe, tube system, 500mL of normal saline), Thrombocid® (pentosan polysulphate sodium) 0.1% ointment 60g (Lacer, Barcelona, Spain), small bandage and 3 days of oral treatment with an NSAID (ibuprofen 1.2 g/day), according to consultation with a panel of experts. The prices of the clinical packs were used for medicines required for management of thrombophlebitis. The costs used in the base case of the model are expressed in 2006 Euros.

Sensitivity Analysis

When interpreting the results of the model, the base case was described using the most probable of all the possible data, and subsequently a sensitivity analysis was performed modifying those parameters with the greatest uncertainty, which allowed the soundness and robustness of the results to be assessed. The base case was calculated for an average patient weighing 68.6kg; however, the mean daily dose (both loading and maintenance dose) of voriconazole IV was determined according to the bodyweight of the patient. Caspofungin has an IV loading dose that is independent of bodyweight (70 mg/day) and a maintenance dose (50 mg/day) that requires adjustment only for bodyweight >80kg. Hence, weight is a sensitive parameter in the model. Consequently, two sensitivity analyses were performed: a simple univariate analysis with bodyweight variations from 40kg to 110kg, and a bivariate analysis in which weight was modified using a range of 40–110kg and duration of IV and oral treatment using the upper and lower limits of the 95% CIs of the variable duration of treatment, calculated from the Fungcost study.[19] For IV treatment of aspergillosis, the 95% CIs were 10.20, 18.39 days; for oral treatment of aspergillosis, the95% CIs were 4.11, 9.16 days. The threshold value, where the expected cost is equal for the two treatments being compared, was determined.

* The use of trade names is for product identification purposes only and does not imply endorsement.


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