Background
Invasive candidiasis (IC), including candidemia, is associated with considerable morbidity and mortality. Managing IC is costly, with an additional healthcare expenditure of nearly US$300 million annually [
1]. Our previous study showed that healthcare-associated infection due to
Candida albicans was associated with a mean additional hospital stay of 18.4 ± 28.5 days and an extra cost of up to US$6584 ± 11,467 when amphotericin B deoxycholate (d-AmB) and fluconazole were the only two parenteral antifungal agents [
2]. Current international guidelines [
3‐
6] suggest the use of echinocandins (caspofungin, micafungin, and anidulafungin) for the primary treatment of IC because of their cidal activity, rarity of resistance, safety profile, and better clinical outcomes compared with those of fluconazole and d-AmB [
7,
8].
However, echinocandins have higher drug acquisition and administration costs. Studies from Spain, the United Kingdom, and Australia have shown that treatment with anidulafungin is cost-effective as compared to that with fluconazole [
9‐
11]. However, cost-effectiveness studies of echinocandins for treating IC are rare in Asia. Also, published economic evaluations [
9,
10] compare fluconazole with anidulafungin only. In general, echinocandins are similar with respect to their broad spectrum of activity and in vitro activity against
C. albicans and non-
albicans Candida spp., but each has its own unique features and drug acquisition cost. There is a lack of a thorough analysis comparing the economic advantages and disadvantages of the three available echinocandins.
A change in the epidemiology of IC has been witnessed in recent decades, with a progressive shift from a predominance of
C. albicans toward a predominance of non-
albicans Candida spp. (including
C. glabrata and
C. krusei, which are less susceptible or resistant to fluconazole) [
12]. In addition, the distribution of
Candida species varies by geographic and healthcare factors [
13]. However, no study has determined whether echinocandins are cost-effective for both
C. albicans and non-
albicans Candida spp. as compared to fluconazole.
In this study, we assess the cost-effectiveness of individual echinocandins versus fluconazole in terms of either reduced hospital stay or better clinical outcomes. Subgroup analyses were conducted for C. albicans and non-albicans Candida spp., respectively.
Discussion
To the best of our knowledge, this is the first study to comprehensively assess the cost-effectiveness of echinocandins versus non-echinocandins such as fluconazole for different species (C. albicans vs. non- albicans Candida spp.) of IC in Taiwan. Our results indicate that among echinocandins, only anidulafungin is cost-effective as compared to fluconazole. For C. albicans-infected patients, the use of echinocandins is likely to be cost-saving as compared to the use of non-echinocandins. For non-albicans Candida-infected patients, there is an 82% chance of the outcome favoring echinocandins.
Three cost-effectiveness studies from other countries compared anidulafungin with fluconazole for IC, providing findings that are consistent with our study. Neoh et al.’s study based on an Australian hospital perspective and Reboli et al.’s trial data [
8] indicated that, as compared to fluconazole, anidulafungin was associated with an ICER of AU$25,740 per LY gained, which was under the Australian ICER threshold, suggesting that anidulafungin is a cost-effective agent [
9]. Our additional analyses, which applied Reboli et al.’s trial data [
8], showed consistent results (Additional file
1: Table S3) with those in Neoh et al.’s study [
9]. Grau et al.’s study from Spain showed that anidulafungin was cost-saving over fluconazole, with a higher clinical success (74% vs. 57%) at a lower total medical cost (€40,047 vs. €41,350) and that the clinical efficacy of antifungal treatment was the most influential factor in the cost-effectiveness analysis [
10], which is consistent with the results of the sensitivity analyses in the present study (Fig.
2). Auzinger et al.’s study, from the perspective of the United Kingdom National Health Service and Personal and Social Services, showed that anidulafungin was cost-effective as compared to fluconazole (ICER: £813 per LY gained) and cost-saving versus caspofungin and micafungin [
11]. However, none of these studies analyzed the cost-effectiveness of antifungal treatments for specific species (i.e.,
C. albicans).
Fluconazole has been commonly used for systemic
Candida infections; however, selected
Candida spp. are intrinsically resistant to or prone to develop resistance to fluconazole. In addition, fluconazole is inactive against
Candida biofilm formation [
6,
7]. Both may contribute to treatment failure. In contrast, echinocandins have very low resistance rates and are active against
Candida biofilm. Echinocandins are associated with higher success rates as compared to those for fluconazole [
7,
8]. The present study shows that, as compared to non-echinocandins, echinocandins are likely to be cost-effective for both
C. albicans and non-
albicans Candida species.
Among the three available echinocandins, anidulafungin is cost-saving as compared to caspofungin and micafungin because of its higher rate of survival combined with a higher probability of treatment success and lower total costs. Anidulafungin has shown better efficacy (i.e., treatment success) versus those of other echinocandins in a mixed treatment comparison [
22]. Also, it does not require dose adjustments, which are required for caspofungin (according to hepatic function). Because anidulafungin is metabolized by slow chemical, rather than enzymatic, degradation, there is no need for dose titration in patients with renal or hepatic impairment. As compared to fluconazole, the use of anidulafungin costs US$8015 per LY gained and has an 89% probability of being cost-effective at a threshold of three times per capita GDP of Taiwan (US$67,065). Therefore, anidulafungin is a treatment option that allows better control of antifungal budgets and leads to better healthcare outcomes (i.e., LY gained) at lower total costs.
The advantage of the present study is that it takes into account the downstream economic consequences of failed first-line antifungal treatment and considerable adverse drug effects (i.e., nephrotoxicity). The findings of this study might be extrapolated to other countries with similar healthcare systems (i.e., universal healthcare insurance coverage). In addition, the efficacy data were based on randomized controlled trials [
7,
8,
22]. The various sensitivity analyses indicate fair robustness of the conclusions of this study. The overall conclusion remained the same in an additional analysis that changed the assumption of the length of IV treatment for patients with treatment success and then survival (i.e., 14 days or 30 days). Also, subgroup analyses for
C. albicans and non-
albicans Candida spp. show consistent favoring cost-effectiveness results for outcome of echinocandins.
However, some potential limitations of this study need to be addressed. First, our decision-analytic tree that was based on the anidulafungin cost-effective model [
11] might only present a simplified model of daily clinical practice. For example, our model and sensitivity analysis did not take into consideration the heterogeneity of the patient population. For example, current guidelines suggest echinocandins for moderately to severely ill patients (from intensive care unit vs. general ward) and neutropenic patients (vs. non-neutropenic) as pooled individual data showed better effectiveness compared to non-echinocandins. Also, since our efficacy data were based on Reboli et al.’s trial [
8] that included predominantly non-neutropenic patients with IC, our economic results may not be generalizable to the population of neutropenic patients with IC. Thus, the current data might underestimate the cost-effectiveness of echinocandins particularly for the aforementioned high-risk patients.
Furthermore, the cost estimates that only included the costs incurred during hospitalization may be underestimated (e.g., lack of long-term economic consequences of treatment or disease). However, because the final results of our interest were presented in the incremental costs between two treatment groups (i.e., a difference in cost estimates between two groups), the exact long-term economic consequences of treatment or disease might offset in the comparison between groups.
Second, our model estimates based on clinical trials might be different from what occurs in practice. Future studies that incorporate actual use of medical resources, including antifungal consumption, additional intervention for treatment failure or drug-associated adverse reactions, and treatments effective against drug-resistant microbes, should provide more valuable information and better reflect actual practice.
Third, although expert opinions are often used when there are no other sources of data available (i.e., LOS [
23,
24]) and are commonly seen in pharmacoeconomic studies [
9‐
11], this approach might bias the study results. Thus, we conducted sensitivity analyses and found that the cost-effectiveness results were robust to different values of LOS value.
Fourth, with regarding to the cost-effectiveness analyses specific to individual
spp.(i.e.,
C. albicans and non-
albicans Candida spp.), the efficacy data (i.e., success and mortality rates) of “non-echinocandins” (Table
1) were obtained from Andes et al.’s study [
7] in which non-echinocandins included polyenes (i.e., amphotericin B and liposomal amphotericin B), and triazoles (i.e., fluconazole and voriconazole). In contrast, the efficacy data for echinocandins were primarily based on Reboli et al.’s study [
8] which only assessed the efficacy of anidulafungin for
C. albicans and non-
albicans Candida spp., respectively. This was done because very limited published studies reported the efficacy of echinocandins for individual
spp.. However, since the efficacies of individual echinocandins appear to be similar [
22], the data from anidulafungin might be representative of echinocandins.
Moreover, all efficacy data (i.e., treatment success) and model assumptions (i.e., average weight of patients receiving liposomal amphotericin B) were from other countries, which might not be applicable to an Asian population (e.g., Taiwan). We found data from Asian countries but the data varied by country (Additional file
1: Tables S4 and S5) and were different from those in international studies (e.g., Mills et al. [
22], Reboli et al. [
8]). Hence, an effectiveness study of antifungal treatments in an Asian population is needed to enable future cost-effectiveness research specific to Asia. The parameters of treatment efficacy (i.e., treatment success, morality rate) might be different depending on the length of the evaluation period. The cost-effectiveness model applied here used a 5-day period to define treatment success and a 6-week period to measure mortality associated with treatment. However, these efficacy data (i.e., survival) might be different if a longer evaluation period is chosen. Also, the treatment success and mortality data in the present study were based on a meta-analysis study [
22], which pooled data based on different evaluation periods. Hence, detailed efficacy data associated with a specific evaluation period is needed. Finally, this economic evaluation was conducted from the perspective of a medical payer, and thus only direct medical costs were included. Further study that considers all economic consequences of disease and treatment (e.g., indirect costs such as productivity losses) is anticipated to give a broader view from a societal perspective.