Received: 28 July 2020 | Revised: 16 September 2020 | Accepted: 21 September 2020 DOI: 10.1111/myc.13189 ORIGINAL ARTICLE The cost-effectiveness of isavuconazole compared to voriconazole, the standard of care in the treatment of patients with invasive mould diseases, prior to differential pathogen diagnosis in Spain José Ramón Azanza1 | Santiago Grau2 | Lourdes Vázquez3 | Pablo Rebollo4 | Carmen Peral5 | Alejandra López-Ibáñez de Aldecoa5 | Vanessa López-Gómez6 1 Clinical Pharmacology Department, Clínica Universidad de Navarra, Pamplona, Abstract Spain Background: Invasive mould diseases are associated with high morbidity, mortality 2 Pharmacy Department, Hospital del Mar, Universitat Autònoma de Barcelona, and economic impact. Its treatment is often started prior to differential pathogen Barcelona, Spain diagnosis. Isavuconazole is approved for treatment of invasive aspergillosis (IA) and 3 Hematology Department, Hospital Clínico invasive mucormycosis (IM) when amphotericin-B is not indicated. Universitario de Salamanca, Salamanca, Spain Objectives: To estimate the cost-effectiveness of isavuconazole vs voriconazole for 4 Ingress-health, Oviedo, Spain the treatment of adult patients with possible IA prior to differential pathogen diag- 5 Pharmacoeconomics Department, Pfizer, nosis, in Spain. Madrid, Spain 6 Methods: A decision tree analysis was performed using the Spanish Healthcare Medical Department, Pfizer, Madrid, Spain System perspective. Among all patients with possible IA, it was considered that 7.81% actually had IM. Costs for laboratory analysis, management of adverse events, hos- Correspondence José Ramón Azanza. Clinical Pharmacology pitalisation and drugs per patient, deaths and long-term effects in life years (LYs) and Department, Clínica Universitari de quality-adjusted LYs (QALYs) were considered. Efficacy data were obtained from clini- Navarra, Pamplona, Spain. Email: jrazanza@unav.es cal trials and utilities from the literature. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Funding information Pfizer Results: In patients with possible IA and when compared to voricanozole, isavucona- zole showed an incremental cost of 4758.53€, besides an incremental effectiveness of +0.49 LYs and +0.41 QALYs per patient. The Incremental Cost Effectiveness Ratio was 9622.52€ per LY gained and 11,734.79€ per QALY gained. The higher cost of isavuconazole was due to drug acquisition. Main parameters influencing results were mortality, treatment duration and hospitalisation days. The PSA results showed that isavuconazole has a probability of being cost-effective of 67.34%, being dominant in 24.00% of cases. Conclusions: Isavuconazole is a cost-effective treatment compared to voriconazole for patients with possible IA for a willingness to pay threshold of 25,000€ per ad- ditional QALY. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 Pfizer SLU. Mycoses published by Wiley-VCH GmbH 66 | wileyonlinelibrary.com/journal/myc  Mycoses. 2021;64:66–77. AZANZA et al. | 67 KEYWORDS cost-effectiveness, decision tree, invasive aspergillosis, isavuconazole, mucormycosis 1 | I NTRO D U C TI O N are exclusively indicated for the treatment of IA, particularly po- saconazole is only indicated when the disease is refractory to L-AMB. Invasive mould diseases (IMD) are life-threatening infections, espe- According to published therapeutic guidelines, isavuconazole is recom- cially in immunocompromised patients such as those with haema- mended as a rescue therapy in IM patients, as well as posaconazole, tologic diseases, those who have been subjected to a solid organ although the recommendation for posaconazole is off-label.11 transplantation or haematopoietic stem cell transplantation (HSCT) The SECURE pivotal trial13 has shown isavuconazole to have 1,2 and in critically ill patients with leukaemia or profound neutropaenia. non-inferior efficacy and survival to voriconazole, and better safety IMDs are caused by fungus of the genus Aspergillus (causing invasive profile, in patients with IA. On the other hand, the VITAL trial has aspergillosis, IA) or other filamentous fungi, for example, Mucorales demonstrated the efficacy of isavuconazole as primary therapy, in (causing invasive mucormycosis, IM). These infections entail an im- refractory patients and salvage, in the treatment of IM.14 portant clinical burden to individuals who are already vulnerable as Isavuconazole, on top of its broad spectrum, being active against they are associated with high morbidity and mortality, with mortality Aspergillus and Mucorales, which is a clear advantage when treating rates ranging from 30% to 80% for IA and up to 97% when untreated patients with possible IA (thus, lacking pathogen confirmation), of- 3,4 IM. Similarly, a delay in the establishment of an adequate therapy fers several additional advantages relative to voriconazole, that en- leads to increased mortality rates in certain type of patients and sig- tail benefits to the patients and could carry economic consequences nificant increase in treatment duration.5 For instance, according to a as well; it has lower drug-drug interactions; therefore, it can be more study analysed by the FDA, a delay of 6 days in the initiation of treat- safely given to patients receiving additional medications; isavuco- ment, increased mortality rates up to almost two times, from 48.6% nazole does not need routinely therapeutic drug monitoring, as it is to 82.9%.6 IMDs have a high economic impact as well.1,7,8 In line with the case for voriconazole; patients receiving it show fewer adverse available data in the website of the Spanish Ministry of Health RAE- events, and dose adjustment is not needed for patients with mild/ CMBD (Registro Atención Especializada- Conjunto Mínimo Básico de moderate hepatic impairment or renal impairment.15,16 Datos),9 length of stay for IA in Spain in 2017 was 54.20 days and the Several economic analyses of isavuconazole vs voriconazole for mean associated costs were 18,235€; regarding IM the length of stay the treatment of IA have been conducted in different countries: in was 70 days and the mean costs were 24,020€. hospitalised patients with IA in the United States17 and in patients Even though it is highly important to establish an early diagnosis with possible IA in Sweden18 and the UK.19 Cost-minimisation mod- for this pathology, the process is challenging because often non-spe- els of isavuconazole vs L-AMB followed by posaconazole for the cific symptoms are present. According to the recently published up- treatment of IM have been also performed in Italy, 20 Germany21 date of the consensus definition of invasive fungal disease (IFD) from and the UK. 22 The clinical situation described in the UK cost-effec- the EORTC and the Mycoses Study Group Education and Research tiveness model19 clearly reflects the real-world treatment approach Consortium, probable IFD requires the presence of a host factor, a in Spain when facing patients with possible IA, in which is neces- clinical feature and mycologic evidence; cases that meet the criteria sary to start treatment before getting the differential diagnosis be- for a host factor and a clinical feature but for which mycological evi- tween IA and IM. Although isavuconazole is more expensive than dence has not been found are considered possible IMD.10 In contrast, voriconazole, it is effective for both IA and IM and has a better safety obtaining a diagnosis of mucormycosis on histomorphological basis is profile. Therefore, the objective of the present study was to conduct challenging, and the most common cause for incorrect morphological a health economic analysis from the Spanish National Health Service diagnosis is the misidentification of Mucorales as Aspergillus spp. The perspective (NHS), by estimating the cost-effectiveness of isavuco- application of immunohistochemistry or PCR techniques on either nazole vs voriconazole, the standard of care in Spain, for the initial fresh or formalin-fixed paraffin-embedded tissue have been shown treatment of IMD prior to differential diagnosis between IA and IM. to be highly specific, although a variation in sensitivity has been re- ported.11 The outcome and the management of the patient depend on a prompt and correct diagnosis and usually treatment is initiated be- 2 | M ATE R I A L S A N D M E TH O DS 3 fore pathogen identification. However, if the treatment turns out to be inappropriate, a delay in receiving the right treatment can increase 2.1 | Economic model the mortality rate, as reported by Chamilos et al where a 6-day delay was associated with a 2-fold increase in mortality rate.12 A cost-effectiveness and cost-utility analysis, with a lifetime horizon Among the therapeutic options currently available to treat IA and and from the perspective of the NHS, was adapted to Spain.19 In order IM, only isavuconazole and amphotericin-B (L-AMB) have approved in- to reflect the short-term patient pathway from initial symptoms to dication for both types of infections. Voriconazole and posaconazole eventual result after antifungal treatment (resolution of infection or 68 | AZANZA et al. F I G U R E 1 Decision tree model structure. IA, Invasive aspergillosis; IM, Mucormycosis; L-AMB, Liposomal amphotericin-B death), a decision tree originally developed with the collaboration of Xhaard et al25 and for 50% of patients - set with the experts’ panel). UK expert's panel was analysed by local experts (1 hospital pharmacist, Regarding all IA patients and those IM patients treated with isavu- 1 clinical pharmacologist and 1 haematologist, from three different au- conazole, pathogen confirmation does not affect the patient flow. tonomous communities of Spain) and considered a representative ap- However, all IM patients with pathogen confirmation in proach of Spanish patients’ pathology pathways (Figure 1). the voriconazole arm will switch to second-line treatment, as First, the model reflects that a population of patients with ‘possible voriconazole is not indicated for the treatment of mucorales. 26 IA’ can either be treated with isavuconazole or voriconazole. Secondly, Patients having IM and not switching are those who failed in getting patients are subdivided into having IA or IM, regardless of a clinical con- a pathogen confirmation and therefore, for a short extra period of firmation. In this step, a prevalence of 7.81% was used to estimate those time (see treatment durations and Figure 1) they remain with inap- patients incorrectly diagnosed with possible IA but actually having IM propriate treatment. instead (tree branches with blue dots in Figure 1). Due to a lack of spe- cific data from Spain, this prevalence was estimated from a UK study.23 Then, depending on treatment response, discontinuations or di- 2.2 | Clinical inputs agnostic confirmation, patients may switch to a second-line treat- ment or stay with the current treatment. Second-line treatment is 2.2.1 | Second-line treatment L-AMB (as recommended in clinical guidelines24), followed by oral posaconazole or oral voriconazole. The percentage of patients receiving second-line treatment was Eventually, the model considers the possibility of having patho- calculated using data from the SECURE and VITAL trials by consid- gen confirmation, that was set on the 11th day of treatment (which is ering the number of patients that discontinued first-line treatment the median time between clinical signs and IM diagnosis observed by due to no or insufficient response to treatment, adverse events or AZANZA et al. | 69 TA B L E 1 Clinical inputs Pts moving to 2nd All-cause Adjusted treatment line13,14 mortality6,12,13 duration (d)13,14,25,30,31 Invasive Aspergillosis 1st line ISAV/ VORI 27.13% 21.00 2nd line - 29.07% 70.70 L-AMB + VORI/ POSA Full coursec ISAV/VORI - 70.70 Mucormycosis 1st line ISAV 14.29% 42.86% 21.00 a 1st line VORI 100% 82.86% 11.00 b 2nd line L-AMB + POSA - - 213.00 c Full course ISAV - 42.86% 213.00 Full coursec VORI - 96.20% 47.00 Abbreviations: ISAV, Isavuconazole; L-AMB, Liposomal Amphotericin-B; Pts, Patients; VORI, Voriconazole. a Of those who have pathogen confirmation;a b Change to second line after pathogen confirmation;b c Patients maintaining 1st line treatment until resolution or death.c intercurrent illness.13,14 Since no statistically differences were found control study14 to reflect real-world dosing (Table 2). For calcula- between isavuconazole and voriconazole, these percentages were tions, weight distribution of the general Spanish population was equally applied for both therapies (Table 1). used, according to the age range of patients included in the SECURE Accordingly, 27.13% of IA patients and 14.29% of IM patients study,13,27 51.10 (±16.20) years for isavuconazole and 51.20 (±15.90) treated with isavuconazole will switch to a second-line treatment. for voriconazole. We then used the weighted average for 3 sub- In case of pathogen confirmation, 100% of IM patients treated with groups (35-44 years, 45-54 years and 55-64 years). voriconazole will switch to a second-line treatment. The model considers that, according to VITAL study data,14 75% patients will start with IV treatment and subsequently step-down to oral therapy, while the remaining 25% will directly start with oral 2.2.2 | All-cause mortality therapy. Second-line treatment consists of IV L-AMB followed by oral All-cause mortality over 84-day from the SECURE trial13 (Table 1) voriconazole/posaconazole at a 50%/50% ratio, except for IM pa- was used to approximate mortality rate in IA patients, regardless tients treated with voriconazole that switch to L-AMB: in this case, of the initial treatment (isavuconazole or voriconazole) since no only oral posaconazole is considered. In IA, oral voriconazole was statistical differences were reported in the trial. In order to avoid included as step-down therapy after L-AMB as fungal load is signifi- double counting in the number of deaths, this mortality was also cantly reduced after therapy with L-AMB and thus voriconazole is assumed for patients with IA that switch to L-AMB. efficacious again (expert panel input). The 84-day all-cause mortality in IM patients treated with isavu- conazole was extracted from the VITAL study14 (Table 1). According to published data,12 an increased mortality probability due to a delay 2.3.2 | Duration in the correct treatment was applied to IM patients treated with voriconazole that switch to L-AMB. On the other hand, patients lack- Treatment durations are summarised in Figure 1 and Table 1. For IA ing pathogen confirmation were assumed to have the same mortality patients, it was calculated by adjusting isavuconazole treatment du- as untreated patients6 (Table 1). ration in the SECURE study (47.0 days in total: 8.1 days IV, 38.9 days oral)28 according to whether patients responded to, and remained on, first-line treatment or discontinued treatment and switched to 2.3 | Treatment regimens, dosing and duration second-line therapy. Since no statistical differences among thera- pies were found, a total treatment duration of 70.70 days for IA 2.3.1 | Dosing was assumed for both therapies. As previously published, the dura- tion of second-line therapy was assumed to be equal to the dura- Dosing of all treatments in the model was aligned to their corre- tion of first-line therapy in patients who responded to treatment sponding SmPC (refs FT) and, for L-AMB, the FungiScope™ matched (70.70 days). 29 70 | AZANZA et al. TA B L E 2 Treatment dosing and costs Price per pack Cost per unit Units per Dose per Treatment (€)32-35 Pack size32 (€)32-35 day 9,13,26,31 day 9,13,26,31 Isavuconazole Intravenous (Day 1 & 2) 384.00 1.00 384.00 3.00 600 mg Intravenous (Day 3 onwards) 384.00 1.00 384.00 1.00 200 mg Oral (Day 1 & 2) 672.00 14.00 48.00 6.00 600 mg Oral (Day 3 onwards) 672.00 14.00 48.00 2.00 200 mg Voriconazole Intravenous (Day 1) 79.99 1.00 79.99 6.00 1200 mg Intravenous (Day 2 onwards) 79.99 1.00 79.99 4.00 800 mg Oral (Day 1) 214.51 28.00 7.66 8.00 800 mg Oral (Day 2 onwards) 214.51 28.00 7.66 4.00 400 mg Liposomal Amphotericine B Intravenous (IA) 834.99 10.00 83.50 8.00 400 mg Intravenous (IM) 834.99 10.00 83.50 8.00 400 mg Posaconazole Oral (Day 1) 399.60 24.00 16.65 6.00 600 mg Oral (Day 2 onwards) 399.60 24.00 16.65 3.00 300 mg Abbreviations: IA, Invasive aspergillosis; IM, Invasive mucormycosis. Switch to second-line treatment was assumed in the 21th treat- 2.4.1 | Drug acquisition costs ment day (at the end of first quarter of an 84-day therapy course). Accordingly, a patient with IA starting with voriconazole and who Acquisition costs (Table 2) were estimated using the ex-factory price must switch to second-line therapy would therefore be on treatment (EFP)32 including the corresponding mandatory deduction outlined for 21.00 + 70.70 days. Specifically, L-AMB treatment was assumed in Royal Decree 08/201033 and the reference price34,35 established 30 to last 14.50 days and oral posaconazole/voriconazole 56.20 days, or the lowest EFP among the available. calculated by subtracting 14.50 to the overall second-line treatment duration (70.70 days). For IM patients, total treatment duration was adjusted as for IA 2.4.2 | Hospitalisations but using data from the VITAL study (15.5 days IV, 133.5 days oral, or 149 days for those not receiving IV). Therefore, total treatment dura- The cost per hospital day used in the model was 568.48€. This was tion for IM patients receiving isavuconazole was set as 213.00 days. calculated from Spanish health system reference costs as the mean The same assumptions regarding the duration of second-line IV and of the latest published prices for hospital stay in every autonomous step-down therapy were made as for IA. The duration of L-AMB community.36 was set to 27.20 days, as observed in the matched cohort from the Length of hospitalisation stay for IA patients was extracted from ™ 31 FungiScope registry. Then, the duration of posaconazole treat- the SECURE study.13,28 Since no statically differences were found ment (185.80 days) was calculated subtracting L-AMB treatment between isavuconazole and voriconazole, isavuconazole's mean days to the total duration of second-line therapy. hospitalisation length stay, 18.60 days, was used for both therapies. According to the model, IM patients treated with voriconazole This duration was also assumed to second-line therapy. 25 and with pathogen confirmation switch treatment after 11.00 days, IM patients with a full course treatment of either isavuconazole meaning patients are treated over 11.00 + 213.00 days. Whereas in or voriconazole were assumed to have the same hospital stay length patients lacking confirmation, the total treatment duration was as- as reported in the VITAL study,14 19.30 days. In the second-line 28 sumed to be 47.00 days. treatment, according to the mean duration of IV therapy observed in the FungiScope™ case-control study,31 it was assumed that patients remain hospitalised during the IV treatment, which was previously 2.4 | Costs set as 27.20 days (see treatment durations). For IM patients treated with voriconazole but switching because of Only direct costs were included in the model, namely: drug acquisi- pathogen confirmation, patients were assumed to be hospitalised for tion, hospitalisations, adverse events (AEs) and laboratory analysis. the entire course of their treatment prior to switching (11 days) plus the All costs were expressed as 2020 Euros. second-line treatment hospitalisation previously detailed (27.20 days). AZANZA et al. | 71 TA B L E 3 Costs included in the model Incidence of adverse event15 Cost (€) per System organ class Adverse event Isavuconazole Voriconazole event36 Eye disorders Visual impairment 0.40% 5.80% 52.00 Reduced visual acuity 0.00% 1.50% 52.00 Hepatobiliary disorders Hyperbilirubinaemia 0.40% 2.30% 133.58 Abnormal hepatic function 0.80% 3.50% 133.58 Hepatic failure 0.00% 1.20% 133.58 Jaundice 0.00% 0.80% 133.58 Cholestasis 0.00% 1.20% 133.58 Laboratory Tests Increased GGT 2.30% 5.40% 157.82 Increased ALP 1.90% 4.20% 157.82 Increased AST 1.90% 4.20% 157.82 Increased ALT 1.60% 4.20% 157.82 QT prolonged 0.40% 3.10% 157.82 Psychiatric disorders Hallucination 0.40% 4.20% 156.35 Visual hallucination 0.00% 3.50% 156.35 Respiratory. thoracic and mediastinal Dyspnoea 3.10% 0.80% 127.51 disorders Liposomal Amphotericine B 37 Renal disorders Nephrotoxicity 19.50% 740.96 Metabolism and nutritional Hipokalaemia38 53.80% 206.00 disorder Laboratory Analysis13,14,24,26,38 Nº per week Pathology Unitary cost €36 Liver function test 2.00 IA & IM 14.78 Therapeutic drug monitoring of 1.00 IA & IM 107.98 antifungal Serum creatininea 2.00 IM 1.80 36 Other costs Unitary cost € Unitary cost €36 Hospitalisation day36 568.48 Abbreviations: IA, Invasive aspergillosis; IM, Mucormycosis. a Only for patients treated with L-AMB. a 2.4.3 | Adverse events 2.4.4 | Laboratory tests The model includes adverse events reported in the SECURE study15 Laboratory monitorisation tests were estimated taking into account for which statistically significant differences between isavuconazole length of treatment, adverse events and precautions included in the and voriconazole treatments were found (see Table 3). For the treat- summary of product characteristics of each drug26 (Table 3). Liver 37 ment with L-AMB, unlike the UK original model, nephrotoxicity function test was performed twice a week in all treatment groups (associated with 9 days of additional hospital treatment 29) and hy- and both for IA and IM.13,14,24,26 Same applied for therapeutic drug 38 pokalaemia were also considered. All the costs of adverse events monitoring (TDM) which was performed once a week.39 In the sensi- were calculated from Spanish health system reference costs as the tivity analysis, a scenario where 10.00% of isavuconazole's patients mean of the latest published prices for related specialist outpatient would be monitored was analysed.39 Finally, for those patients hav- 36 visit in autonomous communities. Due to a lack of specific infor- ing IM and treated with L-AMB the model includes serum creati- mation, hypokalaemia cost was assumed to correspond to a nephrol- nine tests twice a week.13,14,24,26 All the costs of laboratory tests ogy specialist visit cost (206€).36 Importantly, the model adjusted were calculated from Spanish health system reference costs as the the average calculated AE costs by the duration of treatment for mean of the latest published prices for related test in autonomous every patient subgroup. communities.36 72 | AZANZA et al. 2.5 | Utility and life expectancy The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. Utility and life expectancy were defined using the most frequent un- No ethical approval was required as the research in this article re- derlying condition of IMD in the SECURE and VITAL trials, which is lated to an economic model based on data from published literature. acute myeloid leukaemia. Therefore, utility was assumed to be 0.82, as reported by Leunis A et al40 and a life expectancy of 17.00 years reported by Bower et al41 was used. This figure was then discounted 3 | R E S U LT S using a 3.00% rate 42 and the present value factor sum method re- sulting in an average discounted life expectancy of 13.56 years. 3.1 | Base case In the situation considered in this economic model, which is the 2.6 | Cost-effectiveness outcomes treatment of IMD prior to differential diagnosis between IA and IM, at the point of treatment initiation, isavuconazole delivered 0.49 Results are presented through the main cost-effectiveness metric more LYs and 0.41 more QALYs per patient than voriconazole at an which is the incremental cost-effectiveness and cost-utility ratio incremental cost of 4,759.53€. The ICER and ICUR were 9,622.52€/ (ICER/ICUR). To calculate it, both long-term effects in life years (LYs) LY gained and 11,734.79€/QALY respectively (Table 4). The higher and quality-adjusted life years (QALYs) were reported. cost of isavuconazole is mainly due to drug acquisition costs since Costs and outcomes were discounted using a 3.00% discount the rest of direct costs considered (management of adverse events, 42 rate. Results of the analysis were checked using a willingness to laboratory tests and hospitalisation days) are reduced when using pay (WTP) threshold of 25,000 Euros per additional QALY gained.43 isavuconazole in comparison to voriconazole. Thus, the evaluated strategy is considered cost-effective when the Regarding LYs and QALYs, the differences between these two ICUR < 25,000 €/QALY. comparators were mostly due to the different effects of the treat- ments in patients with IM (higher mortality rates among patients with IM treated with voriconazole compared with those treated 2.7 | Sensitivity analysis with isavuconazole). Importantly, isavuconazole was associated with a significant reduction of 10.79% deaths and 52.95% adverse Sensitivity analyses were performed in order to evaluate the robust- events. ness of the model and analyse the uncertainty around the param- eter's estimates and assumptions. 3.2 | Deterministic sensitivity analysis 2.7.1 | Deterministic sensitivity analysis Values for 122 parameters were tested in the deterministic sensi- tivity analysis. As shown in Figure 2, main parameters influencing A deterministic sensitivity analysis was conducted to analyse the fol- results were mortality, treatment duration and number of hospitali- lowing parameters: costs, mortality, quality of life, epidemiology and sation days. It was seen that results were especially sensitive to a life expectancy, treatment, clinical practice, laboratory analysis and reduction in mortality of IA patients treated with isavuconazole in a hospitalisation. In the analysis upper and lower values for param- 20%, or an increase of this same input for voriconazole in the same eters bounded between 0 and 1 were limited between their bound- percentage; the ICER was decreased to 2,600€/QALY. Additionally, ing figures. For each variable, upper and lower bounds of +20% and treatment length of IA patients and length of hospital stay did have –20%, respectively, were assessed. also important influence in the results. An increase in the number of hospital days for isavuconazole by 20% or a decrease for voricona- zole, doubled the ICERs. 2.7.2 | Probabilistic sensitivity analysis A probability distribution was defined for each parameter accord- 3.3 | Probabilistic sensitivity analysis ing to the nature of the data: parameters bounded by 0 and 1, such as percentages and health utilities, were given a beta distribution; In the probabilistic sensitivity analysis, the average ICUR was com- parameters with positive figures and bounded at 0 (i.e. costs) were pared with a WPT of 25, 000€ per QALY.43 Results showed that given a gamma distribution. The model was run repeatedly 10,000 65.36% of simulations (that represent the differences in costs and times, taking each time a randomly selected value for each of the effects between comparators) were in the top right quadrant, indi- different inputs from its respective probability distribution (Monte cating that isavuconazole is more efficient and more expensive in Carlo simulations). Mean costs and mean QALYs were calculated most of the cases. Besides, 24.00% of the simulations were domi- using these values and results were subsequently summarised.44 nant meaning more health gains and less expensive (Figure 3). AZANZA et al. | 73 TA B L E 4 Base case analysis results Isavuconazole Voriconazole IA IM Combined IA IM Combined Difference Costs (€) € Drug 10, 824.92 2,058.46 12, 883.37 6,352.79 1,291.34 7,644.14 5,239.24 Hospital 15, 841.83 1,240.52 17, 082.35 15, 841.83 1,277.27 17, 119.10 −36.74 AEs 374.45 17.63 392.08 422.71 58.14 480.85 −88.77 Laboratory analysis 291.03 55.20 346.24 673.82 26.61 700.43 −354.20 Total costs 27, 332.24 3,371.80 30, 704.04 23, 291.15 2,653.36 25, 944.52 4,759.53 Effects AEs (%) 33.14 2.10 35.25 69.84 5.08 74.91 −39.67 Deaths (%) 26.80 3.35 30.15 26.80 7.00 33.79 −3.65 LY 8.87 0.61 9.47 8.87 0.11 8.98 0.49 QALY 7.27 0.50 7.77 7.27 0.09 7.36 0.41 ICER per LY gained (€/LY) 9,622.52 ICUR per QALY gained (€/QALY) 11, 734.79 Abbreviations: AEs, Adverse events; IA, Invasive aspergillosis; ICER, Incremental cost-effectiveness ratio; ICUR, Incremental cost-utility ratio; IM, Mucormycosis; LYs, Life year gains; QALY, Quality-adjusted life years. Data were represented in a cost-effectiveness acceptabil- differential diagnosis between IA and IM is very challenging, so in ity curve (CEAC) in order to estimate the probability of isavuco- real life setting usually treatment is initiated before pathogen iden- nazole of being cost-effective for a range of WPT ranging from 0 tification, because a delayed treatment initiation can severely influ- to 100,000€/QALY (Figure 4). According to these results, isavuco- ence the outcomes.5 Under these circumstances, isavuconazole and nazole has a probability of 67.34% of being cost-effective for a WPT voriconazole are two main therapeutic options that can be chosen of 25, 000€/QALY. by the physician, taking into account both clinical and economic fac- tors, however, only isavuconazole is effective and indicated for treat- ing both IA and IM.13,14,26 Taking into consideration this context, this 4 | DISCUSSION modelling study was undertaken to compare, from the Spanish NHS perspective, the cost-effectiveness of the use of isavuconazole vs the Invasive mould diseases are very severe infections that have a high standard of care, voriconazole, when at the time of therapy initiation, morbidity and mortality, entailing high associated costs. The early the differential diagnosis between IA and IM has not been achieved. F I G U R E 2 Deterministic sensitivity analysis. IA, Invasive Aspergillosis; ICUR, Incremental cost-utility ratio; IM, Mucormycosis; Isa, Isavuconazole; QALY, Quality-adjusted life years; Vori, Voriconazole 74 | AZANZA et al. F I G U R E 3 Probabilistic sensitivity analysis. WTP threshold 25 000€. QALY, Quality-adjusted life years; WTP, Willingness to pay threshold The base case analysis suggests that isavuconazole is cost-effec- and 0.49 LYs per patient. Regarding the economic cost, the main tive compared with voriconazole at a WTP threshold of 25,000€/ difference is the drug acquisition cost (12, 883.37€ per patient QALY. Although there is not a specific WTP threshold to be applied for isavuconazole vs 7,644.14€ for voriconazole), but these costs in health economic analyses in Spain, it has been proposed a range are partially compensated by a reduction in hospitalisation, lab- 43,45 between 25, 000 and 60, 000 € per additional QALY gained, oratory analysis and adverse event costs, because of clinical meaning the analysis was made using the more conservative pub- outcomes improvement. Treatment with isavuconazole was also lished threshold. associated with a 10.79% reduction in deaths and an import- While isavuconazole is 8.23% more expensive than ant reduction in adverse events (52.95%) when compared with voriconazole, it is also associated with an increase of 0.41 QALYs voriconazole. F I G U R E 4 Cost-effective acceptability curve. QALY, Quality-adjusted life years AZANZA et al. | 75 The results of the original UK model,19 in which this analysis This study presented some limitations. In order to obtain results was based, also favoured the use of isavuconazole with 0.39 QALYs for the base case population, several assumptions were made re- and 0.48 more LYs per patient than voriconazole at an incremental garding clinical practice, patient's underlying condition and quality cost of 3,228£, resulting in an ICUR of 8,242£ per additional QALY of life. Firstly, a conservative prevalence of 7.81% for IM patients gained and an ICER of 6,759£ per additional LY gained. This was with possible IA diagnosis was used in the model, but higher rates mainly due to the efficacy of isavuconazole against IA and IM, as have been published reporting up to 10.7%.46 Secondly, assuming opposed to voriconazole, which is only effective against IA. The that the patients with IA had an underlying morbidity, the applica- small difference in QALYs and LYs between the original UK model tion of the quality of life decrease associated to this morbidity had and the present model is due to the different discount rate applied an impact in the results. Moreover, the model assumed that the to the life expectancy: 3.5% in the UK model and 3% in the present patients surviving a fungal infection did not have any disutility due one. According to the deterministic sensitivity analysis, the model to the infection, and this might not reflect the real quality of life of was primarily sensitive to IA patients’ mortality, treatment dura- these patients in the real world. Other assumptions are related to tion and number of hospital days. The results of the Spanish model the decision tree and the numbers for mortality and treatments. The described in this paper are, therefore, well-aligned with the previ- incidence of IM is low and there is a lack of data in the long-term ously published UK model as both are favourable to isavuconazole consequences of antimycotic treatments, thus assumptions had to in the treatment of IA prior to differential pathogen diagnosis. be made to overcome this lack of real data in the area. Other economic analysis comparing isavuconazole vs Another limitation of this cost-effective analysis would be that voriconazole in different settings have achieved similar results, the clinical parameters considered for IA patients were the same highlighting the favourable cost-effectiveness results of isavuco- for both treatment arms (isavuconazole and voriconazole). Thus, nazole. A study conducted in the US comparing, from the hospital the differences in QALYs and LYs are mainly due to the fact that perspective, isavuconazole vs voriconazole in first-line treatment voriconazole is not effective in treating IM, resulting in high mor- of patients with IA,17 showed that isavuconazole was associated tality rates for these patients because there is a delay in effective with a 7,418$ lower total cost per patient than voriconazole. therapy initiation (at the time the pathogen is identified); together Results were robust in the deterministic sensitivity analysis, with with an improvement in IA outcomes such as reduction in mortality, isavuconazole being dominant vs voriconazole in most cases, as laboratory costs, adverse events and hospitalisations. well as in probabilistic sensitivity analysis where isavuconazole was cost-effective in 82.00% of the simulations at the $50, 000 WTP threshold. A cost-effectiveness analysis conducted from 5 | CO N C LU S I O N S Swedish healthcare payer perspective18 achieved similar results of this study: isavuconazole resulted in an ICUR of 174, 890 Swedish In conclusion, isavuconazole is cost-effective over voriconazole krona (SEK) per additional quality-adjusted life year (QALY) for the treatment of patients with possible IA. Considering the gained. Sensitivity analyses of this model showed that the average demonstrated efficacy of isavuconazole against Aspergillus spp. ICUR consistently fell below the WTP threshold of 1, 000, 000 and Mucorales spp and its additional clinical benefits, these results SEK. Deterministic analysis showed that the model was primarily strongly suggest that using isavuconazole instead of voriconazole sensitive to mortality. could provide clinical and economic advantages for IA patients with- To test the uncertainty of the parameters and, therefore, the ro- out pathogen identification at the moment of therapy initiation and bustness of the model results, a range of sensitivity analyses were thus being beneficial for patients and for the Spanish NHS. performed. In the deterministic sensitivity analysis, it was found that the results were robust under a series of alterations in the main pa- C O N FL I C T O F I N T E R E S T rameters. The model was sensitive to changes in mortality of IA pa- This analysis was sponsored by Pfizer (Spain). PR was employee of tients, length of treatment and hospital stay. This analysis shows the Ingress-health Spain who received an honorarium from Pfizer (Spain) dependence of the results on the model inputs and underlying cases in connection with the development of this manuscript. Medical around the treatment of IA patients. Interestingly, all the results of writing support was provided by PR (Ingress-health Spain) and ALI-A the deterministic sensitivity analysis stayed below the 25, 000€/ (Pfizer) and was funded by Pfizer. CP, ALI-A and VL-G are employees QALY threshold. of Pfizer (Spain). JRA has received speaker and advisory honoraria Results of the probabilistic sensitivity analysis, scattered mainly from Pfizer (Spain), and SG has received speaker and advisory hono- in the upper and lower right quarters, show the uncertainty about raria from Pfizer (Spain), and LV has received speaker and advisory the parameters used in the model. The observed uncertainty along honoraria from Pfizer (Spain). the horizontal axis (QALY) is mainly due to the small size of the samples. However, according to the CEAC, the probability of being AU T H O R C O N T R I B U T I O N S cost-effective was 67.34% with a WTP threshold of 25, 000€/QALY José Ramón Azanza: Conceptualization (equal); Methodology and increases up to 82.08% with a WTP threshold of 60, 000€/ (equal); Supervision (lead); Validation (equal); Writing-original QALY, which is the range of the proposed threshold for Spain.43,45 draft (equal); Writing-review & editing (equal). Santiago Grau: 76 | AZANZA et al. Conceptualization (equal); Methodology (equal); Validation (equal); 12. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among Writing-original draft (equal); Writing-review & editing (equal). patients with hematologic malignancy who have zygomycosis. Clin Lourdes Vázquez: Conceptualization (equal); Methodology (equal); Infect Dis. 2008;47(4):503-509. Validation (equal); Writing-original draft (equal); Writing-review & 13. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus editing (equal). Pablo Rebollo: Conceptualization (equal); Formal voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): analysis (equal); Methodology (equal); Writing-original draft (equal); a phase 3, randomised-controlled, non-inferiority trial. Lancet. Writing-review & editing (equal). Carmen Peral: Conceptualization 2016;387(10020):760-769. (equal); Funding acquisition (equal); Writing-review & editing (equal). 14. Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole Alejandra López-Ibáñez: Conceptualization (equal); Funding ac- treatment for mucormycosis: a single-arm open-label trial and case-control analysis. 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