Cost-effectiveness of three echinocandins and fluconazole in the treatment of candidemia and/or invasive candidiasis in nonneutropenic adult patients

Figures & data

Figure 1 Decision-tree model.

Table 1 Variables and assumptions of the model

Item	Value/assumption	References/sources
Efficacy/treatment successa
Anidulafungin	77.49%/68.81%	9 (calculated)
Micafungin	75.98%/65.27%	9 (calculated)
Caspofungin	76.10%/64.23%	9 (calculated)
Fluconazole	63.00%/49.08%	9 (calculated)
Liposomal amphotericin B	72.98%	9
Hepatic adverse effectsb
Anidulafungin	2.8%	13
Micafungin	5.7%	13
Caspofungin	7.2%	13
Fluconazole	10.0%	13
Renal toxicityd
Anidulafunginc	8.4% (3.0%–11.0%)	14,16,27
Micafunginc	8.4% (3.0%–11.0%)	14,16,27
Caspofunginc	8.4% (3.0%–11.0%)	14,16,27
Fluconazolee	12.1% (4.3%–15.8%)	28
Treatment durationd
First-line treatment	4 days (3–7 days)	Delphi panel
First-line effectiveness assessment	5th day (3rd–8th day)	Delphi panel
AE assessment/starting second-line	5th day (3rd–8th day)	Delphi panel
Second-line effectiveness assessment	8th day (10th day)	Delphi panel
Pharmacological treatment total duration	14 days	Delphi panel,15
Drug doses (loading dose/dose increase/daily dose)
Anidulafungin	200 mg/NA/100 mg	19
Micafungin	NA/200 mg/100 mg	20
Caspofungin	70 mg/NA/35 and 50 mg	21
Fluconazole	800 mg/NA/400 mg	22
Liposomal amphotericin B	NA/NA/195 mg	23
Drug prices (ex-factory)
Anidulafungin (Ecalta 100 mg, one vial powder)	€360.00	18
Micafungin (Mycamine 100 mg, one vial powder)	€428.57	18
Caspofungin (Cancidas 50 mg, one perfusion vial, 10 mL)	€448.76	18
Caspofungin (Cancidas 70 mg, one perfusion vial, 10 mL)	€570.81	18
Fluconazole 0.2% perfusion bag, 100 mL	€4.33	18
Amphotericin B (Ambisome 50 mg, ten vials, 15 mL)	€1,300.61	18
Amphotericin B (Abelcet 50 mg, ten vials, 10 mL)	€572.19	18

Notes:

a Effectiveness of treatment: clinical and microbiological response in the first line of treatment according to the mixed-treatment comparison meta-analysis by Mills et al.⁹ Treatment success: efficiency without liver or kidney adverse effects, resulting in multiplying the likelihood of effectiveness by the probability of suffering such adverse effects;

b transaminase elevation, with or without drug withdrawal;¹³

c in the case of anidulafungin and micafungin, because no data were available on renal toxicity, the percentage observed with caspofungin vs fluconazole^14,16,27 was assumed, assuming a class effect of echinocandins;

d values used in deterministic and probabilistic sensitivity analyses given in parentheses;

e it was assumed that fluconazole renal toxicity variability was similar to that observed with echinocandins for performing the probabilistic analysis.

Abbreviations: AE, adverse effect; NA, not applicable.

Table 2 Base case results

Item	Anidulafungin	Micafungin	Caspofungin	Fluconazole
Effectivenessa	68.81%	65.27%	64.23%	49.08%
Cost per branch treatment	€5,483	€5,968	€6,231	€2,088
Cost per additional success
vs Micafungin	Dominantb	–	–	–
vs Caspofungin	Dominantb	Dominantc	–	–
vs Fluconazoled	€17,199	€23,962	€27,339	–

Notes:

a Effectiveness of first-line treatment, without liver or kidney adverse effects;

b anidulafungin is more effective and costs less than micafungin or caspofungin;

c micafungin is more effective and costs less than caspofungin;

d compared to fluconazole, the cost of getting an additional success case.

Table 3 Deterministic sensitivity analysis results

Variable modified		Cost per additional success with the treatment (€)a
Treatment days	Day for adverse effect assessment	Anidulafungin vs micafungin	Anidulafungin vs caspofungin	Anidulafungin vs fluconazole	Micafungin vs caspofungin	Micafungin vs fluconazole	Caspofungin vs fluconazole
First-line treatment
3	3	Dominantb	Dominant	€13,989	Dominant	€19,337	€25,121
3	4	Dominant	Dominant	€15,375	Dominant	€21,315	€27,339
5	5	Dominant	Dominant	€17,549	Dominant	€24,524	€30,930
5	6	Dominant	Dominant	€18,935	Dominant	€26,502	€33,148
7	7	Dominant	Dominant	€21,110	Dominant	€29,712	€36,740
7	8	Dominant	Dominant	€22,496	Dominant	€31,689	€38,958
Second-line treatment
Efficacy assessment +2 days	Success assessment -2 days	Dominant	Dominant	€16,354	Dominant	€23,018	€26,691
Doses/regimens
Micafungin dose not increased; patients treated with amphotericin B		Dominant	Dominant	€17,199	Dominant	€23,390	€27,339
Caspofungin not considered as second-line treatment; after fluconazole, 50% receiving anidulafungin and 50% micafungin		Dominant	Dominant	€17,288	Dominant	€24,071	€27,455
Caspofungin daily dose: 70 mgc		Dominant	Dominant	€16,430	Dominant	€23,024	€34,023
Caspofungin daily dose: 35 mgc		Dominant	€23,915	€18,474	€152,275	€25,516	€16,828

Notes:

a Cost of gaining an additional success with the first treatment. For example, the cost of an additional success with anidulafungin vs fluconazole is €13,989, with 3 days first-line treatment duration and the assessment of adverse effects performed on day 3;

b drug mentioned first is dominant. For example, in this case anidulafungin is dominant, because it would be more efficient and generate fewer costs than micafungin;

c in patients with a body weight of 80 kg, after the initial loading dose of 70 mg, 70 mg daily doses of caspofungin must be administered. In adult patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), a daily dose of 35 mg of caspofungin is recommended based on pharmacokinetic data.

Figure 2 Probabilistic analysis (Monte Carlo simulation). Cost differences per patient.

Notes: (A) Anidulafungin vs micafungin; (B) anidulafungin vs caspofungin.

Table 4 Probabilistic analysis results (Monte Carlo simulation): anidulafungin vs comparators

Item	Anidulafungin	Micafungin	Caspofungin	Fluconazole
Effectivenessa	75.9%±3.81%	70.41%±2.90%	72.87%±4.26%	63.00%±4.44%
Hepatic toxicitya	2.80%±1.04%	5.70%±0.90%	7.20%±0.79%	10.00%±1.14%
Renal toxicitya	8.4%±2.6%	8.4%±2.6%	8.4%±2.6%	12.1%±2.8%
Drug average cost (per branch)	€5,494	€5,968	€6,226	€2,092
95% CI lower limit for costs	€5,440	€5,889	€6,167	€1,956
95% CI upper limit for costs	€5,554	€6,041	€6,292	€2,234
Cost per effectiveness unit	–	Anidulafungin is dominantb	Anidulafungin is dominantb	€27,021 (€26,354–€27,759)

Notes:

a Effectiveness and liver and kidney toxicity of first-line treatment, obtained directly from randomized clinical trials. The same renal toxicity was assumed for echinocandins;

b anidulafungin is more effective and costs less than micafungin and caspofungin.

Abbreviation: CI, confidence interval.

MillsEJPerriDCooperCAntifungal treatment for invasive Candida infections: a mixed treatment comparison meta-analysisAnn Clin Microbiol Antimicrob200982319558681

 PubMed Web of Science ®Google Scholar

WangJLChangCHYoung-XuYChanKASystematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infectionAntimicrob Agents Chemother2010542409241920308378

 PubMed Web of Science ®Google Scholar

US Food Drug AdministrationCancidas (caspofungin acetate) [prescribing information]2013 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021227s031lbl.pdfAccessed July 13, 2014

 Google Scholar

GrauSSalavertMCarlos Pozo LaderasJGarcía VargasMBarruetaJAMirNCost-effectiveness of anidulafungin in confirmed candidaemia and other invasive Candida infections in SpainJ Mycol Med20132315516323849341

 PubMed Web of Science ®Google Scholar

Mora-DuarteJBettsRRotsteinCComparison of caspofungin and amphotericin B for invasive candidiasisN Engl J Med20023472020202912490683

 PubMed Web of Science ®Google Scholar