Infection Control & Hospital Epidemiology
Methods Model structure
This study follows the guidance provided by the International Society of Pharmacoeconomics and Outcomes Research for the design, conduct, and analyses of pharmacoeconomic models.17–20 This CEA was performed using a decision analysis tree with 3 arms: bezlotoxumab plus vancomycin, vancomycin alone, and fidaxomicin. Table 1 summarizes the evaluated treatment regimens and the time to recurrence (among patients who experience sub- sequent recurrences). For recurring patients, it was assumed that they were in a healthy state in the period between the end of initial treatment to onset of recurrence. Bezlotoxumab plus fidaxomicin was not evaluated as an option because the clinical trials involving bezlotoxumab had few patients treated with that combination. Fecal microbial transplantation (FMT) was also not included as a treatment option because most clinical evaluations have reported only using that therapy for patients with multiple recurrences.21 Figure 1 illustrates the decision-tree progressions. Specifically,
for each patient who presented as an outpatient with the first episode of recurrent CDI, a treatment strategy can be chosen. In addition, depending on the condition of the patient at presenta- tion, the clinician chose whether to admit the patient for treat- ment. Regardless of admission, patients experienced either a failure or a cure with the initial treatment choices. Those who failed initial treatment could progress sequentially to vancomycin taper, and then to either FMT via colonoscopy or colectomy. Those who experienced a cure could develop subsequent recur- rent CDI, which could also be sequentially treated with vanco- mycin taper, FMT via colonoscopy, or colectomy. Up to 2 subsequent recurrent CDIs were modelled. Patients who experi- enced a cure and no subsequent recurrences progressed to the end of the study with risks of death similar to those of patients who experienced CDI recurrence.10 TreeAge version 2016 software (TreeAge, Williamstown, MA) was used to construct the model and to populate the parameters. The time horizon eval- uated was 1 year, which was sufficient to capture all treatments and recurrences.
Model inputs
A search of studies for the evaluation of recurrent CDI treatment was performed. Principal studies included the landmark studies
Table 1. Medication Regimens and Time to Recurrence
Treatment Vancomycin Fidaxomicin
Bezlotoxumab + vancomycin
Dose 125mg Every 6 h
10 mg/kg 125 mg
Once 6h
Vancomycin taper 125mg
Every 6 h Every 12 h Every 24 h Every 48 h Every 72 h
Frequency Duration 10 d
200mg Every 12 h 10 d
Once 10 d
14 d 7 d 7 d 7 d 7 d
Time to Recurrence (in recurring patients)
8 d22 20 d22 8d11,22 10 d25
925
comparing bezlotoxumab to the standard of care11 and a study comparing fidaxomicin to vancomycin in a subset of patients with recurrent CDI.22 These 2 studies provided much of the clinical information needed to evaluate the 3 treatment strategies. Out- comes associated with vancomycin taper, FMT via colonoscopy, and colectomy and the risk for hospitalization were derived from published sources.10,23–25 The efficacy outcome evaluated was quality-adjusted life years
(QALY). Utility describes the quality of life for different health states and ranges from 0 (death) to 1 (perfect health). Utility values for each patient undergoing CDI treatment as an inpatient, outpatient, healthy 65-year-old, and postcolectomy patient were extracted from current literature.12,26,27 Utility values were mul- tiplied by the amount of time each patient spent in each of those states to determine QALY. Among hospitalized patients, it was presumed that they completed their treatment course in the hospital and discharged after treatment was completed, except for vancomycin taper, for which it was assumed that the first 2 weeks of the taper was performed in the hospital prior to discharge. For patients who experienced cure, they were considered healthy until time to recurrence, which varied based on initial treatment choice. The base case values and ranges for utilities are sum- marized in Table 2. The cost was taken from a payer’s perspective, which included
direct costs, such as medication, procedures, and hospitalization. Costs include those associated with medication, hospitalization, colectomy, FMT, and subsequent therapies for further recurrent infections. Cost evaluations did not include indirect costs, such as loss of productivity and patient travel times. Cost data were obtained from public sources, such as average wholesale price for medications (as of October 1, 2017) and 2017 CMS reimburse- ment rates for doctor visits and procedures. When a medication was manufactured by more than 1 drug company, the median cost for the medication was used. For patients treated in the hospital, the cost of vancomycin was calculated based on using the intravenous formulation of the medication compounded and administered orally. All costs gathered from previous economic analyses were inflated to current medical costs using medical cost inflation rates from the consumer price index.28 Cost parameters and ranges are summarized in Table 2.
Base case and sensitivity analysis
Baseline values for costs, utilities, and clinical probabilities were used for the base-case analysis. The primary outcome measure was the incremental cost-effectiveness ratio (ICER) between dif- ferent therapies, where the incremental costs were divided by the number of QALYs gained. The ICER was compared to a willingness-to-pay (WTP) threshold, which was set at $100,000 for this study. To evaluate for the robustness of the model and the effect of
parameter uncertainty, one-way sensitivity analyses were com- pleted for nondominated strategies by fluctuating individual cost and probability variables within prespecified ranges. Ranges for clinical probabilities were determined using a binomial distribu- tion–derived 95% confidence interval. Ranges for medication costs were determined using the median average wholesale price ±50%.29 Ranges for procedural and hospital charges were gath- ered from Centers for Medicare and Medicaid Services reimbur- sements ±25%.30 Results of one-way sensitivity analyses were illustrated using tornado diagrams.17 Probabilistic sensitivity analysis (PSA) was conducted using 10,000 second-order Monte
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