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Simon W. Lam et al
Fig. 1. Recurrent Clostridium difficile clinical course model. Black arrows denote negative clinical sequelae (eg, failure, recurrence). White arrows denote positive clinical sequelae (eg, cure, no recurrence). Gray arrows denote additional clinical decision points. NOTE. FMT, fecal microbial transplantation.
Carlo simulations, where each input was sampled randomly from distribution values of each input parameter. Probabilities and utilities were modelled using a beta distribution, whereas costs were modelled using a gamma distribution. The 10,000 patient simulations were used to generate a WTP acceptability curve.31 Ranges and distributions of all parameters are summarized in Table 2.
Results Base case analysis
Our model generated cost and health outcomes for each of the 3 treatment options for patients presenting to an outpatient phy- sician with their first recurrence of CDI. Table 3 highlights the cost and relative effectiveness of each strategy. Utilizing oral vancomycin alone as an initial treatment strategy was associated with the lowest cost and a QALY gain of 0.8019. Fidaxomicin was the second least costly agent, with modest gains in QALY (0.8046) over vancomycin alone. This strategy led to an ICER of $500,975 per QALY gained if fidaxomicin was used in lieu of vancomycin. Bezlotoxumab plus vancomycin was associated with a cost that was higher than that of fidaxomicin alone, but with an incre- mental decrease in QALY; hence this regimen was dominated in the current analysis. Based on our WTP threshold, our base case analysis demonstrated that vancomycin alone is the most cost- effective regimen because the ICER of fidaxomicin was >$100,000 per QALY gained.
Sensitivity analysis
Results of one-way sensitivity analysis for ICER for vancomycin versus fidaxomicin is shown as a tornado diagram in Figure 2. The diagram depicts the effect of each input across the range of fluctuations. The inputs are stacked in decreasing order of width to depict the descending order of effect each input has on the outcome. As illustrated in the diagram comparing vancomycin versus fidaxomicin, several of the model inputs could have independently shifted the ICER to below the WTP threshold. Those include the probability of fidaxomicin cure (>89.7%), the probability of recurrence associated with vancomycin (>38.5%) and fidaxomicin (<14.2%), the cost per tablet of fidaxomicin (<$166.68), and the probability of a vancomycin cure (<77.9%). No other model parameters were independently capable of bringing the ICER below $100,000 per QALY gained. In threshold analyses, if the probabilities of the initial cure rates of fidaxomicin and relapse were <80.8% and >24.8%, respectively, then
bezlotoxumab plus vancomycin would be considered cost- effective at a WTP of 100,000 per QALY gained. Notably, fluctuating the cure and relapse rates of bezlotoxumab plus vancomycin within the sensitivity ranges did not produce an ICER <$100,000 per QALY gained. We performed a probability sensitivity analysis, and we con-
structed a cost-effectiveness acceptability curve to illustrate the simulations (Figure 3). The curve reveals the preferred strategy when using a range of WTP thresholds. It demonstrates that, at a WTP threshold of $100,000 per QALY gained, vancomycin has a 68.4% probability of being the most cost-effective therapy, while fidaxomicin has a 29.2% probability and bezlotoxumab plus vancomycin has a 2.4% probability. In the model, when the WTP threshold was increased to $500,000 per QALY gained, the probabilities for being the most cost-effective changed to 48.0%, 45.1%, and 6.9%, respectively, for vancomycin, fidaxomicin, and bezlotoxumab plus vancomycin.
Discussion
The current analysis is the first since bezlotoxumab became available to evaluate the cost-effectiveness of CDI treatment in patients presenting to their outpatient physician with their first recurrent episode. We determined that vancomycin alone was the most cost-effective regimen. Fidaxomicin led to higher QALY gained; however, it came at a cost well above the WTP threshold. Furthermore, according to the PSA, it was unlikely to be cost effective at a WTP of $100,000 per QALY gained. Even at a WTP threshold of $500,000 per QALY gained, fidaxomicin was still less likely to be cost-effective than vancomycin. The regimen of bezlotoxumab plus vancomycin was dominated by fidaxomicin because it cost more, generated fewer QALY, and was unlikely to be cost-effective, even at a WTP threshold of $500,000 per QALY gained. The ideal treatment of recurrent CDI is unknown. Clinical
evidence supports the decrease of recurrences when patients are treated with fidaxomicin or regimens including bezlotox- umab.11,22 Separate clinical studies have demonstrated significant differences in the rates of recurrence of either regimen when compared to oral vancomycin.11,22 The decrease probability of recurrence with fidaxomicin and bezlotoxumab was reflected in the current model. However, the 3 arms modelled in the current study had remarkably similar overall effectiveness, as measured in QALY. In the case of bezlotoxumab, the decreased probability of recurrence may be overshadowed by the fact that the probability of cure was higher in those who received fidaxomicin and
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