A cost-effectiveness and budget impact analysis of first-line fidaxomicin for patients with Clostridium difficile infection (CDI) in Germany

Clostridium difficile infection (CDI) is a debilitating condition associated with mortality, substantial morbidity, and hospitalization [1, 2]. Treatment options for CDI patients have been vancomycin and metronidazole for a number of years. However, CDI recurs in approximately 20–25 % of patients treated with these agents [3, 4]. Recurrent CDI places a heavy burden on patients, including prolonged symptoms, repeated courses of antibiotics, and the attendant risk of side-effects and rehospitalization [5]. Certain subgroups of patients are more susceptible to recurrence, e.g., those with severe CDI, cancer or renal impairment, those with a previous recurrence, those aged ≥65 years, and those receiving concomitant antibiotics [6‐9]. Severe CDI and patients with recurrence are recognized as identifiable patient subgroups in the real-world clinical setting by ESCMID guidelines [10]; elderly patients are at higher risk of severe or severe-complicated CDI [11]. Patients with cancer, with impaired renal function or receiving concomitant antibiotics have been associated with lower cure rates and longer time to resolution of diarrhea [7, 12, 13].

CDI also represents a significant economic healthcare burden due to the costs associated with increased length of hospital stay [14]. Moreover, the costs associated with recurrent CDI may be greater than those associated with the initial episode, not only as a result of longer hospital stay, but also the need for environmental decontamination, rigorous hygiene in patient care, and in some cases, cohort isolation and ward closure [5]. Indeed, a recent US study confirmed a greater healthcare utilization and mortality in patients with recurrent CDI compared with non-recurrent disease [15]. Moreover, the direct treatment costs of C. difficile-associated diarrhea (CDAD) in a German hospital were recently estimated at €73,898 per patient with ≥1 recurrence [16]. Clearly, the ability to decrease the risk of recurrent CDI is likely to benefit patients, by reducing morbidity and mortality, and also healthcare systems, by reducing costs.

Fidaxomicin is the first in a new class of macrocyclic antibiotics licensed to treat CDI. In two phase III trials, fidaxomicin was shown to be non-inferior to vancomycin in terms of clinical cure and produced significantly lower recurrence rates and significantly higher sustained cure rates [3, 17]. In patients with severe CDI and those with a first CDI recurrence, recent studies in Scotland and Ireland, respectively, have shown that fidaxomicin was cost-effective compared with vancomycin [18] and less costly and more effective than vancomycin or metronidazole [19].

In Europe, the annual management costs of CDI were estimated at around €3 billion, and since CDAD occurs predominantly among the elderly, this is expected to increase in future as the proportion of elderly people in the European population increases [20]. In Germany, CDAD has been associated with an annual cost burden of €464 million for the German healthcare system [21]. This study evaluates the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin in Germany in the first-line treatment of patient subgroups with CDI at increased risk of recurrence.

We developed a semi-Markov decision analytic model to assess the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin as the first-line treatment of patient subgroups with CDI at increased recurrence risk, from the German payer perspective. Based on a willingness-to-pay threshold of €50,000, fidaxomicin was found to be dominant (less costly and more effective) in patients with cancer and cost-effective in all of the other subgroups.

Despite the substantially higher acquisition cost of fidaxomicin compared with vancomycin, this is offset by the reduction in costs associated with treating recurrence and by the reduced hospitalization costs; therefore, fidaxomicin is cost-saving in the cancer subgroup and associated with incremental costs of €291 to €461 per patient in the other groups.

The deterministic sensitivity analyses showed that the key drivers of cost-effectiveness are recurrence, clinical cure rates, and CDI-attributable mortality. This type of sensitivity analysis has some limitations, including an evaluation of the impact of only a small number of parameters, and the lack of account for the potential interdependence between parameters. However, it is useful for assessing the key drivers of cost-effectiveness. The findings of the current deterministic analyses reflect the results of phase III trials, showing that fidaxomicin was associated with lower rates of recurrence and higher rates of sustained response/global cure rates than vancomycin in patients ≥65 years, those with a previous episode of CDI [3, 17], those with severe CDI at baseline [3, 17], those taking concomitant antibiotics [7], or with renal impairment [13] or cancer [12]. Differences were statistically significant (p ≤ 0.05) for both variables for those with cancer or taking concomitant antibiotics [12, 13], for recurrence in those ≥65 years or with severe CDI in one study [3] and with chronic kidney disease stage 2 in another [13] and for sustained response in those with severe CDI at baseline [17]. Moreover, analysis of the combined data for these trials showed that overall, fidaxomicin reduced persistent diarrhea, recurrence, or death by 40 % compared with vancomycin [30]. These effects of fidaxomicin are likely to reduce hospital readmission rates; indeed, in the current budget impact analysis, hospitalization costs were lower with fidaxomicin than vancomycin in all subgroups. A recent analysis of a patient discharge database showed that reductions in hospital-onset CDI and readmission of patients with an index CDI can provide tremendous cost savings to hospitals [31]. A reduced recurrence rate is likely in turn to reduce hospital readmission rates and the overall number of bed-days with fidoxamicin. Hospital bed-days have been reported to account for up to 94 % of the cost of CDAD treatment [32]. Furthermore, a recent real-world study showed that the overall readmission rate of fidaxomicin-treated patients was low (6.9 %) [33].

Cost-effectiveness in CDI treatment is important in the German setting as shown by a recent German hospital study that found CDAD generates a yearly overall cost of €464 million to the healthcare system [21]. In this study, recurring cases were associated with higher costs (€20,755 per case) than those with CDAD as a primary diagnosis (€4132) [21]. Recurring cases were associated with higher costs in a recent cost-of-illness analysis assessing the impact of CDAD and CDAD recurrence in the German health system [16]. In that analysis, the mean overall direct treatment costs in the recurrence group were €73,898 such that additional direct costs related to CDAD were €59,367 in the recurrence group compared with matched non-CDAD control patients [16].

Our analysis complements previous cost-effectiveness studies with fidaxomicin. A study from the perspective of Scottish public healthcare providers showed that fidaxomicin was cost-effective in patients with severe CDI and in those with a first CDI recurrence [18]. A US study from the third-party payer perspective found that fidaxomicin may be a more cost-effective option for the treatment of CDIs compared with vancomycin under most scenarios tested [34]. In addition, a recent cost-utility analysis from an Irish Health Service Executive perspective showed that fidaxomicin was dominant to vancomycin or metronidazole for the treatment of CDI [19]. Finally, a cost-utility study from the Spanish National Health Service perspective showed that the treatment of CDI with fidaxomicin would be cost-saving and lead to improved quality of life when compared with vancomycin in patients with cancer, renal impairment, or treated with concomitant antibiotics [35].

Limitations of the model include the need to make assumptions to address uncertainties. In the current model, the 6.5 % mortality rate was based on 30-day all-cause mortality from phase III trials. However, this is consistent with literature estimates for CDI-attributable mortality (5.7–6.9 %) [22‐24]. Furthermore, in view of its more favorable sustained cure and recurrence rates, this is likely to be a conservative approach regarding the benefits of fidaxomicin vs. vancomycin. Indeed, it has been shown that recurrent CDI is associated with significantly higher mortality rates [36]. The model also applied the same recurrence risk to first and subsequent recurrence—again, this is a conservative assumption as in practice, the risk of a second recurrence is likely to be higher [37]. It was also assumed that all cases of CDI were treated on a general ward in hospital. In a real-world setting, it is likely that some patients with CDI will be treated in intensive care or an infectious diseases unit, while others may be treated in the outpatient setting. The assumptions for hospitalization costs and lengths of stay used in the model (€348/day on a general ward and 14.6 days) appear very conservative since a recent German hospital cost-of-illness study on the economic burden of CDAD [16] found that patients with recurrence spent 62 additional days in hospital (compared with those without recurrence), resulting in excess overall direct treatment costs of €55,438 per patient. Finally, another limitation of the model is that metronidazole was not included as a treatment option. This was because there are no direct comparative studies between fidaxomicin and metronidazole, although the results from a recent network meta-analysis indicate that fidaxomicin is associated with a significantly lower recurrence rate in CDI than metronidazole [38].

Using a semi-Markov decision analytic model, our analysis in a German hospital setting showed that in patient subgroups with CDI at increased recurrence risk, first-line fidaxomicin was cost-effective vs. vancomycin, and less costly and more effective in patients with cancer over a 1-year time horizon. This is despite the higher acquisition cost of fidaxomicin and is a result of savings associated with lower hospital readmissions as more recurrences are prevented with fidaxomicin. These results are highly relevant given the emphasis on reducing hospital admissions and overall length of stay in European healthcare systems.