Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials

Abstract

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

Figure 1.

Results of primary and secondary outcomes for studies 003 and 004. Individual results for each prespecified primary and secondary outcome are presented for studies 003 and 004 separately and are combined using fixed-effects meta-analysis in the modified intent-to-treat and per-protocol populations. The primary endpoint Clinical Cure is shown as the converse No Clinical Cure, and the secondary endpoint Global Cure, as the converse No Global Cure, so that relative risks for fidaxomicin versus vancomycin of <1 consistently indicate reduced risk for poor outcome with fidaxomicin. Abbreviations: CI, confidence interval; RR, relative risk.

Figure 2.

Persistent diarrhea, recurrence, or death. Study treatment was administered for 10 days and clinical cure was assessed at 12 days, at which time persistent diarrhea (>3 stools/24 hours and toxin A and/or B positive or requiring anti–Clostridium difficile infection [CDI] treatment) was defined as clinical failure. The events occurring before day 12 are deaths and the step increase in events at day 12 represents cases assessed to have persistent diarrhea at the posttreatment assessment. Events from day 13 to day 40 represent CDI recurrence or deaths. Abbreviation: HR, hazard ratio.

Figure 3.

Comparison of intent-to-treat (ITT), modified ITT (mITT), and per-protocol analyses of the combined 003 and 004 study populations. For the ITT analysis, persistent diarrhea or death refers to events occurring in the first 12 days of the 40-day follow-up as in the time-to-event analysis depicted for days 0–12 in the Kaplan-Meier curve. Persistent diarrhea, recurrence, or death refers to events occurring during the entire study period, days 0–40. For the mITT and per-protocol analyses, No Clinical Cure refers to the converse of Clinical Cure assessed at day 12. No Global Cure refers to the converse of Global Cure and included the 40-day follow-up. The converse of each endpoint is depicted so that relative risks for fidaxomicin versus vancomycin of <1 consistently indicate reduced risk of poor outcome with fidaxomicin. Abbreviations: CI, confidence interval; RR, relative risk.

Figure 4.

Subgroup analysis for persistent diarrhea, recurrence, or death through day 40. The results depicted are from the intent-to-treat analysis and include events occurring from day 0 to day 40. Abbreviations: CDI, Clostridium difficile infection; CI, confidence interval; RR, relative risk.

Figure 5.

Persistent diarrhea or death through day 12. The results depicted are from the intent-to-treat analysis and include events occurring from day 0 to day 12. Abbreviations: CDI, Clostridium difficile infection; CI, confidence interval; RR, relative risk.