Learning Objectives. A Critical Analysis of Recent Fidaxomicin & Nesiritide Trials. Fidaxomicin vs. Vancomycin. Outline 1/3/2012

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1 Learning Objectives A Critical Analysis of Recent Fidaxomicin & Nesiritide Trials Amy E. Lodolce, PharmD, BCPS Assistant Director, Drug Information Group UIC College of Pharmacy Describe the methods and key findings of the papers presented. Discuss the differences between fidaxomicin and vancomycin for the treatment of C. difficile associated diarrhea. Discuss the place in therapy of nesiritide for acute decompensated heart failure based on the results of the trial. I have no actual or potential conflicts of interest in relation to this program. Outline Pertinent background Study objective Results Critique/clinical implications IDSA/SHEA guidelines 2010 Metronidazole 500 mg po tid x 10 to 14 days for mild to moderate infection Vancomycin 125 mg po qid x 10 to 14 days for severe infection 1st recurrence: usually same regimen No metronidazole beyond 1 st recurrence Severe, complicated infection: po and rectal vancomycin +/ metronidazole Infect Control Hosp Epidemiol. 2010;31(5): SHEA/IDSA Treatment Criteria Definition (expert opinion) Clinical data* Mild or moderate WBC 15,000 cells/μl SrCr <1.5 x baseline Severe ere Severe, complicated WBC 15,000 cells/μl SrCr 1.5 x baseline Hypotension/shock Ileus Megacolon Objective: to compare the safety and efficacy of fidaxomicin to vancomycin in treating C difficile infection RCT, MC, DB, NI 16 years with CDAD (primary or 1 st recurrence) Up to 4 doses of prior treatment allowed Could have failed at least a 3 day course of metronidazole Excluded: life threatening infection, toxic megacolon, IBD, >1 occurrence within 3 months *Age is also considered. Infect Control Hosp Epidemiol. 2010;31(5):

2 Interventions: Stratification based on primary or 1 st recurrence Fidaxomicin i i 200 mg po q12h (n=287) Vancomycin 125 mg po q6h (n=309) Both given for 10 days Patients who were cured were followed for 28 days after last dose for recurrence Primary endpoint: clinical cure Secondary endpoint: recurrence (assessed between days 36 and 40) Oh Other Microbiolgoic evaluation PK Safety Demographics 596 mitt population, 548 PP, 623 safety Mean age 62 years, 56% female 59% inpatient 5% lack of response to metronidazole 39% treated within previous 24 hours 17% previous episode of C difficile 38% NAP1/BI/027 Results Clinical cure (mitt): 253 (88.2%) of 287 fidaxomicin vs. 265 (85.8%) of 309 vancomycin (lower bound CI limit of 3.1%, met NI criteria) Recurrence (mitt): 39 (15.4%) of 253 fidaxomicin vs. 67 (25.3%) of 265 vancomycin (reduction 9.9%, 95% CI 16.6 to 2.9) Recurrence rates similar among those with NAP1/BI/027 (11 [24.4%] of 45 fidaxomicin vs. 13 [23.6%] of 55 vancomycin, p=0.93) Safety: no significant differences in SAEs More SAEs related to laboratory abnormalities with fidaxomicin (4.7% vs. 1.2%, p=0.01) no obvious patterns More common with fidaxomicin: Dizziness (4% vs. 1.2%, p=0.0405) Rash (3% vs. 0.6%, p=0.0315) Strengths NI design is appropriate Reasonable to assess superiority once NI is established Vancomycin dose appropriate External validity (US and Canada) N Engl J Med. 2011;364(5): N Engl J Med. 2011;364(19):1875 Limitations 10 days of therapy NAP1/BI/027 Antibody levels to C difficile toxin A Disease severity Pretreatment Pharmacoeconomics? 2

3 Nesiritide approved in 2001 based on results of the VMAC trial VMAC endpoint: self reported dyspnea at 3 hours Safety concerns emerged: renal dysfunction/increased mortality Objective: to evaluate the effect of nesiritide + standard of care on rates of self reported dyspnea at 6 and 24 hours, rehospitalization for HF or death from any cause at 30 days, and renal dysfunction MC, RCT, DB, PC Patients hospitalized for HF Excluded: patients at high risk for hypotension N Engl J Med. 2011;365(1): Interventions: Nesiritide (n=3496) mcg/kg/minute for 24 hours up to 7 days (2 mcg/kg bolus optional) Placebo (n=3511) All received standard therapy (determined by investigator): Diuretics Morphine Vasoactive medications Co primary endpoints: Change in self reported dyspnea at 6 & 24 hours Composite of rehospitalization for HF or death from any cause (randomization until day 30) Secondary endpoints: Self reported well being (6 & 24 hours after drug initiation) Composite of persistent or worsening HF and death from any cause Composite of death from CV cause and rehospitalization due to CV causes Safety endpoints: Death from any cause Death from CV causes Sudden death from CV causes Need for RRT Investigator reported hypotension Power: 89% for composite of rehospitalization for HF or death from any cause 99% for dyspnea endpoint US and Europe regulatory agencies differed in opinions on endpoints 2 analyses P values adjusted for US analysis Prespecified subgroup analyses 3

4 Demographics (groups well balanced) Median age 67 years 66% male 56% white Median creatinine 1.2 mg/dl 90% treated with diuretics, 6.5% inotropes, 15% vasodilators Results % Patients moderately or markedly better (dyspnea) 6 hours 24 hours Placebo 42.1% 66.1% Nesiritide 44.5% 68.2% Results Results Secondary endpoints: no significant differences Safety (nesiritide vs. placebo) Death thfrom any cause: 36% 3.6% vs. 4% ( 0.4%, 04% 95% CI 1.3 to 0.5) Renal impairment: 31.4% vs. 29.5% (OR 1.09, 95% CI 0.98 to 1.21) Hypotension: 26.6% vs. 15.3% (p<0.001) Strengths Adequately powered, large n Clinically important endpoints Standard therapy allowed Limitations Broad range of subjects Difficulty in assessing dyspnea Regulatory differences (US and Europe) Based on the results of the trial, institutions should re evaluate the use of nesiritide for acute decompensated HF. A. True B. False 4

5 Fidaxomicin demonstrated less recurrence of Clostridium difficile among patients with the NAP1/BI/027 strain. A. True B. False Which of the following statements is TRUE regarding noninferiority trials? A. The standard of care is used as the active control. B. Placebo is used as the control. C. Superiority cannot be assessed. D. Confidence intervals that contain 0 or 1 are not significant. References Which of the following is a reasonable conclusion regarding nesiritide based on the trial? A. It increasesthe risk of deathfrom any cause. B. It improves dyspnea in patients with acute decompensated HF. C. It causes renal failure. D. It is neither helpful nor harmful in managing acute decompensated HF. Fidaxomicin vs. vancomycin 1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridum difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5): Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridum difficile infection.. 3. Supplementary appendix to Fidaxomicin versus vancomycin for Clostridum difficile infection. oa _appendix.pdf. Accessed August 12, DuPont HL. The search for effective treatment of Clostridium difficile infection. N Engl J Med. 2011;364(5): Safdar N, Craig WA. Fidaxomicin for Clostridium difficile infection. N Engl J Med. 2011;364(19):1875. References 1. Topol EJ. The lost decade of nesiritide. N Engl J Med. 2011;365(1): O Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. 5