Correspondence

Voriconazole versus Liposomal Amphotericin B for Empirical Antifungal Therapy

N Engl J Med 2002; 346:1745-1747May 30, 2002

Article

To the Editor:

The report by Walsh et al. (Jan. 24 issue)1 of a trial of voriconazole, as compared with liposomal amphotericin B, for patients with neutropenia and persistent fever and the accompanying editorial and letter to the editor2,3 leave many questions about what the trial actually demonstrated and how the findings should be applied. The abstract implies that the study showed equivalence and concludes, “Voriconazole is a suitable alternative to amphotericin B preparations.” Yet the text and the accompanying editorial point out that the prespecified statistical criterion for equivalence was not met. To confuse the issue further, correspondents from the Food and Drug Administration provide alternative data, indicating that voriconazole was actually statistically inferior to liposomal amphotericin B with respect to overall success rates.3 Thus, whether the study showed equivalence, near equivalence, or frank inferiority remains unclear.

Even if equivalence had been demonstrated, the clinical implications of the findings would remain uncertain. Therapeutic decision making must take into account not just efficacy and safety, as emphasized in the editorial,2 but also cost. Avoidance of toxic effects may allow a net cost savings despite higher drug acquisition costs,4 but that possibility requires empirical demonstration.

James R. Johnson, M.D.
Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417
johns007@tc.umn.edu

4 References

1. 1

   Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225-234
   Full Text | Web of Science | Medline

2. 2

   Marr KA. Empirical antifungal therapy -- new options, new tradeoffs. N Engl J Med 2002;346:278-280
   Full Text | Web of Science | Medline

3. 3

   Powers JH, Dixon CA, Goldberger MJ. Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever. N Engl J Med 2002;346:289-290
   Full Text | Web of Science | Medline

4. 4

   Cagnoni PJ, Walsh TJ, Prendergast MM, et al. Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. J Clin Oncol 2000;18:2476-2483[Erratum, J Clin Oncol 2000;18:3064.]
   Web of Science | Medline

To the Editor:

The trial by Walsh et al., which compared voriconazole with liposomal amphotericin B for the empirical treatment of neutropenic fever, presents a dilemma in conducting this type of study. Major goals in the empirical treatment of neutropenic fever include survival, defervescence, and the prevention of infections. Whether this composite end point is appropriate for the evaluation of an antifungal drug remains controversial. A previous trial reported by Walsh et al. underscores this problem. Numerous unknown additional variables in both studies probably account for the difference in the efficacy rates for liposomal amphotericin B despite a similar study design (effective in 129 of 422 patients [30.6 percent] in the current trial vs. 172 of 343 [50.1 percent] in the earlier trial).1,2 In our opinion, the main end points for this type of trial should focus only on the prevention of fungal infections, survival, and tolerance of the new drug.

Andrew J. Ullmann, M.D.
Claus Peter Heussel, M.D.
Johannes Gutenberg University, 55101 Mainz, Germany

Oliver A. Cornely, M.D.
University of Cologne, 50924 Cologne, Germany

2 References

1. 1

   Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-771
   Full Text | Web of Science | Medline

2. 2

   Heussel CP, Kauczor HU, Heussel GE, et al. Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography. J Clin Oncol 1999;17:796-805
   Web of Science | Medline

To the Editor:

Walsh et al. used a composite scoring system similar to those validated in other studies.1-3 However, they failed to point out or explain why the rate of response to liposomal amphotericin B in their study (30.6 percent) was much lower than the rates in previous studies in patients with febrile neutropenia (50 to 64 percent).1,4 Like itraconazole, voriconazole is metabolized by hepatic P-450 cytochromes, including CYP2C9, CYP2C18, and CYP3A4.5 Patients at risk for invasive fungal infections tend to receive multiple medications that could potentially interact with these cytochrome enzymes. Since the authors did not mention that patients with drug interactions were excluded from their study, we wonder whether the lower response rates in this study could be related to actual or potential drug interactions.

Anucha Apisarnthanarak, M.D.
J. Russell Little, M.D.
Pablo Tebas, M.D.
Washington University School of Medicine, St. Louis, MO 63110
anucha@gwu.edu

5 References

1. 1

   Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-771
   Full Text | Web of Science | Medline

2. 2

   Winston DJ, Hathorn JW, Schuster MG, Schiller GJ, Territo MC. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy in febrile neutropenic patients with cancer. Am J Med 2000;108:282-289
   CrossRef | Web of Science | Medline

3. 3

   Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in febrile neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: a randomized controlled trial. Ann Intern Med 2000;135:412-422
   Web of Science

4. 4

   Prentice HG, Hann IM, Herbrecht R, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 1997;98:711-718
   CrossRef | Web of Science | Medline

5. 5

   Patterson BE, Roffey S, Jezequel SG, Jones B. UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: disposition in man. In: Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 17–20, 1995. Washington, D.C.: American Society for Microbiology, 1995:126. abstract.
   

Author/Editor Response

The authors reply:

To the Editor: The overall response rate that Apisarnthanarak and colleagues cite is measured by a set of criteria that were formulated in 1994 and used in a study comparing liposomal amphotericin B with conventional deoxycholate amphotericin B,1 and in subsequent studies.2-4 We included the resolution of fever as one of these criteria for a response in recognition of the time-honored use of this end point in previous studies of antibacterial and antifungal treatment in patients with febrile neutropenia. However, we have learned over time that although fever in this setting is a valuable marker for the risk of infection, the resolution of fever is not necessarily a reliable marker for a therapeutic response.

In the current study, patients were prospectively stratified as being at high or moderate risk of infection. The moderate-risk group included patients who received the study drug for a relatively short period. In our earlier study, the median period of treatment with the study drug was 10.4 days,1 whereas in the current study, it was 7.0 days. A shorter period of treatment with the study drug allowed less time for the fever to resolve before recovery from neutropenia. This lower rate of defervescence resulted in a lower overall response rate in both groups. We included the resolution of fever as a criterion for success. However, if one removes this criterion, the overall response rate is substantially higher in both groups, and the 95 percent confidence intervals demonstrate noninferiority (Table 1Table 1Effect of Resolution of Fever as a Criterion of Success on the Overall Rate of Response to Empirical Antifungal Therapy.). The lower response rates in the current study were not related to plasma voriconazole concentrations, which were higher than the minimal inhibitory concentrations for most medically important fungal pathogens.

We concur with Ullmann et al. that the main end points for future trials of antifungal agents should exclude the resolution of fever and focus on the prevention of breakthrough invasive fungal infections, survival (in cases of invasive mycosis), and the response to treatment of base-line fungal infections. Fever can be assessed separately as a secondary end point.

In response to Dr. Johnson: our noninferiority trial of voriconazole as compared with liposomal amphotericin B demonstrated that the lower limit of the 95 percent confidence interval for the point estimate falls just outside the lower limit of –10 percentage points specified by the protocol (95 percent confidence interval, –10.6 to 1.6 percentage points). The point estimate and 95 percent confidence interval are presented in the abstract and text of our report. Examination of the individual elements of the composite score for success indicates that the two treatments are similar, with the prospectively defined stratum of high-risk patients having the greater benefit (95 percent confidence interval, –9.0 to 12.4 percentage points). In addition, voriconazole was superior in reducing documented breakthrough fungal infections, particularly in the high-risk cohort.

With regard to the type of analysis performed, the prospectively developed and approved statistical plan of the National Institute of Allergy and Infectious Diseases Mycoses Study Group was based on a primary analysis of raw data. The corporate sponsor submitted a primary stratified analysis and a secondary analysis of raw data. With regard to the issue of cost effectiveness, a prospective analysis of resource utilization in the current study demonstrated a significant reduction in the number of hospital days among high-risk patients treated with oral voriconazole, suggesting potentially important cost savings. Pharmacoeconomic studies should be performed once the acquisition cost per unit of voriconazole is known.

Thomas J. Walsh, M.D.
National Cancer Institute, Bethesda, MD 20892

Peter G. Pappas, M.D.
University of Alabama at Birmingham, Birmingham, AL 35294

Drew J. Winston, M.D.
University of California, Los Angeles, Los Angeles, CA 90049

4 References

1. 1

   Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764-771
   Full Text | Web of Science | Medline

2. 2

   Prentice HG, Hann IM, Herbrecht R, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 1997;98:711-718
   CrossRef | Web of Science | Medline

3. 3

   Winston DJ, Hathorn JW, Schuster MG, Schiller GJ, Territo MC. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med 2000;108:282-289
   CrossRef | Web of Science | Medline

4. 4

   Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: a randomized controlled trial. Ann Intern Med 2001;135:412-422
   Web of Science | Medline

Citing Articles (10)

Citing Articles

1. 1

   M. J. G. T. Rüping, J. J. Vehreschild, A. Groll, C. Lass-Flörl, H. Ostermann, M. Ruhnke, O. A. Cornely. (2011) Current issues in the clinical management of invasive aspergillosis - the AGIHO, DMykG, ÖGMM and PEG web-based survey and expert consensus conference 2009. Mycoses 54:5, e557-e568
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2. 2

   Jenna J Ferrara, Conan MacDougall, Jason C Gallagher. (2011) Empiric Antifungal Therapy in Patients with Febrile Neutropenia. Pharmacotherapy 31:4, 369-385
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3. 3

   Maria J. G. T. Rüping, Jörg J. Vehreschild, Oliver A. Cornely. (2010) Primary antifungal prophylaxis in acute myeloblastic leukemia and myelodysplastic syndrome – still an open question?. Leukemia & Lymphoma 51:1, 20-26
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4. 4

   Jane A Cecil, Richard P Wenzel. (2009) Voriconazole: a broad-spectrum triazole for the treatment of invasive fungal infections. Expert Review of Hematology 2:3, 237-254
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5. 5

   Suganthini Krishnan-Natesan, Pranatharthi H Chandrasekar. (2008) Current and Future Therapeutic Options in the Management of Invasive Aspergillosis. Drugs 68:3, 265-282
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6. 6

   Nadine Shehab, Daryl D DePestel, Emily R Mackler, Curtis D Collins, Kathleen Welch, Harry P Erba. (2007) Institutional Experience with Voriconazole Compared with Liposomal Amphotericin B as Empiric Therapy for Febrile Neutropenia. Pharmacotherapy 27:7, 970-979
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7. 7

   George Aperis, Eleftherios Mylonakis. (2006) Newer triazole antifungal agents: pharmacology, spectrum, clinical efficacy and limitations. Expert Opinion on Investigational Drugs 15:6, 579-602
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8. 8

   P. Gothard, T. R. Rogers. (2004) Voriconazole for serious fungal infections. International Journal of Clinical Practice 58:1, 74-80
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9. 9

   Helen W Boucher, Andreas H Groll, Christine C Chiou, Thomas J Walsh. (2004) Newer Systemic Antifungal Agents. Drugs 64:18, 1997-2020
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10. 10

    Leonard B. Johnson, Carol A. Kauffman. (2003) Voriconazole: A New Triazole Antifungal Agent. Clinical Infectious Diseases 36:5, 630-637
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