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Empirical Anti-Candida Therapy among Selected Patients in the Intensive Care Unit: A Cost-Effectiveness Analysis

Yoav Golan, MD; Michael P. Wolf, MD; Stephen G. Pauker, MD; John B. Wong, MD; and Susan Hadley, MD
[+] Article and Author Information

From Tufts-New England Medical Center, Boston, Massachusetts.


Note: This paper was presented in part at the 31st Congress of The Society of Critical Care Medicine, San Diego, California, 26-30 January 2002.

Acknowledgments: The authors thank Jerome Wilson, MA, PhD; Yehuda Carmeli, MD; and Corrado Marini, MD, for their contribution to this work, and Debra Poutsiaka, MD, for reviewing this manuscript.

Grant Support: In part by Pfizer Inc. and the National Library of Medicine (T15 LM07092-11).

Potential Financial Conflicts of Interest: Consultancies: S. Hadley (Schering-Plough); Honoraria: Y. Golan (Cubist Pharmaceuticals, Wyeth, Merck & Co. Inc.); J.B. Wong (Schering-Plough, National Library of Medicine, National Institute of Drug Abuse, Agency for Healthcare Research and Quality), S. Hadley (Merck & Co. Inc., Pfizer Inc.); Grants received: J.B. Wong (National Library of Medicine, National Institute of Drug Abuse, Agency for Healthcare Research and Quality, Schering-Plough), S. Hadley (Astellas Pharma, Pfizer Inc.).

Requests for Single Reprints: Yoav Golan, MD, Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, 750 Washington Street, Box 041, Boston, MA 02111; e-mail, ygolan@tufts-nemc.org.

Current Author Addresses: Drs. Golan and Hadley: Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Box 041, 750 Washington Street, Boston, MA 02111.

Dr. Wolf: 613 Woodhills Drive, Goshen, NY 10924.

Dr. Pauker: Department of Medicine, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111.

Dr. Wong: Division of Clinical Decision Making, Informatics, and Telemedicine, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111.

Author Contributions: Conception and design: Y. Golan, M.P. Wolf, S.G. Pauker, J.B. Wong, S. Hadley.

Analysis and interpretation of the data: Y. Golan, M.P. Wolf, S.G. Pauker, J.B. Wong, S. Hadley.

Drafting of the article: Y. Golan, S.G. Pauker, J.B. Wong, S. Hadley.

Critical revision of the article for important intellectual content: Y. Golan, M.P. Wolf, S.G. Pauker, J.B. Wong, S. Hadley.

Final approval of the article: Y. Golan, M.P. Wolf, S.G. Pauker, J.B. Wong, S. Hadley.

Provision of study materials or patients: Y. Golan.

Statistical expertise: Y. Golan, S.G. Pauker, J.B. Wong.

Obtaining of funding: Y. Golan, J.B. Wong, S. Hadley.

Administrative, technical, or logistic support: Y. Golan, J.B. Wong.

Collection and assembly of data: Y. Golan.


Ann Intern Med. 2005;143(12):857-869. doi:10.7326/0003-4819-143-12-200512200-00004
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Invasive candidiasis is emerging as an important nosocomial infection, particularly among patients in the ICU, and its mortality remains high. A treatment strategy that does not depend on positive culture results and can be initiated early is particularly attractive because it might overcome problems of culture sensitivity and irreversibility of advanced infection. However, such an early intervention strategy will expose many patients without invasive candidiasis to anti-Candida agents, risking morbidity related to drug toxicity, perhaps increasing costs of care, and contributing to an accelerated emergence of drug resistance. Empirical therapy is an early intervention strategy, but a clinical trial has not yet evaluated it. Before our analysis, the theoretical disadvantages of such a strategy seemed to offset its potential advantages. Consequently, using conservative probability estimates, we developed a decision analysis model that compared the cost-effectiveness of empirical fluconazole or caspofungin therapy given to selected patients in the ICU with that of other treatment strategies.

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Figure 1.
Estimating the fraction of candidemic and noncandidemic invasive candidiasis and the fraction of intensive care unit (ICU) population that is included in the target group.

A. Estimating the fraction of candidemic invasive candidiasis (IC) included in the target group (FRACTIONcandidemicIC |target). On the basis of available ICU databases, the proportion of cases of ICU candidemia that are diagnosed on day 4 or later in the ICU is 0.75. Of these, 0.7 occur in patients who received at least 3 days of antibacterial therapy, and 0.8 of these patients with candidemia present with fever, hypothermia, or unexplained hypotension. These patients are unlikely to resolve their symptoms with antibacterial therapy. B. Estimating the fraction of noncandidemic IC included in the target group (FRACTIONnoncandidemicIC|target). On the basis of available ICU databases, 0.5 of all diagnosed cases of noncandidemic IC in patients in the ICU (mostly intraabdominal) are diagnosed on day 4 or later in the ICU. Of these, 0.8 occur in patients who received at least 3 days of antibacterial therapy. Of those who receive at least 3 days of antibacterial therapy, 0.5 remain febrile, hypothermic, or hypotensive. This relatively low fraction reflects the fact that many intraabdominal isolates of Candida are not clinically relevant; thus, 0.5 of patients with Candida isolated from their intraabdominal cavity resolve symptoms when receiving antibacterial therapy. C. Estimating the fraction of the ICU population included in the target group (FRACTIONallICUpts |target). On the basis of available ICU databases, 0.6 of patients stay in the ICU for more than 2 days. Of patients who stay more than 2 days, 0.6 will receive 3 or more days of antibacterial therapy. Of those who receive 3 or more days of antibacterial therapy, 0.2 remain febrile, hypothermic, or hypotensive despite therapy. In summary, 0.07 of all patients in the ICU are included in the study's target cohort.

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Figure 2.
Tornado diagram for marginal cost-effectiveness (CE) ratio per discounted life-year (DLY) saved.

The darker portion of each bar represents the higher values for the corresponding sensitivity range tested. For example, for fluconazole-related mortality, 0.75% is to the right of the bar. For invasive candidiasis (IC) prevalence, 20% is to the left of the bar. The upper 3 analyses and the lower 10 analyses examined the effect of varying the value of base-case estimates on the marginal CE ratio of empirical caspofungin and fluconazole, respectively. The horizontal axis represents the discounted incremental CE ratio for each value on the vertical axis. The width of the bar associated with each variable illustrates the range for the CE ratio. The upper and lower limits followed by the base-case value for each variable tested are in parentheses. The bars are ordered from least width at the bottom to the greatest width at the top. The comparator for analyses of fluconazole CE ratio, excluding the analysis of fluconazole resistance rates, is culture-based fluconazole, the next most effective treatment strategy. For the analysis of fluconazole resistance rates, culture-based fluconazole is replaced with culture-based caspofungin as the next most effective strategy at a fluconazole resistance rate of 17%. The comparator for analyses of caspofungin CE ratio, excluding the analysis of fluconazole resistance rates, is empirical fluconazole, the next most effective treatment strategy. For the analysis of fluconazole resistance rates, empirical fluconazole is replaced with culture-based caspofungin at a fluconazole resistance rate of 34%. Because the effectiveness and cost of both empirical and culture-based caspofungin are not affected by fluconazole resistance, any further increase in fluconazole resistance rates has no effect on the marginal CE ratio of empirical caspofungin. ICU = intensive care unit.

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Appendix Figure 1.
The decision tree comparing 9 anti-Candidatreatment strategies.

Circles denote chance nodes; each is assigned a probability estimate. Entering the branch are patients in the intensive care unit (ICU) with fever, hypothermia, or unexplained hypotension despite 3 days of antibiotic therapy. Culture specimens are assumed to be obtained from all patients. Candida culture results can be positive or negative. Positive results may represent an infection or culture contamination. Negative results may represent no infection or a false-negative result. In the 4 branches of empirical therapy, all patients receive therapy regardless of culture result. In the 4 branches of culture-based therapy, only patients with Candida-positive cultures receive therapy, that is, patients with false-negative results remain untreated. In the branch representing no therapy, no patient receives therapy regardless of culture results. For both patients with true-positive or false-negative culture results, Candida infection might result in death or survival. Patients who die of their infection may die early (on average, 3 days after culture specimen was obtained) or late (on average, 7 days after culture specimen was obtained) due to fulminant infection. Those who survive or are not infected may have anti-Candida drug-related toxicity, that is, renal failure requiring dialysis, and may die of toxicity. Those who survive to this point may still die of other causes that are unrelated to Candida infection or drug toxicity, such as an underlying comorbid condition. Each sub-branch describes a subpopulation that followed its pathway. Lipid formulation of amphotericin B.

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Appendix Figure 2.
Results of meta-analysis of 4 trials evaluating the efficacy of fluconazole versus comparator in treating invasive candidiasis in patients older than 13 years of age.
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Cost-per-life-year calculation requires to include all costs of life extension
Posted on January 3, 2006
Afschin Gandjour
Institute of Health Economics and Clinical Epidemiology, University of Cologne, Cologne, Germany
Conflict of Interest: None Declared

Yoav Golan and colleagues present a cost-effectiveness analysis of several anti-Candida strategies for high-risk patients in the intensive care unit (1). They evaluate treatment effectiveness by the number of life years gained resulting from a reduction of hospital mortality. As a cost they include initial hospitalization costs. This approach, however, overestimates treatment cost-effectiveness and provides unduly favorable cost-effectiveness ratios. When assessing treatment effectiveness by the number of life years gained, costs for health care services required to provide this gain must be included too (2). After all, not only the anti- Candida therapy and the initial hospital stay are responsible for the life years gained, but also health care services delivered in the years between hospital discharge and death. Therefore, the appropriate approach is to include all health care costs - or at least those responsible for life extension - incurred during the period between hospital discharge and death.

References

1. Golan Y, Wolf MP, Pauker SG, Wong JB, Hadley S. Empirical anti- Candida therapy among selected patients in the intensive care unit: a cost -effectiveness analysis. Ann Intern Med. 2005;143(12):857-69.

2. Nyman JA. Should the consumption of survivors be included as a cost in cost-utility analysis? Health Econ. 2004;13(5):417-27.

Conflict of Interest:

None declared

Survivor costs in cost-effectiveness analysis?
Posted on February 8, 2006
Yoav Golan
Tufts-New England Medical Center
Conflict of Interest: None Declared

Dr. Gandjour raises an interesting point: in cost-effectiveness analysis the exclusion of survivor costs (costs associated with a treatment because it extends the patient's life) could impact upon the calculated cost-effectiveness ratio. He suggests that by excluding such costs, we calculated unduly favorable cost-effectiveness ratios.

The purpose of cost-effectiveness analysis is to provide a metric of comparison of potential uses of limited resources (the "medical commons" [1]). There is no gold standard threshold willingness to pay. To be useful such analyses must use standard methodology, as we have done [2, 3].

In response to Dr. Grandjour's suggestion, we searched PUBMED to identify all cost-effectiveness analyses published from January 1st 2003 to December 31st 2005 in five major medical journals (JAMA, Annals of Internal Medicine, The New England Journal of Medicine, Lancet, and British Medical journal). Only two of 43 identified articles included survivor costs, both of which were partial and disease-unadjusted.

Reading Nyman's paper [4], there is little consensus regarding the inclusion of survivor costs in cost-effectiveness analysis. Even those who favor the inclusion of such costs, disagree regarding the type of costs to be included. Consequently, a dependable methodology that enables the inclusion of survivor costs has not been developed. Furthermore, the inclusion of such costs would bias analyses toward non-intervention unless an adjustment of willingness-to-pay thresholds occurred.

When the calculated cost-effectiveness ratio is close to the acceptable threshold and survivor's future cost-of-care is expected to offset future earnings, the addition of survivor costs could render an otherwise cost-acceptable intervention to an unacceptably expensive one. Invasive candidiasis in ICU patients, the subject to our analysis, is described to be associated with a high case-fatality rate and a lower survivor's life expectancy, both incorporated into the analysis, but not with impaired future productivity [2]. If one includes survivor costs, then such productivity might also be included. Hence, the inclusion of survivor costs would make our analysis less useful and generalizable, while not affecting our conclusion that selective empiric use of anti- candida therapy in patients in the intensive care unit is a reasonable strategy.

References

1. Hiatt HH. Protecting the medical commons: who is responsible?. NEJM 1975; 293:235-241.

2. Golan Y, Wolf MP, Pauker SG, Wong JB, Hadley S. Empirical anti- Candida therapy among selected patients in the intensive care unit: a cost -effectiveness analysis. Annals of Internal Medicine, 2005;143:857-869

3. Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost- effectiveness in health and medicine. New York: Oxford University Press, 1996.

4. Nyman JA. Should the consumption of survivors be included as a cost in cost-utility analyses? Health Economics 2004;13:417-427.

Conflict of Interest:

None declared

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