Exploring Utilities and Outcomes With Infliximab Therapy

Editorial Exploring Utilities and Outcomes With Infliximab Therapy he provocative study presented by Siegel et al1 in this issue of Clinical Gastroenterology and Hepatology provides a framework by which we might quantitatively compare the benefit of disease remission with the adverse events potentially associated with infliximab therapy for Crohn’s disease. This editorial serves to comment on the methodologic process used to conduct the study in addition to the clinical implications of the results. It is notable that any intervention is able to achieve absolute gains in quality-adjusted life years. Infliximab is predicted to achieve this despite conservative estimates regarding the short-term efficacy of the medication. The benefit of infliximab was derived from the ACCENT I study in which the calculated response rate of infliximab-treated patients was 25%, with a remission rate of 19% after 1 year of therapy.2 Although an improvement over standard therapy, it is considered that these response and remission rates are likely an underestimate of the potential efficacy of this medication. In fact, analysis of the entire ACCENT I study population, including patients who received additional infliximab despite failing to respond initially or losing response temporarily, indicates that response and remission rates at the end of 1 year of therapy are in the range of 56%– 63% and 35%– 41%, respectively.3 Improved response and remission rates will lead to fewer hospitalizations, operations, and deaths directly related to disease activity and therefore might improve quality of life in addition to reducing resource use.4 The overall benefit of infliximab was also predicted, despite using high estimates of risk associated with infliximab therapy. In the base-case analysis, use of infliximab was associated with an increase in all-cause mortality compared with standard therapy, with the primary cause of death being sepsis. This increase in infliximabassociated mortality was derived from controlled clinical trials, single-center and population-based cohorts. Caution, however, must be exercised when interpreting these studies because of a lack of suitable controls. The actual magnitude of the risk of serious infliximab-related complications and mortality remains an open question. The authors of the decision analysis chose not to include recently published data from the TREAT registry with more than 3000 patients with Crohn’s disease treated with infliximab because of selective patient enrollment.5 Data from this registry are reassuring, with no significant increase in mortality associated with infliximab therapy. In addition, the authors might have underestimated the risks assigned to standard therapy, at least when standard therapy included chronic corticosteroid use. Re-

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cent data from the TREAT registry and other studies indicate that corticosteroid use is a critical independent predictor of serious infection and death.5,6 It is important to note that in the pooled analysis, 4 of 9 patients who died while taking infliximab were also taking corticosteroids. Furthermore, the authors assumed that corticosteroid use was equivalent in both treatment strategies; however, data from ACCENT 1 indicate that upward of 50% of patients receiving infliximab are able to taper and remain off corticosteroids.3 Another source of excess mortality associated with infliximab therapy is the potential risk of lymphoma. This association is reinforced by the case report from Schwartz et al,7 which appears in this issue of the journal; however, the magnitude of the lymphoma risk remains uncertain. In the base-case analysis of the Siegel model, the risk was assumed to be 2/1000 patients. The confidence intervals around this estimate are wide, given that the rate is based on just 5 cases. Data from postmarketing safety reports and the TREAT registry suggest that the rate might be lower, but the paucity of data on this subject precludes a definitive answer. What is important to point out, however, is that across the clinically plausible range of lymphoma risk that might be associated with immunomodulatory or infliximab therapy, treatment remained associated with an absolute gain in quality-adjusted life years (QALYs). The finding that infliximab provides greater QALYs despite an increase in mortality deserves comment. In most cases, increases in QALYs are associated with increases in survival. How, in this case, are these 2 outcomes divergent? The answer is rooted in the decrement in “utility” assigned to represent symptomatic Crohn’s disease. Utilities are a measure of patients’ preferences for various states of health and disease. Generally the range of values varies from 0 (dead) to 1 (perfect health), although it is possible to include a state “worse than death” to which the patient conceivably could prefer death. The inclusion of utilities in an economic analysis incorporates patients’ preferences associated with morbidity of disease to weight time spent in good health more favorably compared with time spent in poor health. In the case of Crohn’s disease, this means that time spent in disease remission is modeled to be of greater value than time spent in disease flares. The methods by which utilities are derived include time trade-off or standard gamble. In time trade-off studies, subjects make decisions to “trade off” lifetime associated with symptomatic disease for a lesser amount of time spent in perfect health. Standard gamble techniques are characterized by offering subjects a chance of disease cure or remission with an intervention that is also associated with a chance of immediate death. Both methods result in a measure of the fraction of perfect CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:976 –978

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health that a particular disease state represents. An economic study that incorporates these measures is defined as a cost-utility analysis, and the outcome is usually stated in terms of QALYs. QALY gains with infliximab therapy therefore reflect the improvement in quality of life perceived by patients who experience remission from symptomatic Crohn’s disease. Patients with moderate to severely active Crohn’s disease have a severely impaired quality of life with major deficiencies in mental and physical functioning, leading to outcomes such as high unemployment rates.4 Remission in Crohn’s disease is associated with reduced hospitalizations, operations, increased employment, and normalization of quality of life.4,8 These gains in quality of life are then compared with the risk of death from side effects of the drug, including sepsis and lymphoma. In this case the investigators concluded that the improvement in quality of life associated with infliximab more than offset the increase in mortality caused by sepsis and lymphoma. Previous cost-utility studies in Crohn’s disease have found that model output is very sensitive to the assigned utility values.9 There must be a threshold value of utility decrement associated with disease flare below which the improvement in quality of life with infliximab would be insufficient to counter the impact of death from adverse effects. Unfortunately, there is a paucity of data on utility values obtained from patients with moderate to severely active Crohn’s disease, especially those treated with infliximab.9 This study provides the perfect rationale to encourage funding of a study in which utilities associated with the health states in Crohn’s disease, lymphoma, and sepsis could be prospectively identified to determine whether inclusion of more accurate values would alter the conclusions of this analysis. The time horizon over which the investigators chose to examine outcomes might have impacted the outcome. Although infliximab can be used to both induce remission and maintain remission indefinitely, this study evaluated outcomes restricted to the first year of therapy. This appears sensible because of the lack of longterm data available for infliximab, but it potentially diminishes the impact of death because this assumes the durability of infliximab response is constant. For example, a patient might choose to accept a therapy that has high chance of immediate death if the durability of remission could be assured to be prolonged; in contrast, that same patient would likely choose a different course if the duration of remission with infliximab was relatively short. By modeling a 1-year time period, the model assumes that preferences concerning therapy would be the same regardless of whether infliximab induced remission for 1 year or 10 years. In a similar manner, the time horizon creates assumptions about the nature of adverse events. If adverse events are “front loaded” or predominantly occur within

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the first year of therapy, extension of the time horizon could result in even greater QALYs gained with infliximab; conversely, if the incidence of sepsis or lymphoma increases over time, a longer time horizon would reveal reduction in benefit. Even if adverse events occurred at a constant rate (ie, a linear assumption), modeling a longer time period would likely adversely impact the infliximab arm as a result of mortality among patients in whom lymphoma developed, but they did not die within the first year of observation. The bottom line is that long-term data on the efficacy and safety of infliximab therapy are urgently needed. Another detail related to the model structure is that the design is a decision tree that does not account for time spent within the various health states. This means that patients who achieve remission at any point in the model are assigned the full value of remission for the entire duration examined. This in itself would not necessarily influence the results; however, crossover from the infliximab strategy to the standard therapy is allowed for subjects who fail, whereas no “salvage” therapy is allowed for patients assigned to initial standard therapy. As a result, the model allows subjects who achieve remission with standard therapy after failing infliximab to receive “full credit” for remission, whereas a similar possibility does not exist for those assigned to initial standard therapy. This discrepancy could potentially bias the results in favor of infliximab, depending on the proportion assumed to achieve remission through the various interventions. Finally, this study did not analyze the costs associated with infliximab versus standard therapy. Other economic studies in Crohn’s disease have found that major direct costs of the illness are related to hospitalizations and operations, so a therapy such as infliximab that limits the needs for these interventions might be costeffective, despite the high costs of the medication.8 The costs of the therapy as a function of the benefit derived (incremental cost-utility ratio) are of major interest to policy makers and third party payers, but it likely has little impact on shared decision making that occurs between patient and clinician. In summary, this study concludes that infliximab therapy for moderate to severely active Crohn’s disease is associated with more QALYs than standard therapy during the initial year of treatment. Therefore in this patient population, the short-term benefits of therapy likely outweigh the risks in most instances. This benefit was realized despite conservative estimates regarding the shortterm efficacy and safety of the medication. Although the analysis is favorable with respect to the use of infliximab, the impact of the study on clinical decision making is hampered by the lack of long-term outcome data. In addition, the study highlights the importance of utilities, and the preference of patients for various states of health and disease, in determining optimal treatment strategies

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for a given patient. These preferences are in great part a function of the quality of life associated with each state. For the “average” patient with moderate to severely active Crohn’s disease, quality of life is markedly reduced, and therapies that can induce remission and improve quality of life are desirable, even if somewhat risky. At the heart of the decision making and informed consent process regarding Crohn’s disease therapy, there is an informal decision analysis conducted by the patient and facilitated by the clinician. For patients to make informed decisions, the best available efficacy and safety data need to be presented. It is then up to the patient to weigh the probabilities of success, failure, and complications of a spectrum of treatment strategies and the “values” they personally assign to each of these outcomes. This study provides an important and practical framework for this type of decision making with respect to infliximab therapy in Crohn’s disease. JOHN M. INADOMI, MD*‡ JONATHAN TERDIMAN, MD‡ ⴱDivision of Gastroenterology San Francisco General Hospital San Francisco, California ‡Center for Colitis and Crohn’s Disease Division of Gastroenterology Department of Medicine University of California, San Francisco San Francisco, California

References 1. Siegel CA, Hur C, Korzenik JR, et al. Risks and benefits of infliximab for the treatment of Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1017–1024. 2. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–1549. 3. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004;126:402– 413. 4. Lichtenstein GR, Yan S, Bala M, et al. Remission in patients with Crohn’s disease is associated with improvement in employment and quality of life and a decrease in hospitalizations and surgeries. Am J Gastroenterol 2004;99:91–96. 5. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621– 630. 6. Agrawal A, Durrani S, Leiper K, et al. Effect of systemic corticosteroid therapy on risk for intra-abdominal or pelvic abscess in nonoperated Crohn’s disease. Clin Gastroenterol Hepatol 2005;3: 1215–1220. 7. Schwartz LK, Kim MK, Coleman M, et al. Case report: lymphoma arising in an ileal pouch anal anastamosis after immunomodulatory therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol 2006;4:1030 –1034. 8. Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource use among patients with Crohn’s disease. J Clin Gastroenterol 2002;35:151–156. 9. Bodger K. Economic implications of biological therapies for Crohn’s disease: review of infliximab. Pharmacoeconomics 2005; 23:875– 888.

doi:10.1016/j.cgh.2006.05.023