Dr. Siegel has served on advisory boards for Abbott Laboratories and UCB, and as a consultant to Elan/Biogen Idec.
Patient perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel disease
Article first published online: 9 OCT 2007
Copyright © 2007 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 14, Issue 1, pages 1–6, January 2008
How to Cite
Siegel, C. A., Levy, L. C., MacKenzie, T. A. and Sands, B. E. (2008), Patient perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel disease. Inflamm Bowel Dis, 14: 1–6. doi: 10.1002/ibd.20283
- Issue published online: 10 DEC 2007
- Article first published online: 9 OCT 2007
- Manuscript Accepted: 16 AUG 2007
- Manuscript Received: 15 AUG 2007
- Crohn's and Colitis Foundation Career Development award
- Abbott Immunology
- Elan/Biogen Idec.
Background: For a patient to make informed, preference based decisions, they must be able to balance the risks and benefits of treatment. The aim of this study was to determine patients' and parents' perceptions of the risks and benefits of infliximab for the treatment of inflammatory bowel disease (IBD).
Methods: Adult patients with IBD and parents of patients attending IBD patient education symposiums were asked to complete a questionnaire regarding the risks and benefits of infliximab.
Results: One hundred and sixty-five questionnaires were completed. A majority (59%) of respondents expected a remission rate greater than 50% at 1 year and 18% expected a remission rate greater than 70% at 1 year. More than one-third (37%) of respondents answered that infliximab is not associated with a risk of lymphoma and 67% responded that the lymphoma risk is no higher than twice that of the general population. When presented a scenario of a hypothetical new drug for IBD with risks mirroring those estimated for infliximab, 64% of respondents indicated that they would not take the medication, despite its described benefits. Thirty percent of these patients were either currently taking or had previously taken infliximab. Patients actively taking infliximab predicted the highest remission rates for the infliximab (P = 0.05), and parents of patients predicted the lowest (P = 0.01). Parents estimated a higher risk of lymphoma than patients (P = 0.003). Risk and benefit perception was independent of gender and age of patient respondents.
Conclusions: Compared to published literature, patients and parents of patients overestimate the benefit of infliximab and underestimate its risks. We conclude that effective methods for communicating risks and benefits to patients need to be developed.
(Inflamm Bowel Dis 2007)
Infliximab is a chimeric monoclonal IgG1 antibody directed against tumor necrosis factor alpha (TNF-α).1 Large randomized controlled trials have confirmed the efficacy of infliximab for the induction and maintenance of both Crohn's disease (CD)2, 3 and ulcerative colitis (UC).4 Based on these data, infliximab was approved by the Food and Drug Administration (FDA) in 1998 for the treatment of CD and in 2005 for the treatment of UC. Since its approval there have been continued discussions about how to weigh the risks and benefits of infliximab.
In the maintenance trials for both CD and UC, ≈60% of patients initially responded to treatment, with about 30% of those patients maintaining remission over the course of the year.2, 4 The overall remission rate at 1 year was ≈20%. Serious side effects of infliximab are rare and can include infusion reactions, heart failure, drug-induced lupus, tuberculosis, life-threatening infections, and lymphoma.5 A black-box warning exists for infliximab regarding the incidence of serious infections and lymphoma.6 Quantifying the exact frequency of these side effects is difficult, but attempts have been made with single-center experiences,5, 7 a population-based cohort,8 data from randomized controlled trials,2, 3 a systematic review,9 and a prospective patient registry.10
The risks of life-threatening infections and lymphoma have been most closely examined and studies have yielded disparate results. The Crohn's Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry10 found that infliximab use was not an independent predictor for serious infections, but the use of corticosteroids, narcotics, and increased disease activity led to the increased risk. In TREAT, infliximab-exposed patients did not have an increased risk of lymphoma when compared to CD patients who were not exposed. On the other end of the spectrum, the Mayo Clinic experience had a 0.8% rate of mortality in infliximab-treated patients and a cohort from Stockholm, Sweden had a 1.6% rate of lymphoma.8 The systematic analysis that was performed to further evaluate this question estimated a 1-year incidence of death from serious infection of 0.4% and a rate of lymphoma of 0.2%.9 The Surveillance, Epidemiology, and End Results (SEER) database reports an annual incidence of lymphoma of ≈0.1% for those in the general population 35–44 years old.11 Therefore, a 0.2% risk of lymphoma is 20-fold higher than what is expected in the general population. This wide range of risk estimates adds a significant amount of uncertainty to this important topic.
For a patient to make informed, preference-based decisions, they must effectively be able to balance the risks and benefits of treatment. This requires an understanding of 1) the chance of responding to therapy, 2) the chance of having a significant side effect, and 3) alternative treatment options. There are no previous data reporting how much patients know about efficacy or side effects of infliximab for the treatment of inflammatory bowel disease (IBD). The purpose of this study was to determine patients' perceptions of the risks and benefits of infliximab for the treatment of IBD.
MATERIALS AND METHODS
A questionnaire was developed and pilot-tested in a sample of patients with IBD. The development process included patient interviews with cognitive debriefing to ensure survey comprehension. After an iterative review process the questionnaire was finalized and distributed to patients. Question format was closed-ended multiple choice response. Questions included: estimation of the initial response rate and the remission rate as a result of infliximab at the end of 1 year; incidence of adverse effects; minimal demanded benefit for a hypothetical drug for the treatment of IBD; and respondent characteristics. Sample questions are shown in Figure 1.
The questionnaire was distributed to adult patients and parents of patients at 2 regional Crohn's and Colitis Foundation of America (CCFA) patient education symposiums (Boston, MA; Chicago, IL). The questionnaires were completed anonymously and collected prior to a lecture on the risks and benefits of IBD therapy given by 1 of the authors (C.A.S.). The results are reported as descriptive statistics. Ordinal survey items were compared between more than 2 groups using the Kruskal–Wallis test and between 2 groups using the Wilcoxon rank sum test. Correlations of ordinal items were estimated and tested using the Kendall U-statistic. Institutional Review Board approval and approval from the CCFA were obtained prior to the distribution of any questionnaires.
There were 165 respondents to the questionnaire (Table 1). Fifty-three percent of respondents were patients and 47% were parents of patients. Of the patients, 73% had CD and 27% had UC. Fifty-nine percent of the children of responding parents had CD and 41% had UC. A majority (68%) of the respondents were female. All respondents were 18 years of age or older and the median age of the adult patient respondents was 46 years. The median age of the children of responding parents was 16 years.
|Total number of respondents||165|
|Parents of patients||74/159 (47%)|
|Age of adult patient (median)||46|
|Age of children (median)||16|
|Respondents who had heard of infliximab||143/159 (90%)|
|Previous or current treatment with infliximab||52/159 (33%)|
|Remember risk/benefit discussion||86/161 (53%)|
Ninety percent of respondents had heard of infliximab. One-third (33%) of the patients were receiving infliximab or had received infliximab in the past. Half (53%) of the respondents recalled discussing the risks and benefits of infliximab with their physician. Forty-five percent did not remember any such discussion and 2% were not sure if this discussion had taken place.
Respondent estimates for the frequency of clinical response to infliximab at 2 weeks are shown in Figure 2. Estimated 1-year remission rates, separated by patients and parents of patients, are shown in Figure 3. The estimated chances of developing lymphoma or dying from a severe infection are shown in Figures 4 and 5. Thirty-six percent of patients gave various levels of minimal demanded benefit of the hypothetical drug for IBD (between <10% and 95% chance of remission), and 64% of patients responded that they would not take the drug even if the medication induced remission 95% of the time (Fig. 6). One-third (33%) of the patients who answered that they would not take the medication were either currently taking or had taken infliximab in the past.
Bivariate analysis was performed to analyze associations between respondent characteristics and the results. Current infliximab users had the highest estimates of the 1-year remission rate (P = 0.05), while parents of patients had the lowest estimates of the 1-year remission rate (P = 0.03). Parents of patients had the highest estimates of the risk of lymphoma (P = 0.003). Recalling a discussion regarding the risks and benefits of infliximab did not impact respondent answers. Estimates were independent of gender, age, type, or length of disease.
Infliximab can be a powerful treatment for patients with IBD. It can induce remission when other treatments have failed2; it may decrease hospitalizations and surgeries12, 13; and, despite its expense, infliximab appears to be a cost-effective treatment strategy.14 Furthermore, even with an increase in adverse events such as life-threatening infection and lymphoma, overall quality of life may be improved in infliximab-treated patients.9 Since each patient has a different threshold for acceptable risks or benefits, individual patient preferences need to be included in the decision-making process. Before patients can be engaged in this process, they first need to understand their chance of improving from treatment and its associated risks.
Results from this survey show that patients and parents of patients have a wide range of estimates of the risks and benefits of infliximab. As compared to the maintenance trials for CD2 and UC4 and a systematic analysis of risks,9 the majority of respondents overestimate the efficacy of infliximab and underestimate its risks. Furthermore, when given a hypothetical scenario of a new treatment for CD with a mortality risk reflecting what has been observed in some centers with infliximab, the majority of patients (> 60%) responded that they would not take the medication, even if it led to remission 95% of the time. Within this majority, about one-third of respondents had previously taken or were currently taking infliximab.
Patients and parents of patients perceive risks and benefits differently. Patients currently taking infliximab were the most optimistic of its benefit, while parents of patients predicted a lower chance of remission and higher risks. Most likely, patients actively being treated with infliximab are responding to treatment (and therefore perceive that the overall response rate must be high), while parents of patients may be more conservative (and protective) in their estimates.
The optimistic perceptions of risks and benefits may be due to a variety of reasons. First, patients (and parents of patients) likely want to maintain a hopeful outlook for the future. Second, physicians who prescribe infliximab may be implying or explicitly conveying this optimistic view. This may be due to their own perception of the data, lack of adequate time for discussion during office visits, or a result of framing the data in such a way to encourage patients to be optimistic about response and less concerned about side effects. Finally, it is likely that marketing plays some role in both patients' and physicians' beliefs.
There are limitations to our study. It is difficult for many patients to comprehend quantitative concepts such as chance and percentages.15 In addition, through a questionnaire it is possible that patients misinterpreted the response choices. Some patients may not have understood the question about minimal demanded benefit, as only 72% of those surveyed responded to this question. However, in pilot testing of the questionnaire this did not seem to be the case, as respondents were accurate and appropriate in their responses. The subjects in this study are a select group of motivated patients and parents of patients attending CCFA patient education symposiums. We are uncertain how this might affect perceptions of treatment efficacy and risk, but it is possible that these perceptions do not reflect those of the general population of patients. Next, the respondents were given hypothetical situations on which to base their answers. Although this technique is effective for standardization, it is possible that patients and parents would answer differently when put in an actual situation deciding on therapy for themselves or their children.
It is important to note that the rates of risks and benefits of infliximab are uncertain. Although it is unlikely that the 1-year remission rates are as high as patient estimates, the 20% overall remission rate seen in the ACCENT 1 study2 is likely to be lower than the rates experienced in clinical practice. In addition, the risks of lymphoma and death as a result of infliximab are controversial. Therefore, we cannot definitively state that the subjects responding to the questionnaire are inaccurate in their estimates. We did not evaluate patient estimates for the risks and benefits of other biologic agents or other classes of IBD medications. Other anti-TNF-α agents appear to have a similar risk/benefit profile to infliximab, but were not included in this survey as they had not been FDA-approved at the time of questionnaire distribution.
We do not know of previous studies of IBD patients' perceptions of treatment risks and benefits or evaluating their minimal demanded benefit of therapy. One recent study of CD patients used conjoint trade-off analysis to study patients' maximal acceptable risk of treatment related side effects (specifically, dying from progressive multifocal leukoencephalopathy, lymphoma, or serious infection).16 In this study, when given a 100% chance of therapeutic response, patients accepted a surprisingly high risk of therapy. Patient perceptions of the rate of side effects or the minimal demanded benefit of therapy were not evaluated.
Future studies on this topic should be performed to understand further how we can improve patient communication. While our study specifically queried knowledge about the risks and benefits of infliximab, it is equally important for patients to learn about all IBD treatment options (including surgery). Currently, patients receive information from a number of sources (their physicians, friends and family, the internet, the media, and direct consumer marketing). Ideally, consistent, evidence-based data could be presented in a clear format for patients to use as a decision-making tool. Then these tools (decision aids) can be studied to see if they can improve patient understanding, decision-making, and ultimately quality of life.
The treatment of IBD is evolving rapidly, and as new medications and treatment algorithms (such as “top-down therapy”) are developed it will become even more important to properly educate patients. This study shows that patients have misperceptions of the risks and benefits of infliximab for the treatment of IBD and may be taking medications with risk/benefit profiles that do not align with their preferences. To ensure that patients are making treatment decisions concordant with their personal values, it is imperative to find effective methods of patient communication.
- 6Remicade (infliximab) for IV injection (prescribing information). Available at: http://www.centocor.com/biomedicines/pdf/REMICADE_PI. pdf#zoom=100. Accessed April 30, 2007.
- 11SEER. Surveillance, Epidemiology, and End Results Database. Available at: http://seer.cancer.gov/. Accessed on May 2, 2007.
- 13Remission 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., , , et al.Direct Link: