The real-world effects of biologic therapy for inflammatory bowel disease (IBD) do not match the promising outcomes observed in randomized controlled trials, a study has shown.
In a review of outcomes of almost 50,000 patients with IBD between 1995 and 2012 — before and after the anti–tumor necrosis factor–α antibody (anti-TNF) drug infliximab (multiple brands) was introduced into the marketplace to treat Crohn disease (CD) (2001) and ulcerative colitis (UC) (2006) — infliximab did not reduce rates of IBD-related hospitalizations or intestinal surgeries.
Rather than being a reflection of the drug's efficacy in this population, the findings likely indicate misguided use of infliximab in patients with CD and underuse of the drug for patients with UC, Sanjay K. Murthy, MD, from the Ottawa Hospital, Ontario, Canada, and colleagues report in an article published online June 12 in Gut.
The researchers studied trends in the aggregate quarterly rates of IBD-related hospitalizations and intestinal resections and quarterly mean public payer prescription drug costs before and after marketplace introduction of infliximab. They compared trends in the rates of health events and costs in the infliximab era with trends that would have been expected in the absence of infliximab. They also conducted a subgroup analysis to assess the effect of publicly funded infliximab treatment.
For the primary and secondary analyses, the number of patients in the nearest quarter following marketplace introduction of infliximab included 21,561 patients with CD (1743 publicly funded infliximab users) and 27,602 patients with UC (585 publicly funded infliximab users).
The data show a trend for reduced hospitalizations of patients with CD prior to marketplace introduction of infliximab and a continuation of that trend after. Conversely, hospitalizations were increasing for patients with UC prior to the introduction of infliximab into the marketplace.
Compared with the model of expected outcomes in the absence of infliximab, rates of CD-related hospitalizations did not significantly decline in the overall cohort (odds ratio [OR], 1.06; 95% confidence interval [CI], 0.811 – 1.39), nor did the rates of CD-related surgeries (OR, 1.10; 95% CI, 0.810 – 1.50). Similarly, marketplace introduction of infliximab did not reduce the rates of UC-related hospitalizations (OR, 1.22; 95% CI, 1.07 – 1.39) or surgeries (OR, 0.933; 95% CI, 0.54 – 1.61).
For patients with CD who received publicly funded infliximab, there were no significant reductions in either outcome. For patients with UC who received publicly funded treatment, there were no reductions in disease-related surgeries, but there was a marked reduction in the rate of IBD-related hospitalizations following the introduction of infliximab. No such reduction was observed among patients with UC who did not receive publicly funded infliximab.
In the cost analyses, the researchers observed a threefold increase in public payer prescription drug costs over expected trends among patients with CD over a 10-year period after the introduction of infliximab (OR, 2.98; 95% CI, 2.29 – 3.86). Expected trends among patients with UC over a 5-year period did not change (OR, 1.06; 95% CI, 0.955 – 1.18).
For patients who received publicly funded infliximab, there was a near 10-fold rise in public payer drug costs (OR, 9.49; 95% CI, 4.45 – 20.3). No change was observed in costs among CD patients who did not receive publicly funded infliximab (OR, 1.17; 95% CI, 0.875 – 1.57), "confirming that the overall rise in drug costs in this population was due to infliximab use," the authors write.
Among patients with UC who received publicly funded infliximab, a near twofold increase in the public payer prescription drug cost (1.88; 95% CI, 1.14 – 3.12) was offset by a reciprocal decrease in the public payer prescription drug cost for UC patients who did not receive publicly funded infliximab (0.790; 95% CI, 0.704 – 0.886).
"Taken collectively, our findings suggest that increasing infliximab usage has not resulted in meaningful declines in disease-related hospitalisation or intestinal resection rates among patients with CD," the authors write. "Conversely, limited infliximab usage among patients with UC may have stifled any potential for declines in event rates at a population level, which were otherwise observed in the small subgroup of infliximab users."
The findings may not be generalizable, the authors state. They note that individuals who received publicly funded infliximab in particular "may have differed in important disease characteristics from the general IBD population." They point out that in this subpopulation, there is a greater number of older patients and patients with more aggressive disease. "Therefore, caution should be exercised when comparing trends in this subgroup with those of the broader IBD population," they explain.
The authors acknowledge that it is not possible to definitively ascertain reasons for their findings from the available data. The results suggest a disconnect between optimal and real-world use of biologics in this patient population, Murthy told Medscape Medical News.
"The fact that these drugs have been shown to reduce hospitalizations and surgeries in clinical trials suggests that inappropriate patient selection or misguided use of the treatment (including delayed treatment initiation, inadequate dosing, and insufficient patient monitoring) could be contributing factors."
In general, Murthy said, "these drugs should be targeted to patients with moderate to severe inflammatory disease, particularly those with poor prognostic factors, well before they develop severe complications necessitating hospitalization or surgery."
Other factors may also play a role, such as insufficient response to treatment in many patients and the ability to optimize treatment with conventional agents in clinical practice, "all of which may have limited the capacity for these agents to exert a significant impact in a real-world setting," he said.
"This is a well-done study and a nice example where efficacy in the clinical trial setting may not necessarily translate into effectiveness in the real-world setting," Edward V. Loftus Jr, MD, consultant, Division of Gastroenterology and Hepatology, and professor of medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, told Medscape Medical News. Loftus was not involved in the current study.
"In the clinical trial setting, at least two of the anti-TNF agents have been shown to reduce surgeries and hospitalizations in IBD. But it is often difficult in a nonrandomized observational study to show the benefit of an intervention because the sickest patients, who are more likely to have worse outcomes, are the ones most likely to receive the intervention," Loftus continued.
Some of the trends observed in the data, though not statistically significant, reflect the potential of biologic therapy in this population, he said. "The 'eyeball test' of the hospitalization data shows that there was clearly already a trend for reduced hospitalizations in CD even before the introduction of infliximab and that this continued along the same trend afterwards. In UC, the trend was increasing, and this is where introduction of infliximab was clearly associated with a break in that trend." Further, the "eyeball test" of the IBD-related surgery data "shows that introduction of infliximab was associated with a reduction in Crohn's surgeries," he said.
"These protein-based biologics are tricky to use and require expertise to monitor drug levels and act appropriately to optimize the use of the drug, so we need to continue to educate providers about how to optimally use these drugs," Loftus said. "Perhaps the advent of small-molecule drugs, which theoretically won't require as much pharmacokinetic monitoring, will make this task easier."
Further work is required to identify specific causative factors for the lack of any observed decline in hospitalization or intestinal resection rates, Murthy stressed.
"For the money being spent on these agents, we would hope for some reduction in these severe health events over time. Undoubtedly, some individuals would have benefited from this treatment and stayed out of hospital. Many individuals would have also experienced an improvement in quality of life due to better symptom control," he said. "But the fact that there is negligible overall reduction in hospitalizations and surgeries at a population level suggests that there is room for improvement in how we are using these agents."
The study was funded by the Department of Medicine, University of Ottawa, the Canadian Institutes of Health Research, and IC/ES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The authors report a variety of relevant financial relationships with numerous pharmaceutical and other healthcare companies. A complete list is available on the journal's website. Loftus has received consulting fees from AbbVie, Allergan, Amgen, Celgene, Celltrion Healthcare, Eli Lilly, Janssen, Napo Pharmaceuticals, Pfizer, Takeda, and UCB and research support from AbbVie, Amgen, Celgene, Genentech, Gilead, Janssen, MedImmune, Robarts Clinical Trials, Seres Therapeutics, Takeda, and UCB.
Gut. Published online June 12, 2019. Full text
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Cite this: Biologics in IBD: More Thoughtful Use Could Improve Outcomes - Medscape - Jun 20, 2019.