Increased Mortality Rates With Prolonged Corticosteroid Therapy When Compared With Antitumor Necrosis Factor-α-Directed Therapy for Inflammatory Bowel Disease

Abstract

Objectives: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that compromise quality of life and may increase mortality. This study compared the mortality risk with prolonged corticosteroid use vs. antitumor necrosis factor-α (anti-TNF) drugs in IBD.

Methods: A retrospective cohort study was conducted among Medicaid and Medicare beneficiaries from 2001 to 2013 with IBD prescribed either >3,000 mg of prednisone or equivalent within a 12-month period or new initiation of anti-TNF therapy, each treated as time-updating exposures. The primary outcome was all-cause mortality. Secondary outcomes included common causes of death. Marginal structural models were used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for anti-TNF use relative to corticosteroids.

Results: Among patients with CD, 7,694 entered the cohort as prolonged corticosteroid users and 1,879 as new anti-TNF users. Among patients with UC, 3,224 and 459 entered the cohort as prolonged CS users and new anti-TNF users, respectively. The risk of death was statistically significantly lower in patients treated with anti-TNF therapy for CD (21.4 vs. 30.1 per 1,000 person-years, OR 0.78, 0.65-0.93) but not for UC (23.0 vs. 30.9 per 1,000 person-years, OR 0.87, 0.63-1.22). Among the CD cohort, anti-TNF therapy was also associated with lower rates of major adverse cardiovascular events (OR 0.68, 0.55-0.85) and hip fracture (OR 0.54, 0.34-0.83).

Conclusions: Compared with prolonged corticosteroid exposure, anti-TNF drug use was associated with reduced mortality in patients with CD that may be explained by lower rates of major adverse cardiovascular events and hip fracture.

Figure 1

Exposure definitions for the primary analysis. Patients were required to have at least 12 months of data before the start of follow-up. Follow-up began with the earliest of either (A) meeting the definition of new user of antitumor necrosis factor-α (anti-TNF) therapy or (B) meeting the cumulative dose threshold for prolonged corticosteroid (CS) use. A patient could switch from the prolonged CS use to anti-TNF use (C), but once a patient was a new user of anti-TNF therapy they were considered exposed to anti-TNF from that point forward even if they discontinued the anti-TNF drug.

Figure 2

Creation of study cohorts. *Excludes 13,088 missing one or more of gender, date of birth, race, or zip code. Anti-TNF, antitumor necrosis factor-α CD, Crohn’s disease; COPD, chronic obstructive pulmonary disease; IBD, inflammatory bowel disease; SLE, systemic lupus erythematosus; UC, ulcerative colitis.

Figure 3

Adjusted odds ratios for primary and secondary outcomes. All odds ratios are for antitumor necrosis factor-α (anti-TNF) therapy with corticosteroid therapy as the reference group. Numbers in parentheses represent the total number of outcomes in the study cohort in Crohn’s disease (a) and ulcerative colitis (b). Weighted incidence rates (IRs) are reported per 1,000 person-years. CI, confidence interval; MACE, major adverse cardiovascular event.

Figure 4

Sensitivity analysis examining different definitions of exposure. Odds ratios and 95% confidence intervals (CIs) are reported for the antitumor necrosis factor-α (anti-TNF) therapy with prolonged corticosteroid (CS) use as the reference group. In model 1 (the primary analysis), follow-up for patients continued until either the outcome of interest occurred or they reached the end of the available data. Medication exposure was unidirectionally time updating, such that patients who initially contributed follow-up time to the prolonged CS use group could later contribute follow-up time to the anti-TNF group if they initiated therapy with an anti-TNF drug. Model 2 was the same as model 1 except that follow-up was censored if an anti-TNF-treated patient discontinued anti-TNF therapy and resumed treatment with CS. Model 3 is an as treated model in which both treatments are bidirectional time-updating variables. Participants contribute follow-up time to the treatment that the patient had most recently received. Model 4 used the initial treatment to define exposure such that patients contribute follow-up time only to the treatment arm that they were in at the time of cohort entry even if the treatment is changed. Follow-up in model 4 is censored 12 months after cohort entry for all patients. Model 5 is a sensitivity analysis limited to those having received an induction course of anti-TNF therapy in the first 56 days of follow-up compared with prolonged CS use with follow-up beginning at day 57 in both groups.