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P-122 Comparative Efficacy of Pharmacological Agents for Moderate-Severe Crohn's Disease in Patients with Prior Exposure to Anti-TNF Agents: A Network Meta-Analysis

Background: Anti-TNF agents are effective in inducing remission in 30% to 40% of biologic-naïve patients with moderate-severe Crohn's disease (CD) in clinical trials. Even patients who initially respond to anti-TNF therapy frequently lose response over time. With several new effective agents recently available or anticipated to become available shortly, a synthesis of comparative efficacy of second line agents may inform clinical decision-making in this patient population. Hence, we conducted a systematic review with network meta-analysis of patients with moderate-severe CD with prior exposure to anti-TNF agents, to inform relative efficacy of second line agents for induction of clinical remission. Methods: We conducted a systematic literature, through August 2016 of multiple electronic databases and conference proceedings, to identify randomized controlled trials (RCTs) in patients with moderate-severe CD treated with anti-TNF agents (infliximab, adalimumab, certolizumab pegol), anti-integrin agents (vedolizumab) or anti-IL 12/23 agents (ustekinumab) for induction of clinical remission. We included trials, which reported efficacy of intervention in a subset of patients with prior exposure to anti-TNF agents. To evaluate comparative efficacy, we performed direct and random-effects network meta-analysis of all treatments, and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. Results: We included 6 RCTs (1606 patients) comparing adalimumab, vedolizumab and ustekinumab in patients with moderate-severe CD with prior exposure to anti-TNF agents. In these patients, high quality evidence supports the use of ustekinumab (failure to achieve remission: OR, 0.39; 95% CI, 0.23–0.67), over placebo. Despite similar summary estimates, only moderate quality evidence supports the use of adalimumab (OR, 0.28; 95% CI, 0.13–0.60) over placebo as second-line biologic agent; evidence was rated down for indirectness due to selective inclusion of only patients with intolerance or secondary loss of response to infliximab, excluding patients with investigator-defined primary non-response to infliximab. Low quality evidence supports the use of vedolizumab (OR, 0.65; 95% CI, 0.33–1.30), over placebo, for inducing remission in patients with prior exposure to anti-TNF agents; evidence was rated down for very serious imprecision. Similar results were observed for the outcome of induction of clinical response (all agents versus placebo—ustekinumab, OR, 0.40 [95% CI, 0.22–0.73]; adalimumab, OR, 0.45 [95% CI, 0.21–0.95]; vedolizumab, OR, 0.61 [95% CI, 0.32–1.18]). There was very low confidence in estimates derived from comparison of active interventions, due to very serious imprecision and intransitivity, and no agent clearly stood out as being superior to others. Conclusions: Among patients with moderate-severe CD with prior exposure to anti-TNF agents, high quality evidence supports the use of ustekinumab whereas low quality evidence supports the use of vedolizumab, over placebo. While adalimumab is effective in patients with intolerance or secondary loss of response to infliximab, it's efficacy in patients with primary non-response is unclear. Head-to-head trials are warranted to inform clinical decision-making with greater confidence.