5-ASA for the treatment of Crohn s disease DR. STEPHEN HANAUER FEINBERG SCHOOL OF MEDICINE, NORTHWESTERN UNIVERSITY, CHICAGO, IL, USA

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1 5-ASA for the treatment of Crohn s disease DR. STEPHEN HANAUER FEINBERG SCHOOL OF MEDICINE, NORTHWESTERN UNIVERSITY, CHICAGO, IL, USA

2 Background RCTs investigating the efficacy of aminosalicylates for treatment of mildly to moderately active Crohn s disease have yielded conflicting results A systematic review was conducted to critically examine current available data on the efficacy of sulfasalazine and mesalamine for inducing remission or clinical response in these patients 1 A systematic review to evaluate the efficacy and safety of oral 5-ASA agents for the maintenance of medically-induced remission in Crohn s disease was also conducted 2 1. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn s disease. Cochrane Database of Systematic Reviews Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn s disease. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD003715

3 Objective To evaluate the efficacy and safety of aminosalicylates compared to placebo, corticosteroids, and other aminosalicylates (alone or in combination with corticosteroids) for treatment of mildly to moderately active Crohn s disease

4 Methods PubMed, EMBASE, MEDLINE and the Cochrane Central Library were searched from inception to June 2015 Reference lists from potentially relevant papers and review articles, as well as proceedings from major annual meetings ( ) were handsearched RCTs that evaluated the efficacy of sulfasalazine or mesalamine for the treatment of mildly to moderately active Crohn s disease compared to placebo, corticosteroids, or other aminosalicylates (alone or in combination with corticosteroids) were included

5 Data collection and analysis Data extraction and assessment of methodological quality independently performed; any disagreement resolved by discussion and consensus Methodological quality assessed using the Cochrane risk of bias tool Overall quality of evidence supporting the outcomes evaluated using GRADE criteria Primary outcome measure: induction of remission or response to treatment; secondary outcomes: mean Crohn s disease activity index (CDAI) scores, adverse events, serious adverse events and withdrawal due to adverse events Dichotomous outcomes: pooled risk ratio (RR) and 95% CI calculated using a random-effects model; continuous outcomes: mean difference (MD) and 95% CI calculated using a randomeffects model Sensitivity analyses based on a fixed-effect model and duration of therapy conducted where appropriate

6 Main results 20 studies (2367 patients) were included 2 studies judged at high risk of bias due to lack of blinding 8 studies judged at high risk of bias due to incomplete outcome data (high drop-out rates) and potential selective reporting 10 studies were judged to be at low risk of bias

7 Sulfasalazine vs placebo or corticosteroids A non-significant trend in favor of sulfasalazine over placebo for inducing remission, with benefit confined mainly to patients with Crohn s colitis 45% (63/141) of sulfasalazine patients entered remission at weeks compared to 29% (43/148) of placebo patients (RR 1.38, 95% CI 1.00 to 1.89, 2 studies) A GRADE analysis rated the overall quality of the evidence supporting this outcome as moderate due to sparse data (106 events) No difference between sulfasalazine and placebo in adverse event outcomes Sulfasalazine was significantly less effective than corticosteroids and inferior to combination therapy with corticosteroids (RR 0.64, 95% CI 0.47 to 0.86, 1 study, 110 patients) 43% (55/128) of sulfasalazine patients entered remission at 17 to 18 weeks compared to 60% (79/132) of corticosteroid patients (RR 0.68, 95% CI 0.51 to 0.91; 2 studies, 260 patients) GRADE analysis rated overall quality of evidence supporting this outcome as moderate due to sparse data (134 events)

8 Sulfasalazine vs placebo Outcome: Induction of remission (CDAI <150), therapeutic response (Van Hees Index decrease >25%) or clinical improvement

9 Sulfasalazine vs corticosteroids Outcome: Induction of remission (CDAI <150)

10 Low-dose mesalamine Low dose mesalamine (1-2 g/day) was not superior to placebo for induction of remission 23% (43/185) of low dose mesalamine patients entered remission at week 6 compared to 15% (18/117) of placebo patients (RR = 1.46, 95% CI 0.89 to 2.40; n = 302) A GRADE analysis indicated overall quality of evidence supporting this outcome was low due to risk of bias (incomplete outcome data) and sparse data (61 events) No difference between low dose mesalamine and placebo in the proportion of patients who had adverse events (RR 1.33, 95% CI 0.91 to 1.96; 3 studies, 342 patients) or withdrew due to adverse events (RR 1.21, 95% CI 0.75 to 1.95; 3 studies, 342 patients)

11 Controlled-release mesalamine (1-2 g/day) vs placebo Outcome: Induction of remission (CDAI <150 + decrease of >50)

12 High-dose mesalamine High dose controlled-release mesalamine (4 g/day) was not superior to placebo, inducing a clinically non significant reduction in CDAI (MD points, 95% CI to 6.7; 3 studies, 615 patients, GRADE = low) High dose controlled-release mesalamine was inferior to budesonide (RR 0.56, 95% CI 0.40 to 0.78; 1 study, 182 patients, GRADE = low) High dose delayed-release mesalamine (3 to 4.5 g/day) was not superior to placebo for induction of remission (RR 2.02, 95% CI 0.75 to 5.45; 1 study, 38 patients, GRADE = very low) No significant difference in efficacy compared to conventional corticosteroids (RR 1.04, 95% CI 0.79 to 1.36; 3 studies, 178 patients, GRADE = moderate) or budesonide (RR 0.89, 95% CI 0.76 to 1.05; 1 study, 307 patients, GRADE = moderate) However, these trials were limited by risk of bias (incomplete outcome data) and sparse data (small numbers of events)

13 Controlled-release mesalamine 4 g/day vs placebo Outcome: Mean change in CDAI from baseline

14 Delayed-release mesalamine 3.2 g/day vs placebo Outcome: Induction of remission (CDAI <150 and decrease >70)

15 Delayed-release mesalamine g/day vs corticosteroids Outcome: Induction of remission (CDAI <150 with or without decrease of at least 60 points)

16 Mesalamine g/day vs budesonide Outcome: Induction of remission (CDAI <150

17 Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn s disease. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD Oral 5-aminosalicylic acid for maintenance of medicallyinduced remission in CD 12 Studies (2146 participants) compared 5-ASA to placebo 7 studies judged to be at low risk of bias 5 were judged to have an unclear risk of bias There was no statistically significant difference in relapse rates at 12 months 53% (526/998) of 5-ASA patients (dose 1.6 g to 4 g/day) relapsed at 12 months compared to 54% (544/1016) of placebo patients (RR 0.98, 95% CI 0.91 to 1.07; 11 studies; 2014 patients; moderate-quality evidence) Sensitivity analyses based on an available case analysis and a random-effects model had no impact on the results One study found no difference in relapse rates at 24 months. Fifty-four per cent (31/57) of 5-ASA patients (dose 2 g/day) relapsed at 24 months compared to 58%(36/62) of placebo patients (RR 0.94, 95% CI 0.68 to 1.29, 119 patients; low-quality evidence) One pediatric study found no statistically significant difference in relapse rates at 12 months

18 5-ASA vs placebo Outcome: Relapse of CD Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn s disease. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD003715

19 Conclusions Sulfasalazine is only modestly effective with a trend towards benefit over placebo and is inferior to corticosteroids for the treatment of mildly to moderately active Crohn s disease High dose mesalamine (3.2-4 g/day) is not more effective than placebo for inducing response or remission However, trials assessing the efficacy of high dose mesalamine (4 to 4.5 g/day) compared to budesonide yielded conflicting results and firm conclusions cannot be made Future large randomized controlled trials are needed to provide definitive evidence on the efficacy of aminosalicylates in active Crohn s disease No evidence to suggest that oral 5-ASA preparations are superior to placebo for maintenance of medically-induced remission Additional randomized trials may not be justified

20 Comments Trials performed in 1970s-1990s No endoscopic assessments or confirmation of active disease No central reading CDAI or HBI as primary endpoints Maintenance trials were not randomized-responders Biologic trials that did not randomize responders were, similarly, negative Why are clinicians reporting that patients are doing well on 5-ASAs? Does it work in a subgroup of patients? (e.g. superficial disease)

21 Khanna et al. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial. Lancet 386(10006): Open-label cluster randomized controlled trial (NCT ) - Community gastroenterology practices in Belgium and Canada randomly assigned to either early combined immunosuppression or conventional management - Up to 60 adult patients per practice with Crohn s disease were followed for 2 years - Primary outcome: patients in corticosteroid-free remission at 12 months Guizzetti et al. Development of Clinical Prediction Models for Surgery and Complications in Crohn s Disease, 2017 (under review) -Development of prediction models for CD-related surgery, CD-related complications (first CD-related surgery, hospitalization or complication within 24 months) based on the REACT data

22 Univariate Associations for CD-Related Complications or CD- Related Surgery Alone: Drug use at Baseline Baseline variable Surgery Complication OR (95% CI) P-value OR (95% CI) P-value Antimetabolite use 0.75 (0.52, 1.08) (0.69, 1.04) Aminosalicylate use 0.49 (0.31, 0.79) < (0.54, 0.87) <0.01 Corticosteroid use 1.43 (0.94, 2.18) (1.11, 1.84) <0.01 TNF-antagonist use 1.45 (1.01, 2.09) (1.24, 1.89) < OR = ASA use at baseline predicts an approximate 50% decrease in the odds of having CD-related surgery within 24 months compared to no 5-ASA use. Guizzetti et al (under review)

23 Logistic Regression Risk Prediction Models for CD-Related Surgery: Drug use at Baseline OR = 0.57 Baseline predictor CD-related surgery OR (optimism corrected) (95% CI) P-value Corticosteroid use Antimetabolite use 0.66 (0.44, 0.98) aminosalicylate use 0.57 (0.35, 0.95) 0.03 TNF-antagonist use Surgery events (prevalence) 130/1,898 (6.9%) 5-ASA use at baseline predicts reduced risk of CD-related surgery after adjustment for other baseline predictors Guizzetti et al (under review)