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• W2058217314 abstract "We read with great interest the paper by Panes et al1Panés J. et al.Gastroenterology. 2013; 145: 766-774Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar regarding the efficacy of early azathioprine (AZA) therapy in early Crohn’s disease (CD). The “AZathioprine for Treatment or Early Crohn’s disease in adults” (AZTEC) study was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial conducted in 31 Spanish hospitals over 3 years. The authors developed a randomized placebo-controlled trial in very early CD patients (<8 weeks of diagnosis) without bowel damage (symptomatic stenotic, penetrating, or perianal disease). After entering clinical remission, patients were randomized to receive AZA or placebo. The end point was steroid-free remission at week 76. Unfortunately, the trial was stopped for futility.Other points, such as patient selection and the definition of the primary end point, should be taken into account when interpreting the data. The disease in the patient population was quite mild and not representative of that regularly seen in clinical practice: 92% of patients had pure inflammatory disease, extensive disease location was observed in only one-third of patients, and complicated disease was excluded. In addition, about 30% of patients did not require steroids as initial therapy. The primary efficacy end point was steroid-free remission at week 76, but relapse was defined by the Crohn’s Disease Activity Index. Nevertheless, there was a benefit of AZA use with a slightly modified definition of relapse (Crohn’s Disease Activity Index >220; absolute difference, 18.4%; P = .01). Finally, the study was clearly underpowered to investigate the potential for disease modification of AZA in early CD. The event numbers of more robust outcomes (eg, fistula development, need for surgery) were too low to allow a meaningful analysis. Therefore, we propose an alternative interpretation of the findings. CD patients with a mild phenotype at diagnosis do not necessarily benefit from systematic early introduction of AZA therapy. The study also highlights that in the future we will need to use composite end points (including objective signs of inflammation such as mucosal healing and biomarker remission) to enable a more objective assessment of efficacy and decrease the placebo effect.In a similar study by the GETAID2Cosnes J. et al.Gastroenterology. 2013; 145: 758-765Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar group, early aggressive therapy with AZA within 6 months of diagnosis was no more effective than “conventional” management in increasing time of clinical remission as assessed by trimesters for 36 months. Overall, these findings are broadly similar to those of the AZTEC trial even though the need for perianal surgery was lesser (4% vs 18%; P = .036) in patients receiving early AZA treatment. Importantly, there were major differences in study design between these 2 trials. Patients were considered as high risk for disabling disease (based on the presence of ≥2 of the following criteria: age <40 years, active perianal lesions, and corticosteroid use within 3 months of diagnosis). However, most CD patients meet these criteria in clinical practice and 61% of the patients in the “conventional” group required AZA within a median of 11 months of diagnosis, which cannot be interpreted as a conservative approach. Therefore, a more accurate interpretation is that authors compared early aggressive AZA therapy with early accelerated AZA. Of note, the primary end point was the proportion of trimesters in remission during patient follow-up, which is probably better representing the clinical outcome then the primary outcome as defined in the AZTEC trial. Of note, in population-based studies 25%–30% of patients present with complicated disease phenotype at or around diagnosis—excluded by definition from both AZTEC and RAPID trials.In conclusion, the AZTEC study shows that we have to better define study end points for disease modification trials as well as it highlights the importance of patient selection. The findings from this study are not generalizable to patient populations regularly seen in the clinical practice. Development of complicated disease or need for surgery would be more optimal outcome measures for the guiding clinical practice and to study the change of the natural history of the disease. Recently, 2 population-based cohorts from Wales and Hungary3Lakatos P.L. et al.Am J Gastroenterol. 2012; 107: 579-588Crossref PubMed Scopus (179) Google Scholar found that early AZA therapy may be associated with beneficial-long term outcomes as assessed by reduced frequency of intestinal resection that is considered to be among the most solid and objective long-term outcome measure. In 2013, whether thiopurine has the potential for disease modification in early CD has yet to be determined. We read with great interest the paper by Panes et al1Panés J. et al.Gastroenterology. 2013; 145: 766-774Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar regarding the efficacy of early azathioprine (AZA) therapy in early Crohn’s disease (CD). The “AZathioprine for Treatment or Early Crohn’s disease in adults” (AZTEC) study was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial conducted in 31 Spanish hospitals over 3 years. The authors developed a randomized placebo-controlled trial in very early CD patients (<8 weeks of diagnosis) without bowel damage (symptomatic stenotic, penetrating, or perianal disease). After entering clinical remission, patients were randomized to receive AZA or placebo. The end point was steroid-free remission at week 76. Unfortunately, the trial was stopped for futility. Other points, such as patient selection and the definition of the primary end point, should be taken into account when interpreting the data. The disease in the patient population was quite mild and not representative of that regularly seen in clinical practice: 92% of patients had pure inflammatory disease, extensive disease location was observed in only one-third of patients, and complicated disease was excluded. In addition, about 30% of patients did not require steroids as initial therapy. The primary efficacy end point was steroid-free remission at week 76, but relapse was defined by the Crohn’s Disease Activity Index. Nevertheless, there was a benefit of AZA use with a slightly modified definition of relapse (Crohn’s Disease Activity Index >220; absolute difference, 18.4%; P = .01). Finally, the study was clearly underpowered to investigate the potential for disease modification of AZA in early CD. The event numbers of more robust outcomes (eg, fistula development, need for surgery) were too low to allow a meaningful analysis. Therefore, we propose an alternative interpretation of the findings. CD patients with a mild phenotype at diagnosis do not necessarily benefit from systematic early introduction of AZA therapy. The study also highlights that in the future we will need to use composite end points (including objective signs of inflammation such as mucosal healing and biomarker remission) to enable a more objective assessment of efficacy and decrease the placebo effect. In a similar study by the GETAID2Cosnes J. et al.Gastroenterology. 2013; 145: 758-765Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar group, early aggressive therapy with AZA within 6 months of diagnosis was no more effective than “conventional” management in increasing time of clinical remission as assessed by trimesters for 36 months. Overall, these findings are broadly similar to those of the AZTEC trial even though the need for perianal surgery was lesser (4% vs 18%; P = .036) in patients receiving early AZA treatment. Importantly, there were major differences in study design between these 2 trials. Patients were considered as high risk for disabling disease (based on the presence of ≥2 of the following criteria: age <40 years, active perianal lesions, and corticosteroid use within 3 months of diagnosis). However, most CD patients meet these criteria in clinical practice and 61% of the patients in the “conventional” group required AZA within a median of 11 months of diagnosis, which cannot be interpreted as a conservative approach. Therefore, a more accurate interpretation is that authors compared early aggressive AZA therapy with early accelerated AZA. Of note, the primary end point was the proportion of trimesters in remission during patient follow-up, which is probably better representing the clinical outcome then the primary outcome as defined in the AZTEC trial. Of note, in population-based studies 25%–30% of patients present with complicated disease phenotype at or around diagnosis—excluded by definition from both AZTEC and RAPID trials. In conclusion, the AZTEC study shows that we have to better define study end points for disease modification trials as well as it highlights the importance of patient selection. The findings from this study are not generalizable to patient populations regularly seen in the clinical practice. Development of complicated disease or need for surgery would be more optimal outcome measures for the guiding clinical practice and to study the change of the natural history of the disease. Recently, 2 population-based cohorts from Wales and Hungary3Lakatos P.L. et al.Am J Gastroenterol. 2012; 107: 579-588Crossref PubMed Scopus (179) Google Scholar found that early AZA therapy may be associated with beneficial-long term outcomes as assessed by reduced frequency of intestinal resection that is considered to be among the most solid and objective long-term outcome measure. In 2013, whether thiopurine has the potential for disease modification in early CD has yet to be determined. Early Azathioprine Therapy Is No More Effective Than Placebo for Newly Diagnosed Crohn's DiseaseGastroenterologyVol. 145Issue 4PreviewA small placebo-controlled trial reported the efficacy of mercaptopurine therapy for children newly diagnosed with Crohn's disease, yet little is known about the efficacy of early thiopurine therapy in adults. Full-Text PDF ReplyGastroenterologyVol. 146Issue 3PreviewWe are pleased with the interest in our recent clinical trial published in Gastroenterology1 and welcome the opportunity to clarify the points raised. Rammohan and Pai are inaccurately mixing the results of our study with the one performed by Panés et al published in the same issue of the Journal.2 The RAPID trial did not compare azathioprine (AZA) vs placebo and did not allow to conclude that “AZA is not better than placebo for achieving corticosteroid free remission in early Crohn’s disease (CD)”. Full-Text PDF ReplyGastroenterologyVol. 146Issue 3PreviewWe thank all authors for the comments relating the AZTEC study.1 Two of the letters mention that the AZTEC trial may have failed to show a benefit of azathioprine over placebo because the population included in the study had mild disease, and is not representative of what is seen in clinical practice. In this regard, it should be noted that the population included in the AZTEC study did not have milder disease compared with the pediatric population included in the Markowitz study showing a benefit of azathioprine. Full-Text PDF" @default.
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• W2058217314 title "Azathioprine in Early Crohn’s Disease: Time to Revisit Patient Selection and End Points for Clinical Trials and/or Azathioprine Efficacy?" @default.
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