Prevention of Postoperative Crohn s disease

Transcription

1 The Natural Course of postop CD Prevention of Postoperative Crohn s disease is clinically silent initially Miguel Regueiro, M.D. Professor of Medicine & Translational Research Associate Chief, Education IBD Clinical Medical Director Senior Medical Lead of Speciality Medical Homes University of Pittsburgh Medical Ctr [1] D Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114: [2] Olaison G, S medh K, Sjodahl R. Gut 1992;33: [3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99: [4] Sachar DB. Med Clin North Am 1990;74: Consultant: Abbvie Amgen Janssen Miraca laboratories Pfizer Takeda UCB Disclosures Research Grants: Abbvie Janssen Takeda Case 1 22 yo male, smoker with Crohn s disease for 5 years. Only prior treatment 5ASAs and 1-2x/year steroids. Now with a small bowel obstruction. CT Enterography Background Postoperative Crohn s disease management through November

2 Case 1 Postop management An ileocolonic resection is performed 10cm of TI with a stricture and active Crohn s as well as the cecum were removed Now what? Case 2 After the abscess is drained and she is given abx, surgery is performed She has an ileocecal resection and primary anastomosis ileal-ileal fistula with an associated abscess No other disease, now what? Case 2 43 yo female with newly dx d Crohn s ileitis develops severe abd pain and fever She has not been on meds as the dx is new She is a smoker, no NSAIDs, no FHx IBD A CT scan is performed Until recently no postop guidelines but, 2 approaches 1. Early treatment for most 2. guidance to decide on rxent Early Treatment: Medications for Preventing Postoperative Crohn s Disease Yellow Arrow = Abscess Red Oval = Phlegmon (inflammatory changes in small bowel 2

3 Summary of Postop RCTs 5ASA, Nitroimidazoles, AZA/6MP Postop Prevention RCTs Clinical Placebo 25% 77% 53% - 79% 5 ASA 24% - 58% 63% - 66% Budesonide 19% - 32% 52% - 57% Nitroimidazole 7% - 8% 52% - 54% AZA/6MP 34% 50% 42 44% % patients Infliximab (n=11) Infliximab vs placebo p= /11 11/13 Placebo (n=13) 84.6 Regueiro M. Inflammatory Bowel Diseases defined as scores of i2, i3, or i4. What about Postop antitnf? The Pittsburgh (Postop) Bus #24 The Pittsburgh Postop Bus RCT: Infliximab Prevents Crohn s Disease after Ileal Resection Regueiro M, Schraut W, Baidoo L, Kip KE, Sepulveda AR, Pesci M, Harrison J, Plevy SE. Gastroenterology 2009;136: PO- Endo Recur antitnf Control Sorrentino 1 (MTX/IFX v 5ASA 2yr) 0% 100% (5ASA) Regueiro 2 (IFX vs PBO RCT 1 yr) 9% 85% (PBO) Yoshida 3 (IFX vs PBO Open 1 yr) 21% 81% (5ASA) Armuzzi 8 (IFX vs AZA Open 1 yr) 9% 40% (AZA) Fernandez-Blanco 4 (ADA) 10% N/A Papamichael 5 (ADA 6m) 0% N/A Savarino 6 (ADA 3yr) 0% N/A Aguas 7 (ADA 1 yr) 21% N/A De Cruz 9 (ADA vs AZA 6mos) 6% 38% (AZA) Savarino 10 (ADA vs AZA vs 5ASA 2 yrs) 6% 65% (AZA), 83%(5ASA) 3

4 ..and most recently the large international postop trial.. The PREVENT Study Primary Endpoint Clinical PREVENT Subjects with Clinical Prior to or at Week 76 and Week Infliximab for Prevention of of Post-Surgical Crohn s Disease Following Ileocolonic Resection: a Randomized, Placebo-Controlled Study (PREVENT) M Regueiro 1, BG Feagan 2, B Zou 3, J Johanns 3, M Blank 4, M Chevrier 3, S Plevy 3, J Popp 4, F Cornillie 5, M. Lukas 6, S. Danese 7, P Gionchetti 8, M Molenda 4, SB Hanauer 9, W Reinisch 10, WJ Sandborn 11, D Sorrentino 12, P Rutgeerts 13 1 University of Pittsburgh Medical Center, 2 Robarts Research Institute, University of Western Ontario, 3 Janssen Research and Development, LLC., 4 Janssen Scientific Affairs, LLC., 5 MSD International, 6 Charles University, 7 Istituto Clinico Humanitas, 8 DIMEC, S. Orsola-Malpighi Hospital, University of Bologna, 9 Northwestern Feinberg School of Medicine, 10 McMaster University, 11 University of California San Diego, 12 Virginia Tech Carilion School of Medicine, 13 Catholic University of Leuven Proportion of Subjects (%) Primary Endpoint 20.0 P= Clinical Prior to or at Week 76 Placebo (N=150) 25.3 P= Clinical prior to or at Week 104 Infliximab 5 mg/kg (N=147) This study was supported by Janssen Scientific Affairs, LLC. P-values based on the Cochran-Mantel-Haenszel chi-square test stratified by the number of risk factors for of active CD (1 or >1) and baseline use (yes/no) of an immunosuppressive (i.e., AZA, 6-MP, or MTX). Secondary Endpoint Results 4

5 PREVENT Secondary Endpoint: Subjects with Prior to or at Week 76 Proportion of Subjects (%) P<0.001 P< Only Based on Criteria (i.e., Rutgeerts score i2) Placebo (N=150) with Treatment Failure Rule and Other Data Handling Rules Applied Infliximab 5 mg/kg (N=147) Nominal p-values based on the Cochran-Mantel-Haenszel chi-square test stratified by the number of risk factors for of active CD (1 or >1) and baseline use (yes/no) of an immunosuppressive (i.e., AZA, 6- MP, or MTX). 25 Crohn s disease management after intestinal resection: a randomized (postoperative Crohn s POCER) trial De Cruz P, Kamm M, et al. Lancet 2014 PREVENT Subjects with Central Results (Rutgeerts Score i0 vs i3) Prior to or at Week 76 Proportion of Subjects (%) % vs. 67% at 18 months in active vs. standard care pts 49% 18 months 67% 0 19/67 54/65 48/67 11/65 Rutgeerts Score i0 Rutgeerts Score i3 or i4 Placebo Infliximab 5 mg/kg.ok, that was the early treatment approach, but what about Watchful Waiting and Treat Postoperative Crohn s? By scoping at 6 mos and intensifying rx 18% lower rate of 49% 18 months 67% 5

6 Prevent vs. Wait for? When should we start anti-tnf? Here? Here? Postop Crohn s disease Guidelines 2017 Ultimate question: when is it too late to start a biologic and when is it just right? Too late = irreversible American Gastroenterological Association Technical Review on the Management of Crohn s Disease After Surgical Resection Miguel Regueiro, MD 1 *; Fernando Velayos, MD 2 *; Julia B. Greer, MD, MPH 1 ; Christina Bougatsos, MPH 3 ; Roger Chou, MD 3 ; Shahnaz Sultan, MD, MHSc 4 ; Siddharth Singh, MD, MS 5 35 So the question still remains: How should we manage a Crohn s ds pt who recently had surgery? 4 clinical questions by PICO: Population (P), Intervention (I), Comparator (C), and Outcomes (O) Are there better evidence based data or guidelines to help us? 6

7 1. Is routine early postoperative pharmacologic prophylaxis superior to endoscopy-guided treatment, i.e. treat only if evidence of at 6-12 months? PICO Question 2 Population Intervention(s) Comparator Outcomes 2 Patients with Anti-TNF Placebo or 1. Reduction in CD with monotherapy active agent, clinical surgically Thiopurine or no and surgical induced monotherapy intervention, >18m remission and Antibiotics after surgery ileocolonic alone [CRITICAL] anastomosis, Thiopurines 2. Adverse events in whom early postoperative combined with antibiotics leading to treatment discontinuation pharmacologic 5- [IMPORTANT] prophylaxis is being aminosalicylate s considered Budesonide Probiotics Anti-TNF combined with thiopurines Vedolizumab monotherapy PICO Question 1 Population Intervention(s) Comparator Outcomes 1 Patients with CD with surgically induced remission and ileocolonic anastomosis Routine early postoperative pharmacologic prophylaxis (started within 2-8 weeks of Endoscopyguided therapy (with routine assessment of neoterminal ileum within 6-12 months of surgery, and treatment only if evidence of ) 1. Reduction in, clinical and surgical, >18m after surgery [CRITICAL outcome of interest] Endo Rec. vs placebo 5ASA IMM antitnf IMM vs 5asa or abx TNFvs5asa or IMM 2. What is the comparative effectiveness of probiotics, budesonide, 5-aminosalicylates, antibiotics, immunomodulators alone or in combination with antibiotics, anti-tnf monotherapy in preventing postop? 3. Is routine monitoring at 6-12 months after surgery superior to no monitoring? Colonoscopy 6-12m 7

8 PICO Question 3 Population Intervention(s) Comparat or 3 Patients with Active No routine CD with surgically monitoring induced remission and ileocolonic anastomosis management with routine evaluation at 6-12 months after surgery, and treatment stepup in case of (regardless of early postoperative management) (regardless of early postoperati ve manageme nt) Outcomes 1. Reduction in, clinical and surgical, >18m after surgery [CRITICAL] this AGA Technical Review informed In pts with asymptomatic after surgical resection, what is the comparative effectiveness of 5-aminosalicylates, antibiotics, thiopurines alone or in combination with antibiotics, anti-tnf monotherapy prevent? Which med prevents? American Gastroenterological Institute Guideline for the Management of Crohn s Disease After Surgical Resection Geoffrey C. Nguyen, 1 Edward V. Loftus Jr 2, Ikuo Hirano 3, Yngve Falck-Ytter 4, Siddharth Singh 5, Shahnaz Sultan 6, and the AGA Institute Clinical Guidelines Committee 47 PICO Question 4 Population Intervention(s) Comparator Outcomes 4 Patients with Anti-TNF Placebo or 1. Reduction in clinical CD with monotherapy active agent and surgical surgically Thiopurine or no, >18m induced monotherapy intervention after surgery remission, with Antibiotics alone asymptomatic Thiopurines [CRITICAL] 2. Achievement of combined with antibiotics remission, >18m after after surgery 5- aminosalicylates Budesonide (regardless of Probiotics intervention in Anti-TNF surgery [CRITICAL] 3. Adverse events leading to treatment discontinuation [IMPORTANT] the immediate postoperative combined with thiopurines period) Vedolizumab monotherapy Why guidelines? These guidelines are intended to reduce practice variation and promote high-value care. - AGA Guidelines committee

9 High GRADE Definitions of Quality/Certainty of the Evidence Moderate Low Very Low We are very confident that the true effect lies close to that of the estimate of the effect. We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. #2 In patients with surgically induced remission of CD, the AGA suggests using anti-tnf therapy and/or thiopurines over other agents. Conditional recommendation, moderate quality of evidence #3: In patients with surgically induced remission of CD, the AGA suggests AGAINST using mesalamine (or other 5-aminosalicylates), budesonide or probiotics. Conditional recommendation, low quality of evidence GRADE Definitions on Strength of Recommendation Strong Conditional For the Patient Most individuals in this situation would want the recommended course of action and only a small proportion would not. The majority of individuals in this situation would want the suggested course of action, but many would not. For the Clinician Most individuals should receive the recommended course of action. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Different choices will be appropriate for different patients. Decision aids may well be useful helping individuals making decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working towards a decision. #4: the AGA suggests routine postoperative monitoring at 6 to 12 months over no monitoring. Conditional recommendation, moderate quality of evidence Colonoscopy 6-12m #1 The AGA Recommends: early pharmacological prophylaxis over endoscopy-guided pharmacological treatment Conditional recommendation, very low quality of evidence #5 Pts with asymptomatic, the AGA suggests initiating or optimizing anti-tnf and/or thiopurine therapy over continued monitoring alone. Conditional recommendation, moderate quality of evidence Treat Here...not Here Optimize Therapy 9

10 Ok, so after all of that, how should we manage postop CD? Need to consider risk for of CD after surgery AGA Illustrative risk groups Lower Risk Higher risk Clinical Characteristics Older patient (>50y); non-smoker; 1 st surgery for a short segment of fibrostenotic disease (<10-20cm); disease duration >10 years Younger patient (<30y); smoker; 2 prior surgeries for penetrating disease, with or without perianal disease risk of clinical risk of 20% 30% 50% 80% AGA Illustrative risk groups Lower Risk Higher risk Clinical Characteristics Older patient (>50y); non-smoker; 1 st surgery for a short segment of fibrostenotic disease (<10-20cm); disease duration >10 years risk of clinical risk of 20% 30% AGA Postop Algorithm No Pharmacological Prophylaxis Ileocolonoscopy at 6-12 months Anti-TNF and/or Thiopurine 2 (Rutgeerts i2) Low risk of or Patient preference/values Surgically-induced CD Remission Pharmacological Prophylaxis Anti-TNF and/or Thiopurine 1 ±Nitroimidazole (3 months) Ileocolonoscopy at 6-12 months (Rutgeerts i2) Optimize or Add Thiopurine/Anti-TNF Patient preference or Intolerance to anti-tnf and thiopurine Nitroimidazole Antibiotic (3 months) 1 Though most clinical trials in postoperative CD have evaluated only monotherapy, combination therapy may improve efficacy and decrease immunogenicity based on indirect evidence from trials of luminal CD. 2 Thiopurine monotherapy may be appropriate for lower risk patients with i2. AGA Illustrative risk groups Clinical Characteristics risk of clinical risk of Lower Risk Higher risk Younger patient (<30y); smoker; 2 prior surgeries for penetrating disease, with or without perianal disease 50% 80% So.after all of these years. my final slide and my approach to postoperative Crohn s disease has not changed

11 Risk of Post-Op Early Rx for ALL but Low Risk Low Moderate High No Meds Colonoscopy 6-12 months post-op 6MP or AZA ± metronidazole Anti-TNF + IMM Colonoscopy 6-12 months post-op No No Colonoscopy every 1-3 yrs Immunomodulator or anti-tnf Colonoscopy every 1-3 yrs anti-tnf or Δ biologics 1 st surgery, Long-standing Penetrating <10yrs CD, long disease, 1 st surgery, stricture > 2 short surgeries inflammatory stricture CD Thank you 11