Management of Functional Dyspepsia (FD)

Management of Functional Dyspepsia (FD) Amy S. Oxentenko, MD, FACG Program Director and Associate Chair, IM Associate Professor of Medicine Mayo Clinic, Rochester Outline Define functional dyspepsia (FD) and subsets Describe the proposed mechanisms behind FD Compare the efficacy of lifestyle modifications, anti-secretory therapy, H. pylori treatment, prokinetics, psychotropic medications and complementary therapies for FD management Page 1 of 16

Dyspepsia Secondary dyspepsia Organic, systemic or metabolic cause identified Functional dyspepsia No identifiable cause found by traditional testing Rome III to Rome IV: Functional Dyspepsia FD remains umbrella term Subcategories: Postprandial nature Epigastric distress Threshold for severity and frequency clarified Bothersome = Severe enough to impact activities Often 2 on a 5-point scale Frequency of symptoms not detailed in Rome III Cutoffs created based on data such that no greater than 5% population would experience the same Stanghellini V, et al. Gastroenterology 2016;150:1380-92. Page 2 of 16

Definition of Functional Dyspepsia Characterized by 1 or more of the following: Post-prandial fullness Early satiation Epigastric pain Epigastric burning No evidence of structural disease (including EGD) that is likely to explain symptoms Fulfilled for the last 3 months with symptom onset at least 6 months before the diagnosis Must fulfill criteria for postprandial distress syndrome or epigastric pain syndrome Stanghellini V, et al. Gastroenterology 2016;150:1380-92. 2 Subcategories of FD Post-prandial distress syndrome (PDS) Overlap Epigastric pain syndrome (EPS) Must include 1 or both of the following at least 3 days per week: 1. Bothersome postprandial fullness Impacts usual activities 2. Bothersome early satiation Prevents finishing regular meal Must include at least 1 of the following symptoms at least 1 day per week: 1. Bothersome epigastric pain AND/OR 2. Bothersome epigastric burning Stanghellini V, et al. Gastroenterology 2016;150:1380-92. Page 3 of 16

PDS and EPS: Other Notes Additional sxs may be present: Bloating, belching, nausea Vomiting warrants a look for other causes Heartburn excluded as a dyspeptic symptom, but may coexist; same with GERD or IBS If symptoms relieved after flatus/stool, this shouldn t be attributed to dyspepsia EPS pain doesn t fulfill biliary pain criteria Stanghellini V, et al. Gastroenterology 2016;150:1380-92. Impact on Patients with FD 55 Reduced QOL Increased distress Increased $$ burden Medical bills Loss of wages SF-8 Mean Score 50 45 40 PF RP BP GH VT SF RE MH Control GERD FD IBS PF = physical functioning RP = role physical BP = bodily pain GH = general health VT = vitality SF = social functioning RE = role emotional MH = mental health Kaji M, et al. J Gastroenterol Hepatol 2010;25:1151-56. Page 4 of 16

Proposed Mechanisms of Functional Dyspepsia Infection Inflammation Gastroesophageal reflux Visceral hypersensitivity Altered accommodation Altered gastric emptying CNS modulation Di Stefano, et al. Am J Gastroenterol 2014;109:1631-9. Bharucha AE, et al. Am J Gastroenterol 2014;109:1910-20. Symptoms suggesting upper GI involvement Hx/Exam EGD YES Alarm Features? NO NEG NO PPI Trial HP testing Functional Dyspepsia Response? YES Continue PPI Sxs Resolve? YES 2 o Dyspepsia Stanghellini V, et al. Gastroenterology 2016;150:1380-92. Page 5 of 16

Lifestyle Modifications in FD What do we tell our patients to do? Avoid caffeine, alcohol and NSAIDs Avoid high fat or high caloric foods Eat small, more frequent meals Very few get improvement with this alone Other data: Fats, not carbs, cause symptoms Fullness/bloating related to fat ingestion and intraduodenal fat infusion 1-3 Others found no difference vs controls 4,5 1 Pilichiewicz AN, et al. CGH 2009;7:317-22. 2 Barbera R, et al. Dig Dis Sci 1995;40:1636-41. 3 Feinle C, et al. Gut 2001;48:347-55 4 Cuperus P, et al. Eur J Clin Nutr 1996;50:520-3. 5 Carvalho RV, et al. Dig Dis Sci 2010;55:60-65. Anti-Secretory Therapy: H2RA Cochrane database meta-analysis 12 RCTs (H2RA vs placebo) 2183 pts; NOT defined as FD by Rome III Significant heterogeneity Patients with GERD likely included H2RA Response (improvement) response (improvement) Gain RRR 95% CI NNT 95% CI 54% 40% 14% 23% 8-35% 7 5-21% 5 other RCTs found only epigastric pain and fullness improved with H2RA Moayyedi P, et al. Cochrane Database Syst Rev 2006;19(2):CD002096 Page 6 of 16

Anti-Secretory Therapy: PPI STUDY DRUG BENEFIT OF NOTE Talley et al Omeprazole 10-20 mg QD X 4 weeks Wong et al Lansoprazole 15-30 mg QD x 4 weeks Peura et al Lansoprazole 15-30 mg QD x 8 weeks Van Zanten et al Esomeprazole 40 mg QD X 8 weeks Van Rensburg et al Pantoprazole 20 mg QD X 4 weeks Talley et al Esomeprazole 80 mg QD X 1 week YES NO SOME NO YES No benefit in those with dysmotility Chinese pts; placebo pts had more benefit HB predominant excluded; some HB more response Those with HB or regurgitation excluded Study confined to those with ulcer-like symptoms NO Looked at sx response at 8 weeks Anti-Secretory Therapy: PPI Meta-analysis of RCTs 7 studies 3725 pts PPI superior to placebo NNT 14.6 Benefit confined to those with: Ulcer-like pain Reflux-like dyspepsia No benefit for those with: Dysmotility-like features Unspecified dyspepsia Wang WH, et al. CGH 2007;5:172-85. Page 7 of 16

H. pylori Treatment in FD Cochrane database meta-analysis 21 RCTs (HP eradication and FD sxs) 17 trials (3566 pts) grouped with dichotomous data and lack of heterogeneity HP eradication vs placebo or PPI HP group Response (improvement) response (improvement) Gain RRR 95% CI NNT 95% CI 36% 29% 7% 10% 6-14% 14 10-25% 12/17 did not show significant benefit Moayyedi P, et al. Cochrane Database Syst Rev 2006;19(2):CD002096 H. pylori Eradication 195 Chinese pts with FD (Rome III) 1 Improvement in epigastric pain/burning H. pylori tx improvement 60.8-65.7% improvement 31.8-33.3% p<0.05 404 Brazilian pts with FD (Rome III) 2 Improvement in symptoms PPI + 2 antibiotic improvement 50% Daily PPI improvement 37% 1 Lan L, et al. World J Gastroenterol 2011;17:3242-7. 2 Mazzaleni LE, et al. Arch Intern Med 2011;171:1929-33. p=0.01 Page 8 of 16

Prokinetic Therapy in FD Cochrane database meta-analysis 19 RCTs with 3178 patients grouped with dichotomous data Prokinetic (cisapride > domperidone) vs placebo Prokinetic Response (improvement) response (improvement) Gain RRR 95% CI NNT 95% CI 57% 47% 10% 33% 18-45% 6 5-12% Small studies,? skewed results Moayyedi P, et al. Cochrane Database Syst Rev 2006;19(2):CD002096 Prokinetic Agents DRUG STUDY BENEFIT OF NOTE Tegaserod 5-HT 4 agonist Itopride D2 antag/ci Mosapride 5-HT 4 agonist Erythromycin Motilin agonist ABT-229 Motilin agonist Vakil N, et al SMALL Increase in days with relief by 4.6% vs placebo; better response if severe Holtmann, et al NO Phase III data no better than placebo (excluded reflux); available in Japan Hallerback, et al NO Available in Japan Arts J, et al NO Small study Talley, et al NO Worsened symptoms with high dose Page 9 of 16

Acotiamide Enhances acetylcholinesterase release Muscarinic antagonist; cholinesterase inhibitor Relaxes fundus, gastroprokinetic Multi-center, RCT, 892 Japanese pts with FD (and PDS) Weekly improvement rate in overall treatment efficacy NNT = 6 Weekly elimination rate for all 3 sxs (fullness, bloating, satiety) NNT = 16 Matsueda K et al. Gut 2012;61:821-828. Psychotropic Agents: Venlafaxine Venlafaxine XR (SNRI) vs placebo RCT, double-blind, placebo-controlled, multi-center trial 170 pts, intention to-treat response 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Baseline 4 weeks 8 weeks 12 weeks 20 weeks On treatment Venlafaxine Van Kerkhoven LA, et al. CGH 2008;6:746-52. Page 10 of 16

Psychotropic Agents: Buspirone A 5-hydroxytryptamine 1A receptor agonist RCT, double-blind, placebo-controlled crossover 17 pts; dosing 10 mg TID Dyspepsia Severity Score 14 12 10 8 6 4 2 0 10.8 Prior to Tack J, et al. CGH 2012;10:1239-45. 9.5 11.5 Prior to Buspirone 7.5 Buspirone Buspirone: What Symptoms Improve? 30 25 20 15 10 ** ** * ** * Run-in Buspirone 5 0 Fullness Bloating Belching Nausea Pain Epigastric burning Tack J, et al. CGH 2012;10:1239-45. Page 11 of 16

Psychotropic Agents: SSRIs Sertraline (SSRI) vs placebo Pilot study, RCT, double-blinded FD (Rome II), ethnic Chinese, normal EGD, HP negative 193 pts, intention to-treat response 43 (22%) drop out by week 8 (19 placebo, 24 SSRI) 95.8% of drop outs in SSRI group by week 4 Significant improvement in Hong Kong Dyspepsia Index at week 8 in SSRI vs placebo in PP but not ITT analysis No differences in subjective global symptom resolution Tan VP, et al. World J Gastroenterol 2012;18:6127-33. Psychotropic Agents: SSRIs and TCAs RCT, double-blind, placebo-controlled; 8 NA sites TCAs vs SSRIs vs placebo; % adequate relief 5 weeks 60% 50% 40% 30% 53% 40% 38% 20% 10% 0% Amitriptyline Escitalopram Talley NJ, et al. Gastroenterology 2015;149;340-9. Page 12 of 16

Psychotropic Agents: SSRIs/TCAs Those with ulcer-like FD more likely to report adequate relief with amitriptyline OR = 3.1 [CI 1.1-9.0] Those with dysmotility-like FD did not respond differently 70% 60% 50% 40% 30% 20% 10% 0% 39% Ulcer-Like 67% 27% Amitriptyline Escitalopram 70% 60% 50% 40% 30% 20% 10% 0% 41% Dysmotility-Like 46% 43% Amitriptyline Escitalopram Talley NJ, et al. Gastroenterology 2015;149;340-9. Psychotropic Agents: SSRIs/TCAs Those with delayed gastric emptying at baseline had lower odds of reporting adequate relief than subjects with normal emptying. OR = 0.4 [CI 0.2-0.8] 60% 50% Normal gastric emptying 58% 60% 50% Delayed gastric emptying 40% 30% 20% 44% 40% 40% 30% 20% 25% 30% 29% 10% 10% 0% Amitriptyline Escitalopram 0% Amitriptyline Escitalopram Talley NJ, et al. Gastroenterology 2015;149;340-9. Page 13 of 16

Psychotropic Agents: SSRIs and TCAs Systematic review, meta-analysis 8 studies (2 RCTs, 2 cross-overs) ALL antidepressants No difference RR 0.85 (95% 0.69-1.03) Lu Y, et al. PLoS ONE 2016;11(6): e0157798. Tricyclic ONLY Difference RR 0.76 (95% 0.62-0.94) P = 0.01 NNT = 7 SSRIs ONLY No difference RR 1.00 (95% 0.86-1.17) *Side effects significantly more common in antidepressant groups Agent Contained Details 1 STW 5-II Bitter candy tuft, matricaria, peppermint caraway, licorice root, lemon balm 2 STW 5 Iberis amara, angelica, chamomile, caraway, thistle, lemon balm, peppermint, celandin, licorice, alcohol CAM Therapies 120 pts Rome I FD 20 drops TID 2 x 4 weeks 315 pts Rome II FD 20 drops TID x 8 weeks 3 STW 5 Same 103 pts Rome II FD 20 drops TID x 4 weeks Treatment Response 43.3% Complete relief 1 Madisch A, et al. Digestion 2004;69:45-52. 2 von Arnim U, et al. Am J Gastroenterol 2007;102:1268-75. 3 Braden B, et al. Neurogastroenterol Motil 2009;21:632-9. Response 3.3% Complete relief P value P<0.001 GIS drop 6.9 GIS drop 5.9 P = 0.04 GIS drop 6.6 GIS drop 4.5 P = 0.03 Page 14 of 16

Take-Home Points Lifestyle modifications: Often advised, but effect may be small and not used in isolation (adjunctive) Lower fat, smaller meals suggested Anti-secretory therapy: H2RA may be of benefit, with small effect, and may be better in those with pain (EPS) PPIs may have modest benefit; may be better in those with pain or heartburn (EPS, not PDS) PPIs are needed for >1 week to assess effect, but should be stopped after 4-8 weeks in non-responders Take-Home Points Helicobacter pylori treatment: There is improvement in some patients with dyspepsia when given H. pylori treatment Approach dependent on prevalence of H. pylori infection Prokinetic therapy: Prokinetics, while appealing for their gastric emptying features, show underwhelming results Meta-analysis suggests benefit, but results largely based on cisapride and small studies Other prokinetic drugs have not shown same beneficial results (need to consider harm) Acotiamide looks promising as it relates to overall dyspepsia symptoms, particularly with PDS features Page 15 of 16

Take-Home Points Psychotropic therapy: SSRIs likely of no benefit; SNRIs likely of no benefit Buspirone may be of benefit for fullness, bloating, belching and nausea (PDS-like), but not in those with pain or burning (EPS-like) TCAs (amitriptyline) may be of benefit in those with ulcertype pain (EPS-like) and normal gastric emptying, but not in those with dysmotility-like features Complementary therapy: STW 5 does show promising results as it relates to improvement in GI symptom scores Thank you! Oxentenko.amy@mayo.edu Page 16 of 16