Number of studies. Endoscopic finding. Number of subjects. Pooled prevalence 95% CI

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1 Clinical Approach to the Patient t with Dyspepsia William D. Chey, MD, FACG Professor of Medicine University of Michigan Prevalence of Endoscopic Findings in Individuals with Dyspepsia Systematic Review and Meta-analysis analysis including 9 studies Endoscopic finding Number of studies Number of subjects Pooled prevalence 95% CI Erosive esophagitis % Barrett s esophagus % Peptic ulcer % Gastric ulcer % Duodenal ulcer % Gastric cancer % Esophageal cancer % Ford, et al. Clin Gastroenterol Hepatol 2010;8:830 1

2 Rome III: Diagnostic Criteria* for Functional Dyspepsia Must include 1. One or more of: a. Bothersome postprandial fullness b. Early satiation c. Epigastric pain d. Epigastric burning AND 2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis Tack, et al. Gastroenterol 2006;130:1466 Functional Dyspepsia: Rome III Subgroups PDS EPS Postprandial Distress Syndrome Postprandial fullness Early satiation Epigastric pain Syndrome Intermittent epigastric pain/burning Tack, et al. Gastroenterol 2006;130:1466 2

3 Clinical Impact of Dyspeptic Symptoms in the General Population Proportion Affected (%) Wgt loss Absenteeism 2025 Belgians 21% had significant dyspepsia 34% had co-morbid GERD symptoms Piessevaux et al. Neurogastro Motil 2009;21:378 Affected Daily Life Led to Healthcare Util Meds Pathogenesis of Functional Dyspepsia Altered Brain-Gut Interactions Genetic Factors Visceral Hypersensitivity y Functional Dyspepsia Microbiome Inflammation Post-infectious Abnormal upper GI motor & reflex functions Psychosocial Factors Saad & Chey. Aliment Pharmacol Ther 2006;24:475 3

4 Current Management of Functional Dyspepsia H. pylori eradication Prokinetic Antisecretory t therapy therapy Current Management of Functional Dyspepsia Diet Lifestyle CAM H. pylori eradication Anti- Nociceptive Prokinetic Antisecretory t therapy therapy 4

5 Dietary Recommendations for Functional Dyspepsia: What s the Evidence? Efficacy of dietary interventions has not been carefully studied in Functional Dyspepsia Smaller meals may better tolerated - Patients develop fullness and other symptoms with smaller volumes of a nutrient drink or water vs. controls - FD symptoms directly related to overall calorie intake Avoid high fat meals - Ingestion of fat or intraduodenal lipid infusion leads to more symptoms in patients vs. controls - Fat but not carbohydrate intake directly related to symptoms Feinle-Bisset, Neurogastroenterol Motil 2006; 18:608 Pilichiewicz, Clin Gastroenterol Hepatol 2009;317 Cochrane Meta-Analysis of H. pylori Cure for Functional Dyspepsia 17 RCTs (3566 patients) Hp eradication therapy vs. placebo or short course of PPI % Symptom Therapeutic Improvement Gain (%) (range) NNT RRR (95% CI) (%) Hp cure 36 (15-75) (10-25) (6-14) Placebo 29 (7-51) 12/17 trials did not show significant benefits with Hp eradication Moayyedi et al. Cochrane Collaboration Feb

The Rationale for Antisecretory Therapy in Functional Dyspepsia Gastric acid secretion in FD similar to controls 1 Acid hypersensitivity - Lowered threshold of mechanosensitive afferents 2, reduced

fasting duodenal motor activity Overlap of GERD and dyspeptic symptoms 7 1 Bechi et al. Dig Dis Sci 1992; 37:378 4 Sansom et al. Gastroenterol 1999; 116:515 2 Coffin et al.

6 The Rationale for Antisecretory Therapy in Functional Dyspepsia Gastric acid secretion in FD similar to controls 1 Acid hypersensitivity - Lowered threshold of mechanosensitive afferents 2, reduced antral motility, jejunal hypercontractions 3 - Increased symptoms with duodenal acid infusion 3, 4 Increased duodenal acid exposure Decreased fasting clearance of exogenous acid - Decreased fasting duodenal motor activity Overlap of GERD and dyspeptic symptoms 7 1 Bechi et al. Dig Dis Sci 1992; 37:378 4 Sansom et al. Gastroenterol 1999; 116:515 2 Coffin et al. Am J Physiol 2001; 280:G904 5 Lee et al. Am J Gastro 2004; 99: DiStefano et al. Neurogastro Motil 2009;21:712 6 Ishii et al. J Sm Muscle Res 2010;46:1 7 Tack et al. Gut 2005; 54:1370 Cochrane Meta-Analysis of PPI therapy for Functional Dyspepsia 10 RCTs (3347 patients) PPI for 2-8 weeks was superior to placebo in relieving FD symptoms % No or Therapeutic minimal Gain NNT RRR (%) symptoms (%) (95% CI) (95% CI) PPI (7-33) (4-20) Placebo 25 No assymetry by funnel plot Moayyedi et al. Cochrane Collaboration

7 PPI for Functional Dyspepsia: Is a 1 week trial adequate? Properties at 8 weeks according to treatment response in week 1 Week 8 Sensitivity Specificity PPV NPV (95% CI) (95% CI) (95% CI) (95% CI) Eso or 80 mg (41-52) (76-84) (54-67) (65-73) Placebo (22-44) (81-93) (45-76) (61-76) N = 1150 Eso 40 mg QD or BID Europe, South America, Canada, Singapore Bottom Line One week of PPI therapy did not reliably identify responders at 8 weeks Talley et al. Aliment Pharmacol Ther 2007;26:673 Which factors predict response to PPI therapy in FD? Patients with reflux symptoms more likely to respond to PPI therapy 1 Patients with dysmotility symptoms are less likely to improve with PPI therapy 1 - Case control studies suggest nausea 2 and bloating/ibs symptoms 3,4 are negative predictors of PPI response 1 Talley APT 1998;12: Meineche-Schmidt Am J Gastro 2000;95: Bolling-Sternevald Aliment Pharmacol Ther 2003;18:117 4 Meineche-Schmidt Aliment Pharmacol Ther 2011;33:41 7

8 How does abnormal gastric physiology contribute to Upper GI Symptoms? Dyspeptic symptoms and meal-related pathophysiologic mechanisms 23% Delayed gastric emptying nausea, vomiting, and post-prandial prandial fullness 35% Hypersensitivity to gastric distension pain, belching, and weight loss 40% Impaired accommodation early satiety, and weight loss Tack et al, Gastroenterology 2004; 127:

9 Types of prokinetics Metoclopramide Domperidone Cisapride Erythromycin y Itopride Tegaserod ABT-229 Dopamine-2 antagonist HT 4 agonist HT 3 antagonist Motilin receptor agonist + ++ Cholinesterase inhibitor ++ QT prolongation Cochrane Meta-Analysis of Prokinetics for Functional Dyspepsia 19 RCTs (3178 patients) % No or Therapeutic minimal Gain NNT RRR (%) symptoms (%) (95% CI) (95% CI) Prokinetics (5-12) (18-45) Placebo 47 Significant assymetry by funnel plot Moayyedi et al. Cochrane Collaboration

Domperidone for Functional Dyspepsia 9 double-blind studies (30-60 mg/day) - Peripheral dopaminergic

gastric emptying - Increases serum prolactin levels Breast tenderness and galactorrhea in <5% - Can

Gastroenterol 2001; 96: 689 Reddymasu,et al. Am J Gastroenterol 2007;102:1 Camilleri et al.

05 compared with placebo EPS: Epigastric pain syndrome; GSOA: Global subject outcome assessment;

10 Domperidone for Functional Dyspepsia 9 double-blind studies (30-60 mg/day) - Peripheral dopaminergic antagonist Reduced CNS side effects - Improvement in global assessment without clear effects on gastric emptying - Increases serum prolactin levels Breast tenderness and galactorrhea in <5% - Can prolong QT interval - Not currently available in the US - IND program available Van Zanten Am J Gastroenterol 2001; 96: 689 Reddymasu,et al. Am J Gastroenterol 2007;102:1 Camilleri et al. Am J Gastroenterol 2013;108:18 Responder Rates with Acotiamide for Functional Dyspepsia * * * *P<.05 compared with placebo EPS: Epigastric pain syndrome; GSOA: Global subject outcome assessment; PDS: Postprandial distress syndrome; t.i.d.: Three-times a day Altan E, et al. Expert Rev Gastroenterol Hepatol 2012;6:533 10

Effect of Buspirone or Placebo on Dyspepsia

05 Randomized, double-blind, placebo-controlled,

placebo (n=10) tid before meals x 4 weeks Tack

Clin Gastroenterol Hepatol 2012;10:1239 Effect

Meal-Related Symptom Severity * ** * *P<.05 vs.

11 Effect of Buspirone or Placebo on Dyspepsia Symptom Severity *P<.05 Randomized, double-blind, placebo-controlled, crossover study: Buspirone (n=7) 10 mg or placebo (n=10) tid before meals x 4 weeks Tack J, et al. Clin Gastroenterol Hepatol 2012;10:1239 Effect of Buspirone or Placebo on Individual Meal-Related Symptom Severity * ** * *P<.05 vs. run-in **P<.005 vs. baseline P<.05 vs. placebo Randomized, double-blind, placebo-controlled, crossover study: Buspirone (n=7) 10 mg or placebo (n=10) tid before meals x 4 weeks Tack J, et al. Clin Gastroenterol Hepatol 2012;10:

12 Psychopharmacological Therapies for Functional Dyspepsia Venlafaxine for Functional Dyspepsia: Double-blind, Placebo-Controlled Trial 50 In a multicenter trial of 160 FD pts, venlafaxine was no more effective than placebo %IT TT Responders Venlafaxine Placebo 0 Baseline Weeks On treatment Van Kerkhoven, et al. Clin Gastroenterol Hepatol 2008;6:746 12

A randomized, controlled trial of Sertraline for Functional Dyspepsia *P=0.

740 N=98 N=95 Rome Ⅱ FD Sertraline 50 mg or Placebo daily for 8 wk 22%

World J Gastroenterol 2012;18:6131 The Functional Dyspepsia treatment

13 A randomized, controlled trial of Sertraline for Functional Dyspepsia *P=0.124 *P=0.740 N=98 N=95 Rome Ⅱ FD Sertraline 50 mg or Placebo daily for 8 wk 22% dropped out No difference in QoL or HAD scores Tan YPY, et al. World J Gastroenterol 2012;18:6131 The Functional Dyspepsia treatment trial: Key Results % Primary Endpoint: Adequate Relief (%)* 5/12 weeks of adequate relief p = % 40% 38% Placebo N = 97 Amitriptyline 50 mg N = 97 Escitalopram 10 mg N = 98 Patients with ulcer-like but not dysmotility-like improved with amitriptyline Locke et al. DDW 13, abs

Take Home Points: Functional dyspepsia and antidepressants Amitriptyline, but not Escitalopram, was efficacious for the global symptoms of functional dyspepsia Treatment effect of amitriptyline was

14 Take Home Points: Functional dyspepsia and antidepressants Amitriptyline, but not Escitalopram, was efficacious for the global symptoms of functional dyspepsia Treatment effect of amitriptyline was greatest in the ulcer-like FD subgroup and in males Response was not predicted by patient characteristics (e.g., anxiety, BMI) or baseline GI physiology test results Locke et al. DDW 13, abs 810 Treatment of Functional Dyspepsia Epigastric Pain Antidepressant or behavioral therapy + Severe Test and treat Hp Moderate and/or empiric PPI + Mild Positive diagnosis Diet, lifestyle advice Reassure, OTC treatments Physician-patient relationship Complimentary Therapies? 14

15 Treatment of Functional Dyspepsia Epigastric Pain Test and treat Hp and/or Empiric PPI Antidepressant or behavioral therapies? Severe Moderate Post-prandial distress + + Fundus Relaxing Agents Prokinetics Anti-emetics + Positive diagnosis Positive diagnosis Diet, lifestyle advice Mild Diet, lifestyle advice Reassure, OTC Reassure, OTC treatments treatments Physician-patient relationship Physician-patient relationship Complimentary Therapies? + 15

Functional Dyspepsia

Functional Dyspepsia American College of Gastroenterology Boston Massachusetts, June 2015 Brian E. Lacy, PhD, MD, FACG Professor of Medicine Geisel School of Medicine at Dartmouth Chief, Section of Gastroenterology