Grigoris Leontiadis, MD PhD McMaster University Upper Gastrointestinal and Pancreatic Diseases Cochrane Group No relevant financial relationships with any commercial interests CDDW/CASL Meeting Session: Dyspepsia management in 2014

CanMEDS Roles Covered in this Session:

Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles,  applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.) Communicator (as Communicators, physicians effectively facilitate the doctor-patient  relationship and the dynamic exchanges that occur before, during, and after the medical encounter.)

Collaborator (as Collaborators, physicians effectively work within a healthcare team to  achieve optimal patient care.)

Manager (as Managers, physicians are integral participants in healthcare organizations,  organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.) Health Advocate (as Health Advocates, physicians responsibly use their expertise and  influence to advance the health and well-being of individual patients, communities, and populations.) Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning,  as well as the creation, dissemination, application and translation of medical knowledge.)

Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.) Agenda

Uninvestigated dyspepsia; functional dyspepsia . definitions . critical appraisal of treatments . of established efficacy . emerging, promising . conclusions Dyspepsia

Evolving definition

Misleading etymology: two ancient Greek words • dys (bad, abnormal, difficult, impaired) • pepsis (digestion) Dyspepsia

Rome III definition

One or more of the following: . epigastric pain . epigastric burning . postprandial fullness . early satiation

It should not be called dyspepsia if the predominant symptoms are heartburn or acid regurgitation

Tack et al. Functional gastroduodenal disorders. In: Rome III, 2006 Functional dyspepsia (FD) Rome III definition

1. One or more of the following: Criteria fulfilled for ≥ 3 months . epigastric pain symptom onset ≥ 6 months prior to diagnosis . epigastric burning . postprandial fullness . early satiation

and 2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms

Tack et al. Functional gastroduodenal disorders. In: Rome III, 2006 Burden of dyspepsia

. Prevalence of dyspepsia: 20‐40% (Marwaha et al. DDW 2009) . Incidence: 1% per year . 70% of patients with dyspepsia have FD (Ford et al. Clin Gastr Hepatol 2010) . Significant reduction of patients’ quality of life . Significant economic burden to the healthcare system . Cause of frustration to physicians because no is currently approved in the US, Canada or the EU for the treatment of FD

Lacy et al. AP&T 2013 Management of uninvestigated dyspepsia

Top three strategies:

. Prompt endoscopy (and treat accordingly) Early endo: more effective in curing dyspepsia, but more costly and not cost-effective Ford et al. Gastroenterol 2005 . H. pylori test (non‐invasively) and treat

No difference in efficacy or cost

Ford et al. AP&T 2008 . Initial acid suppression (and scope the failures) Management of uninvestigated dyspepsia

Clinical practice guidelines . NICE 2004 . Canadian 2005 . AGA 2005 . ASGE 2007 . Asian Pacific 2012 . (Lacy et al. AP&T 2012) Management of uninvestigated dyspepsia

Uninvestigated dyspepsia  no other obvious causes  age < 50  no alarm features

If H. pylori prevalence < 10% H. pylori test (UBT) (+)ve (‐)ve ‐ Reassurance Treat for PPI trial Endoscopy ‐ Reassess Fails H pylori Fails 4‐6 weeks Fails diagnosis (+)ve (‐)ve

Manage Functional accordingly dyspepsia Van Zanten et al. Can J Gastroenterol 2005 Talley et al. Gastroenterol 2005 Functional dyspepsia FD subgroups

. FD probably includes multiple different entities with distinct underlying pathophysiologies

. Ideally, the therapeutic approach should target the underlying pathophysiology

. However, it has been very difficult to identify FD subgroups reliably based on symptoms Pathophysiology of FD

Causative Pathophysiological agents change Symptoms FD subgroups

Rome III definitions

. Postprandial distress syndrome (PDS) may co-exist . Epigastric pain syndrome (EPS) FD subgroups

Rome III definitions

. Postprandial distress syndrome (PDS)

Several times a week, one or both of: 1. Bothersome postprandial fullness, occurring after ordinary‐size meals 2. Early satiation that prevents finishing a regular meal

Tack et al. Functional gastroduodenal disorders. In: Rome III, 2006 FD subgroups

Rome III definitions

. Epigastric pain syndrome (EPS)

All of the following: 1. Pain or burning localized to the epigastrium of at least moderate severity, at least once per week 2. Intermittent 3. Not generalized or localized to other abdominal or chest regions 4. Not relieved by defecation or passage of flatus 5. Not fulfilling the criteria for gallbladder or SOD disorders

Tack et al. Functional gastroduodenal disorders. In: Rome III, 2006 Dyspepsia from an evolutionary perspective

. “Proximate” causes of dyspepsia (microorganisms, foods, drugs, other environmental factors, genes, combinations of the above)

. “Ultimate” causes of dyspepsia: Q: “Does dyspepsia serve the human species’ interest, and if so, how?” A: possibly yes; it is beneficial for a population (it confers a survival advantage) to have: 1. a warning mechanism against life‐threatening behaviours (some variability among individuals would be inevitable) 2. a proportion of individuals with chronic, moderate dyspepsia. Why? Management options for FD

. H. pylori eradication therapy . probiotics . dietary modifications . acid suppression . prokinetics . antidepressants . psychological therapy . anti‐nociceptive agents . herbal therapies . acupuncture H pylori eradication therapy in FD

Systematic review & meta‐analysis of 21 RCTs . Outcome: dyspepsia cure at 3‐ 12 months

. Comparator: placebo, PPI, H2RA, prokinetic . Results: . RR for H pylori eradication group . control: 0.90 (95%CI 0.86‐0.94) . NNT 14 (95%CI 10 to 25) Moayyedi et al. Cochrane DatSystRev 2006

. Informally updated; results hardly changed: NNT 13 Moayyedi. Arch Intern Med 2011 H pylori eradication therapy in FD

Systematic review & meta‐analysis of 21 RCTs . Outcome: dyspepsia cure at 3‐ 12 months

. Comparator: placebo, PPI, H2RA, prokinetic . Results: . RR for H pylori eradication group vs. control: 0.90 (95%CI 0.86‐0.94) . NNT 14 (95%CI 10 to 25) Moayyedi et al. Cochrane DatSystRev 2006

. Informally updated; results hardly changed: NNT 13 Moayyedi. Arch Intern Med 2011

. The beneficial effect of H pylori eradication Rx applies equally to “epigastric pain” and “dysmotility” FD subgroups Suzuki & Moayyedi. Nat Rev Gastroenterol 2013 H pylori eradication therapy in FD

. “It is possible that the antibiotics used in H pylori eradication therapy are treating other organisms rather than H pylori, and this is the reason for their effect in functional dyspepsia” Moayyedi. Arch Intern Med 2011

. What is the proportion of patients who were cured from dyspepsia after unsuccessful H pylori eradication treatment? GI microbiota

• Several studies have systematically examined the role of small bowel microbiota in IBS • No studies have systematically examined the role of the microbiota of the stomach, duodenal and proximal jejunum in FD • No RCTs on the efficacy of probiotics in FD

103 H pylori +(ve) patients, scoped for various reasons (not all had FD) . 43 species of bacteria cultured and isolated from 65% of the patients

Hu et al. World J Gastroenterol 2012 GI microbiota Management of FD

Functional dyspepsia

Eradicate if H. pylori (+)ve

All 7 CPGs published since 2009 agree on this approach . The benefit is small (NNT 14), but . the effect is long term . H. pylori eradication has additional benefits (prevention of PUD, esp. complicated PUD, possibly prevention of gastric cancer) Suzuki & Moayyedi. Nat Rev Gastroenterol 2013

What if this approach fails to cure FD? Diet in FD

. “Which foods should I avoid, doctor?” Diet in FD

. Nine studies have assessed dietary patterns/eating behavior in FD . Inconsistent results (except with fatty foods) . Patients identify specific foods as triggers of their symptoms, but blind challenge tests provide inconsistent results . Possible cognitive factors (anticipation due to previous negative experience with certain foods)

. No studies have assessed the efficacy of targeted dietary interventions in FD . Is there a role for GFD or low FODMAP diet for FD? . Should all dyspeptics be tested for celiac disease or non‐celiac gluten sensitivity?

Feinle‐Bisset & Azpiroz. Nat Rev Gastroenterol 2013 Diet (and lifestyle) in FD

Probably reasonable suggestions (but, very low quality of evidence): . smaller meals (? better chewing, slower eating) . reduced fat intake . ? diet calendar? . related lifestyle modifications ‐ reduce / modify alcohol consumption ‐ stop smoking (tobacco, marihuana)

Ford & Moayyedi. BMJ 2013 Lacy et al. AP&T 2012 Acid suppression in FD

A Cochrane SR&MA:

. Antacids vs. placebo (1 RCT): no difference

. H2RAs vs. placebo (12 RCTs): RRR 23% (95% CI 8% to 35%); NNT=7  unexplained heterogeneity  publication bias

. PPIs vs. placebo (10 RCTs): RRR 13% (95% CI 4% to 20%); NNT=10  unexplained heterogeneity

Moayyedi et al. Cochrane DatSystRev 2006 PPIs in FD

SR&MA and economic analysis (US setting): . Different efficacy according to FD dyspepsia subgroup

Moayyedi et al. Gastroenterol 2004 Prokinetics in FD

Logical choice...

2006 Cochrane review of 24 RCTs (being updated currently) . Most of the RCTs used . Cisapride withdrawn . Unexplained heterogeneity, likely publication bias, no effect seen in high quality studies . Insufficient evidence for other prokinetics

Moayyedi et al. Cochrane DatSystRev 2006 Prokinetics in FD

Newer prokinetics .

. tegaserod

. acotiamide

. buspirone Prokinetics in FD

Newer prokinetics Phase IIb RCT (Germany) . itopride . n= 554

dopamine D2 antagonist & . Superior to placebo inhibitor Holtman et al. NEJM 2006

. tegaserod Two phase III RCTs (international & N. American) . n=1170 . Excluded patients with heartburn . acotiamide . No difference from placebo Talley et al. Cut 2008

. buspirone Prokinetics in FD

Newer prokinetics Two RCTs (US, Canada, UK, South Africa) . itopride . n= 2,667 women with “dysmotility‐like” FD . Small improvement in dyspepsia scores, of doubtful clinical importance . tegaserod . Tegacerod withdrawn selective 5‐HT4 agonist Vakil et al. Am J Gastroenterol 2008 . acotiamide

. buspirone Prokinetics in FD

Newer prokinetics . itopride Four phase II RCTs (Japan, US, Europe)  total n = 1363  100 mg TD : slightly better than placebo (for partial improvement) . tegaserod Tack et al. DDW 2011 Matsueda et al. NGM 2010 Talley et al. DDW 2008 . acotiamide Phase III RCT (Japan) release promoter  n= 892 (PDS only) acetylcholinesterase inhiditor  100 mg TID: slightly better than placebo . buspirone  NNT=6 (partial improvement)  NNT=16 (complete resolution) Matsueda et al. Gut 2012 Prokinetics in FD

Newer prokinetics . Itopride

. Tegaserod

. acotiamide Fundic relaxant (not a prokinetic per se) Crossover RCT (Belgium) . buspirone . n= 17 . 5‐HT1A agonist Reduced bloating and postprandial fullness

Tack et al. Clin Gastr Hepatol 2012 Gut‐brain axis in FD

. Psychopathological factors (esp. anxiety and depression) are positively associated with FD Tack et al. Functional gastroduodenal disorders. In: Rome III, 2006

. This justifies two additional therapeutic approaches for FD: . psychological therapy . antidepressants Psychological therapies for FD

Insufficient evidence for benefit: . Cochrane systematic review of 4 RCTs (Soo et al. Cochrane DatSystRev 2006) . One subsequent RCT on cognitive behavioural therapy (Haag et al. AP&T 2007) Antidepressants in FD

Tricyclic antidepressants (TCAs)

Two TCAs were shown to be superior to placebo in RCTs:

. Imipramine ► n=107 (Hong Kong) Wu et al. DDW 2011

. Amitriptyline ► n= 292 (US & Canada) Locke et al. DDW 2013 ‐ amitriptyline was also superior to escitalopram (SSRI)

► Three small RCTs (US; Japan; Europe) Mertz et al. Am J Gastroenterol 1998 Otaka et al. AP&T 2005 Braak et al. AP&T 2011 Antidepressants in FD

SSRIs not different from placebo in RCTs

. Escitalopram ► n= 292 (US & Canada) Locke et al. DDW 2013

. Sertaline ► n=193 (Hong Kong) Tan et al. WJG 2012

SNRIs not different from placebo in an RCT

. Vanlafaxine ► n=160 (Netherlands) van Kerkhoven et al. Clin Gastr Hepatol 2008 Anti‐nociceptive agents in FD

Pregabalin . Post hoc analysis of data from 6 RCTs ‐ Patients with generalized anxiety disorder and severe/ very severe “GI symptoms” (Item #11 in Hamilton Anxiety Scale) ‐ Small improvement in “GI symptoms” (as well as in anxiety levels)

Stein et al. Int Clin Psychopharmacol 2009 Herbal therapies for FD

Iberogast (extracts from 9 plants): a systematic (?) review of 4 RCTs . Slightly better than placebo . Equally safe to placebo . No meta‐analysis Acupuncture in FD

Two well‐performed RCTs (China) . n=712; n= 72 . Superior to sham therapy . Functional brain changes on PET‐CT Ma et al. AP&T 2012 Zeng et al. Am J Gastroenterol 2012 Take home messages

Uninvestigated dyspepsia management

. If >50 yrs or alarm features: scope and treat

. If <50 yrs and no alarm features: test for H. pylori (UBT) and treat or PPI trial Take home messages

FD management . Test for H. pylori and treat . PPIs . [Reassess diagnosis] . Dietary and lifestyle modifications . Consider: • Tricyclic antidepressants • Prokinetics • Anti‐nociceptive agents • Psychological therapies • Herbal /complementary therapies, acupuncture Final thoughts

. We cannot expect to find a silver bullet that works for all FD patients –FD is more than one diseases . We need a better understanding of the pathophysiology of FD:  carve out entities out of FD (? biomarkers)  role of microbiota  role of psychological factors  mechanism of action of the (partially) effective treatments; identify prognostic markers for response (? biomarkers) Thank you for your attention!