Grigoris Leontiadis, MD PhD. McMaster University Upper Gastrointestinal and Pancreatic Diseases Cochrane Group

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: epigastric pain epigastric burning postprandial fullness early satiation Criteria fulfilled for 3 months symptom onset 6 months prior to diagnosis 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 medication 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) H. pylori test (non invasively) and treat Early endo: more effective in curing dyspepsia, but more costly and not cost-effective Ford et al. Gastroenterol 2005 No difference in efficacy or cost Initial acid suppression (and scope the failures) Ford et al. AP&T 2008

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 H. pylori test (UBT) (+)ve ( )ve If H. pylori prevalence < 10% Treat for H pylori Fails PPI trial 4 6 weeks Fails Reassurance Reassess diagnosis Endoscopy Fails (+)ve ( )ve Manage accordingly Functional 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 agents Pathophysiological change Symptoms

FD subgroups Rome III definitions Postprandial distress syndrome (PDS) Epigastric pain syndrome (EPS) may co-exist

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, H 2 RA, 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

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) What if this approach fails to cure FD? Suzuki & Moayyedi. Nat Rev Gastroenterol 2013

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 H 2 RAs 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 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 itopride tegaserod acotiamide buspirone

Prokinetics in FD Newer prokinetics itopride dopamine D 2 antagonist & acetylcholinesterase inhibitor tegaserod acotiamide Phase IIb RCT (Germany) n= 554 Superior to placebo Holtman et al. NEJM 2006 Two phase III RCTs (international & N. American) n=1170 Excluded patients with heartburn No difference from placebo Talley et al. Cut 2008 buspirone

Prokinetics in FD Newer prokinetics itopride tegaserod selective 5 HT 4 agonist acotiamide Two RCTs (US, Canada, UK, South Africa) n= 2,667 women with dysmotility like FD Small improvement in dyspepsia scores, of doubtful clinical importance Tegacerod withdrawn Vakil et al. Am J Gastroenterol 2008 buspirone

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

Prokinetics in FD Newer prokinetics Itopride Tegaserod acotiamide Fundic relaxant (not a prokinetic per se) Crossover RCT (Belgium) buspirone 5 HT 1A agonist n= 17 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!