The PPI Doesn t Work, Now What? PPI Non-responsive Dyspepsia. Disclosures

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1 The PPI Doesn t Work, Now What? PPI Non-responsive Dyspepsia Lana Bistritz MD FRCPC Royal Alexandra Hospital GI Update 2016 Disclosures I have no relevant financial disclosures I will be discussing off label therapy 1

Objectives Apply the CanDys guidelines to a patient with dyspepsia List a differential diagnosis for dyspepsia not responsive to empiric therapy Describe treatment options for nonresponsive dyspepsia

2 Objectives Apply the CanDys guidelines to a patient with dyspepsia List a differential diagnosis for dyspepsia not responsive to empiric therapy Describe treatment options for nonresponsive dyspepsia Dyspepsia Prevalence 10-40% Epigastric pain or burning NOT in chest or below umbilicus Mislabeling location of dyspepsia predicts noncompliance to practice guidelines (P<0.01) Early satiety Postprandial fullness Marwaha, Gastroenterology 2009; Mak, Aliment Pharmacol THer 2012; Tack, Gastro 2006; Speigel, Aliment pharmacol Ther

3 CanDys Guidelines Dyspepsia Other causes? Age > 50 or alarm symptoms? Cardiac, Pancreatic/Biliary, Dietary Vomiting, Bleeding/Anemia, Dysphagia, Weight loss, Mass Upper Endoscopy Stop NSAIDS PPI Trial Test and Treat H Pylori Still symptoms? Endoscopy Van Zanten Can J Gastro ASGE Standards of Practice GIE 2015;82:

Utility of Alarm Symptoms Positive predictive value low (<11%) Malignancies found are usually advanced Negative predictive value high (97%) Due to low prevalence of UGI malignancy Meta-analysis of

4 Utility of Alarm Symptoms Positive predictive value low (<11%) Malignancies found are usually advanced Negative predictive value high (97%) Due to low prevalence of UGI malignancy Meta-analysis of 57,000 patients Vakil Gastroenterology 2006 Choosing Wisely Canada Avoid performing an endoscopy for dyspepsia without alarm symptoms for patients under 55 Avoid using upper GI series to investigate dyspepsia 80-90% specific, 54% sensitive Try to reduce or stop PPI at least once a year in most patients Sadowski CMAJ 2015; Dooley Ann Int Med

5 Endoscopic Findings Reflux esophagitis 43% Benign stricture 3.5% Barrett s esophagus 2.4% Peptic ulcer 6% Erosions 15% Malignancy 0.002% CADET-PE study Thomson 2003 $80,000 per case of upper GI cancer with endoscopy first strategy Vakil Clin Gastro Hep 2009 What about an EGD for reassurance? Young patients with EGD 63% with a normal gastroscopy improved at 1 year 16% normal gastroscopy as reason for improvement No change in anxiety, depression, health related quality of life after endoscopy After empiric PPI treatment Valle Hepatogastroenterology 2010; van Kerkhoven Endoscopy

6 Stop NSAIDS 30% patients with dyspepsia are taking NSAIDS (including ASA) Stopping or reducing dose may improve symptoms ASA risk of dyspepsia OR 1.4 NSAIDs 6 month risk of dyspepsia 20-25% COX-2 inhibitors 6 month risk 16-23% If ASA/NSAID can t be stopped Consider testing for H pylori especially if prior ulcer Consider adding PPI (evidence for GI bleeding not dyspepsia) Van Zanten Can J Gastro 2005 Helicobacter pylori Seroprevalence in Canada 30% Higher in immigrants, First Nations Urea breath test preferred test NNT = 13 for dyspepsia Triple therapy no longer first line choice Moayyedi Arch Int Med 2011; Sadowski CMAJ

Treatment Success Triple therapy (PPI-CA) Graham et al, Gut 2010;59:1143-53 Sequential Therapy 10 days PPI bid Amoxicillin 1 g bid x 5 days

7 Treatment Success Triple therapy (PPI-CA) Graham et al, Gut 2010;59: Sequential Therapy 10 days PPI bid Amoxicillin 1 g bid x 5 days PPI bid Clarithromycin 500 mg bid Metronidazole 500mg bid x 5days OR for eradication 2.92, NNT=8 over triple therapy (Gatta Am J Gastro 2009) 7

8 Upcoming Canadian Consensus Guidelines CLAMET quadruple therapy PPI BID Clarithromycin 500 BID Amoxicillin 1 g BID Metronidazole 500 BID For 14 days Bismuth based quadruple therapy (80%) PPI BID Bismuth 2 tabs QID Metronidazole 500 tid Tetracycline 500 qid For 14 days Van Zanten personal communication 2015 Empiric PPI 8 week trial NNT = 10 Treats peptic ulcer r/o NSAIDs r/o H pylori Trial of PPI cessation Treats GERD Use minimal effective dose Lifestyle modification Weight loss, smoking, alcohol, fatty food, caffeine Moayyedi Cochrane Database Syst Rev 2006; 8

9 PPI-Non Responsive Dyspepsia Unlikely to be acid related- Stop PPI Endoscopic cause Upper GI Malignancy, non-healing ulcer, gastroparesis Celiac disease not increased in dyspepsia Non-endoscopic organic cause Pancreatic, Biliary, Cardiac, Colonic, Mesenteric ischemia Functional Dyspepsia By far the most common Endoscopy normal Distinguish from IBS Functional Dyspepsia 75% patients with dyspepsia no structural cause Life expectancy normal Reduced quality of life High cost of investigations, medications Illness related work absenteeism Financial impact $18.4 billion/yr USA Ford Curr Opin Gastro 2013; Lacy Aliment Pharmacol Ther

10 Functional Dyspepsia Altered microbiome Delayed gastric emptying Impaired accommodation PAIN Visceral hypersensitivity CNS: Anxiety, depression Food Ford Curr Opin Gastr 2013 Functional Dyspepsia Treatment Placebo response is high (30-40%) Make it a positive diagnosis Stress reduction, anxiety management Small, regular, low-fat meals Avoid opiods: dependence, dysmotility No better than placebo Antacids Bismuth Sucralfate Talley NEJM

Prokinetics Cochrane meta-analysis: RRR 33% not effective when only high quality trials included Most used cisapride Buspirone 5-hydroxytryptamine 1A agonist Enhances gastric accommodation Small

11 Prokinetics Cochrane meta-analysis: RRR 33% not effective when only high quality trials included Most used cisapride Buspirone 5-hydroxytryptamine 1A agonist Enhances gastric accommodation Small crossover RCT improved bloating, postprandial fullness 10 mg tid Moayyedi Cochrane Database Syst Rev 2006; Tack Clin Gastro Hep 2012 Prokinetic- Acotiamide Acetylcholinesterase inhibitor Improved bloating, fullness, early satiety NNT 6 No improvement in pain Approved in Japan Symptom response 52% vs 35% placebo N= 897 Matsueda Gut

Antidepressants Modification of central pain processing Sertraline N=139, 28% symptom relief vs 28% placebo Venlafaxine N=160, 37% symptom free vs 39% placebo SSRI s and SNRI s not recommended Van

12 Antidepressants Modification of central pain processing Sertraline N=139, 28% symptom relief vs 28% placebo Venlafaxine N=160, 37% symptom free vs 39% placebo SSRI s and SNRI s not recommended Van Karkhoven Clin Gastro Hep 2008; Tan World J Gastro 2012 Antidepressants Multicentre RCT (n=292) Placebo vs amitriptyline 50mg vs escitalopram 10mg x 10 weeks Tricyclic superior Better for pain symptoms Ineffective if baseline delayed gastric emptying Talley Gastroenterology

13 Antidepressants: Mirtazapine Antagonist of H1, 5HT2, 5HT3, alpha2 adrenergic receptors RCT N= 34, 15mg QD 8 weeks Dyspepsia with >10% weight loss, no baseline depression or anxiety Improvement in early satiety, quality of life, weight, and intake (p<0.05) No improvement in pain Total symptom score did not meet significance between groups Tack Clin Gastro Hep 2016 Complementary Therapy Used by 50% of patients with dyspepsia 50% patients willing to accept a 13% risk of sudden death for a curative drug Lahner Eur Gastro J 2013; Lacy Clin Transl Gastroenterol

Complementary Therapy Insomnia, disordered sleep more common in functional dyspepsia than healthy controls Melatonin (5mg QD) RCT vs placebo (N=60) 56% had complete symptom resolution at 12 weeks vs

14 Complementary Therapy Insomnia, disordered sleep more common in functional dyspepsia than healthy controls Melatonin (5mg QD) RCT vs placebo (N=60) 56% had complete symptom resolution at 12 weeks vs 7% placebo (p<0.01) Improved sleep latency and prolonged sleep Antioxidant, stimulates prostaglandins Klupinska J Clin Gastro 2007 Complementary Therapy Iberogast 9 herb combination Relaxation of gastric fundus Small RCT superior to placebo Symptom score improved by 7 pts vs 6 pts Capsaicin Reduced symptom scores more than placebo in small RCT (60% vs 30%) Psychological therapy: Cochrane review (Soo 2005) Needs more study, consider if psychiatric Sx Acupuncture: Cochrane Review (Lan 2014) Not enough evidence to determine effectiveness Von Armin Am J Gastro 2007; Botolotti Aliment Pharmacol Ther 2002; Soo Cochrane Database Syst Rev

Recommended Treatment Algorithm for Patients with a Provisional

Tricyclic antidepressants Predominantly fullness, early satiety,

15 Recommended Treatment Algorithm for Patients with a Provisional Diagnosis of Functional Dyspepsia. Talley NJ, Ford AC. N Engl J Med 2015;373: My Quasi-Evidence Based Take: PPI Non-Response Predominantly Pain Tricyclic antidepressants Predominantly fullness, early satiety, nausea domperidone Mirtazepine Buspirone Iberogast? Concomitant anxiety, depression, insomnia Melatonin, treat comorbid psychiatric illness 15

Conclusions Endoscopy indicated in dyspepsia> 50, alarm symptoms, non-responsive to PPI If young, no alarm symptoms stop NSAIDs, exclude H pylori, PPI trial Most will

16 Conclusions Endoscopy indicated in dyspepsia> 50, alarm symptoms, non-responsive to PPI If young, no alarm symptoms stop NSAIDs, exclude H pylori, PPI trial Most will have functional dyspepsia Complete symptom relief uncommon Studies are weak Tailor medications to symptoms Attempt to discontinue medications periodically Questions? 16

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

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