How to Manage Refractory Heartburn

Transcription

1 May 2018 How to Manage Refractory Heartburn C. Prakash Gyawali, M.D. Professor of Medicine Division of Gastroenterology Disclosures: Medtronic (research, speakers bureau); Allergan (speakers bureau); Ironwood (consulting); Torax (consulting); Quintiles (consulting)

2 DEFINITIONS AND INITIAL TREATMENT INVESTIGATION OF REFRACTORY HEARTBURN MANAGEMENT OF REFRACTORY HEARTBURN

3 Definitions Are Important! GERD a condition that develops when the reflux of gastric content causes troublesome symptoms or complications Vakil N et al, Am J Gastroenterol 2006;101:1900

4 sensitivity Questionnaire & History 75 Gold Standard PPI trial, troublesome GERD symptom PCP history GI history GERDQ -Esophagitis on endoscopy -Acid exposure time (AET) >5.5% -Symptom association probability >95% -AET % & symptom improvement 60 RDQ 55 PPI trial, foregut symptom Questionnaires, history and specificity PPI trial outcomes are neither sensitive nor specific for a GERD diagnosis Jones R et al. APT 2009;30: Dent J et al. Gut 2010;59: Bolier EA et al. Dis Esophagus 2015;28:105-20

5 Cost-Analysis: Symptom Based Management symptom based n=174 R x GERDQ stratification GERDQ GERDQ R x cost savings: 146/$ % Primary care referral: 347 pts R similar symptom relief test based n=173 GERDQ blinded EGD/ ph-metry R x GERDQ blinded R x GERDQ blinded 80.1% baseline 4 weeks 8 weeks Jonasson C et al. APT 2012;35:

6 Hierarchy of GERD Management Radiofrequency application Transesophageal incisionless fundoplication Injection of bulking agent Novel Endoscopic Surgical therapy Electrical stimulation of LES Bile sequestrant (colsevelam) Antireflux surgery Magnetic sphincter augmentation Roux-en-Y gastric bypass Proton pump inhibitors H2 receptor antagonists Acid manipulation Over the counter medications: antacids, alginates Lifestyle Gyawali CP, Fass R. Gastroenterology 2018 (epub)

7 Short-Term PPI Response PPI Placebo NNT Resolution of uninvestigated heartburn 1 71% 46% 2.2 Resolution of heartburn without esophagitis 1 40% 13% 3.7 Resolution of heartburn with esophagitis 2 56% 8% 2.1 Resolution of esophagitis 3 83% 18% 1.5 Symptom improvement with treatment does not necessarily mirror endoscopic healing 1 Sigterman KE et al. Cochrane Reviews Dean BB et al, Clin Gastroenterol Hepatol 2004;2: Khan M et al, Cochrane Reviews 2007

8 PPI use by patients Suboptimal dosing is common! 27.8% 29.6% 38.9% 54% > 60 min before meal After meals At bedtime As needed Optimal PPI dosing Suboptimal PPI dosing Gunaratnam NT et al. AP&T 2006; 23:1473-7

9 Predictors of Response to PPI The role of functional GI disorders 153 patients with typical symptoms Abnormal endoscopy and/or ph-impedance monitoring Treated with esomeprazole 20 mg for 8 weeks 62.1% were designated as responders Odds ratio (OR) PPI Response 95% Confidence interval P value Pathological acid reflux IBS + FD overlap IBS overlap Depression Wang AJ et al. Dig Liver Dis 2013

10 DEFINITIONS AND INITIAL TREATMENT INVESTIGATION OF REFRACTORY HEARTBURN MANAGEMENT OF REFRACTORY HEARTBURN

11 All Burning Sensations are not Reflux 9 functional heartburn 12 NERD Blinded acid perfusion Time to first perception Symptom score on VAS Functional heartburn has a longer lag time to acid perception Perceived symptom intensity is similar to NERD Functional heartburn is not triggered by acid, but feels similar to acid triggered symptoms Weijenborg PW et al, Neurogastroenterol Motil 2016;28:1649

12 Spectrum of Heartburn GERD NERD RH FH Functional chest pain Achalasia Rumination Functional Heartburn GERD or NERD 106 typical reflux patients endoscopy negative PPI refractory ph impedance testing off PPI Reflux Hypersensitivity Galmiche, et al, UEG Journal 2013 Herregods TVK et al. Neurogastroenterol Motil 2015;27:1267

13 Definitions Are Important! Refractory Heartburn Heartburn not responding to stable double dose PPI over 12 weeks Implication: symptoms may or may not be from reflux Refractory GERD Symptoms caused by reflux of gastric content not responding to stable double dose PPI over 12 weeks Implication: symptoms are from inadequate management of reflux Fass R, Sifrim D. Gut 2009;58: Sifrim D, Zerbib F. Gut 2012;61:

14 Mechanisms of Esophageal Symptoms GERD or NERD Symptoms suspicious for reflux disease Functional Esophageal Disorders Non esophageal disorders: Cardio pulmonary disorders Laryngeal disorders Other esophageal disorders: Mucosal disorders (EoE) Motor disorders

15 Persistent Reflux Symptoms Careful history What is the reflux symptom What is the expected benefit Is the PPI dosed correctly Are there confounding esophageal diagnoses Endoscopy Manometry Eosinophilic esophagitis Infectious esophagitis Pill esophagitis Other non-reflux processes Achalasia Esophageal outflow obstruction Are refractory symptoms reflux related Ambulatory Reflux Monitoring

16 ph Monitoring Reflux episodes Symptom reflux association Acid Exposure Time (AET) Cumulative time ph<4 as a percentage of the duration of recording 2 min heartburn

17 ph-impedance Monitoring Impedance signature of a bolus passing across a pair of sensors Antegrade and retrograde bolus movement across multiple pairs of sensors

18 Predictors of GERD Symptom Improvement ph-impedance in a real world setting GLOBAL SYMPTOM SEVERITY (GSS) CHANGE age gender study off PPI typical symptoms abnormal AET* abnormal RET SAP (acid reflux) SAP (all reflux)** number of reflux events n= ±0.9 yrs 70.6% female 50.3% tested off PPI 61% typical symptoms 39.9 ±1.3 mo follow-up *p= **p= Patel A, Sayuk GS, Gyawali CP. CGH 2015;13:

19 Acid Suppression Aziz Q, Fass R, Gyawali CP, et al, Gastroenterology 2016;150:1368

20 Definitions Are Important! GERD NERD a condition that develops when the reflux of gastric content causes troublesome symptoms or complications Symptoms from reflux of gastric content in the absence of visible evidence of mucosal injury in the esophagus Implication: endoscopy is negative, ambulatory reflux monitoring is positive Vakil N et al, Am J Gastroenterol 2006;101:1900 Aziz Q et al, Gastroenterology 2016;150:1368

21 ENDOSCOPY ph or ph-impedance HRM CONCLUSIVE EVIDENCE FOR PATHOLOGIC REFLUX LA grades C&D esophagitis Long segment Barrett s mucosa Peptic esophageal stricture AET>6% BORDERLINE OR INCONCLUSIVE EVIDENCE LA grades A&B esophagitis AET 4-6% Reflux episodes ADJUNCTIVE OR SUPPORTIVE EVIDENCE* Histopathology (score) Electron microscopy (DIS) Low mucosal impedance Reflux-symptom association Reflux episodes>80 Low MNBI Low PSPWI Hypotensive EGJ Hiatus hernia Esophageal hypomotility EVIDENCE AGAINST PATHOLOGIC REFLUX AET<4% Reflux episodes<40 *factors that increase confidence for presence of pathologic reflux when evidence is otherwise borderline or inconclusive Gyawali CP et al, Gut 2018 (in press)

22 DEFINITIONS AND INITIAL TREATMENT INVESTIGATION OF REFRACTORY HEARTBURN MANAGEMENT OF REFRACTORY HEARTBURN

23 Expected Benefit: Acid Suppression Complete Response Number of studies Erosive Esophagitis 32 Heartburn negative endoscopy Heartburn, no endoscopy Heartburn negative endoscopy, positive ph study NERD Complete response 72.0% ( )* 50.5% ( ) 49.5% ( ) 73.5% ( )* Number of studies Partial Response Partial response 75% ( ) 65% ( ) 71% ( ) 85.0% ( ) Weijenborg PW et al. Neurogastroenterol Motil 2012;24:747-57

24 1 Gut Luminal/Mucosal Therapy Acid neutralization preparations with lidocaine, alginates Acid suppression 312 heartburn patients endoscopy negative PPI trial for 8 weeks ph impedance testing off PPI NERD RH FH RH: reflux hypersensitivity FH: functional heartburn 0 PPI response PPI non-response di Bortoli N et al. Neurogastroenterol Motil 2014;26:28-35

25 H2RA and Esophageal Perception 18 patients with functional heartburn Ranitidine 150 mg bid or placebo Double blind randomized crossover design Balloon distention and acid infusion Pain assessed using Likert scales * * H2RAs may modulate esophageal perception *p=0.04 Rodriguez-Stanley S et al, Aliment Pharmacol Ther 2004; 20:

26 1 Gut Luminal/Mucosal Therapy Acid neutralization Acid suppression Bile acid sequestrants preparations with lidocaine, alginates optimize in acid driven syndromes? role for H2RA ~12% gain in reducing heartburn severity when used with PPI over PPI alone Morrison, Ironwood Pharmaceuticals press release, 2017

27 2 Gut-Directed Regulators Adenosine antagonists Potential benefit in chest pain Non-traditional drugs TLESR inhibitors: baclofen Van Herwaarden et al, Aliment Pharmacol Ther 2002; 16: Beaumont H et al, Am J Gastroenterol. 2009;104:

28 2 Gut-Directed Regulators Adenosine antagonists Potential benefit in chest pain Non-traditional drugs Modulators of esophageal sensation TLESR inhibitors: baclofen TRPV1 inhibitor: unsuccessful Melatonin: limited data suggests benefit Ono-8539 Prostanoid EP1 receptor antagonist Acid perfusion test used to trigger heartburn Kondo T et al, J Gastroenterol 2017; (in press)

29 3 Central Processing Modulation Tricyclic antidepressants Global symptom management Open label, randomized trial of PPI refractory chest pain Normal endoscopy, ph-impedance testing and manometry Amitriptyline 10 mg + rabeprazole 20 mg (n=17) vs. rabeprazole 20 mg bid (n=19) Park SW et al, World J Gastroenterol 2013;19:4958

30 3 Central Processing Modulation Tricyclic antidepressants Global symptom management Randomized trial of PPI refractory heartburn Normal endoscopy, ph-impedance testing and manometry 83 patients FH: 31 RH: 39 No Sx: 13 After exclusions: Imipramine: 43 Placebo: 40 Dropout: 16 Limsrivilai S et al, Am J Gastroenterol 2016;111:

31 Tricyclic Antidepressants Receptor Affinity Predicts Side Effects Receptor Affinities* 3 o amines Amitriptyline Imipramine Doxepin - 2 o amines Nortriptyline Desipramine - * For acetylcholine, histamine, and -adrenergic receptors

32 3 Central Processing Modulation Tricyclic antidepressants Global symptom management Other antidepressants Indirect effects In functional heartburn: IBS: OR 2.8 (95% CI ), p=0.001 Anxiety: OR 10.8 ( ), p= * * * IBS Anxiety Depression *p <0.001 compared to other 2 groups de Bortoli N et al, Am J Gastroenterol 2016;111:1711

33 % heartburn free days 3 Central Processing Modulation Tricyclic antidepressants Global symptom management Other antidepressants Indirect effects Fluoxetine in Functional Heartburn Heartburn Endoscopy negative Failed PPI trial Randomized to: Omeprazole (n=48) Fluoxetine (n=48) Placebo (n=48) pre vs. post treatment * Treated for 6 weeks Differences significant when phbut not when ph + omeprazole fluoxetine placebo p< compared to omeprazole group Ostovaneh MR et al, Neurogastroenterol Motil 2014;26:670

34 Sertraline in Functional Chest Pain 115 patients Sertraline dose mg Coping Skills Training provided by trained psychologists Keefe FJ et al, Pain 2011;152:730

35 Venlafaxine in Functional Chest Pain Randomized, double-blind, placebo controlled, crossover trial of functional chest pain Normal endoscopy, ph-impedance testing and manometry Venlafaxine 75 mg vs. placebo, 2 week washout period (n=43) Lee H et al, Am J Gastroenterol 2010;105:1504

36 Maraday-Romero C, Fass R. Clin Gastroenterol Hepatol 2015;13:260 Weijenborg PW et al, Clin Gastroenterol Hepatol 2015;13:251 Gyawali CP, Fass R. Gastroenterology Central Processing Modulation Tricyclic antidepressants Global symptom management Other antidepressants Indirect effects

37 Antidepressants for the Non-Psychiatrist Tricyclics Newer SSRIs Others Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Fluvoxamine (Luvox) Citalopram (Celexa) Citalopram isomer (Lexapro)

38 Antidepressants for the Non-Psychiatrist Tricyclics Newer SSRIs Others Venlafaxine (Effexor) SNRI Mirtazapine (Remeron) Bupropion (Wellbutrin) NDRI Trazodone (Desyrel) Nefazodone (Serzone) SNRI Reboxetine (Edronax) Duloxetine (Cymbalta) SNRI

39 Major Pros and Cons of Antidepressants Type Pros Cons* TCA SSRI Low dosage effect, anticholinergic,?rapid onset Better tolerated, weight neutral SNRI Pain relief Sedation Sedation, anticholinergic, weight gain, metabolic syndrome Insomnia; GI upset NDRI Weight loss, less sexual side effects Anxiety/agitation *All have sexual side effects, seizure potential, and other potential adverse effects

40 3 4 Adjunctive Measures Tricyclic antidepressants Global symptom management Other antidepressants Indirect effects Reassurance, supportive care Advised for all subjects Psychotherapy High satisfaction

41 3 4 Adjunctive Measures Tricyclic antidepressants Global symptom management Other antidepressants Indirect effects Reassurance, supportive care Advised for all subjects Psychotherapy High satisfaction Hypnotherapy Increasing favorable data Acupuncture For motivated patients Riehl ME et al, Dis Esophagus 2016;29:490-6

42 Targeted Treatment of Persisting Esophageal Symptoms Core Management luminal peripheral central Antacids, alginates Viscous lidocaine Acid suppression Gut-directed regulators Central processing modulation; Comorbid affective disorders Adjunctive measures; hypnosis

43 Summary Refractory GERD requires optimization of PPI therapy first Prudent, directed testing can provide further management direction Refractory heartburn may arise from functional mechanisms Functional heartburn sounds like reflux, behaves like IBS Neuromodulators are the mainstay of management Adjunctive and complementary measures are of benefit

44 Birthplace of High Resolution Manometry St. Louis, Missouri, USA