Art Burne. Art Burne. Updates in the upper GI tract

Transcription

1 Updates in the upper GI tract Jeffrey Fox, MD, MPH UCSF Primary Care Medicine: Update 2010 Art Burne 45 yo white overweight male Has substernal burning once per week before he goes to sleep at night No dysphagia, weight loss, blood in stool, or jaundice Responds well to trial of OTC Prilosec Flares of symptoms correlate with stress Art Burne When is it OK to do empiric therapy for his symptoms without further evaluation? What therapy should we choose? When do we need to do endoscopy? Is it safe to use proton-pump inhibitors long-term? Does stress play a role?

2 GERD burden (GERD-en?) Very common 25% of Americans use antacids/antisecretory meds 3X/mo $8 billion/year spent antacids/h2rb/ppi Detrimental effects on quality of life found with symptoms as infrequent as once weekly Ronkainen et.al. Aliment Pharmacol Ther 2006

3 MO THLY GERD SYMPTOMS The Gallup Organization, 1988 WEEKLY GERD SYMPTOMS Locke, Gastroenterol, 1997 DAILY GERD SYMPTOMS Nebel, et.al. Am J Dig Dis, 1976

4 BARRETT S ESOPHAGUS Ronkainen et al, Gastroenterol 2005 ESOPHAGEAL ADE OCARCI OMA ESOPHAGEAL ADE OCARCI OMA Sharma et.al., Gastroenterol, in 20,000

5 Defining GERD Symptom pattern heartburn, regurgitation, dysphagia How often is disease Pathologic lesion erosive esophagitis Combo of symptoms and esophagitis highly specific (97%) vs. ph testing What about those with the symptoms but without the lesion NERD Gold-standard ph monitoring best but imperfect Whom should I treat empirically? Typical symptoms No alarm features At least partial relief with OTC measures Age <55 Lifestyle measures Raise head of bed Don t eat late; >3 hours between meal and bedtime Avoid fatty foods, caffeine, alcohol, citrus, tomato, peppermint Stop smoking Weight loss Stop offending meds

6 Lifestyle measures Systematic review of effectiveness of common measures in reducing symptoms Randomized controlled trials: NONE Retrospective/case-control studies: Elevating head of bed yes Sleeping in left lateral decubitus position yes Losing weight yes (Now USPSTF grade B rec) Dietary measures No (!!) Included tobacco/alcohol cessation Kaltenbach, et.al. Arch Intern Med, 2006 Offending meds Decrease LES pressure Calcium channel blockers Nitrates Theophylline Anticholinergics (TCAs, antihistamines) HRT Mucosal injury Tetracyclines Quinidine ASA/NSAIDs Bisphosphonates Potassium Iron Empiric therapy H2RAs (ie H2 blockers) Step-up approach Eliminate symptoms in 50% with BID dosing Maintains remission in only about 25% of patients Appropriate empiric therapy in setting where cost difference between H2RA and PPI is large

7 Empiric therapy PPIs Effective for symptom relief and esophagitis in 85-90% once-daily dosing PPI test 83% sensitive compared to ph probe/ esophagitis gold standard Fass, et.al. Aliment Pharacol Ther, 2000 In primary care GERD symptom population, likelihood ratio of positive PPI test 1.2 (CI ) for ph-proven GERD relative to negative PPI test Aanen, et.al. Aliment Pharacol Ther, 2006 PPIs: Which one? 6 agents (omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and dexlansoprazole) all FDA approved and effective for GERD Esomeprazole (Nexium) decreases number hrs ph held above 4 at standard doses and heals esophagitis in slightly higher % of patients than others Miner,et al. Am J Gastroenterol, 2003

8 PPIs: Which one? However, NO AGENT SUPERIOR for symptom relief when agents compared head to head. HENCE: Choose the one on formulary; otherwise, would choose omeprazole because generic PPIs: How long? Erosive esophagitis 8 weeks Barrett s esophagus lifetime GERD symptoms 4-8 weeks, then on demand Many need long term maintenance therapy

9 GERD relapses after cessation of therapy Sandmark, et.al. Scand J Gastroenterol, 1988 Long-term PPI Safety Endocrine Serum gastrin elevated theoretical trophic risk in gestation, though not proven Gastric carcinoids in rats, none in humans (except one with MEN) Nutritional Can lower cobalamine (B12) absorption Not thought to significantly affect iron homeostasis Dent, et.al. Gut, 1994 Klinkenburg-Knol, et.al. Ann Int Med, 1994 Hip fracture Long-term PPI Safety Case/control study in UK Duration Hip fracture of therapy Adjusted OR (CI) 1yr 1.22 ( ) 2yr 1.41 ( ) 3yr 1.54 ( ) 4yr 1.59 ( ) Yang et.al. JAMA 2006

10 Long-term PPI Safety Hip fracture Higher risk for high dose (over 1.75 doses per day) OR 2.65 for high dose/long term Lower risk for H2RB though still statistically significant increased risk. Cases also were more likely than controls to take: anxiolytics (OR 1.76), antidepressants (2.17), NSAIDs (1.38), antipsychotics (3.34), antiseizure meds (3.42), antiparkinsonian meds (3.83), corticosteroids (2.25), and thyroxine (1.40) Yang et.al. JAMA 2006 Long-term PPI Safety Why hip fractures? Theoretically, acid inhibition interferes with calcium absorption in the small intestine However, PPIs do NOT appear to be associated with osteoporosis or accelerated bone mineral density loss Targownik LF, et al. Gastroenterol, 2010 Confounders? Osteoclast proton-pump inhibition? Long-term PPI Safety Community-acquired Clostridium difficile Case/control study in UK For people taking PPIs: OR 2.9 For people taking H2RBs: OR 2.0 Theoretical basis is decrease in gastric acidity may be permissive to enteric infection Counterintuitive given that C.diff spreads through acid-resistant spores, so acidity shouldn t make much difference Dial et.al. JAMA 2005

11 What about PPIs and Plavix? Plavix effect on platelets thought to be mitigated by PPIs in ex-vivo platelet aggregation studies (P450 CYP2C19) Observational data mixed on event rates Ho PM, et al, JAMA 2009 Ray WA, et al. Ann Intern Med 2010 Randomized trial of PPI + plavix vs. plavix alone (COGENT) no difference in cardiac events PPI/plavix group had 50% bleeding risk Bhatt, et al. unpublished 2009 Long-term PPI Safety PPIs are made of rubber No prospective data proving harm Needs further study Questions raised in a given patient: Does my patient need this medication? Can I get him/her off of it or onto a less potent one? PPI maintenance: On-demand Symptom-driven therapy Single-dose (true on-demand ) Short course ( intermittent therapy ) Controlled by patients, not providers PPI on-demand therapy may be most cost-effective of all maintenance strategies Fewer meds Fewer adverse reactions (realized & potential) Fewer office visits Gerson, et.al. Am J Gastroenterol, 2000

12 Refractory patients Standard dosing regimen once-daily not working for classic symptoms after 1 month trial once-daily PPI OPTIONS: Twice-daily (breakfast/dinner) eg omeprazole 20 BID Add H2RA for nocturnal acid breakthrough Recently shown to be of little benefit, but anecdotally some improve Vakil et.al. Aliment Pharmacol Ther, 2006 Twice-daily double dose (eg omeprazole 40 BID) Can be helpful in subset Leite, et.al. Am J Gastroenterol, 1996 Other agents: sucralfate, prokinetics (treat concomitant gastric emptying disorder) Animal model GERD and stress Rats subjected to stress have more esophageal mucosal permeability and dilated intercellular spaces relative to controls Farre R et.a. Gut 2007 Acid exposure in humans is similar in stress and non-stress, but perception of acid higher in stress Non-erosive GERD: NERD! Endoscopy-negative GERD, functional heartburn, IBS of the esophagus 50-70% of those with classic GERD symptoms Less likely to have abnormal ph study Mechanisms Hypersensitivity Disordered motility Psychological factors High correlation with female gender, functional GI disorders, mood disorders Can respond to mix of acid reducing meds, TCAs, anxiolytics, psychotherapy Chey WD, Am J Med, 2004

13 If GERD-like symptoms but no better on acid reduction: STOP/REDUCE ACID REDUCTION THERAPY TRY SOMETHING ELSE Meds don t work: What else? Referral to specialist Anti-reflux surgery Endoscopic intervention Naturopathic/alternative GERD alarm symptoms Dysphagia Odynophagia Weight loss Bleeding (melena, hematemesis) Anemia Anorexia Nausea/vomiting Severe or persistent symptoms despite Rx

14 The further evaluation Endoscopy Ambulatory ph testing/impedence testing Esophageal manometry Barium esophagram Other Laryngogram Cardiac stress testing PFTs Serum gastrin Anti-reflux surgery Defect in mechanical barrier to reflux corrected Laparoscopic Nissen fundoplication Success largely operator dependent Best candidates: those with GERD on both subjective and objective measures Poor candidates: poor surgical candidates, atypical symptoms Initial success 90-95% in eliminating sx and healing esophagus (many studies)

15 Medical vs. Surgical Rx year follow-up No significant difference between medical and surgical arms in physical and mental well-being or overall satisfaction 62% of surgical patients taking meds for GERD symptoms?increased mortality in surgical arm % 62% Percent using GERD meds Medical Surgical Spechler, et.al. JAMA 2001 GERD and asthma Acid reflux can cause bronchoconstriction NIH asthma guidelines recommend investigating GERD in asthma patients, even without GERD symptoms Randomized trial Nexium vs placebo in asthmatics with no or minimal GERD sx No difference between groups in symptoms or PFTs, even those with silent reflux American Lung Association Asthma Clinical Research Centers, NEJM, 2009 Remember GERD is chronic disease meds control most people s symptoms to a manageable level (75-80% improvement) but do not eliminate them Reassurance is enormous part of job Empiric therapy appropriate for uncomplicated disease; alarm symptoms should warrant GI referral PPIs are OK but stop if not helping

16 Art Burne returns When discussing GERD with his friend, he was told that he could be at risk for esophageal cancer. Should he be screened? What is his risk of esophageal cancer if he has Barrett s esophagus? Barrett s esophagus Worth the hype?

17 Definition Barrett s esophagus (BE): A change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy Pre-malignant lesion for esophageal adenocarcinoma (EAC) Most EAC accompanied by BE Epidemiology Primary identifiable risk factors for Barrett s esophagus and esophageal adenocarcinoma male Caucasian chronic symptomatic GERD age obesity smoking

18 GERD a risk for esophageal adenoca GERD sx at least once/wk Controls Esophageal adenocarcinoma OR (Adjusted) No 685 (84%) 76 (40%) ref Yes 135 (16%) 113 (60%) 7.7 Lagergren et.al., N Eng J Med, 1999 Barrett s: Why shouldn t I care? Estimates of EAC arising in BE range from 1/48 (2.1%) to 1/441 (0.2%) per year Strong correlation between the size of the study and estimated cancer risk smaller studies predict higher risk than larger, population-based studies PUBLICATION BIAS likely overestimated CA risk Shaheen, et al. Gastroenterol 2000 Barrett s Esophagus Study Trial ( BEST ) 1376 patients followed avg 4.12 years 0.5% annual risk EAC (1/200 per pt-yr) Sharma, et.al. Clin Gastroenterol Hepatol 2006 Sikkema M, et.al. Clin Gastroenterol Hepatol 2010 Barrett s: Why shouldn t I care? GERD is the most common risk factor, but about 40% of patients found to have esophageal adenocarcinoma didn t complain of prior GERD symptoms Hard to select subset to screen Lagergren et.al., N Eng J Med, 1999 Those diagnosed with Barrett s tend to die of non-esophageal causes more frequently than of esophageal cancer. Anderson, et.al. Gut, 2003 Solaymani-Dodaran, et.al. Am J Gastroenterol 2005

19 Causes of death in BE patients: A meta-analysis Sikkema M, et.al. Clin Gastroenterol Hepatol 2010 Barrett s: Why we should care Incidence of EAC has increased 10-fold over last 30 years Incidence is increasing 4-10% per year Steeper rise than any other type of cancer Incidence of Barrett s esophagus appears to be rising at a comparable rate Van Soest, et.al. Gut 2005 Esophageal AdenoCA Incidence 3.6/100,000 in SEER data, 2000

20 Barrett s: Why we should care Overall mortality from EAC increasing (reflecting increasing incidence since it is rarely found in curable stage) In those diagnosed with cancer, survival to 1 and 5 yrs improved over last 25 years, but is still poor <13-20% overall 5-year survival Esophagectomy only cure Large morbidities associated SEER data, 2006 Barrett s management: Treatment of GERD Medical therapy (proton pump inhibitors) and surgical therapy 75-90% effective at treating symptomatic GERD and esophagitis GERD contributes to risk of dysplasia and EAC arising from BE Other factors are important medical GERD therapy & antireflux surgery not proven to revert BE to normal mucosa or to prevent EAC Smith et al, Am J Surg Pathol, 1984 Sharma et.al., Am J Gastroenterol 1997 Spechler et.al., JAMA, 2001 Parilla et.al., Ann Surg, 2003 Barrett s management: Other approaches Ablation Photodynamic therapy, radiofrequency ablation Concern for subepithelial recurrence Randomized trial for dysplastic BE showed decreased risk of adeonoca Biomarkers Identifying genetic abnormalities in tissue Helps to risk stratify Chemoprevention NSAIDs and aspirin promising; RCTs pending

21 Barrett s management: Endoscopic surveillance Endoscopic surveillance is currently the only widely accepted means for attempting to decrease the risk of advanced EAC in patients with non-dysplastic BE Goals detect dysplasia (risk stratification) detect early cancer (improve outcomes) ACG Surveillance Guidelines No dysplasia Low-grade dysplasia Every 3 yrs Every 1 yr High-grade dysplasia Focal: Every 3 months Multifocal: Ablation Mucosal Irregularity: EMR Wang KK, et al, Am J Gastroenterol, 2008 Effect of surveillance 70% 60% 50% 40% 30% Surveillance No Surveillance 20% 10% 0% Stage 1 Stage 2 Stage 3 Stage 4 TNM Stage at diagnosis Corley et.al., Gastroenterol, 2002

22 Endoscopic surveillance Retrospective data show that performance of BE surveillance is associated with earlier diagnosis and improved survival No randomized or prospective trials showing surveillance prolongs or improves lives Other issues Lack of standardization Poor observer agreement in level of dysplasia Impact on quality of life Cost-Effectiveness: Endoscopic Screening & Surveillance Surveillance in patients with BE is probably cost-effective compared to no intervention Screening patients with GERD for BE and cancer is not cost-effective unless we ignore those with non-dysplastic BE 1 Not likely, difficult to justify ignoring premalignant condition 1 Inadomi et.al., Ann Int Med, 2003 Who should I screen for Barrett s esophagus?

23 Risk of esophageal adenocarcinoma Adjusted odds ratio Highest vs. lowest quartile > 30 vs. <22 > 30/reflux vs. <22/no reflux BMI Lagergren et.al., Ann Int Med 1999; JAMA 2000 Who should I screen for Barrett s esophagus? CONSIDER caucasian, obese men with chronic GERD (e.g. >5yrs), especially those who smoke, for a one- time EGD to screen for Barrett s These are at the highest risk for Barrett s and EAC Screening of general asymptomatic population NOT recommended Capsule endoscopy: the next frontier? Who should receive surveillance for Barrett s? All patients with well-documented Barrett s esophagus Consider forgoing surveillance where treatment of early-detected lesion unlikely to be tolerated (eg advanced age, comorb) All patients with Barrett s should be on a daily proton pump inhibitor whether or not they have symptoms

24 Bill Leeder 68 yo male with severe osteoarthritis comes to your for post-hospitalization visit Recent admission for UGI bleed from gastric ulcer Takes aspirin, ibuprofen, and zoloft in addition to newly started omeprazole; he was told to stop some medication but cannot remember which Bill Leeder Should he have been switched to a Cox-2 selective inhibitor? Which medicaton (s) should he have stopped? Medications and UGI bleeding

25 COX-2 inhibitors and GI safety Main advantage of COXIBs has been fewer peptic ulcers and better tolerability than nonselective NSAIDs Supported by recent Cochrane Meta-Analysis Compared to standard NSAIDs, COXIBs had: Fewer gastroduodenal ulcers (RR 0.26; CI ) Fewer ulcer complications (RR 0.39; CI ) Fewer withdrawals for GI sx (RR 0.65;CI ) Need to weigh higher cardiovascular risk, which appears to be directly correlated to degree of Cox- 2 selectivity Rostom A, et.al. Clin Gastroenterol Hepatol 2007 NSAID gastroprotection In patients taking NSAIDs, which is safer? COX-2 inhibitor vs. standard NSAID plus PPI Medicare peptic ulcer hospitalizations/yr Nonselective NSAID/no gastroprotection: 5.6/1000 Nonselective NSAID plus PPI: reduced 54% (CI 27-72%) Cox-2 inhibitor plus PPI: reduced 50% (CI 27-66%) No significant difference between to groups Ray WA, et.al. Gastroenterol 2007 Ray WA, et.al. Gastroenterol 2007

26 SSRIs and UGI bleeding Current, recent, or past SSRI use is associated with a 1.67, 1.88, and 1.22 OR of an UGI bleed Risk was increased with concurrent use orf NSAIDs or aspirin and decreased with concurrent use of PPI Inhibition of platetet activity possible mechanism Dall M, et al. Clin Gastroenterol Hepatol 2009 Stopping aspirin after GI bleed? Patients with peptic ulcer bleed on aspirin randomized to PPI + aspirin vs. PPI + placebo PPI plus baby aspirin PPI plus placebo Rebleed risk after 8 weeks All-cause mortality after 8 weeks 10% 5% 1% 13% Sung, JJY, et.al, Ann Int Med, 2010 Billie Aiken 38 yo black woman comes into your office with epigastric pain, non-radiating, constant, inconsistently associated with meals for months She was born in Haiti but moved to this country when she was 10 Denies any blood in stool, early satiety She takes no medications Only medical problem is IBS

27 Billie Aiken What is the most appropriate initial approach to her symptoms? How likely is she to have H.pylori? What is the relevance of the IBS? Dyspepsia Pain or discomfort in epigastrium

28 Approach to dyspepsia Numerous possible approaches H.pylori test and treat Empiric antisecretory (H2RB or PPI) Endoscopy H.pylori: Who has it? Prevalence in adults in mid 1990s 50% developed world 80% developing world Risk factors Lower socioeconomic status Poor living conditions, eg crowding, lack of running water, housing density Pounder RE, et.al. Aliment Pharmacol Ther 1995 H.pylori and ethnicity NHANES stored sera from Non-Hispanic White Mexican American African American Prevalence 26.2% 61.6% 52.7% Odds ratio compared to White NA 6.3 ( ) 3.9 ( ) Everhart JE et.al. J Infect Dis 2000

29 H.pylori: Declining prevalence Within a given country, appears to relate to improvements in economic status and sanitation In Japan, H.pylori seropositivity Born prior to 1950: > 70% Born : 45% Born after 1960: 25% Asaka M, et.al. Gastroenterology 1992 H.pylori associations Duodenal and gastric ulcers Gastric cancer MALT Gastric adenoca Atrophic gastritis/gastric intestinal metaplasia Functional dyspepsia H.pylori and ulcers Strong association between H.pylori and duodenal ulcers, less strong for gastric Synergistic effect with H.pylori and NSAIDs in ulcer incidence Effective eradication of H.pylori clearly reduces ulcer recurrence

30 H.pylori and gastric cancer H.pylori is associated with gastric adenocarcinoma and its precursors Treatment of H.pylori in MALT lymphoma when early stage can be curative Treatment of H.pylori may reduce risk of gastric adenocarcinoma Wong BC, et.al. JAMA 2004 H.pylori and functional dyspepsia Controversial association between functional dyspepsia (FD) and H.pylori Evidence that H.pylori eradication in FD improves symptoms is mixed Meta-analysis shows SMALL but statistically significant improvement in HP eradication in FD 1 NNT 18 for 1 improvement over placebo 1 Moayyedi P, et.al. Cochrane Database Syst Rev 2005 Serology Urea breath test H.pylori testing Stool antigen Endoscopic biopsy Histology Culture

31 Serology Urea breath test H.pylori testing Stool antigen Endoscopic biopsy Histology Culture H.pylori treatment First-line therapy (AOC) X days 1 Amoxacillin 1000mg BID Eradication Clatrithomycin 500mg BID 80% PPI standard dose BID PCN allergic: Switch Flagyl 500mg BID for Amoxacillin 7 days nearly as effective as days 2 Treatment-failures, numerous regimens 1 Chey WD, et.al. Am J Gastroenterol Fuccio L, et.al. Ann Intern Med 2007 H. Pylori and GERD Try to distinguish GERD symptoms from dyspepsia!! Often difficult overlapping and multiple complaints Poor correlation between patient & clinician symptom assessement (kappa ) Treatment of H.pylori may WORSEN GERD H.pylori infection in some observational studies lower in patients with GERD symptoms Randomized trial did NOT confirm GERD higher in H.pylori treated patients McColl, et.al. Am J Gastroenterol 2005 Moayyedi, et.al. Gastroenterol 2001

32 Use of endoscopy in dyspepsia Always with alarm symptoms Alarm symptoms poor predictor of organic pathology Failure to improve despite numerous rounds of empiric therapy Appropriate age cut off is controversial Guidelines vary from UGI cancer rare prior to age 55 How to approach a patient with dyspepsia yes Alarm symptoms or age > 55? no normal abnormal yes no no yes findings Symptom resolution? neg no yes

33 Functional dyspepsia Pain in epigastrium without identifiable organic cause (endoscopy negative) What s wrong then? Not clear. Motility disorder? Visceral hypersensitivity? Psychosocial factors? Altered brain-gut axis? Overlap with other functional GI disorders (eg NERD, IBS) 1 2/3 of pts presenting with dyspepsia have FD 1 Corsetti M et.al. Am J Gastroenterol 2004 Functional dyspepsia: Medical Management Therapy NNT PPI 9 H.pylori eradication 18 Prokinetics 4 (included cisapride) TCA/anxiolytics 4 Anatacids, bismuth, sucralfate No better than placebo NNT = Number needed to treat = 1/effect size Saad RJ, et.al. Aliment Pharmacol Ther 2006 Functional dyspepsia: Anything else? Psychotherapy Individual trials suggest benefit Systematic review unable to synthesize 1 Studies too diverse High dropout rates in control groups Complementary alternative medicine 2 STW 5 (Iberogast) Capsaicin red chili pepper Artichoke leaf extract Soo S et.al. Am J Gastroenterol Saad RJ et.al. Aliment Pharmacol Ther

34