GERD burden (GERD-en?) Controversies in the Upper GI Tract Jeffrey Fox, MD, MPH UCSF Primary Care Medicine: Update 2012 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 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 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 Empiric therapy Decrease LES pressure Calcium channel blockers Nitrates Theophylline Anticholinergics (TCAs, antihistamines) HRT Mucosal injury Tetracyclines Quinidine ASA/NSAIDs Bisphosphonates Potassium Iron 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
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 0.9-1.6) 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
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 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 1 st trimester pregnancy use: no increase in birth defects Pasternak B, et al. NEJM, 2010 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
Long-term PPI Safety Hip fracture Case/control study in UK Duration Hip fracture of therapy Adjusted OR (CI) 1yr 1.22 (1.15-1.30) 2yr 1.41 (1.28-1.56) 3yr 1.54 (1.37-1.73) 4yr 1.59 (1.39-1.80) Yang et.al. JAMA 2006 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) FDA warning 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? PPI vs aspirin Number needed to harm (NNH) = number of people who need to be prescribed medication to have 1 complication above the level of placebo GI hemorrhage on annual basis with aspirin treatment: NNH 100 Hip fracture on annual basis with PPI treatment: NNH 330
Long-term PPI Safety Community-acquired infections Clostridium difficile: Case/control study in UK 1 For people taking PPIs: OR 2.9 For people taking H2RBs: OR 2.0 Community acquired pneumonia: meta-analysis of case-control studies 2 OR for CAP 1.36 for PPI relative to controls Significant heterogeneity and only modest risk Theoretical basis is decrease in gastric acidity may be permissive to enteric infection (in Cdiff) and reflux/microaspiration (CAP) Dial et.al. JAMA 2005 1 Johnstone J, et.al. Aliment Pharmacol Ther 2010 2 Long-term PPI safety Hypomagnesemia FDA safety alert March 2011: Hypomagnesemia is rare but possible adverse effect from long-term PPI use Special care in patients also on other meds that can cause hypomg (eg diuretics, digoxin) Can result in muscle spasm, seizures, and cardiac events 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 Banergee S et al. Am J Cardiol 2011 Randomized trial of PPI + plavix vs. plavix alone (COGENT) no difference in cardiac events PPI/plavix group had 50% bleeding risk Bhatt, et al. NEJM 2010 ACC/AHA/ACG position In patients taking clopidogrel+asa 2008 ACC/AHA/ACG take PPI co-therapy 2009 FDA BOXED WARNING on omeprazole/esomeprazole plus clopidogrel 2010 ACC/AHA/ACG position update: There may be an important interaction In high risk patients for UGI bleed, benefits of PPI co-therapy outweigh risks In average risk patients, case-by-case approach Use non-omeprazole/esomeprazole PPIs when on plavix if PPI is needed/advised
Long-term PPI Safety PPIs are made of rubber No prospective randomized data proving harm Enough retrospective evidence of potential harm to be cautious 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 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), baclofen GERD and stress Animal model 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 If GERD-like symptoms but no better on acid reduction: STOP/REDUCE ACID REDUCTION THERAPY TRY SOMETHING ELSE Chey WD, Am J Med, 2004 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
The further evaluation Endoscopy Ambulatory ph testing/impedence testing Esophageal manometry Barium esophagram Other Laryngoscopy 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) Medical vs. Surgical Rx GERD and asthma 10-13 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 100 90 80 70 60 50 40 30 20 10 0 92% 62% Percent using GERD meds Medical Surgical 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 Spechler, et.al. JAMA 2001 American Lung Association Asthma Clinical Research Centers, NEJM, 2009
GERD and extraesophageal sx Laryngitis, chronic cough, asthma USPSTF position: Treatment recommended when extraesophageal symptoms accompany typical esophageal symptoms (grade B) Treatment not recommended in absence of typical esophageal symptoms (grade D) Kahrilas PJ, et al. Gastroenterol 2008 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 COX-2 inhibitors and GI safety Medications and UGI bleeding 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 0.23-0.3) Fewer ulcer complications (RR 0.39; CI 0.31-0.5) Fewer withdrawals for GI sx (RR 0.65;CI 0.57-0.73) 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 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 of NSAIDs or aspirin and decreased with concurrent use of PPI TCAs did not show this association Inhibition of platetet activity possible mechanism Dall M, et al. Clin Gastroenterol Hepatol 2009 Low dose aspirin and GIB Meta-analysis of dosages 75-325mg/day RR* Decreased overall mortality 0.93 Increased risk of GI bleeding 1.55 In combination with aspirin, vs aspirin alone Other antiplatelet/anticoagulants 1.86 PPI 0.34 *All statistically significant Stopping aspirin after GI bleed? Patients with peptic ulcer bleed on aspirin randomized to PPI + aspirin vs. PPI + placebo Rebleed risk after 8 weeks All-cause mortality after 8 weeks PPI plus baby aspirin PPI plus placebo 10% 5% 1% 13% Lanas A et al. Clin Gastroenterol Hepatol 2011 Sung, JJY, et.al, Ann Int Med, 2010
Approach to dyspepsia Dyspepsia Pain or discomfort in epigastrium 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 H.pylori and ethnicity NHANES stored sera from 1988-1991 Non-Hispanic White Mexican American African American Prevalence 26.2% 61.6% 52.7% Odds ratio compared to White NA 6.3 (4.8-8.3) 3.9 (3.1-4.9) Pounder RE, et.al. Aliment Pharmacol Ther 1995 Everhart JE et.al. J Infect Dis 2000
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 1950-1960: 45% Born after 1960: 25% H.pylori associations Duodenal and gastric ulcers Gastric cancer MALT Gastric adenoca Atrophic gastritis/gastric intestinal metaplasia Functional dyspepsia Asaka M, et.al. Gastroenterology 1992 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 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 H.pylori testing Serology Urea breath test Stool antigen Endoscopic biopsy Histology Culture H.pylori treatment First-line therapy (AOC) X 10-14 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 10-14 days 2 Treatment-failures, numerous regimens 1 Chey WD, et.al. Am J Gastroenterol 2007 2 Fuccio L, et.al. Ann Intern Med 2007 H.pylori sequential vs standard Eradication (intention to treat) Eradication Sequential PPI + Amox X 5 days then PPI + Biaxin + Flagyl X 5 days Standard PPI + Amox + Biaxin X 14 days 85.9% 75% p = 0.006 (per protocol) 92.6% 85% p=0.019 Resistance to standard triple therapy increasing Sequential therapy may improve eradication over standard triple therapy Kim YS, et al. Aliment Pharmacol Ther 2011
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 0.17-0.53) 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 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 45-55 UGI cancer rare prior to age 55 McColl, et.al. Am J Gastroenterol 2005 Moayyedi, et.al. Gastroenterol 2001 yes Alarm symptoms or age > 55? no normal How to approach a patient with dyspepsia abnormal yes no no yes findings Symptom resolution? neg no yes
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 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 1 Corsetti M et.al. Am J Gastroenterol 2004 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 2004 1 Saad RJ et.al. Aliment Pharmacol Ther 2006 2