Dilemmas of the I have no conflicts of interest Upper GI Tract to disclose Jeffrey Fox, MD, MPH UCSF Primary Care Medicine: Update 2013 Art Byrne What should we recommend? • 42 yo white overweight male A. Anti-reflux behavioral management only • Has substernal burning once per week B. Upper endoscopy before he goes to sleep at night for 10 C. Test for H.pylori and treat if positive years D. Trial of H2RB + behavioral measures • No dysphagia, weight loss, early satiety, E. Trial of PPI + behavioral measures blood in stool, or jaundice • Responds to self-use of antacids • Flares of symptoms correlate with stress 1
Art Byrne questions • 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? GERD burden (GERDen) • 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 2
MONTHLY GERD SYMPTOMS WEEKLY GERD SYMPTOMS The Gallup Organization, 1988 Locke, Gastroenterol, 1997 DAILY GERD SYMPTOMS BARRETT’S ESOPHAGUS Nebel, et.al. Am J Dig Dis, 1976 Ronkainen et al, Gastroenterol 2005 3
ESOPHAGEAL ADENOCARCINOMA ESOPHAGEAL ADENOCARCINOMA 1 in 20,000 Sharma et.al., Gastroenterol, 2006 Defining GERD Whom should I treat empirically? • Symptom pattern – heartburn, regurgitation, • Typical symptoms dysphagia • No alarm features – How often is “disease” • At least partial relief with OTC measures • Pathologic lesion – erosive esophagitis – Combo of symptoms and esophagitis highly • Age <55 specific (97%) vs. pH testing – What about those with the symptoms but without the lesion – “NERD” • “Gold-standard” – pH monitoring best but imperfect 4
Lifestyle measures Lifestyle measures • Raise head of bed • Systematic review of effectiveness of common measures in reducing symptoms • Don’t eat late; >3 hours between meal and bedtime – Randomized controlled trials: NONE – Retrospective/case-control studies: • Avoid fatty foods, caffeine, alcohol, citrus, • Elevating head of bed – yes tomato, peppermint • Sleeping in left lateral decubitus position – yes • Stop smoking • Losing weight – yes (Now USPSTF grade B rec) • Weight loss • Dietary measures – No (!!) – Included tobacco/alcohol cessation • Stop offending meds Kaltenbach, et.al. Arch Intern Med, 2006 Empiric therapy Empiric therapy • H2RAs (ie H2 blockers) • PPIs • “Step-up approach” • Effective for symptom relief and esophagitis in 85-90% once-daily dosing • Eliminate symptoms in 50% with BID dosing • PPI “test” 83% sensitive compared to pH probe/ • Maintains remission in only about 25% of patients esophagitis “gold standard” • Appropriate empiric therapy in setting where cost difference between H2RA and PPI is large 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 5
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 6
GERD relapses after cessation of PPIs: How long? therapy • Erosive esophagitis – 8 weeks • Barrett’s esophagus – lifetime • GERD symptoms – 4-8 weeks, then stop to see if strict behavioral measures will be effective • Many need long-term maintenance therapy Sandmark, et.al. Scand J Gastroenterol, 1988 Long-term PPI Safety Long-term PPI Safety • Endocrine • Hip fracture – Serum gastrin elevated – theoretical “trophic” risk in – Case/control study in UK gestation Duration Hip fracture – 1 st trimester pregnancy use: no increase in of therapy Adjusted OR (CI) birth defects Pasternak B, et al. NEJM, 2010 1yr 1.22 (1.15-1.30) – Gastric carcinoids in rats, no cancer increase in 2yr 1.41 (1.28-1.56) humans Fiocca R et al. Alim Pharmacol Ther 2012 3yr 1.54 (1.37-1.73) • Nutritional 4yr 1.59 (1.39-1.80) – Can lower cobalamine (B12) absorption – Not thought to significantly affect iron homeostasis Yang et.al. JAMA 2006 Dent, et.al. Gut, 1994 Klinkenburg-Knol, et.al. Ann Int Med, 1994 7
Long-term PPI Safety Long-term PPI Safety • Hip fracture • Hip fracture – Higher risk for “high dose” (over 1.75 doses per day) – Higher risk for “high dose” (over 1.75 doses per day) • OR 2.65 for high dose/long term • OR 2.65 for high dose/long term – Lower risk for H2RB though still statistically significant – Lower risk for H2RB though still statistically significant increased risk. increased risk. – Cases also were more likely than controls to take: – Cases also were more likely than controls to take: anxiolytics (OR 1.76), antidepressants (2.17), NSAIDs anxiolytics (OR 1.76), antidepressants (2.17), NSAIDs (1.38), antipsychotics (3.34), antiseizure meds (3.42), (1.38), antipsychotics (3.34), antiseizure meds (3.42), antiparkinsonian meds (3.83), corticosteroids (2.25), antiparkinsonian meds (3.83), corticosteroids (2.25), and thyroxine (1.40) and thyroxine (1.40) 2010 FDA warning Yang et.al. JAMA 2006 Yang et.al. JAMA 2006 Long-term PPI safety Long-term PPI Safety • Nurses health study • Why fractures? – Prospective cohort study – Theoretically, acid inhibition interferes with calcium absorption in the small intestine – 565,786 person-years follow-up – However, PPIs do NOT appear to be – Hip-fracture risk associated with osteoporosis or accelerated • Current PPI users 2/1000 person-years bone mineral density loss • Non-users 1.5/1000 p-y Targownik LF, et al. Gastroenterol, 2010 – Attributable risk 1/2000 p-y Targownik LF, et al. Am J Gastroenterol 2012 – Adjusted HR 1.35 – Confounders? • Risk disappears after 2 years cessation – Osteoclast proton-pump inhibition? • Smoking appears to be cofactor 1 Khalili H, et al. BMJ 2012 8
Long-term PPI Safety Long-term PPI safety • Community-acquired infections • Hypomagnesemia – Clostridium difficile : Case/control study in UK 1 – FDA safety alert March 2011: • For people taking PPIs: OR 2.9 Hypomagnesemia is rare but possible • For people taking H2RBs: OR 2.0 adverse effect from long-term PPI use – Community acquired pneumonia: meta-analysis of case-control studies 2 – Special care in patients also on other meds • OR for CAP 1.36 for PPI relative to controls that can cause hypoMg (eg diuretics, digoxin) • Significant heterogeneity and only modest risk – Can result in muscle spasm, seizures, and – Theoretical basis is decrease in gastric acidity may be cardiac events “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 What about PPIs and Plavix? ACC/AHA/ACG position • In patients taking clopidogrel+ASA • Plavix effect on platelets thought to be – 2008 – ACC/AHA/ACG “take PPI co-therapy” mitigated by PPIs in ex-vivo platelet – 2009 – FDA BOXED WARNING on aggregation studies (P450 CYP2C19) omeprazole/esomeprazole plus clopidogrel • Observational data mixed on event rates – 2010 – ACC/AHA/ACG position update : Ho PM et al, JAMA 2009 Ray WA et al. Ann Intern Med 2010 • There may be an important interaction Banergee S et al. Am J Cardiol 2011 • Randomized trial of PPI + plavix vs. plavix • In high risk patients for UGI bleed, benefits of PPI co-therapy outweigh risks alone (COGENT) • In average risk patients, case-by-case approach – no difference in cardiac events • Use non-omeprazole/esomeprazole PPIs when on – PPI/plavix group had 50% bleeding risk plavix if PPI is needed/advised Bhatt, et al. NEJM 2010 9
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