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Specialty Medicine with Commitment, Care and Compassion

GERD in 2016: What do the Guidlelines Recommend?

Michael Phillips, MD

The Oregon Clinic, GI East

April 2016

GERD

• Objectives – Understand pathophysiology of GERD

– Review key evidence based guidelines for GERD

– Review recent data on PPIs

– Be familiar with new surgical treatments for GERD

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GERD: How Common?

• GERD is arguably the most common disease encountered by the gastroenterologist

• 25-40% of healthy adult Americans experience symptomatic GERD, most commonly manifested clinically by pyrosis, at least monthly

• 7-10% of the population in the United States experiences such symptoms on a daily basis

• GERD is as common in men as in women. However, the male-to-female incidence ratio for esophagitis is 2:1-3:1. The male-to-female incidence ratio for Barrett esophagus is 10:1

• White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations

GERD Pathophysiology• Esophageal Defense

– Esophageal clearance• Esophageal motility• Abnormal peristalsis was identified in 25% of patients with mild esophagitis and 48% of patients with severe

esophagitis.– Mucosal Defense

• Lower Esophageal Sphincter– LES must be located in the abdomen so that the diaphragmatic crura can assist the action of the

LES, thus functioning as an extrinsic sphincter. This is the HPZ, High Pressure Zone.– LES must have a normal length and pressure and a normal number of episodes of transient

relaxation (relaxation in the absence of swallowing)– LES Dysfunction

• Transient LES relaxation (most common mechanism)• permanent LES relaxation• transient increase of intra-abdominal pressure that overcomes the LES pressure.

– Causes of transient LES relaxation (TLESR)• foods (coffee, alcohol, chocolate, fatty meals)• medications (beta-agonists,nitrates, calcium channel blockers, anticholinergics)• hormones (eg, progesterone)• nicotine.

• Delayed gastric emptying– objective studies have produced conflicting data regarding the role of delayed gastric emptying in the

pathogenesis of GERD.• Hiatal hernia• Obesity

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GERD: Anatomy

GERD: Diagnosis

• A diagnosis of GERD based on the presence of typical symptoms is correct in only 70% of patients.

• As many as 50% of symptomatic patients with GERD demonstrate no evidence of esophagitis on endoscopy.

• Diagnostic Tests:• http://www.nature.com/ajg/journal/v108/n3/pdf/ajg20124

44a.pdf

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Indications for Endoscopy

Endoscopy for GERD

• Recommended in the presence of alarm symptoms and for screening of patients at high risk of complications

• Repeating endoscopy is not indicated in patients without Barrett’s esophagus in the absence of new symptoms

• Biopsy from the distal esophagus are not recommended to diagnose GERD

• Screening for H pylori is not recommended in GERD patients

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24 hour pH Monitoring

• Ambulatory pH or impedance-pH is the only test that allows for determining the presence of abnormal esophageal acid exposure, reflux frequency, and symptom association with reflux episodes

• Sensitivity of 96% and a specificity of 95%

• Telemetry capsule (Bravo) or transnasal catheter

Indications for 24 hour pH

• Indications for esophageal manometry and prolonged pH monitoring include the following: – Persistence of symptoms while taking adequate

antisecretory therapy, such as PPI therapy BID– Recurrence of symptoms after discontinuation of

acid-reducing medications– Investigation of atypical symptoms, such as chest

pain or asthma, in patients without esophagitis– Confirmation of the diagnosis in preparation for

antireflux surgery

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24 Hour pH Monitoring: On or Off PPI?

• Indication Driven:– Low pre-test

probability; off PPI

– High pre-test probability; on PPI

Treatment for GERD: Stepwise

• Lifestyle

• Medication– Antacids

– H2 Blockers

– PPI

– Baclofen

• Surgery

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Lifestyle Changes for GERD

• Lose weight (if overweight)• Avoiding alcohol, chocolate, citrus juice, and

tomato-based products (2005 guidelines from the American College of Gastroenterology [ACG] also suggest avoiding peppermint, coffee, and possibly the onion family ) <– data limited

• Avoiding large meals• Waiting 3 hours after a meal before lying down• Elevating the head of the bed 8 inches• Sleeping on the left side

Medications for GERD

• 80% of patients have GERD that is controlled with medications

• Medications:– Antacids– H2RAs– PPIs– Baclofen

• Identifying the 20% of patients who have a progressive form of the disease is important, because they may develop severe complications, such as strictures or Barrett esophagus

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H2RAs

• Can be used as a maintenance option in patients without erosive disease if they provide relief

• Bedtime H2RA can be added to daytime PPI in patients with nighttime symptoms

• Tachyphylaxis after several weeks of use

Promotility/Sucralfate

• Prokinetic agents should not be used in GERD without prior diagnostic evaluation

• No role for sucralfate in non-pregnant GERD patients

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Baclofen

• A GABA-beta agonist

• Has been shown to decrease reflux episodes and symptoms due to all types of reflux

• Decreases TLESR events; recognized as a key reason for reflux treatment failure

• 10 mg BID slowly increased to 20 mg TID depending on side-effects

PPIs

• 2 month course of PPIs is therapy of choice and for healing erosive esophagitis

• No difference between PPIs• Take 30-60 min before first meal of the day• May increase to BID dosing if needed for 2 months

– Consider switch to different PPI if failure with one

• Non-responders to PPI referred for GI evaluation• Maintain patients with chronic symptoms,

complications or Barrett’s on PPI• Safe in pregnant patients if indicated

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PPI’s: are they safe?

• Risks:– Community acquired pneumonia– Clostridium difficile infection– Acute interstitial nephritis– Vitamin B12 deficiency– Magnesium deficiency– Drug interactions: Clopidogril– Hip Fractures (2006)– Renal insufficiency (2016)– Dementia (2016)

PPIs Hip Fractures

• Hip Fractures (2006)– United Kingdom evaluated a nested case-control

study of cohorts over 50 years of age of users of PPI therapy and nonusers of acid suppression.

– There were 13,556 hip fracture cases and 135,386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59).

– The risk increased with longer therapy.– Other studies have suggested similar

observation, also with H2 blockers.

Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006 Dec 27. 296(24):2947-53.

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PPIs: Renal Insufficiency

• Renal insufficiency– JAMA study 2016: Observational Cohort Study: 10482 patients

from the ARIC study and 250,000 patients in Geisinger.– 1996 to 2011, looked at prescription drugs, not OTC's– Looked for eGFR less than 60 mL/min/1.73m2; claims data on

discharge summaries– Use of prescription PPIs– No incident risk with H2 blockers.– Incident Risk; HR,1.45, [95% CI, 1.01-1.90]; higher if taking PPI

BID.– Group on PPIs at baseline statistically had lower GFR, higher

BMI to start with; high incidence of HTN, CV disease, and concomitant medications (diuretics, aspirin, statins and antihypertensives).

Lazarus B, Chen Y, Wilson FP, et a. JAMA Intern Med. 2016;176:238‐246.

PPIs: Dementia

• There is evidence that PPIs might effect cognition from German study 2016– PPI uses is associated with B12 Vitamin

deficiency; which in turn is associated with cognitive decline

– PPIs observed to enhance beta-amyloid levels in the brains of mice by affecting the enzymes beta- and gama-secretase.

Gomm W, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA

Neurol. 2016 Feb 15.

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PPIs: Dementia

• 2291 patients, 75 years of age or older

• Took into account: age, sex, education level, ApoE4 allele status, depression, diabetes, stroke, ischemic heart disease and poly-pharmacy

• Biologic plausibility

Gomm W, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis.

JAMA Neurol. 2016 Feb 15.

PPIs: Dementia

• Detected a significant association between PPI and incident dementia HR 1.33 [95%, CI, 1.04-1.83] and an increased risk of Alzheimer’s disease (HR, 1.44[95% CI, 1.01-2.06]).

• A 1.4 fold increase in dementia, as suggested by this study would increase the estimated incident rate of dementia from 6.0% per year to approximately 8.4% per year.

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PPIs: Dementia

• Based on 2010 US Census data– If there were 13,500,000 people age 74 to 85 of

age and 3% were receiving PPIs (n=400,000) then this could result in an increase of about 10,000 new cases of incident dementia per year just in this age group.

PPIs: Dementia

• Association is not causal; the study only provides a statistical association bet PPI use and the risk of dementia.

• Polypharmacy was a risk factor and did not preclude the association of PPI use with dementia.

• Specific drugs may be associated with both PI use and dementia

• Higher prevalence of comorbidities and disease also increase the contact with physicians and the medical community, increasing likelihood of the risk of dementia (the Berksonian bias).

• Further studies are needed– determine if there is a causal biological mechanism– need randomized prospective clinical trial to evaluate and establish

if there are direct cause and effect relationships between PPI use and indecent dementia in the elderly.

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PPIs and Clopidogrel

• Clopidogril update in 2015– Meta analysis by Melloni et al– 35 studies available for review– Discordant results have been reported on the effects

of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. They conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the post discharge treatment of unstable angina/non–STsegment–elevation myocardial infarction patients.

Circ Cardiovasc Qual Outcomes. 2015;8:47-55.

PPIs and Clopidogrel

• Clopidogril update in 2015– the results from randomized controlled trials

evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole.

– Editorial response by Dr. Peter Berger of Geisinger Cardiology said:

• "What does seem clear, however, is that warnings about the coadministration of PPIs with clopidogrel ought be removed…”

Circ Cardiovasc Qual Outcomes. 2015;8:47-55.

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Surgery for GERD: Indications

• Patients with symptoms not completely controlled by PPI therapy can be considered for surgery; surgery can also be considered in patients with well-controlled GERD who desire definitive, one-time treatment

• Barrett esophagus is an indication for surgery (whether acid suppression improves the outcome or prevents the progression of Barrett esophagus remains unknown, but most authorities recommend complete acid suppression in patients with histologically proven Barrett esophagus)

• Extra-esophageal manifestations of GERD:– respiratory manifestations (eg, cough, wheezing, aspiration)– ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis

media)– dental manifestations (eg, enamel erosion)

• Young patients• Poor patient compliance with regard to medications• Postmenopausal women with osteoporosis• Patients with cardiac conduction defects• Cost of medical therapy

Linx Device

• The USDA approved the LINX Reflux Management System in March 2012

• Augments the LES creating reflux barrier

• Laparoscopically placed interlinked titanium beads with magnetic cores

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Linx in 2015

• 14 centers, 100 patients, BMI 28, 53 yrs old, 10 yrs symptoms, on PPI 5 yrs

• 50% reduction in GERD-HRQL in 83% at 5 yrs

• 50% or more decrease in PPIs in 89% of pts at 5 yrs

• Device removed in 7 patients

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Linx for GERD

• Risk and Benefits:– Dysphagia in 68% of patients; removal of the device

in 3% of patients.– Pain in 24%, resolves in most by 3 months.– Bloating in 14%; mild to moderate in most– Has only been studied 5 years– MRI conditional up to 1.5 Tesla depending on the

device used– Not studied in patients with Barrett’s, or hiatal hernias

greater than 3 cm– Less invasive than Nissen fundoplication– Ability to resume a normal diet following surgery

Key Evidence Based Guidelines for GERD 2016

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Establishing the Diagnosis of GERD

• Diagnose GERD by symptoms; treat empirically with PPI*

• EGD not required in the absence of alarm symptoms or high risk of Barrett’s*

*Strong recommendation, moderate level of evidence

Management of GERD

• An 8-week course of PPIs is the therapy of choice for symptom relief and healing of erosive esophagitis. There are no major differences in efficacy between the different PPIs **

• PPI therapy should be initiated at once a day dosing, before the first meal of the day*

• For patients with partial response to once daily therapy, tailored therapy with adjustment of dose timing and/or twice daily dosing should be considered in patients with night-time symptoms, variable schedules, and/or sleep disturbance ^

*Strong recommendation, moderate level of evidence **Strong recommendation, high level of evidence^Strong recommendation, low level of evidence

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Surgical Options for GERD

• Surgical therapy is a treatment option for long-term therapy in GERD patients**

• Surgical therapy is generally not recommended in patients who do not respond to PPI therapy**

• Preoperative ambulatory pH monitoring is mandatory in patients without evidence of erosive esophagitis. All patients should undergo preoperative manometry to rule out achalasia or scleroderma-like esophagus *

• Surgical therapy is as effective as medical therapy for carefully selected patients with chronic GERD when performed by an experienced surgeon**

• The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy*

*Strong recommendation, moderate level of evidence **Strong recommendation, high level of evidence

Risks with PPIs

• PPI therapy does not need to be altered in concomitant clopidogrel users as there does not appear to be an increased risk for adverse cardiovascular events **

• Patients with known osteoporosis can remain on PPI therapy. Concern for hip fractures and osteoporosis should not affect the decision to use PPI long-term except in patients with other risk factors for hip fracture ^^

**Strong recommendation, high level of evidence^^Conditional recommendation, moderate level of evidence

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Extra-GI Symptoms

• GERD can be considered as a potential co-factor in patients with asthma, chronic cough, or laryngitis. Careful evaluation for non-GERD causes should be undertaken in all of these patients *

• A diagnosis of reflux laryngitis should not be made based solely upon laryngoscopy findings*

• Surgery should generally not be performed to treat extra esophageal symptoms of GERD in patients who do not respond to acid suppression with a PPI*

*Strong recommendation, moderate level of evidence

Refractory GERD

• Reflux monitoring off medication can be performed by any available modality (pH or impedance-pH). Testing on medication should be performed with impedance-pH monitoring in order to enable measurement of nonacid reflux *

*Strong Recommendation, moderate evidence

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Refractory GERD

• Negative pH/Impedance testing

• Most who fail PPI have NERD and more than half of these don’t have reflux

• If no GERD is present, then stop medications– 42% of patient continue meds that are not

warranted**

• Consider and treat esophageal hypersensitivity*– Trazadone, TCA’s or SSRI

**Gawron AJ, Rothe J, Fought AJ et al.Clin Gastroenterol Hepatol 2012;10:620–5

*Weijenborg PW et al. Clin Gastroenterol Hepatol 2015;13(2):251

GERD Complications

• Continuous PPI therapy is recommended following peptic stricture dilation to improve dysphagia and reduce the need for repeated dilations *

• Repeat endoscopy should be performed in patients with severe GERD after a course of antisecretory therapy to exclude underlying Barrett’s esophagus##

• Symptoms in patients with Barrett’s esophagus can be treated in a similar fashion to patients with GERD who do not have Barrett’s esophagus*

• Patients with Barrett’s esophagus found at endoscopy should undergo periodic surveillance according to guidelines*

*Strong Recommendation, moderate evidence##Conditional Recommendation, low evidence

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Barrett’s Esophagus

• Screening considerations– Caucasian males, over 50, long standing GERD

– Many have no symptoms however

• Surveillance considerations

Wang KK, Sampliner RE. Am J Gastroenterol 2008;103:788–97.

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Questions?

Questions?