May 2, 2015

Dean N Silas Co-Medical Director

Digestive Health Institute Advocate Lutheran General Hospital

Clinical Background

Treatment Approaches

PPI Side Effects

Acid Pocket

Endoscopic Therapy for GERD

Passage of gastric contents (gastroesophageal reflux) into esophagus is a normal physiologic process

GERD = Montreal definition “a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.”

NERD = Non Erosive Reflux Disease – no visible injury on EGD

Erosive Esophagitis – visible breaks in mucosa of distal esophagus

GERD patients do not hypersecrete acid

Acidic

Weakly acidic (non acid reflux)

Diminished gastric motility

Delayed esophageal clearance

Visceral hypersensitivity

TSLER

Acid Pocket

Common in Primary Care and GI Practice

Prevalence – 10-20% in Western populations

“Troublesome” heartburn in 6%

8.9 million OP visits

7.7 billion in annual US health care costs

Associated with BMI & waist circumference

Approx 25-42% do not respond to PPI including bid ppi

Katz et al. Guidelines for the Diagnosis and Management of GERD, Am J Gastroenterol 2013

Heterogeneous disorder

Typical symptoms – heartburn & regurgitation

Atypical sx – dyspepsia, bloating, belching, epigastric pain, nausea

Other causes are more likely

Extraesophageal sx – laryngitis, cough, asthma

Significant effects on QOL

Sleep disturbances!

Initial studies from tertiary referral centers suggested annual progression to EAC as high as 2.4%

Recent population based studies report much lower risk

Netherlands 0.4%

Ireland 0.27%

Denmark 0.12%

US Veterans 0.32%

Shakhatreh MH et al. Am J Gastroenterol, 2014

Controversial

Particularly considering low incidence of EAC

Consider in males > 50 with

Long standing symptoms (> 5 yrs?)

Smokers

Elevated BMI

Intra-abdominal fat distribution

Katz et al. Guidelines for the Diagnosis and Management of GERD, Am J Gastroenterol 2013

EGD not required in presence of typical sx

Specific finding (erosive esophagitis, Barrett’s, stricture) present in minority

Cardiac chest pain should be excluded

EGD for

“Alarm symptoms” dysphagia, bleeding, wt loss, chest pain require EGD

If diagnosis is uncertain

Distal esophageal biopsy not required

Effect of evaluation for EoE

Katz et al. Guidelines for the Diagnosis and Management of GERD, Am J Gastroenterol 2013

Optimal treatment is controversial Mainstay of treatment is pharmacologic

Step Up Therapy Start with low dose H2RA and increase

For treatment naïve patients with mild, infrequent (<2x/wk) sx

Potential lower costs, delayed response

Step Down Therapy Start with daily PPI

Consider trial of drug withdrawal Not in LA Class C, D or Barrett’s

PPI’s Work Here

Digestion of protein

Absorption of iron, calcium, and vitamin B12

Prevents bacterial overgrowth in small intestine, enteric infections, and possibly community acquired pneumonia

Early studies of medical treatment of endoscopic healing of erosive esophagitis

PPI 84% H2RA 52% Sucralfate 39% Placebo 28%

Recommended initial course of treatment

8 week trial of once daily PPI

30 minutes before first meal of day

No significant differences between PPI’s

Tailor dose to response

Adjust timing

Consider BID dosing if partial response

Consider nighttime H2RA for nocturnal sx

No significant differences in efficacy between PPI’s

Small (relevance uncertain – NNT- 25) improved healing and symptom relief with esomeprazole (Omep – NaHCO3 & dexlansoprazole not included in metanalysis)

All PPI’s are delayed release EXCEPT

Omeprazole-NaHCO3 – immediate release

Possible role for nocturnal dosing?

Dexlansoprazole – dual delayed release

Remarkably well tolerated Headache, diarrhea most common

Recent interest in long term complications C difficile

Large Metaanalyses show OR ~1.6-2

Multiple possible confounders in analysis

Be aware of the possible association with c. diff, (but not recurrent c. diff?)

Consider stopping PPI in pts with documented c. diff

Caution with PPI in hospitalized pts on antibiotics

Community Acquired Pneumonia

Risk is greatest in first few days of rx, particularly high dose

Johnson DA & Oldfield EC. Clin Gastroenterol Hepatol 2013

Bone Fracture

Gastric acid contributes to calcium absorption, but clinical effect of PPI on calcium absorption is minimal

FDA product label warning 2010

But, data is conflicting and studies are poor

If there is a risk for fracture, it is low

No need to stop PPI for appropriate indications in appropriate doses

No need for calcium supplements

Hypomagnesemia Rare, < 50 case reports Mechanism unknown – not renal or GI wasting No typical patient profile FDA Alert (2011)

“Healthcare professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia”

FDA alert seems impractical

Vitamin B12 Deficiency Acid involved in releasing B12 from protein Inconsistent data regarding clinical relevance PPI should have no impact on absorption of medicinal B12

Infections in cirrhotics

Increased risk of SBP and increased mortality in decompensated cirrhotics

Consider stop PPI, or switch to H2RA

Microscopic colitis

Interstitial nephritis

Sucralfate No role except pregnant women

Baclofen Reduces frequency of TSLER (transient spontaneous lower

esophageal relaxation), reflux episodes, nocturnal reflux, and belching

5-20 mg tid Side effects – somnolence, dizziness, constipation

Prokinetic agents Metoclopramide

Improves LES Pressure, esophageal clearance, gastric emptying No large clinical studies Significant side effects

Alginic acid Discussed later

Post prandial reflux is hallmark symptom of GERD

Intragastric acidity varies in different areas of the stomach

pH studies demonstrate that pH of refluxate is more acidic than the gastric body

The “acid pocket” concept was proposed in 2001 Zone of highly acidic gastric juice

Extends for 2-3 cm below GEJ

Not buffered by stomach contents

Thought to be due to gastric acid layering on the meal Poor contractility of the proximal stomach

Mixing occurs in gastric antrum

Pre Meal 3 min pc

17 min pc Acid pocket 43 min pc

Reflux episode 73 min pc

Kahrilas et al. Am J Gastroenterol, 2013

Importance of postural recommendations

Alginates (Gaviscon) Natural polysaccharide polymers – Norwegian seaweed

Precipitate on contact with acid forming neutral pH low density (floating) gel

NaHCO3 -> CO2 trapped in viscous gel forming a “raft” and “capping” the acid pocket

Recent studies document that alginate Co-localized with Acid Pocket

Displaced acid pocket away from GEJ

Decreased reflux episodes

Delayed time to first reflux

Higher pH of refluxate Kwiatek MA, et al. Aliment Pharmacol Ther 2011 Rohof WO et al. Clin Gastroenterol Hepatol 2013

Acid pocket is larger and extends further into esophagus in GERD patients Pocket frequently located in

supradiaphragmatic location in pts with HH

Increases likelihood of reflux

Concept of acid film coating mucosa in LES Long contact time with GEJ

mucosa causing contributing to esophagitis and Barrett’s?

Mild heartburn/reflux without alarm symptoms

Heartburn in pregnant women

On demand therapy for pts with post prandial symptoms

Add on therapy with PPI? Different mechanism of action than PPI

No effect on gastric acid secretion

Limited data

Rationale

Symptom relief

Stop medications

Normalize acid exposure to esophagus

Avoid risks/complications/costs of surgical rx

Gas/bloat

Dysphagia

Diarrhea

Radiofrequency Ablation (Stretta)

Initially released early 2000’s

Re-introduced to market 2010

Lipka et al. Clin Gastroenterol Hepatol 2014

LES pressure HCQOL

pH < 4 Stop PPI

No improvement in objective parameters or QOL Not Recommended

Hunter JG et al. Gastroenterol 2015

Multicenter - TIF/placebo vs Sham/PPI

Barrett’s < 2 cm

Hiatal hernia < 2 cm

No LA Grade C or D esophagitis

Primary Endpoint – relief of regurgitation

TIF – 67% Sham/PPI – 45%

Reduced reflux episodes / 6 months

pH improved, not normalized

PPI does not normalize reflux

Hunter JG et al. Gastroenterol 2015

Short term improvement in regurgitation

Long term results not available

If extrapolate from Nissen data, then sx may recur over time

No direct comparison to other endoscopic therapies or surgical therapy

Option available for motivated highly selected patients

Titanium beads with magnetic core connected with titanium wire to form “bracelet”

Magnetic beads keep LES closed

Swallowing force overcomes magnetic force

Placed with minimally invasive surgery

FDA approved 3/2012

Minor side effects in small studies

Dysphagia, odynophagia, chest pain, nausea, vomiting

Pt can NOT undergo MRI

Role not clarified

GERD is an extremely common GI disorder

Heterogeneous pathophysiology

Acid & non acid reflux

Role of Acid Pocket

PPI’s remain mainstay of treatment

Long term use of PPI controls symptoms in most

Recent publicity re: PPI side effects are overstated

Endoscopic therapies available

Role is not clarified

Consider in only highly selected patients