Download Acid Peptic Disease : Therapeutic Concepts

Acid Peptic Diseases
Clinical Management Course
February 2007
Walter Smalley, MD MPH
Acid - Peptic Diseases
• Drugs
• Antacids
• H2RAs (“H-2 blockers”)
• Proton Pump Inhibitors (PPI’s)
• Selective COX-II inhibitors
• Conditions Covered
• Heartburn
• Gastroesophageal Reflux (GERD)
• Peptic Ulcer Disease
• H. Pylori
• NSAIDs
Antacids
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Immediate effect on gastric pH
Effect is short-lived
Typical dose 30-60 cc
Frequent use may cause diarrhea
H-2 Receptor Antagonists
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Inhibit H-2 receptors (competitive inhibition)
Partially inhibit acid production
Relatively safe drugs
Less effective than PPI’s
Less expensive than PPI’s
Available over the counter: at prices more expensive
than prescription costs
Cimetidine : Safety Considerations
• Brand name Tagamet
• Induces cytochrome p450 system
• Drug interactions with coumadin, theophylline,
dilantin and others
• Rarely clinically relevant
• But “why not use ranitidine”
• Confusion in the elderly
• Thrombocytopenia
H2 blockers :
No difference in efficacy within group
Ulcer
treatment
Cimetidine
(Tagamet)
Ulcer
GE Reflux
maintenance treatment
(BID to QID)
800 - 900mg QHS 300 mg QHS > 1200 mg QD
Ranitidine
(Zantac)
300 mg QHS
150 mg QHS > 300 mg QD
Nizatidine
(Axid)
300 mg QHS
150 mg QHS > 300 mg QD
Famotidine
(Pepcid)
40 mg QHS
20 mg QHS
> 40 mg QD
Proton Pump Inhibitors
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Raise gastric pH to > 5 for several hours
Binds covalently to H+/K+ pump
Prodrugs: bioavailable at acid pH
Maximal effectiveness
• After several doses
• When taken before meals
• After a long fast
• (Prior to breakfast)
Proton Pump Inhibitors
• Omeprazole
• (generic cost about 80% of prescription costs )
• Immediate release omeprazole
• Lansoprazole
• Rabeprazole
• Pantoprozole – oral and IV form
• Esomeprazole
• Very effective, no important predictable differences in
efficacy
• Very expensive ($2-4/day)
• ~ $1 per day generic
Case 1
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35 year old healthy man
Occasional heartburn
Occurs only with large meals, EtOH ingestion
No dysphagia
Heartburn : Summary
• How soon does the patient want relief ?
• How long does it need to last ?
• How much are they willing to pay ?
Heartburn : Summary
• Prevention
• Antacids are effective immediately in reducing acid work for 1-2 hours
• H2-blockers are effective in 1-2 hours - they work for
> 6-8 hours
• Available over the counter
Case 1
• Consider not eating large meals
• Consider PRN antacids
• Consider OTC H2 blockers
• On the horizon ?
• Immediate release omeprazole –
• Direct to consumer marketing
• Marginal benefit vs other PPIs
Case 2
• 50 yo with frequent nocturnal heartburn
• No dysphagia
• Trial of lifestyle modification only minimally
effective
• Antacids ineffective
GERD: When to perform diagnostic tests
• Endoscopy
• Dysphagia
• Weight loss
• Age > 50
• Failure of medical therapy
• Motility : prior to fundoplication
• pH monitoring: might resolve diagnostic uncertainty in
absence of esophagitis
Gastroesophageal Reflux
• Reflux of gastroduodenal contents
• Acid ( gastric)
• Alkaline (biliary, pancreatic)
• Decreased lower esophageal sphincter (LES) tone
• Decreased rate of gastric emptying
• Increased intra-abdominal pressure
• Decreased salivary clearance
GERD: Lifestyle Modification
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weight loss, avoid tight-fitting clothes
NPO 3-4 hours before bedtime
elevate head of bed 8''
avoid foods and drugs that decrease LES pressure or
gastric emptying rate
• fat, EtOH, tobacco , peppermint, garlic, onions,
chocolate, Ca++channel blockers, nitrates,
theophylline, antidepressants
• No strong RCT evidence to support important effect
of lifestyle modification
Case 2
• 50 yo with frequent nocturnal heartburn
• No dysphagia
• Trial of lifestyle modification only minimally
effective
• Antacids ineffective
• EGD - distal esophageal erosions
GERD : Overview
• Antacids: temporary relief
• H2-antagonists:
• high (“double”) doses, frequent dosing
• Prokinetics: as effective as H2RA’s
• Metoclopramide
• Proton pump inhibitors:
• most effective
• most expensive
GERD: H2-antagonists
• NO BETWEEN - DRUG DIFFERENCES IN
EFFICACY
• symptomatic relief < 60 - 70% cases
• endoscopic improvement < symptomatic relief
• higher doses (>2X ulcer doses) improve efficacy
slightly
GERD : Prokinetic Agents
• Metoclopramide
• As effective as H2RAs
• Adverse reactions:
– fatigue, lethargy, extrapyramidal symptoms
occur in 10% - 30%.
Case 2
• Continue lifestyle modification
• Trial of H2 blockers at high doses
Case 3
• Patient #2 returns after 8 week trial of H2 blockers
• Therapy only minimally effective
GERD : Proton Pump Inhibitors
• Causes healing and resolution of symptoms in 80%
of patients with disease resistant to H2-blockers
• Expensive, single source drugs ($ 2 - 4 / day)
• Over the counter more expensive than prescription
• Not on Wal-mart list
• Generic omeprazole still > $1 per day
Case 3
• Proton pump inhibitor
Case 4
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Patient from Case 3 returns
Symptoms well controlled on omeprazole
Symptoms recur immediately after stopping drug
“Hates taking meds”
GERD: Anti - Reflux Surgery
• Indications:
• patient preference over drug treatment
• young patients with severe esophagitis
• difficult to dilate strictures
• recurrent esophageal ulcers
• GER-respiratory/ENT syndromes
• 80 - 90% of cases have some improvement
GERD: Anti - Reflux Surgery
• Side effects: about 10 % cases
• "gas bloat"
• dysphagia
• strictures
• other
• Usually won’t work if PPI’s don’t work
Utilization of GERD pharmaceuticals in patients
treated medically and surgically
Acid suppression days
per quarter
Most fundoplication
patients end up taking
some acid meds
after operation
Khaitan et al, Arch Surgery 2003
Endoscopic therapies for GERD
• Stretta: radiofrequency destruction of GEJ myenteric
plexus
• Endoscopic Plication: sewing gastric cardia mucosa to
augment GEJ
• Injection of GEJ with plastic (removed from market)
• All should be considered experimental at this point
Case 4
• Consider anti reflux procedure
• Weighing potential benefits of not taking medication
vs. risk of side effects from surgery (probably 1- 3% in
experienced hands)
Case 5
• 40 yo with epigastric pain
“ALARM FEATURES”
•unexplained weight loss
• anorexia
• early satiety
• vomiting
• progressive dysphagia
• odynophagia
• bleeding
• anemia
• jaundice
• abdominal mass
• lymphadenopathy
• family history of upper GI
cancer
• history of peptic ulcer,
previous gastric surgery or
malignancy.
ACG dyspepsia management guidelines
Case 5
• 40 yo with epigastric pain
• Relieved with meals
• No clinical signs of bleeding
• No vomiting
• Reasonable approaches
• Empiric trial of acid suppression
• “Test and treat” for H pylori
• Refer for endoscopy
Case 5
• 40 yo with epigastric pain
• 8 week trials of PPI fails
• EGD : duodenal ulcer
• H pylori positive
• no NSAIDs confirmed
Ulcer Disease : Basic Concepts
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H. pylori is associated with GU and DU
NSAID use is associated with GU and DU
Most ulcers are not the result of excess acid
Acid suppression aids in healing ulcers
Prior to the H pylori era: most of the cost of ulcer
disease had been in “maintenance” therapy
H pylori : Concepts
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H pylori infection is chronic
Prevalence in US adults = 50 - 80%
Lifetime risk of ulcer disease = 10%
Associated with chronic gastritis - a histological
diagnosis
• H pylori is a risk factor for gastric adenocarcinoma
H pylori - Diagnosis
• EGD –
• Biopsy for histology and CLO
• Breath Tests –
• commercially available
• big hassle
• Serology –
• widely available,
• followup is problematic (positivity persists
months after eradication)
• Stool antigen test:
• problem = it’s stool.
H pylori. treatment - Efficacy
• For treatment of duodenal ulcer > gastric ulcer
• Eradication of H.pylori alone = treatment with H2blockers alone
• For preventing recurrent duodenal ulcer:
• Eradication of H.pylori >> continuous H2-blocker
therapy
• Marginal (if any) benefit in treating non ulcer
dyspepsia
H pylori. treatment - Options
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Many different regimens
No "standard of care"
Best therapy yet to be determined
Big problems
• compliance
• resistance
• Current (2/07) favorite combination
• Amoxicillin, PPI, Clarithromycin
• Metrondazole, PPI, Clarithromycin
Peptic Ulcer: Treatment Outcomes
Efficacy :
8 weeks
Efficacy :
1 year
chronic acid
suppression
Efficacy :
1 year
without acid
suppression
Sucralfate
70 - 90%
NA
60 - 70%
H2-antagonists
70 - 90%
70 - 90%
50 - 75%
Omeprazole
> 95%
70 - 90%
50 - 75%
H. pylori
eradication
> 95%
>90%
> 90%
Case 5
• Treatment with acid suppression
• QD H2 blockers, or
• proton pump inhibitor
• Treat H pylori
• Amoxicillin 1000 BID
• Clarithromycin 500 BID
• Omeprazole 20 BID
Case 6
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65 yo male with osteoarthritis with recent ulcer
On ibuprofen 1800 mg per day
Ulcer has healed
H pylori negative
NSAIDs and Ulcers - Concepts
• Higher doses ---> greater risk
• Long time users still have increased risk after 12
months
• Absolute risk is high
• about one ulcer hospitalization per 100 person
years in the elderly
• About 2/3 of ulcers in NSAID users are due to the
NSAID use
• By far our most important complication of
pharmaceutical use
NSAIDs and PUD : Treatment
• Stop NSAIDs
• Acid suppression
Drug
• Omeprazole
• H2-Blockers
• Misoprostol
• Sucralfate
Healing at 6 - 8 weeks
> 90%
70-90%
70-90%
not effective
NSAIDs and Ulcers - Prevention
• Does the patient really need NSAIDs ?
• objective = pain control
• NSAIDs do not prevent progression in
osteoarthritis
• little evidence demonstrating superiority of
NSAIDs over acetaminophen in osteoarthritis
patients.
• No NSAID is "safe".
NSAIDs and Ulcers - Prevention
• Misoprostol - a synthetic PGE analog
• Prevents GU and DU
• Expensive therapy - for prevention.
• Debate on cost effectiveness continues.
• Side effects: diarrhea (10%), abdominal pain (10 20%)
• Causes spontaneous abortions - do not use in
potentially fertile women
NSAIDs and Ulcers - Prevention
• H-2 blockers at high doses may be reliable preventive
agents for DU prevention
• Misoprostol is very effective in preventing ulcers in
clinical trials.
• PPI’s are as probably as effective as misoprostol and
better tolerated
• Eradicating H pylori is helpful in preventing
recurrence (RCT evidence)
Selective COX-II Inhibitors: COXIBs
• Celecoxib, rofecoxib, valdecoxib, etoricoxib and
lumiracoxib
• NO more effective than traditional NSAIDs
• Potential benefit is GI safety
• Still have renal toxicity, other toxicities ?
• Large trials demonstrate decreased ulcer rate
• Decrease of about 50%
• Do high-risk patients still need acid suppression ?
• Risk of cardiac events has led to the removal of
rofecoxib and valdecoxib
Results from a polyp prevention trial
Case 6
• Consider alternatives to NSAIDs
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narcotics
non-narcotics
physical therapy
topical therapy
• Consider misoprostol
• Consider acid suppression with PPI
• For now would not consider any COXIB drugs left on
the market
Peptic Ulcer Disease
• Stop NSAIDs.
• Acid suppression acutely
• Test for H pylori and treat if present.
Case 7
• 75 yo admitted with hematemesis, shock
• Intubated for airway protection (NPO)
• EGD reveals gastric ulcer with visible vessel
• Treatment with heater probe controls bleeding
Acid Suppression
• There is evidence that acid suppression may decrease
rebleeding rates, surgical rates, and hospital days
• There is no evidence that it saves lives
• (studies would have to be huge)
• Most IV PPI data is based on trials using IV
OMEPRAZOLE which is not available in the US
• Most studies involved bleeding ulcers requiring
endoscopic therapeutic interventions (injection therapy
or heater probe)
Proton pump inhibitor (IV or PO)
Moderate effects on:
•reduced rebleeding (table left)
•OR 0.46, 95%CI 0.33 to 0.64
•NNT =12
•surgery
•OR 0.59 95%CI 0.46 to 0.76
•NNT = 20
treatment had no significant effect
on mortality
•OR 1.11, 95%CI 0.79 to 1.57
•NNT = incalculable
Lancet 2005
PPI’s Summary
• In the select group of patients who require
endoscopic therapy the few published studies
demonstrated potential advantage for IV
Omeprazole
• In our settings most endoscopies will be done
quite early - there is little advantage in starting IV
PPI’s prior to EGD in most cases
• Oral PPIs may have some protective effect
compared to placebo
Case 7
• Start IV Pantoprazole (80 mg bolus followed by 8 mg
per hour)
• Start PPI of choice after patient is taking oral meds