Post on 27-Sep-2020
March 7, 2019
Dalhousie Refresher Course
Stacey Williams
DISCLOSURES No relevant disclosures
CONSENSUS
STATEMENT The Toronto Consensus for the
Treatment of Helicobacter pylori
Infection in Adults Carlo A. Fallone,1 Naoki Chiba,2,3 Sander Veldhuyzen
van Zanten,4 Lori Fischbach,5 Javier P. Gisbert,6
Richard H. Hunt,3,7 Nicola L. Jones,8 Craig Render,9
Grigorios I. Leontiadis,3,7 Paul Moayyedi,3,7 and John
K. Marshall3,7
1Division of Gastroenterology, McGill University Health Centre, McGill University,
Montreal, Quebec, Canada; 2Guelph GI and Surgery Clinic, Guelph, Ontario, Canada;
3Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada;
4Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton,
Alberta, Canada; 5Department of Epidemiology, University of Arkansas for Medical
Sciences, Little Rock, Arkansas; 6Gastroenterology Service, Hospital Universitario de la
Princesa, Instituto de Investigacion Sanitaria Princesa (IIS-IP) and Centro de
Investigacion Biomedica
en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Spain;
7Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton,
Ontario, Canada; 8Division of Gastroenterology, Hepatology, and Nutrition, The Hospital
for Sick Children, Departments of Paediatrics and Physiology, University of Toronto,
Toronto, Ontario, Canada; and 9Kelowna General Hospital, Kelowna, British Columbia,
Canada
This article has an accompanying continuing medical education activity, also eligible for
MOC credit, on page e25. Learning Objective: Upon completion of this examination,
successful learners will be able to establish a treatment plan for patients with H pylori
infection.
ACG Clinical
Guideline:
Treatment of
Helicobacter pylori
Infection William D. Chey, MD, FACG1, Grigorios I. Leontiadis, MD,
PhD2, Colin W. Howden, MD, FACG3 and Steven F. Moss,
MD, FACG
Most common chronic bacterial infection in the world
Usually acquired during childhood
Adults: more common in men (29.4% vs 14.9%)
Prevalence varies with: Age
Socioeconomic Status
Number of Siblings
H. pylori status of parents
Ethnicity
Occupation
Reacquisition is <2% of persons per year
WHO SHOULD BE TESTED?
ACCORDING TO THE AGA
Active Peptic Ulcer Disease (strong)
Prior Peptic Ulcer Disease with No Confirmed Eradication (strong)
Low-grade Gastric MALT (strong)
Endoscopic resection of Early Gastric Cancer (strong)
Uninvestigated dyspepsia age <60 no alarms (conditional)
Patients with dyspepsia undergoing gastroscopy (strong)
Patients on long term low dose ASA/NSAIDs (conditional)
Patients initiating NSAIDs/ASA (strong)
Unexplained iron deficiency (conditional)
Adults with ITP (conditional)
PPI use within one to two weeks and bismuth/antibiotic use within four weeks of testing can (significantly) decrease the sensitivity of all endoscopic and non invasive tests for active H pylori infection
Translation: If negative result obtained while patient on ppi, you should repeat testing in some form once patient can hold ppi for at least a week
Sensitivity Specificity
Biopsy Urease Testing 90% 95%
Histology 95% 98%
Bacterial Culture 85% 99%
Urea Breath Test 88-95% 95-100%
Stool Antigen Test 94% 97%
Serology 85% 79%
Goal eradication rate for first line therapy = 90%
Probably less realistic today than it was in 2007
Choice of first line therapy should take into consideration local antibiotic resistance patterns
(where available)
Patients should be asked about any previous antibiotic exposure
PPI bid + Amoxicillin 1g bid + Clarithromycin 500 mg bid has been the mainstay of therapy for >25 years
Rate of Clarithromycin Resistance:
1990s: 1-8%
2010s: 16-24%
Ansari et al, 2018
“Clarithromycin Triple Therapy remains a recommended treatment option in regions where H pylori Clarithromycin resistance is known to be <15% and in patients with no previous history of macrolide exposure for any reason”
(Conditional Recommendation)
FOOD FOR THOUGHT
Americans receive, on average, one outpatient antibiotic prescription per person per year and Azithromycin is the most frequently prescribed antibiotic!!!!
Hicks et al, NEJM 2013
In patients with H pylori infection, treatment duration of 14 days is recommended
(Strong Recommendation)
Clarithromycin resistance reduces efficacy of clarithromycin containing triple therapies by:
42% during 7 day treatment
33% during 10 day treatment
22% during 14 day treatment
Filipec et al, 2009
Bismuth Quadruple (PBMT) PPI + Bismuth +
Metronidazole + Tetracycline
14 Days
Concomitant NonBismuth
Quadruple (PAMC)
PPI + Amoxicillin +
Metronidazole +
Clarithromycin
14 Days
PPI Triple (PAC, PMC, or PAM)
**Restricted option
PPI+ Amoxil+Clarithro
PPI+Metro+Clarithro
PPI+ Amoxil+Metro
14 Days
**Restricted to areas with known low (<15%) local Clarithromycin resistance or proven high
local eradication rates (>85%)
Venerito et al, Digestion 2015
Recommended dosing: PPI Bid
Bismuth subsalicylate 2 tabs qid
Metronidazole 500 mg tid or qid
Tetracycline 500 mg qid
How to increase compliance:
Consider prescribing the Metronidazole qid
Ask pharmacist to create a blister pack. They are free!
PAMC: PPI + Amoxicillin 1g BID + Clarithromycin 500 mg BID + Metronidazole 500 mg BID No North American trials
PAL: PPI + Amoxicillin 1g BID + Levofloxacin 500mg OD X 14 days Eradication rate <80% thus not first line
PAR: PPI + Amoxicillin 1g BID + Rifabutin 150 mg BID X 7 days Reserved for patients with multiple failures due to worry re myelotoxicity
SALVAGE THERAPY: GENERAL
CONCEPTS
If a patient fails a Clarithromycin containing regimen once, never use Clarithromycin again
Ditto for Levofloxacin
TAKE HOME MESSAGES
Accuracy of H pylori testing is improved by holding PPI therapy at least one week prior
Given the high prevalence of Clarithromycin resistant strains in North America and the very frequent use of Macrolides, the role of Clarithromycin containing regimens is becoming less clear
Expert opinion is that longer duration therapy is better
If possible don’t use the same drug twice (or if you do, increase the dose)
Vaezi et al,Gastro 2017
Unrelated to Acid Inhibition Related to Acid Inhibition
Collagenous Colitis
Acute Interstitial Nephritis
Chronic Kidney Disease
Drug Interactions
Dementia
Cerebral Ischemic Disease
Ischemic Cardiac Disease
Pneumonia
Changes in Gut Microbiome
C. Difficile infection
Hypomagnesemia
Bone Fracture
Vitamin B12 Deficiency
Iron Deficiency
Targownik, Am J Gastro 2018;113(4)
Adverse Event Effect Size (95% CI) Reference
Enteral Infection OR 2.55 (1.53-4.26) Leonard et al
Community Acquired
Pneumonia
OR 1.49 (1.16-1.92) Lambert et al
C. Difficile OR 1.26 (1.12-1.29) Cao et al
Hip Fracture OR 1.26 (1.16-1.36) Zhou et al
Dementia HR 1.44 (1.36-1.52) Gomm et al
Vitamin B12 Deficiency HR 1.83 (1.36-2.46) Jung et al
Chronic Renal Failure RR 1.36 (1.07-1.72) Nochaiwong et al
Myocardial Infarction OR 1.16 (1.09-1.24) Shah et al
(BIG) CAVEAT
Nearly all studies demonstrating PPI-associated adverse events are observational and retrospective
Most data originates from retrospective analysis of large health care utilization data sets which did not randomly assign PPI exposure status
A “False Alarm” Conclusion is an inherent risk of this type of study
IMPACT OF PPI THERAPY ON NUTRIENT
ABSORPTION: QUICK FACTS
Long term PPI therapy is
associated with B12 malabsorption but absorption of
oral B12 supplements is not
affected
Absorption of insoluble calcium
(eg Calcium Carbonate) is
decreased by acid suppression
Absorption of water soluble
calcium salts (eg Calcium Citrate) and calcium in
dairy products is not impacted by
PPI use
PPI induced hypochlorhydria
can augment osteoclastic
activity
PPI’S AND RENAL FAILURE
Proposed mechanism is
AIN: an idiosyncratic drug reaction
PPI induced AIN may occur
without systemic allergic
manifestations
Elderly patients may
be at increased risk
Recurrent episodes of
AIN may lead to Chronic
Renal Impairment
PPI’S AND DEMENTIA
H+/K+ ATPase is expressed in CNS and PPIs can cross the blood brain barrier
Animal studies have linked PPI use to increased production of amyloid beta peptide and tau protein
Retrospective studies have suggested a link between PPI use and Dementia. Subsequent prospective studies and systematic reviews have not confirmed this
At present there is no consensus on the risk of dementia in patients on PPI therapy
PPI’S AND CLOPIDOGREL
Clopidogrel is a prodrug requiring metabolism by CYP2C19
CYP2C19 activity can be inhibited by PPI therapy, particularly Omeprazole
In vitro studies suggest that Omeprazole reduces the antiplatelet activity of Clopidogrel
In vivo studies have not shown a link between PPI use and cardiovascular outcomes
If a patient on Clopidogrel has an indication for a PPI, avoid Omeprazole and Esomeprazole
Patients should be prescribed the lowest dose of PPI that will control their symptoms
Most patients on PPIs should try to wean off or reduce the dose of PPI at least once a
year
WHO SHOULD BE ON A PPI?
Treatment of erosive esophagitis and prevention of relapse
Treatment of PPI responsive esophageal eosinophilia
Prevention of Peptic Ulcer Disease and its complications in patients on ASA/NSAIDs with risk factors for PUD
Prevention of Progression of Barrett’s Esophagus
Zollinger-Ellison Syndrome
Absence of a known indication Use in a non absolute indication without a trial of PPI cessation
HOW DO I DEPRESCRIBE A
PPI?
On Demand
Therapy
Dose Reduction
Gradual Wean to
Discontinuation
Conversion to an
H2RA
12 month symptom recurrence rate in patients with mild to moderate reflux:
43% in patients maintained on steady daily dose
49% in patients maintained on a lower daily dose
3-6 month symptom recurrence rate in patients with mild to moderate reflux:
9% in patients remaining on steady daily dose
16% in patients using on demand dosing
Patients using on demand dosing use on average 3.8 fewer pills per week
Cochrane Review, 2017
IF MY PATIENT NEEDS TO STAY ON A PPI, WHAT
DO I NEED TO MONITOR?
Mg, Cr, Vitamin B12, Iron, Calcium: Baseline and periodically during therapy
Manage osteoporosis risk factors
If patient develops diarrhea: consider C. difficile or Collagenous Colitis
If patient requires Clopidogrel: avoid Omeprazole/Esomeprazole
Like all medictions, PPI’s have the potential for adverse effects
The true magnitude of these effects remains unclear
Ensure patients on PPI therapy have a good indication to be on it
Patients on PPI therapy should be on the lowest effective dose