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