gastroprotection & h. pylori: why they still matter um...post-therapy h. pylori testing •...

Gastroprotection & H. pylori: Why They Still Matter

William D. Chey, MD, AGAFProfessor of MedicineUniversity of Michigan

Causes of PUD

• Drugs• H. pylori (and other Helicobacter) infection• Post‐surgical• Cameron’s lesions• Malignancy• Rare Causes

– ZES, Crohn’s, Eosinophilic Gastroenteritis, Mastocytosis, Menetrier’sdisease, Radiation, Viral infection

• True Idiopathic Ulcers

Malfertheiner, et al. Lancet 2009;374:1449

Risk Factors for PUD

• H. pylori• NSIADs and Aspirin• Advanced Age• Anticoagulants• History of PUD of UGIB• Steroids?

The impact of adding aspirin to warfarin without an indication

• Registry cohort study of 3688 pts on warfarin for A. fib or DVT followed prospectively at anticoagulation clinics (valve replacement or recent ACS excluded)– 37.5% without a clear indication were on aspirin– No difference in thrombotic events between groups

Schaefer et al. JAMA Intern Med. 2019;179:533-541

Gastroprotection:Now more than ever…

Why it still matters…

Aging Population Increasing anti-thrombotic drugs

Concerns about PPI safety

Pressures to minimize opioid

prescriptions

• PUD affects approximately ~4.5 million people annually • GI Hemorrhage leads to >500 million hospital admissions/year• PUD is a leading cause of hemorrhage and death

Meta‐analysis of effects of gastroprotection drugs in RCTs

• Gastroprotection drugs reduced development of endoscopic ulcers (OR 0.27, 95% CI 0.25–0.29; p<0∙0001), symptomatic ulcers (0.25, 0.22–0.29; p<0∙0001), and upper GI bleeding (0.40, 0.32–0.50; p<0∙0001), but did not significantly reduce mortality (0.85, 0.69–1.04; p=0.11)

• Larger proportional reductions in upper GI bleeding were observed for PPIs than for other gastroprotection drugs (PPIs 0.21, 99% CI 0.12–0.36; prostaglandin analogues (0.63, 0.35–1.12; H2RAs 0.49, 0.30–0.80; phet=0.0005)

Scally, et al. Lancet Gastroenterol Hepatol 2018; 3: 231–41

Effects of gastroprotectionon endoscopic ulcers

Scally, et al. Lancet Gastroenterol Hepatol 2018; 3: 231–41

Morbidity & Mortality from UGI bleeding in Elderly High Risk Patients• Prospective population‐based cohort study of patients with a

first TIA/ischemic CVA/MI treated with antiplatelet therapy between 2002‐2012

• In patients over age 75, most major upper GI bleeds were disabling or fatal (45 of 73 [62%])

• The estimated NNT for routine PPI use to prevent one disabling or fatal upper gastrointestinal bleed over 5 years fell from 338 for individuals younger than 65 years, to 25 for individuals aged 85 years or older.

Li, et al. Lancet 2017; 3: 231–41

Trends in use of gastroprotection

• Systematic review of observational studies of gastroprotection prescription in elderly patients (>65 y/o) using NSAIDs

• A median of 24% (range, 10%–69%) of elderly patients taking NSAIDs received a co‐prescription

• For gastroprotective agents, this percentage was only slightly higher in the oldest age groups.

Medlock et al. CLIN GASTRO HEP 2013;11:1259–1269

Rates of gastroprotection use in studies of elderly NSAID users

Medlock et al. CLIN GASTRO HEP 2013;11:1259–1269

Worldwide prevalence of H. pylori

PrevalenceNot known<20%20-34.9%

Created with mapchart.net ©

35-54.9%55-69.9%70%

Zamani et al Aliment Pharmacol Ther 2018;47:868

Indications for H. pylori Testing & Treating:Absolute

• PUD or a history of PUD

• MALToma

• Early gastric cancer

Chey et al. Am J Gastroenterol 2017;112:212

• Uninvestigated dyspepsia

• Functional dyspepsia

• Aspirin or NSAIDs

• Unexplained iron deficiency

• Idiopathic thrombocytopenic purpura

Chey et al. Am J Gastroenterol 2017;112:212

Indications for H. pylori Testing & Treating

Diagnostic Tests

• Antibody detection• Urease tests• Fecal antigen detection

• Rapid urease test• Histology• Culture/Molecular

Nonendoscopic

Endoscopic

ELISA Testing for H. pylori• Meta-analysis of 21 studies• No significant differences in accuracy

between tests

Sensitivity Specificity

85% 79%

Loy CT, et al. Am J Gastroenterol. 1996;91:1138-1144

Saad and Chey, Gastroenterol 2007

Urea Breath Tests• 13C/14C-urea breath tests• Accurate for pre- or post-Rx testing

– >90% sensitive & specific– >4 weeks after completion of therapy

• FN results with – Antibiotics or bismuth within 2 to 4

weeks– PPIs within 1 to 2 weeks– High dose H2RAs

Fecal Antigen Test• Fecal antigen detected by EIA

• Stool can be stored at 2-8°C for 3d and at -20°C indefinitely

• Accurate for pre- and post-Rx testing– >90% sensitive & specific

• Timing of eradication testing similar to UBT

• FN results occur with antibiotics, bismuth or PPIs

Positive predictive value of testing isinfluenced by H. pylori prevalence

Chiba et al, Can J Gastroenterol 1999; 13(8): 681Chiba et al, Can J Gastroenterol 1999; 13(8): 681

First-line H. pylori Therapies

Current US Treatment Paradigm for H. pylori

Triple Therappy

Vakil & Vaira, J Clin Gastroenterol 2013;47:383–388

First LineTriple Therapy

SalvageQuadruple Therapy

SalvageLevo Triple Therapy

First-line Therapies for H. pyloriRecommended First-Line Therapies for H pylori Infection

Regimen Drugs (doses) Dosing Frequency

Duration(Days)

FDA approval

Clarithromycin Triple PPI (standard or double dose)Clarithromycin (500 mg)Amoxicillin (1 grm) or Metronidazole (500 mg TID)

BID 14 Yes*

Bismuth Quadruple PPI (standard dose)Bismuth subcitrate (120-300 mg) or subsalicylate (300 mg)Tetracycline (500 mg)Metronidazole (250-500 mg)

BIDTID or QID

10-14 No**

Concomitant PPI (standard dose)Clarithromycin (500 mg)Amoxicillin (1 grm)Nitroimidazole (500 mg)^

BID 10-14 No

Chey et al. Am J Gastroenterol, 2017;112:212

15 year US, single center experience with Triple Therapy for H. pylori

79.3 80 79.9 77.6

0

20

40

60

80

100

2001-15 2001-5 2006-10 2011-15

Eradication Rates (%)

N=699 N=170 N=333 N=196

All pts referred for post-treatment UBT at UMHS

Baker JR, Chey SW, Saad R, Chey WD. ACG 2016

• FDA is advising caution before prescribing the antibiotic clarithromycin (Biaxin) to patients with heart disease because of a potential increased risk of heart problems or death that can occur years later. FDAs recommendation is based on a review of the results of a 10-year follow-up study of patients with coronary heart disease from a large clinical trial that first observed this safety issue.

• Healthcare professionals should be aware of these significant risks and weigh the benefits and risks of clarithromycin before prescribing it to any patient, particularly in patients with heart disease and even for short periods, and consider using other available antibiotics. Advise patients with heart disease of the signs and symptoms of cardiovascular problems, regardless of the medical condition for which you are treating them with clarithromycin.

www.fda.gov

Posted 2/22/18

First-line Therapies for H. pyloriRecommended First-Line Therapies for H pylori Infection

Regimen Drugs (doses) Dosing Frequency

Duration(Days)

FDA approval

Clarithromycin Triple PPI (standard or double dose)Clarithromycin (500 mg)Amoxicillin (1 grm) or Metronidazole (500 mg TID)

BID 14 Yes*

Bismuth Quadruple PPI (standard dose)Bismuth subcitrate (120-300 mg) or subsalicylate (300 mg)Tetracycline (500 mg)Metronidazole (250-500 mg)

TID or QID 10-14 No**

Concomitant PPI (standard dose)Clarithromycin (500 mg)Amoxicillin (1 grm)Nitroimidazole (500 mg)^

BID 10-14 No


Meta-analysis of First-line H. pylori Therapies

73

85 88

0

20

40

60

80

100

Triple 7 B-Quad 10-14 Concomitant 5-10

Eradication Rates (%)

Li et al. BMJ 2015;351:h4052Gisbert Clin Exp Gastroenterol 2012;5:23-34

Concomitant vs. Triple Therapy: A meta-analysis

• 23 RCTs including 3305 patients in the concomitant & 3327 in triple groups. – Overall, Concomitant therapy superior to triple therapy

[RR: 1.15; 95% CI: 1.09–1.21; p < 0.001]– Significant heterogeneity (I2 = 74.0%, p < 0.001)– More AEs with Concomitant [RR: 1.2]– Subgroup analyses: Concomitant for 5 or 10 days superior to 7- or 10-

day triple therapy but NOT 14-day triple therapy– Concomitant may offer benefits for Cl-R resistant Hp

Chen et al. Am J Gastroenterol 2018;113:1444

Other First-line TherapiesSequential PPI (standard dose) + Amoxicillin (1 grm)

PPI, Clarithromycin (500 mg) + Nitroimidazole (500 mg)^

BIDBID

5-7 5-7

No

Hybrid PPI (standard dose) + Amox (1 grm)PPI, Amox, Clarithromycin (500 mg), Nitroimidazole(500 mg)^

BIDBID

77

No

Levofloxacin Triple PPI (standard dose)Levofloxacin (500 mg)Amox (1 grm)

BIDQDBID

10-14 No

Levofloxacin Sequential PPI (standard or double dose) + Amox (1 grm)PPI, Amox, Levofloxacin (500 mg QD), Nitroimidazole (500 mg)^

BIDBID

5-75-7

No

LOAD Levofloxacin (250 mg)PPI (double dose)Nitazoxanide (500 mg)Doxycycline (100 mg)

QDQDBIDQD

7-10 No


Antibiotic Resistance of H. pylori:Single Center Data from the Houston VAMC

Antibiotic resistance rates of H. pylori strains in the US, 2009-2011 Data based on single center study of 128 strains of H. pylori obtained from US veterans

Shiota et al Clin Gastroenterol Hepatol 2015;13:1616

Antibiotic Resistance Rate (%)

Metronidazole 20Clarithromycin 16Levofloxacin 31Tetracycline <2Amoxicillin <2

Effect of Previous Antibiotic Use on H. pylori Resistance

No. of patients & % resistant

Antibiotic course

Antibiotic sensitivity tested

0 courses 1 course 2+courses RR 95% CI

Quinolone Levofloxacin 114 (4%) 7 (14%) 11 (27%) 1.8 1.24-2.49

Metronidazole Metronidazole 114 (28%) 13 (38%) 5 (100%) 1.6 1.46-1.75

Clarithromycin Clarithromycin 103 (7%) 21 (19%) 8 (25%) 1.5 0.92-2.41

Erythromycin Clarithromycin 104 (8%) 15 (20%) 13 (15%) 1.1 0.82-1.59

*This is the ratio of the risk of being resistant per unit increase in number of courses

McNulty CAM, et al. Aliment Pharmacol Ther 2012;35:1221

First Line H. pylori TherapyKey Questions:

1. Is there a penicillin allergy?2. Has a macrolide antibiotic been taken in the past (for any reason)?

(‐) Penicillin(‐) Macrolide

Treatments:Bismuth quadruple

Concomitant Triple therapy

(‐) Penicillin(+) Macrolide


Levofloxacin therapiesConcomitant?

(+) Penicillin(‐) Macrolide


PCM

(+) Penicillin(+) Macrolide

Treatment:Bismuth quadruple


Post-Treatment H. pylori Testing

Post-Therapy H. pylori Testing• Whenever H. pylori infection is identified and

treated, testing to prove eradication should be performed using a urea breath test, fecal antigen test or biopsy based testing at least 4 weeks after the completion of antibiotic therapy and after PPI therapy has been withheld for 1-2 weeks

• There may be infrequent situations which make eradication testing impractical or unnecessary


Antibiotic Sensitivity Testing• Traditional Culture & Sensitivity

– Cumbersome– Technically challenging– Expensive– Not widely available

• Molecular Testing– fresh, frozen, paraffin embedded gastric bxs– PCR, fluorescently-labeled nucleic acid hybridization– Identify mutations associated with resistance to

specific antibiotics– More scalable & less costly than culture & sensitivity

Chey et al. Am J Gastroenterol 2017;112:212Nishizawa et al Front Mol Biosci 2014;1:19

Salvage Therapy for Persistent or Recurrent

H. pylori Infection

Salvage Therapy for H. pylori• Do not use the same antibiotics• Stress the importance of compliance

and review possible side effects• Treat for 10-14 days• Use high dose PPI BID• Consider culture and sensitivity testing

after 2 failed attempts at empiric treatment

Chey, et al. Am J Gastroenterol 2017;112:212Song M, Ang TL World J Gastroenterol 2014;20(6): 1517

Salvage Regimens for Persistent H. pylori

Salvage Therapies for H pylori InfectionRegimen Drugs (doses) Dosing

FrequencyDuration(Days)

FDA approval

Bismuth Quadruple PPI (standard dose)Bismuth subcitrate (120-300 mg) or subsalicylate (300 mg)Tetracycline (500 mg)Metronidazole (500 mg)

BIDQIDQID

TID or QID

14 No**

Levofloxacin Triple PPI (standard dose)Levofloxacin (500 mg)Amox (1 grm)

BIDQDBID

14 No

Concomitant PPI (standard dose)Clarithromycin (500 mg)Amoxicillin (1 grm)Nitroimidazole (500 mg)

BIDBIDBID

BID or TID

10-14 No

Rifabutin triple PPI (standard dose)Rifabutin (300 mg)Amox (1 grm)

BIDQDBID

10 No

High-dose dual PPI (standard to double dose)Amox (1 grm TID or 750 mg QID)

TID or QIDTID or QID

14 No


ACG Guideline Recommendations• Bismuth quadruple or levofloxacin salvage regimens

are the preferred treatment options if a patient received a first-line treatment containing clarithromycin.

• Clarithromycin- or levofloxacin salvage regimens are the preferred treatment options if a patient received first-line bismuth quadruple therapy.

• Selection of the best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics


Take Home Points: • Don’t forget about gastroprotection in high risk

patients • Key factors to consider when choosing primary

therapy for Hp:– PCN allergy?– Previous macrolide (or quinolone) exposure?– Quadruple therapies are replacing traditional triple

therapy• Key Factors to consider when choosing salvage

therapy:– Avoid drugs used previously– Treat for 14 days– Quadruple therapies and Levofloxacin therapies are

preferred– HD PPI & Amoxicillin and Rifabutin Triple therapies are

other considerations

gastroprotection & h. pylori: why they still matter um...post-therapy h. pylori testing •...

Documents