Management of PUD in 2018: Bugs & Drugs

1. Management of PUD in 2018: Bugs & Drugs William D. Chey, MD, AGAF Professor of Medicine University of Michigan

2. 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’s disease, Radiation, Viral infection • True Idiopathic Ulcers Malfertheiner, et al. Lancet 2009;374:1449

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

4. 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

5. Gastroprotection:Now more than ever…

6. Why it still matters… • 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

8. 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

9. Effects of gastroprotectionon endoscopic ulcers Scally, et al. Lancet Gastroenterol Hepatol 2018; 3: 231–41

10. 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

11. 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

12. Rates of gastroprotection use in studies of elderly NSAID users Medlock et al. CLIN GASTRO HEP 2013;11:1259–1269

13. Worldwide prevalence of H. pylori Zamani et al Aliment PharmacolTher 2018;47:868

14. 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

15. Indications for H. pylori Testing & Treating • Uninvestigated dyspepsia • Functional dyspepsia • Aspirin or NSAIDs • Unexplained iron deficiency • Idiopathic thrombocytopenic purpura Chey et al. Am J Gastroenterol 2017;112:212

16. Antibody detection Urease tests Fecal antigen detection Rapid urease test Histology Culture/Molecular Diagnostic Tests Nonendoscopic Endoscopic

17. ELISA Testing for H. pylori • Meta-analysis of 21 studies • No significant differences in accuracy between tests Sensitivity Specificity 79% 85% Loy CT, et al. Am J Gastroenterol. 1996;91:1138-1144

18. Saad and Chey, Gastroenterol 2007

19. 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

20. 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

21. Positive predictive value of testing isinfluenced by H. pylori prevalence Chiba et al, Can J Gastroenterol 1999; 13(8): 681 Chiba et al, Can J Gastroenterol 1999; 13(8): 681

22. First-line H. pylori Therapies

23. Current US Treatment Paradigm for H. pylori Triple Therappy First Line Triple Therapy Salvage Quadruple Therapy Salvage Levo Triple Therapy Vakil & Vaira, J ClinGastroenterol 2013;47:383–388

24. Current US Treatment Paradigm for H. pylori Triple Therappy First Line Triple Therapy Salvage Quadruple Therapy Salvage Levo Triple Therapy Vakil & Vaira, J ClinGastroenterol 2013;47:383–388

25. First-line Therapies for H. pylori Chey et al. Am J Gastroenterol, 2017;112:212

26. 15 year US, single center experience with Triple Therapy for H. pylori N=170 N=699 N=333 N=196 All pts referred for post-treatment UBT at UMHS Baker JR, Chey SW, Saad R, Chey WD. ACG 2016

27. Posted 2/22/18 • 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

28. First-line Therapies for H. pylori Chey et al. Am J Gastroenterol, 2017;112:212

29. Meta-analysis of First-line H. pylori Therapies Li et al. BMJ 2015;351:h4052 GisbertClinExpGastroenterol 2012;5:23-34

30. 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

31. Other First-line Therapies Chey et al. Am J Gastroenterol, 2017;112:212

32. 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 ClinGastroenterolHepatol 2015;13:1616

33. Effect of Previous Antibiotic Use on H. pylori Resistance McNulty CAM, et al. Aliment PharmacolTher 2012;35:1221

34. First Line H. pylori Therapy Chey et al. Am J Gastroenterol, 2017;112:212

35. Post-Treatment H. pylori Testing

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

37. 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;112:212 Nishizawa et al Front MolBiosci 2014;1:19

38. Salvage Therapy for Persistent or Recurrent H. pylori Infection

39. 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;112:212 Song M, Ang TL World J Gastroenterol 2014;20(6): 1517

40. Salvage Regimens for Persistent H. pylori Chey et al. Am J Gastroenterol, 2017;112:212

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

42. Take Home Points: • Don’t forget about gastroprotection in high risk patients • Key factors to consider when choosing primary therapyfor 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