Conflict of Interest. On the Menu. How many Canadians take PPIs? PPIs the Good: They work!

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Paula Lester
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1 Conflict of Interest From Gums to Bums GI Update for Primary Care Mike Kolber MD, CCFP, MSc ASA March 2017 Academic Family Physician with clinical work in Peace River, Alberta RelaMonships with commercial interests: None. No funding from industry, no grants or speakers honoraria or consulmng fees Supported by University of Alberta department of Family Medicine and ACFP On the Menu PPIs: the good, the bad, the labs, the costly CAN H. Pylori guideline: Evidence, who needs evidence What the $%#* is a FODMAP diet but will it get my IBS pament out of my office? PancreaMc cancer: moving up the mortality ladder 5 ways to improve consmpamon management Without eamng super colon blow cereal Lab tests in GI: Fecal calprotecmn, ATTG, FIT Proton Pump Inhibitors (PPIs) The Good The Bad The Labs and The Costly PPIs the Good: They work! Disease Outcome NNT vs Placebo UninvesMgated GERD Symptoms 2 4 Erosive EsophagiMs Endoscopic NegaMve Reflux Disease 1 prevenmon pepmc ulcers in NSAID users Healing or symptoms 2 4 Symptoms 4 8 PepMc ulcers (endoscopic) prevenmon PUD Recurrent PUD HPE > PPI 8 NNT vs H2ANT Non ulcer dyspepsia Symptoms 10 NSS Rxfiles 2015: accessed Jan 2017 No evidence HPE = Helicobactor pylori eradicamon How many Canadians take PPIs? 27 million Rxs 2013, 18% adults (CIHI 2016) All PPIs in top 50 in Canada: Panto #4, Rabrep #26, Eso #27, Lans #29, Omep #50 50% may not have appropriate indicamon 40% admined to medicine ward LT care 3 : 27% demenma - 18% last week of life! Asthma, cough, atypical ENT symptoms: does not work! 4,5 hnp:// reports/top drugs /4 BMJ 2008;336:2, 2 Ann Pharmaco 2006;40:1261, 3 J Am Geriatr Soc 2010: 58; 880, 4 NEJM 2009;360:1487, 5 Chest 2005; 128:1128, 6 Dig Dis Sci (2015) 60:2280 CMAJ DOI:

PPIs - The Bad Outcome Pa=ents / Outcome Study Type Results Are PPI associated Adverse Events due to residual confounding?

27%) in 3m CAP (pneumonia) All Cohort 1% ARI per year CAP (pneumonia) Recurrent Cohort 4% ARI (8-12%) in 5 years OsteoporoMc # Women Cohort NNH 2000 for 1 addimonal # over 8 years Plavix plus PPI CVD

cases, 180k controls) 1: Odds VB12 deficiency: ~1.

million Rxs 2013 2012: Esomeprazole + Apo PPIs = $380 million Switch à Rabeprazole = save $227 million /year Long term PPIs and > 65 yo! check Vb12 Long term PPIs and on diure=cs! check Mg 1 JAMA.

2 PPIs - The Bad Outcome Pa=ents / Outcome Study Type Results Are PPI associated Adverse Events due to residual confounding? Diarhea All cause RCT 3-8% CDAD Community Cohort 1/10,000 à 2/10,000 CDAD Inpa=ents + Abx Cohort 8-10% CDAD Recurrent Cohort ~7% ARI (20!27%) in 3m CAP (pneumonia) All Cohort 1% ARI per year CAP (pneumonia) Recurrent Cohort 4% ARI (8-12%) in 5 years OsteoporoMc # Women Cohort NNH 2000 for 1 addimonal # over 8 years Plavix plus PPI CVD paments Cohort recurrent CVE Plavix plus PPI CVD pa=ents RCT No difference CVE Please see handout for references J Gen Intern Med 2012; 28(2): PPI the labs VB12: 1 Case- control: Kaiser: (25K cases, 180k controls) 1: Odds VB12 deficiency: ~1.65 PPI Baseline B12 deficiency >65 yo: 10% à 16% Magnesium: 2-5 case control, cohort, re- challenge SR: 9 heterogneous studies; 27% vs 18% in~5 years Especially if taking diuremcs PPIs the Costly 27 million Rxs : Esomeprazole + Apo PPIs = $380 million Switch à Rabeprazole = save $227 million /year Long term PPIs and > 65 yo! check Vb12 Long term PPIs and on diure=cs! check Mg 1 JAMA. 2013;310(22): Aliment Pharmacol Ther 2012; 36: 405, 3 Am J Kidney Dis. 66(5):775 4 PLoS ONE 2015; 9(11): e Expert Opin. Drug Saf. 2013; 12(5):709 reports/top drugs /4 Price Comparison of Commonly Prescribed PharmaceuKcals in Alberta 2017 Alberta Blue Cross 2017 Maximal Allowable Costs Can paments stop PPIs? Yes ~25% successfully dc 1,3 Predictors of success: older paments, dyspepsia 2 Less successful: GERD Study Pa=ents Recruitment Interven=on Propor=on successful DC Bjornsson (mostly GERD) Pharmacy survey Gastroscopy (normal) 1 year Krol dyspepsia GPs EMR GP lener 5 months Murie Walsh NUD, GERD GP EMR HP tx, educate, self tx plan, 46 mostly GERD EMR pre- PHE Reminder / tool for GP 1 year 10 weeks 1 Aliment Pharm 2006 ;24: Am J Gastro 2009; 104:S27, 3 Family PracKce, 2014; 31: (6): 625, Quality Primary Care 2012; 20: 141, J PRIM HEALTH CARE 2016;8(2):164, AP&T2004; 19: 917 2

Taper PPIs interval between doses (ex q 2 days x 2-4 weeks), then DC PPI Teaching Points Good: PPIs work: 3-6- 9 GERD rule Bad: PPIs associated with potenmal AEs: C Diff: Hospital admit, needs Abx à

cost Network MA BMJ 2015 Therapy Eradica=on (%) Adverse events (%) # Pills Triple therapy 7d 73% (71-75) 21% (18-26) 56 (7d) Triple therapy 10-14 day* 81% (78-84) 24% (18-29) 112 (14 d) SequenMal 10

3 Taper PPIs interval between doses (ex q 2 days x 2-4 weeks), then DC PPI Teaching Points Good: PPIs work: GERD rule Bad: PPIs associated with potenmal AEs: C Diff: Hospital admit, needs Abx à try to stop PPI C Diff or Pneumonia: stop PPI ( recurrence) Labs: Long term PPIs: check VB12, Magnesium Costly: MAC /LCA Stopping PPIs: 25% successful taper then DC How to choose Hp treatment? EffecMveness: determined by macrolide resistance (< 20% ok) Avoid macrolide if recent use 80% success was previous standard Keep it Simple: improves adherence Cost: double length of therapy = double cost Network MA BMJ 2015 Therapy Eradica=on (%) Adverse events (%) # Pills Triple therapy 7d 73% (71-75) 21% (18-26) 56 (7d) Triple therapy day* 81% (78-84) 24% (18-29) 112 (14 d) SequenMal 10 days 87% (85-90) 22% (17-27) 70 (10d) CLAMET 7 days** 94% (89-98) 26% (10-48) 168 (14 d) Quadruple: days 85% (82-89) 23% (17-30) 336 (14 d) *Cochrane Review: vs 7 day TT ~10% AR Increase eradicamon **CLAMET: based on 1 low quality study of 119 Japanese paments: Clarithro resistance > 20%, no studies directly comparing 10 or 14 days to 7 days TT TFP 2011, 2015 Bugs and Drugs 2012 BMJ 2015;351:h4052, Cochrane 2013, Issue 12. Art. No.: CD008337, World J Gastro Pharmacol Ther 2012; 6; 3(1): 1-6 Canadian Hp EradicaMon Rates 17 trials of CAN paments: diff tx lengths EradicaMon: Triple (PAC): 84% (79-90) Triple (PMC): 82% (76-88) Quadruple: 87% (80-95) If >75% of meds taken: QT TT (91-94%) 2016 Canadian HP Guidelines *14 days Treatment* 1 st line: CLAMET: PPI, Clarithro, Amoxil, Metro 2 nd line: QUAD: PPI, bismuth, Tetra, Metro 3 rd line: LEVOQUIN: PPI, amoxil, Levoquin Removed: triple and sequenmal therapy! Rogers, Can J. Gastro 2007; 21(5): 295 Gastroenterology 2016;151:

2016 HP Guidelines (and Evidence) TOP 2016 HP Guidelines 14/15 statements: strongly recommend doing X 14 /15 statements: supported by very low or low quality evidence Discussion: The lack of

4 2016 HP Guidelines (and Evidence) TOP 2016 HP Guidelines 14/15 statements: strongly recommend doing X 14 /15 statements: supported by very low or low quality evidence Discussion: The lack of availability of data on local suscepkbility payerns and eradicakon success rates was idenkfied as a knowledge gap that has a major impact on the choice of therapy and hence best management. Gastroenterology 2016;151:51 69 Teaching Point: If fail HP eradicamon à use different regimen HP 2017 Summary In Canada: unml local resistance known no need to change HP regimens TT: days ~80% success (7d = 70%) Sequen=al 10 days: ~90% success Quadruple Therapy x 14 days = 336 pills! If fail one treatment: use a different regimen What the $%&# is a FODMAP DIET (and what is the evidence)? Fermentable oligo-, di-, monosaccharides, and polyols [FODMAPs] Kolber personal communicamon 2016, TOP HP guidelines FODMAP RCTs Highest quality RCT: 6- week, open- label, 123 Danish IBS paments, specialist care point symptom scale (MCID = 50): LFD improved ~150 points, probiomc~80, normal diet~30 points. More LFD paments (14 vs 8%) withdrew: difficulty w diet. Issues: ++ invesmgamons: colonoscopy, genemc tesmng for lactase deficiency, per- protocol analysis 3 other RCTs: small numbers (one = 2 days!), authors have financial COI FODMAP diet for IBS TFP 142: Low FODMAP diet may improve symptoms for pa=ents with primarily diarrhea subtype IBS. However, most studies were low quality (small #s, short dura=on) More high quality studies are needed. World J Gastroenterol. 2014; 20(43): 1621 Gastroenterology 2014;146: 67, J. Nutr 2012: 142: 151 J Gastro Hepatol. 2010; 25: 1366 TFP #142, 2015, Hacken, Can Fam Phys 2015, 691 4

17-03- 04 Meta- Analysis FODMAP diets FODMAP diet Summary More research required to establish long

n of 1 trial LFD is eﬃcacious in treamng funcmonal GI symptoms2 1Aliment Pharmacol Ther 2015; 41:

1007 PancreaMc Cancer We Are #4 FODMAP Diet Reduce: diet pops (armﬁcial sweeteners), wheat, dairy and

org/content/dam/shc/for- paments- component/ programs- services/clinical- nutrimon- services/docs/pdf-

Things to do for ConsMpaMon 1. Hold the Colace! 5.

placebo in increasing stool frequency and is inferior to other products for trea?ng cons

Best RCTS: 74 PalliaMve pts: senna + docusate or placebo à No diﬀ in BM or sx in 10 days 74

5 Meta- Analysis FODMAP diets FODMAP diet Summary More research required to establish long term eﬃcacy1 May improve symptoms in diarrhea predominant IBS paments Healthy SkepMcism: possibly try n of 1 trial LFD is eﬃcacious in treamng funcmonal GI symptoms2 1Aliment Pharmacol Ther 2015; 41: 1256, 2Eur J Nutr 2015; DOI PancreaMc Cancer We Are #4 FODMAP Diet Reduce: diet pops (armﬁcial sweeteners), wheat, dairy and FARTY FOODS (cabbage, onions, beans) hnps:// stanfordhealthcare.org/content/dam/shc/for- paments- component/ programs- services/clinical- nutrimon- services/docs/pdf- lowfodmapdiet.pdf. Canadian Cancer Stats Things to do for ConsMpaMon 1. Hold the Colace! 5.6 million Rx 2015: BC, ONT, NB, PEI (provinces that cover) TFP 2016: Docusate appears similar to placebo in increasing stool frequency and is inferior to other products for trea?ng cons?pa?on. Best RCTS: 74 PalliaMve pts: senna + docusate or placebo à No diﬀ in BM or sx in 10 days 74 hospitalized paments: cross- over RCT docusate or placebo: over 30 days Docusate BMs by ~ 1 / week (LimitaMons: 26% LTFU, study 1960s) Other RCTs: comatose paments, poor quality, unblinded Post- op paments: Senna + docusate vs: Placebo: 1st BM ~1 day sooner likely due to senna. PEG: 1st BM 1-2 days sooner with PEG. TFP #161 April 25, CADTH 2014 Dioctyl Sulfosuccinate or Docusate (Calcium or Sodium) for the PrevenMon or Management of ConsMpaMon: 5

6 2. Use Osmo=c Agents (PEG) In adult and pediatric pakents with chronic conskpakon, PEG is more effeckve than other agents. Compared to placebo, it relieves conskpakon in one in every 2-3 pakents and adds 1-3 BMs per week PEG vs lactulose: stool frequency and intervenmons (especially in peds) StarMng Doses: Adults: 17 grams daily Peds: 0.6 grams/kg/day (or 5-12 grams/day) 3. Consider a clean out 1-2 litres x 2-4 days TFP # , updated 2015, Am J Gastro 2007;102: Gut 2011; 60: 209 Cochrane 2010 CD007570, 2 Arch Dis Child 2009;94:156, Cochrane 2012, CD Evidence Free Zone 4. Ok to Use s=mulants Do SMmulants lead to Dependence or GI nerve abnormalimes? 1968: refractory consmpamon surgery = altered myenteric plexus conclude due to senna 1 Chronic laxamve users (18Xs recommended) Colonic biopsy = altered myenteric plexus AssociaMon vs causamon? Global symptom improvement: NNT = 3 Gut 1968;9:139, 2 Am J Gastro 2005;100:232 Ford, Gut 2011;60: Don t use new medica=ons Prucalopride or Linaclo=de PRU: middle aged who BM ~ q 2 weeks weekly BMs: 0.5 à 1 (placebo)à 2 (PRU) 1-3 PEG vs PRU: 4 PEG effecmve, PRU AEs SystemaMc Reviews: Unfunded: 5 no evidence that effeckve Industry affiliated: 6 efficacy on pakent- important outcomes and a favourable safety profile support the use highly seleckve 5 HT4 agonists Prucolapride (Restoran) Safety...Fool me once, shame on you Fool me twice shame on me! 5- HT 3 AGO: Alostron (Lotronex): Ischemic colims 5- HT 4 AGO: Cisapride (Prepulsid), Tegaserod (Zelnorm): CV events 1 NEJM 2008; 358;22: 2344; 2 Alim Phar Ther 2009; 29: 315, 3 Gut 2009;58:357 4 Aliment Pharm Ther 2013; 37: 876, 5 Health Tech Assess 2011 DOI: Aliment Pharm Ther 2014; 39: 239 6

ComparaMve Shopping Price per Poop Bisacodyl: 10 mg od = $10 /month = $0.65 /poop Lactulose*: 15ml qd = $12 /month = $1.

70 /poop Linaclo=de: 145ug qd = $120 /month = $10 /poop Prucalopride: 2mg qd = $125 / month = $30 /poop

CalprotecMn (adults) Evidence limited; small studies, mostly termary care, in known (or high prevalence) IBD paments*

1 à helps rule out IBD If > 50 LR+ = 7-15 à helps rule in IBD EsMmate: if >250: LRs >10 If 50-250: LRs: ~2-5 *Needs

Alberta: 2-3% posimve Don t need to order IGA: EDM / NZ Likelihood RaMos: ATTG Belgium *Needs Alberta primary care

7 ComparaMve Shopping Price per Poop Bisacodyl: 10 mg od = $10 /month = $0.65 /poop Lactulose*: 15ml qd = $12 /month = $1.00 /poop PEG 3350: 17g qd = $20 /month = $1.70 /poop Linaclo=de: 145ug qd = $120 /month = $10 /poop Prucalopride: 2mg qd = $125 / month = $30 /poop Methylnaltrexone (Relistor) = $55 / inj *covered by Alberta Blue Cross Fecal calprotecmn ATTG FIT GI Labs 2017 Fecal CalprotecMn (adults) Evidence limited; small studies, mostly termary care, in known (or high prevalence) IBD paments* If < 50: LR- = <0.1 à helps rule out IBD If > 50 LR+ = 7-15 à helps rule in IBD EsMmate: if >250: LRs >10 If : LRs: ~2-5 *Needs Alberta primary care study BMJ 2010;341:c3369, Health Technol Assess 2013;17(55) ATTG 250 / day in N. Alberta: 2-3% posimve Don t need to order IGA: EDM / NZ Likelihood RaMos: ATTG Belgium *Needs Alberta primary care study PEIP 2016 Higgins, Am J Gastro 2013; 108: y.o. minimally traumatic ankle #, myalgias, calcium, Vb12 and coagulopathy False POS: (serology +, biopsy - ): patchy disease, pathologist misclassificamon False NEG: (serology -, biopsy +): GFD prior to tesmng, IGA deficiency Clinica Chimica Acta 2010; 411: 13, Am J Gastro 2013; 108:656 7

8 AnMcipated findings: FIT + Spanish RCT: FIT vs colon: 55K pts, yo average risk 1 75ng/ml cutoff (same as AB) à 7.2%+ CRC = 1/180 colon, 1/18 FIT+ BC cohort: yo, 2 FITs q 2 years 2 : 1555 colons 8.6%+, 1/20 FIT+ = CRC, 8 FIT- had 2.5 years 3 perforamons, 6 bleeds Calgary cohort 3 : 10k average risk, 4k FIT colons ADR: FIT+ =60%, Average risk screen =30% AFPEE cohort: 422 FIT + colons: summer NEJM 2012;366:697, 2 CMAJ Open DOI: , 3 Am J Gastro 2016 advance online publicamon doi: Summary PPIs: the good, the bad, the labs (VB12, Mg) and the costly HP eradicamon: SequenMal x 10, Triple x 14 Use different regimen if fail eradicamon PancreaMc cancer: It s #4 ConsMpaMon: no colace, use osmomcs +/- smmulants, try clean out, don t use new meds Labs: fecal cal, ATTG, FIT, CRP mkolber@ualberta.ca QuesMons 8

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