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From Gums to Bums GI Update for Primary Care Mike Kolber MD, CCFP, MSc
ASA March 2017
Conflict of Interest
• 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
NNT vs H2ANT
UninvesMgated GERD Symptoms 2 4 Erosive EsophagiMs Healing or
symptoms 2 4
Endoscopic NegaMve Reflux Disease
Symptoms 4 8
1’ prevenMon pepMc ulcers in NSAID users
PepMc ulcers (endoscopic)
4-‐9 No evidence
2’ prevenMon PUD Recurrent PUD HPE > PPI 8 Non ulcer dyspepsia Symptoms 10 NSS
Rxfiles 2015: accessed Jan 2017 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 care3: 27% demenMa -‐ 18% last week of life! – Asthma, cough, atypical ENT symptoms: does not work!4,5
hnp://www.canadianhealthcarenetwork.ca/pharmacists/news/special-‐reports/top-‐100-‐drugs-‐19660/4 BMJ 2008;336:2, 2Ann Pharmaco 2006;40:1261, 3J Am Geriatr Soc 2010: 58; 880, 4NEJM 2009;360:1487, 5Chest 2005; 128:1128, 6Dig Dis Sci (2015) 60:2280 CMAJ 2015. DOI:10.1503
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PPIs -‐ The Bad Outcome Pa=ents / Outcome Study Type Results
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
Are PPI associated Adverse Events due to residual confounding?
J Gen Intern Med 2012; 28(2):223–30
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% à16%
• Magnesium:2-‐5 – case control, cohort, re-‐challenge – SR: 9 heterogneous studies; 27% vs 18% in~5 years – Especially if taking diureMcs
Long term PPIs and > 65 yo ! check Vb12 Long term PPIs and on diure=cs ! check Mg
1JAMA. 2013;310(22):2435 2Aliment Pharmacol Ther 2012; 36: 405, 3Am J Kidney Dis. 66(5):775 4PLoS ONE 2015; 9(11): e112558. 5Expert Opin. Drug Saf. 2013; 12(5):709
PPIs the Costly
• 27 million Rxs 2013 • 2012: Esomeprazole + Apo PPIs = $380 million
• Switch à Rabeprazole = save $227 million /year
www.canadianhealthcarenetwork.ca/pharmacists/news/special-‐reports/top-‐100-‐drugs-‐19660/4 Price Comparison of Commonly Prescribed PharmaceuKcals in Alberta 2017
Alberta Blue Cross 2017 Maximal Allowable Costs
Can paMents stop PPIs?
• Yes ~25% successfully dc1,3 • Predictors of success: older paMents, dyspepsia2 – Less successful: GERD
1Aliment Pharm 2006 ;24: 945 2Am J Gastro 2009; 104:S27, 3Family PracKce, 2014; 31: (6): 625, Quality Primary Care 2012; 20: 141 , J PRIM HEALTH CARE 2016;8(2):164, AP&T2004; 19: 917
Study Pa=ents Recruitment Interven=on Propor=on successful DC
Bjornsson1 2006
97 (mostly GERD)
Pharmacy survey
Gastroscopy (normal)
27% @ 1 year
Krol 20046 113 dyspepsia GPs EMR GP lener 13% @ 5 months
Murie 20124
166 NUD, GERD GP EMR HP tx, educate, self tx plan,
34% @ 1 year
Walsh 20165
46 mostly GERD EMR pre-‐PHE Reminder / tool for GP
26% @ 10 weeks
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Taper PPIs
↑interval between doses (ex q 2 days x 2-‐4 weeks), then DC
www.rxfiles.ca
PPI Teaching Points
• Good: PPIs work: 3-‐6-‐9 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
TFP 2011, 2015 Bugs and Drugs 2012
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 days 87% (85-‐90) 22% (17 -‐27) 70 (10d)
CLAMET 7 days** 94% (89-‐98) 26% (10-‐48) 168 (14 d)
Quadruple: 10 -‐ 14 days 85% (82-‐89) 23% (17 -‐30) 336 (14 d)
BMJ 2015;351:h4052, Cochrane 2013, Issue 12. Art. No.: CD008337, World J Gastro Pharmacol Ther 2012; 6; 3(1): 1-‐6
**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
*Cochrane Review: 10-‐14 vs 7 day TT ~10% AR Increase eradicaMon
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%)
Rogers, Can J. Gastro 2007; 21(5): 295
2016 Canadian HP Guidelines *14 days Treatment*
• 1st line: CLAMET: PPI, Clarithro, Amoxil, Metro • 2nd line: QUAD: PPI, bismuth, Tetra, Metro • 3rd line: LEVOQUIN: PPI, amoxil, Levoquin • Removed: triple and sequenMal therapy!
Gastroenterology 2016;151:51–69
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2016 HP Guidelines (and Evidence) • 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
TOP 2016 HP Guidelines
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: 10-‐14 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
Kolber personal communicaMon 2016, TOP HP guidelines 2016
What the $%&# is a FODMAP DIET (and what is the evidence)?
Fermentable oligo-‐, di-‐, monosaccharides, and polyols [FODMAPs]
4 FODMAP RCTs Highest quality RCT: 6-‐week, open-‐label, 123 Danish IBS paMents, specialist care. • 500-‐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
World J Gastroenterol. 2014; 20(43): 1621 Gastroenterology 2014;146: 67, J. Nutr 2012: 142: 151 J Gastro Hepatol. 2010; 25: 1366
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.
TFP #142, 2015, Hacken, Can Fam Phys 2015, 691
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Meta-‐Analysis FODMAP diets “More research required to establish long term efficacy1”
“LFD is efficacious in treaMng funcMonal GI symptoms2”
1Aliment Pharmacol Ther 2015; 41: 1256, 2Eur J Nutr 2015; DOI 10.1007
FODMAP diet Summary
• May improve symptoms in diarrhea predominant IBS paMents
• Healthy SkepMcism: possibly try n of 1 trial
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.
PancreaMc Cancer “We Are #4”
Canadian Cancer Stats 2016
5 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, 2016. CADTH 2014 Dioctyl Sulfosuccinate or Docusate (Calcium or Sodium) for the PrevenMon or Management of ConsMpaMon:
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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)
TFP #45 2011, updated 2015, Am J Gastro 2007;102:1436 2Gut 2011; 60: 209 Cochrane 2010 CD007570, 2Arch Dis Child 2009;94:156, Cochrane 2012, CD009118
3. Consider a clean out • 1-‐2 litres x 2-‐4 days
Evidence Free Zone
4. Ok to Use s=mulants
Ford, Gut 2011;60:209
Global symptom improvement: NNT = 3
Do SMmulants lead to Dependence or GI nerve abnormaliMes?
• 1968: refractory consMpaMon surgery = altered myenteric plexus – conclude due to senna1
• Chronic laxaMve users (18Xs recommended) – Colonic biopsy = altered myenteric plexus
• AssociaMon vs causaMon?
Gut 1968;9:139, 2Am J Gastro 2005;100:232
5. 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”
1NEJM 2008; 358;22: 2344; 2Alim Phar Ther 2009; 29: 315,3Gut 2009;58:357 4Aliment Pharm Ther 2013; 37: 876, 5Health Tech Assess 2011 DOI: 10.3310 6Aliment Pharm Ther 2014; 39: 239
Prucolapride (Restoran) Safety ...Fool me once, shame on you …Fool me twice shame on me! • 5-‐HT3 AGO: Alostron (Lotronex): Ischemic coliMs • 5-‐HT4 AGO: Cisapride (Prepulsid), Tegaserod (Zelnorm): CV events
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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
GI Labs 2017
• Fecal calprotecMn • ATTG • FIT
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 50-‐250: LRs: ~2-‐5
BMJ 2010;341:c3369, Health Technol Assess 2013;17(55)
*Needs Alberta primary care study
ATTG • 250 / day in N. Alberta: 2-‐3% posiMve – Don’t need to order IGA: EDM / NZ
PEIP 2016 Higgins, Am J Gastro 2013; 108:656
65 y.o. minimally traumatic ankle #, myalgias, ↓ calcium, Vb12 and coagulopathy
Likelihood RaMos: ATTG Belgium
Clinica Chimica Acta 2010; 411: 13, Am J Gastro 2013; 108:656
False POS: (serology +, biopsy -‐): patchy disease, pathologist misclassificaMon False NEG: (serology -‐, biopsy +): GFD prior to tesMng, IGA deficiency
*Needs Alberta primary care study
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AnMcipated findings: FIT +
Spanish RCT: FIT vs colon: 55K pts, 50-‐69 yo average risk1 • 75ng/ml cutoff (same as AB) à 7.2%+ • CRC = 1/180 colon, 1/18 FIT+ BC cohort: 50-‐74 yo, 2 FITs q 2 years2: 1555 colons • 8.6%+, 1/20 FIT+ = CRC, 8 FIT-‐ had CRC @ 2.5 years • 3 perforaMons, 6 bleeds Calgary cohort3: 10k average risk, 4k FIT colons • ADR: FIT+ =60%, Average risk screen =30% AFPEE cohort: 422 FIT + colons: summer 2017
1NEJM 2012;366:697, 2CMAJ Open 2016. DOI:10.9778, 3Am J Gastro 2016 advance online publicaMon doi:10.1038
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
QuesMons
