Medical Debaters: Brooks Cash, MD Lin Chang, MD Moderator: Philip Schoenfeld, MD William D. Chey, MD Mark Pimentel, MD This activity is supported by an educational grant from Salix Pharmaceuticals, Inc. Jointly sponsored by the Gi Health Foundation and Purdue University College of Pharmacy. This event is neither sponsored by nor endorsed by the American College of Gastroenterology. Accredited by: Sponsored by: 1
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Medical Debaters: Philip Schoenfeld, MD William D. … annually (2005-2010) from NHANES Fecal Incontinence Severity Index • Participants: ... fecal incontinence, but she does not
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Medical Debaters:
Brooks Cash, MDLin Chang, MD
Moderator:
Philip Schoenfeld, MD William D. Chey, MDMark Pimentel, MD
This activity is supported by an educational grant from Salix Pharmaceuticals, Inc. Jointly sponsored by the Gi Health Foundation and Purdue University College of Pharmacy.
This event is neither sponsored by nor endorsed by the American College of Gastroenterology.
Accredited by: Sponsored by:
1
Breaking News: ACG 2012Philip Schoenfeld, MD
Mesalamine granules 1500 mg once daily for 12 weeks provides adequate relief of IBS symptoms in IBS with diarrhea: Results
from a Phase 2 trial
Aron J et al. Program no. 7
Design
• Background: Mesalamine granules are approved for ulcerative colitis
• Study design– Randomized, double-blind, placebo-controlled, multicenter study– 148 patients with IBS-D (Rome III criteria)– Placebo (n=50) vs Mesalamine granules 750 mg qd (n=47) vs
mesalamine granules 1500 mg once daily (n=51)
• Endpoint: Monthly responders for both abdominal pain and stool consistency during the 3-month treatment period
Results
Mon
thly
Res
pond
ers
for 3
mon
ths
Fecal incontinence in US adults from 2005-10: Epidemiology and Risk Factors
Ditah I et al. Program no. P445
Design• Purpose: Estimate prevalence of FI and identify risk factors
• Study design: Population-based survey of US residents. Data obtained annually (2005-2010) from NHANES Fecal Incontinence Severity Index
• Participants: Men and women aged ≥20 years (N=52,195)
Results• Prevalence of fecal incontinence in 2009-2010 survey: 9.01%
• FI occurred at least weekly in 1.13% of participants
• Prevalence similar in women (9.13%) and men (7.36%)
• Among individuals ≥70 years old: Prevalence = 17.46%
• Other independent risk factors: diabetes and level of education
Effects of linaclotide on abdominal and bowel symptoms over the first 7 days of
treatment in patients with IBS with constipation
Chang L et al. Program no. P1559
Design• Purpose: Assess changes from baseline in abdominal discomfort and bowel
symptoms in IBS-C patients during first 7 days of linaclotide
• Methods: IBS-C patients (Rome II) randomized to linaclotide 290 µg or placebo– Data from first 7 days of treatment analyzed for daily percent change from
baseline in abdominal symptoms and stool consistency– Percentages of patients having ≥1 spontaneous bowel movement (SBM)
and complete SBM (CSBM) on each of the first 7 days of treatment and mean number of SBMs and CSBMs calculated
Results• Significantly more linaclotide patients had an SBM (50% vs 6%) and CSBM
(20% vs 6%) on day one
• Linaclotide statistically significantly improved abdominal bloating and fullness on day one, pain and discomfort by day two, and cramping by day three
• Weekly SBM (6.6 vs 3.5) and weekly CSBM (2.4 vs 0.9) were significantly higher in linaclotide patients vs placebo. (P<.001)
• Diarrhea incidence during the first seven days of treatment was 10% (n=80) and 0.4% (n=3) for linaclotide and placebo patients, respectively
Medical Debaters:
Brooks Cash, MDLin Chang, MD
Moderator:
Philip Schoenfeld, MD William D. Chey, MDMark Pimentel, MD
This activity is supported by an educational grant from Salix Pharmaceuticals, Inc. Jointly sponsored by the Gi Health Foundation and Purdue University College of Pharmacy.
This event is neither sponsored by nor endorsed by the American College of Gastroenterology.
Accredited by: Sponsored by:
12
Faculty Introductions
History• 52-year-old senior account executive for oil exploration company
• Got “food poisoning” during trip to Central America one year ago
• For the last 11 months, has been seeing a primary care physician for intermittent diarrhea with abdominal pain and severe urgency
• When questioned carefully, indicates that she experiences occasional episodes of FI (≥2 times monthly)
– She feels urgency but can’t always make it to the bathroom in time – Notes that she has never discussed this with her primary care physician.
History• She also experiences occasional urinary incontinence when
coughing, laughing, or sneezing
• She has dramatically curtailed her travel schedule because of her fecal incontinence, but she does not feel this is something she can discuss or admit to her supervisor
• Has taken Imodium, which decreases diarrhea and reduces fecal incontinence but results in severe bloating and cramping
History• She has 2 children, both delivered vaginally, the last
being 12 years ago• No history of diabetes, rheumatologic disease, anorectal
surgeries• Current medications
– Taking fiber supplements
Physical Exam and Diagnostic Evaluations
• Physical exam– Some skin irritation in perianal region– Anal sphincter tone at rest is slightly decreased– Mild augmentation of anal sphincter tone during squeeze command– No anatomic sphincter defects were noted
• Anorectal manometry– Slightly decreased anal sphincter tone at rest – An adequate anal sphincter squeeze pressure could not be sustained– Rectal compliance decreased– Sensory thresholds normal
Physical Exam and Diagnostic Evaluations
• Anal endosonography– Some mild scarring of the EAS (external anal sphincter)
• Colonoscopy – Normal; random biopsies are normal
• Capsule endoscopy– Normal
• Laboratory evaluations– Normal TFTs, CBC, ESR, CRP, LFTs
CBC=complete blood count; CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; LFT=liver function tests; TFT=thyroid function test.
Fecal Incontinence:Diagnosis
Types of Fecal Incontinence• Passive incontinence1,2
– Unaware of stool or gas passage; associated with diseased or disrupted IAS
• Urge incontinence1,2
– Release of feces despite awareness and attempted retention; 88% associated with EAS dysfunction
• Fecal seepage1,2
– Presence of small amount of fecal material on undergarments; thought to be due to impaired rectal sensation
1. Rao SS et al. Am J Gastroenterol. 2004;99:1585-1604; 2. Rao SS et al. 2004;126:S14-S22.
Injectable Gel Treatment for FI• Biocompatible, injectable gel consisting of dextranomer
microspheres in stabilized hyaluronic acid• FDA approved for the treatment of fecal incontinence in patients
aged ≥18 years who have failed conservative therapy• Administration
– Done in physician office or hospital out-patient department– Four injections through an anoscope– Injected into submucosal layer of the anal canal– No anesthesia required
How Does the Presence of FI Affect the Diagnosis/Pretest Probability of IBS-D
Rome III Criteria for IBS
Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or
more of the following:
Improvement with defecation
Onset associated with a change in
frequency of stool
Onset associated with a change in
form of stool
*Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis
Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.
Rome III Criteria for Functional Fecal Incontinence
I. Recurrent uncontrolled passage of fecal material in an individual with a developmental age of at least 4 years and one or more of the following:a. Abnormal functioning of normally innervated and structurally intact musclesb. Minor abnormalities of sphincter structure and/or innervationc. Normal or disordered bowel habits (retention or diarrhea)
—AND—II. Exclusion of all of the following:
a. Abnormal innervation from lesion in brain, spinal cord, sacral roots, mixed lesions, neuropathy
b. Anal sphincter disorders associated with systemic diseasec. Structural or neurogenic abnormalities believed to be the major or primary
cause of fecal incontinence
*Criteria fulfilled for the last 3 monthsFunctional Anorectal Disorders. In Rome III: The Functional Gastrointestinal Disorders, 2006.
Colonoscopy Yield in IBS
Lesions
IBSPatients(n=466) N (%)
Controls(n=451) N (%)
P value
Adenomas 36 (7.7) 118 (26.1) <.0001
Hyperplastic polyps 39 (8.4) 52 (11.5) NS
Colorectal adenocarcinoma 0 (0.0) 1 (0.2) NS
Inflammatory bowel disease 2 (0.4) 0 (0.0) NS
Microscopic colitis 7 (1.5) NA N/A
Microscopic colitis more common in IBS-D patients aged ≥45 years
IBD=inflammatory bowel disease; NS=not significant.Chey WD et al. Am J Gastroenterol. 2010;105:859-865.
The prevalence of structural abnormalities is not higher in nonconstipated IBS
Linkage Between Fecal Incontinence and IBS/FGID
• Common associations (urinary incontinence, somatic disorders)• Diarrhea and rectal urgency are both risk factors for fecal
incontinence– Loperamide can increase the IAS tone– Diphenoxylate can improve diarrhea/incontinence
• Constipation associated with fecal incontinence– Regularized defecation patterns (laxatives, bulking agents, digital
maneuvers, biofeedback) can decrease fecal incontinence associated with constipation
Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.
Fecal Incontinence and IBS • Presence of fecal incontinence should prompt diagnostic
evaluations– DRE, lower GI endoscopy, ARM, endoanal U/S
• Normal results of diagnostic testing increase the likelihood of IBS as an etiology of fecal incontinence
• Concomitant improvement in symptoms of IBS and fecal incontinence suggest linkage
PI-IBS=post-infectious IBS1. Neal KR et al. Gut. 202;3:410-413; 2. Neal KR et al. BMJ. 1997;314:779-782; 3. Gwee KA et al. Gut. 1999;44:400-406; 4. Dunlop SP et al. Gastroenterology. 2003;125:1651-1659.
Risk for PI-IBS Increases 7-fold After Infectious Gastroenteritis*
9.8% IBS in cases vs 1.2% IBS in controls
2.8 (1.0-7.5)
8.7 (3.3-22.6)
10.7 (2.5-45.6)
10.1 (0.6-181.4)
6.6 (2.0-22.3)
2.7 (0.2-30.2)
9.9 (3.2-30.0)
11.3 (6.3-20.1)
7.3 (4.8-11.1)
0.1 0.5 1 10 50
Protective Effect Increased Risk OR (95% Cl) Study (year/bacteria)
Ji (2005/Shigella)
Mearin (2005/Salmonella)
Wang (2004/Unspecified)
Okhuysen (2004/Unspecified)
Cumberland (2003/Unspecified)
llnyckyj (2003/Unspecified)
Parry (2003/Bacterial NOS)
Rodriguez (1999/Bacterial NOS)
Pooled estimate
*Systematic review of 8 studies involving 588,061 subjects; follow-up ranged from 3 to 12 months.Halvorsen HA et al. Am J Gastroenterol. 2006;101:1894-1899.
Characteristics of Acute Illness Identify Patients at Risk for PI-IBS
-2
0
2
4
6
8
10
Age FemaleDiarrhea>7 days
BloodyStools
Abdominal Cramps
Weight Loss
>10 lbs
OR
for I
BS
Afte
r A
cute
Gas
troe
nter
itis*
P=.029P=.006
P=.013
P=.001
P=.0001
P=.0001
Marshall JK et al. Gastroenterology. 2006;131:445-450.
*Identified from multiple logistic regression analysis from 2069 participants in the Walkerton Health Study.
Debate 3Does the presence of PI-IBS change approach
to management?
VS
Lifestyle Modifications
for IBS?
n=38 n=37
• 102 IBS patients by Rome II
• 12-week intervention
• 20-60” moderate to vigorous activity 3-5 times/week
• Durable results up to 3 years reported
IBS Severity Scoring System, IBS Score
Johannesson E et al. Am J Gastroenterol. 2011;106:915-922;Johannesson E et al. Abstract presented at DDW 2012.
500
400
300
200
100
0
Control group Physical activity group
P=.001Start Weeks
Impact of Physical Activity on IBS
Food allergy or intolerance
Up to two-thirds of IBS patients associate
symptoms with eating a meal
Gastrocolonicresponse
Psychological Factors
Microbiome/ Fermentation
Gas Handling
1. Simren M et al. Clin Gastroenterol Hepatol. 2007;5:201-218; 2. Eswaran S et al. Gastroenterol Clin North Am. 2011;1:141-162.
Ford AC et al. Am J Gastroenterol. 2009;104:1831-1843.
Efficacy of Alosetron (5-HT3 Antagonist) in IBS:A Meta-Analysis of RCTs
• Only for women with severe diarrhea-predominant IBS who have– Chronic IBS symptoms (6 months) – No evidence of anatomic or biochemical abnormalities of the GI tract – Failed to respond to conventional therapy
• IBS is severe if it includes diarrhea and 1 of the following:– Frequent, severe abdominal pain / discomfort– Frequent bowel urgency or fecal incontinence– Disability or restriction of daily activities due to IBS
Drug NNT NNH Benefit to HarmDesipramine 8 18.3 2.3
Alosetron 7.5 19.4 2.6
Rifaximin 10 8971 897.1
NNT=number needed to treat; NNH=number of subjects treated for 1 subject to withdraw due to an adverse event that was greater than the equivalent with placebo.
Shah E et al. Am J Med. 2012;4:381-393.
Harm With Drugs in IBS
Drug Excess of Placebo OnlyDesipramine Dry mouth, flushing, constipation, insomnia,
Shah E et al. Abstract presented at Digestive Disease Week 2012.
This activity is supported by an educational grant from Salix Pharmaceuticals, Inc. Jointly sponsored by the Gi Health Foundation and Purdue University College of Pharmacy.
This event is neither sponsored by nor endorsed by the American College of Gastroenterology.