1. BREAKTHROUGH PAPERS 2011
LOWER GI TRACT
Charles J. Kahi, MD, MSc
Indiana University School of Medicine
Richard L. Roudebush VA Medical Center
Indianapolis, Indiana
15th Annual GI Update
May 4, 2012

2. DISCLOSURE
Speaker Relationship with Industry, including
Consultant
Speaker
Ownership/ Partnership
Principal Research
Institutional, Organizational or Other Financial Benefit:
NONE

3. Rifaximin Therapy for Patients with Irritable
Bowel Syndrome without Constipation
Mark Pimentel, M.D., Anthony Lembo, M.D.,
William D. Chey, M.D., Salam Zakko, M.D.,
Yehuda Ringel, M.D., Jing Yu, Ph.D., Shadreck M.
Mareya, Ph.D., Audrey L. Shaw, Ph.D., Enoch
Bortey, Ph.D., and William P. Forbes, Pharm.D., for
the TARGET Study Group
N Engl J Med 2011; 364: 22-32

4. BACKGROUND
•
Treatment of IBS can be challenging
•
Patients with IBS may have altered intestinal microbiota
•
Systemic antibiotics have been used in the past with
mixed results
•
Rifaximin is a minimally absorbed broad-spectrum
antibiotic which has shown efficacy for IBS in small-scale
studies
•
Two identical RCTs (TARGET 1 and TARGET 2)
assessing relief of IBS symptoms after a 2-week course
of rifaximin.

5. METHODS
•
Two multicenter industry-supported RCTs
•
1260 patients with IBS (Rome II criteria), without
constipation
•
Rifaximin 550 mg po TID, or placebo
•
1:1 randomization
•
Treatment for 2 weeks, then 10-week follow-up
•
Primary endpoint: Proportion of patients who reported
adequate relief of IBS symptoms for at least 2 of the 1st
4 weeks after completion of treatment
•
Secondary endpoint: Relief of IBS-related bloating.

6. RESULTS
RESPONSE Rifaximin Placebo P value
Primary 40.7% 31.7% < 0.001
endpoint (global
relief)
IBS-related 40.2% 30.3% < 0.001
bloating
Daily IBS-related 43.6% 35.3% 0.003
abdominal pain
Daily stool 76.4% 65.9% < 0.001
consistency
•
Durable response to rifaximin over 3 months
•
Safety profile of rifaximin similar to placebo.

7. COMMENTS
•
Strong evidence that rifaximin may be helpful in some
patients with IBS (esp. with bloating)
•
Very high response rate in placebo arm
•
Consequences of large-scale (and longer term) use are
unknown
•
Cost may be prohibitive (about $22.5 per 550 mg pill)
•
Other options for IBS without constipation are available
and need to be considered based on clinical scenario.

8. Fidaxomicin versus Vancomycin for
Clostridium difficile Infection
Thomas J. Louie, M.D., Mark A. Miller, M.D.,
Kathleen M. Mullane, D.O., Karl Weiss, M.D.,
Arnold Lentnek, M.D., Yoav Golan, M.D.,
Sherwood Gorbach, M.D., Pamela Sears, Ph.D.,
and Youe-Kong Shue, Ph.D., for the OPT-80-003
Clinical Study Group
N Engl J Med 2011; 364: 422-31

9. BACKGROUND
•
Clostridium difficile infection (CDI) usually treated with
metronidazole or vancomycin, with increasing disease
severity and recurrence rates
•
Fidaxomicin is a new macrocyclic antibiotic with no
cross-resistance with other antibiotics
•
In vitro studies: Fidaxomicin more active than
vancomycin against C. difficile isolates (including
NAP1/BI/027 strains)
•
Phase II trial: Good clinical response and low CDI
recurrence rate
•
Non-inferiority phase III trial comparing fidaxomicin to
vancomycin.

10. METHODS
•
Multicenter, industry-supported RCT in the USA and Canada
•
629 adults with CDI
•
Fidaxomicin 200 mg BID or vancomycin 125 mg QID, orally
•
1:1 randomization
•
Treatment for 10 days, then 4-week follow-up
•
Primary endpoint: Clinical cure defined as resolution of
diarrhea and no need for additional CDI therapy
•
Secondary endpoint: CDI recurrence within 4 weeks after
therapy.

11. RESULTS
•
Clinical cure rates with fidaxomicin were non-inferior
compared to vancomycin (88.2% vs. 85.8%)
•
Recurrence rates significantly lower in the fidaxomicin
group (15.4% vs. 25.3%, p=0.005)
•
Lower recurrence rates seen in patients with non-NAP1
strains (69% relative reduction)
•
Adverse events and safety profile similar between the 2
therapies.

12. COMMENTS
•
New therapies for CDI are sorely needed
•
Fidaxomicin bactericidal specifically against C. difficile,
but preserves normal anaerobic flora (less recurrence,
possibly less VRE)
•
Fidaxomicin potentially advantageous because reduction
in recurrence also likely decreases person-person
transmission (“global cure”)
•
High cost: $2800 for 10-day course
•
Additional studies needed to define its role in prevention
of CDI recurrence.

13. Use of Aspirin or Nonsteroidal Anti-
inflammatory Drugs Increases Risk for
Diverticulitis and Diverticular Bleeding
Lisa L. Strate, Yan L. Liu, Edward S. Huang,
Edward L. Giovannucci, and Andrew T. Chan
Gastroenterology 2011; 140: 1427-33

14. BACKGROUND
•
Case-control studies have suggested a higher
prevalence of NSAID use in patients with complicated
diverticular disease (bleeding, diverticulitis)
•
Magnitude of risk uncertain
•
Study limitations due to ascertainment bias and few data
regarding medication type, dose, duration of use
•
Prospective study of a large cohort of men enrolled in
the Health Professionals Follow-up Study.

15. METHODS
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47,210 men, age 40-75 at baseline in 1986
•
Detailed medical and dietary questionnaires
•
Supplementary questionnaires to include diverticular
complications beginning 2006
•
Complicated diverticular disease: fistula, abscess,
perforation, obstruction
•
Diverticular bleeding: Rectal bleeding leading to
hospitalization, transfusion, or intervention
•
Regular use of aspirin/NSAIDs: ≥ 2 times/week
•
Primary endpoints: Diverticulitis and diverticular bleeding.

16. RESULTS
•
939 incident cases of diverticulitis and 256 cases of
diverticular bleeding (22 years of follow-up)
•
Risk of diverticulitis higher among NSAID users (HR 1.72,
1.40-2.11) than aspirin users (HR 1.25, 1.05-1.47)
compared to non-users
•
NSAID use more strongly associated with complicated
diverticulitis (HR 2.55, 1.32-4.95)
•
Aspirin: HR 1.13 (0.61-2.10) for complicated diverticulitis

17. RESULTS
•
Bleeding: Risks similar for aspirin and NSAIDs (HR 1.7)
•
Men who took 2 to 6 standard 325 mg aspirin per week
had the highest risk of bleeding (HR 2.32, 1.34-4.02)
•
Baby aspirin (81 mg) increased risk of diverticular
bleeding but not diverticulitis
•
Longer duration of aspirin or NSAID use ( ≥ 10 years)
associated with greater risk for diverticulitis and bleeding.

18. COMMENTS
•
Regular use of aspirin and NSAIDs is associated with
increased risk of diverticulitis and diverticular bleeding
•
Limitations regarding generalizability and unmeasured
confounders
•
Important clinical and public health implications given
prevalence of diverticulosis and NSAID use in the elderly
•
NSAID use should be considered with caution in patients
with complicated diverticular disease.

19. Two Randomized Trials of Linaclotide for
Chronic Constipation
Anthony J. Lembo, M.D., Harvey A. Schneier, M.D.,
Steven J. Shiff, M.D., Caroline B. Kurtz, Ph.D.,
James E. MacDougall, Ph.D., Xinwei D. Jia, Ph.D.,
James Z. Shao, M.S., Bernard J. Lavins, M.D., Mark
G. Currie, Ph.D., Donald A. Fitch, M.P.H., Brenda I.
Jeglinski, Paul Eng, Ph.D.,Susan M. Fox, Ph.D., and
Jeffrey M. Johnston, M.D.
N Engl J Med 2011; 365: 527-36

20. BACKGROUND
•
Chronic constipation is common clinical problem
•
Few safe and effective long-term therapies
•
Linaclotide is a synthetic peptide that activates the
guanylate cyclase C receptor on the surface of intestinal
epithelial cells
•
Increased cGMP increases chloride and bicarbonate
secretion into the intestinal lumen
•
Net effect is accelerated transit
•
Two RCTs assessing safety and efficacy of Linaclotide in
adults with chronic constipation.

21. METHODS
•
Two similar multicenter industry-supported RCTs (USA and
Canada)
•
1276 adults with chronic constipation
•
Linaclotide 145 µg or 290 µg or placebo once daily
•
Treatment for 12 weeks
•
The primary efficacy endpoint: Three or more complete
spontaneous bowel movements (CSBMs) per week and
an increase of one or more CSBMs from baseline during
at least 9 of the 12 weeks.

22. RESULTS
Linaclotide Linaclotide Placebo P value
145 µg 290 µg
Primary 16.6-21.2% 19.4-21.3% 3.3-6.0% < 0.01
Endpoint
Mean CSBMs 2.2-2.4 2.4-2.9 0.9 < 0.001
per week
•
Other secondary endpoints significantly improved:
- Stool consistency
- Straining severity
- Abdominal discomfort and bloating
- Treatment satisfaction at week 12
•
Adverse events similar between groups except
diarrhea (4.2% d/ced treatment in linaclotide group).

23. COMMENTS
•
Promising new therapeutic option for chronic
constipation
•
Not FDA-approved yet
•
Additional studies regarding efficacy and safety for long-
term treatment.

24. Mucosal Healing Predicts Late
Outcomes After the First Course of
Corticosteroids for Newly Diagnosed
Ulcerative Colitis
Sandro Ardizzone, Andrea Cassinotti, Piergiorgio
Duca,Cristina Mazzali, Chiara Penati, Gianpiero Manes,
Riccardo Marmo, Alessandro Massari, Paola Molteni,
Giovanni Maconi, and Gabriele Bianchi Porro
Clinical Gastroenterology and Hepatology
2011; 9: 483-9

25. •
Patients with UC traditionally treated to clinical remission
•
Mucosal healing may be better predictive of long-term remission
•
5-year prospective study from Italy
•
157 patients with newly diagnosed moderate-severe UC, first
course of systemic corticosteroids within 12 months of dx
•
At 5-year follow-up, patients with clinical and endoscopic
remission had lower rates of hospitalization (25% vs. 49%),
immunosuppressive therapy (5% vs. 26%), and colectomy (3%
vs. 18%) compared to patients with clinical remission alone
•
Lack of mucosal healing predictive of more aggressive course
•
Some patients may benefit from endoscopic assessment after
systemic steroids and be considered for escalation of therapy.

26. Assessment of Thiopurine S-
Methyltransferase Activity in Patients
Prescribed Thiopurines: A Systematic
Review
Ronald A. Booth, PhD; Mohammed T. Ansari, MBBS,
MMedSc, MPhil; Evelin Loit, PhD; Andrea C. Tricco, PhD;
Laura Weeks, PhD; Steve Doucette, MSc; Becky Skidmore,
MLS; Margaret Sears, PhD; Richmond Sy, MD; and Jacob
Karsh, MDCM
Annals of Internal Medicine
2011; 154: 814-23

27. •
Evidence for TPMT testing before thiopurine therapy unclear
•
Systematic review of 55 studies
•
Sensitivity of genotyping for patients with low to intermediate
TPMT activity ranged from 70% to 86% (specificity 100%)
•
Compared with noncarriers, heterozygous and homozygous
genotypes were both associated with leukopenia (OR 4.29 and
20.84 respectively).
•
Compared with intermediate or normal activity, low TPMT
enzymatic activity was significantly associated with myelotoxicity
(OR 19.12) and leukopenia (2.56).
•
Available evidence not rigorous and underpowered to look at
patients with low to absent TPMT activity
•
Enzymatic testing probably a bit better than genotyping due to
variable genotype sensitivity.

28. Bowel Preparation with split-dose
polyethylene glycol before
colonoscopy: A meta-analysis of
randomized controlled trials
Todd W. Kilgore, MD, Abdillahi A. Abdinoor, MD, Nicholas M. Szary, MD,
Samuel W. Schowengerdt, BS, Jamie B. Yust, BS,
Abhishek Choudhary, MD, Michelle L. Matteson, APN,
Srinivas R. Puli, MD, John B. Marshall, MD, Matthew L. Bechtold, MD
Gastrointestinal Endoscopy
2011; 73: 1240-5

29. •
Meta-analysis of 5 RCTs comparing split-dose PEG with
standard dosing (4 liters evening before)
•
Satisfactory prep more likely with split regimens
(OR 3.7, 95% CI: 2.8-4.9, p<0.01)
•
Willingness to repeat prep increased with split regimens
(OR 1.76, 95% CI: 1.06-2.91, p=0.03)
•
Incidence of nausea less with split regimens
(OR 0.55, 95% CI: 0.38-0.79, p<0.01)
•
Compliance better with split regimens
Prep discontinuation (OR 0.53; 95% CI: 0.28-0.98; P< 0.04)
•
Abdominal cramping, bloating, vomiting, sleep disturbances,
missing work or school: NS.