15th Annual GI UpdateMay 4, 2012

BREAKTHROUGH PAPERS 2011LOWER GI TRACT

Charles J. Kahi, MD, MScIndiana University School of Medicine

Richard L. Roudebush VA Medical CenterIndianapolis, Indiana

DISCLOSURE

Speaker Relationship with Industry, including

Consultant

Speaker

Ownership/ Partnership

Principal Research

Institutional, Organizational or Other Financial Benefit:

NONE

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

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.

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.

RESULTS

RESPONSE Rifaximin Placebo P value

Primary endpoint (global

relief)

40.7% 31.7% < 0.001

IBS-related bloating

40.2% 30.3% < 0.001

Daily IBS-related abdominal pain

43.6% 35.3% 0.003

Daily stool consistency

76.4% 65.9% < 0.001

• Durable response to rifaximin over 3 months• Safety profile of rifaximin similar to placebo.

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.

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

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.

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.

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.

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.

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

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.

METHODS

• 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.

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

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.

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.

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

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.

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.

RESULTS

Linaclotide 145 µg

Linaclotide 290 µg

Placebo P value

Primary Endpoint

16.6-21.2% 19.4-21.3% 3.3-6.0% < 0.01

Mean CSBMs per week

2.2-2.4 2.4-2.9 0.9 < 0.001

• 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).

COMMENTS

• Promising new therapeutic option for chronic constipation

• Not FDA-approved yet• Additional studies regarding efficacy and safety for long-

term treatment.

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

• 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.

Assessment of Thiopurine S-Methyltransferase Activity in PatientsPrescribed Thiopurines: A Systematic

ReviewRonald 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 Medicine2011; 154: 814-23

• 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.

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 Endoscopy2011; 73: 1240-5

• 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.• Overall: Split is more effective, better tolerated, more likely to be

complied with.