The July 2012 Digital Edition of Gastroenterology and Endoscopy News

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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 7 • July 2012 40th ANNIVERSARY 1972–2012

Most PPI Users Still Experience GERD

Colonoscopy 2012: How Can We Make ake It Better?

BY TED BOSWORTH

Expert Says Technique Tru umps Gadgets

SAN DIEGO—A survey sponsored by the American Gastroenterological Association (AGA) indicated that most patients on proton pump inhibitors (PPIs) for symptoms of gastroesophageal reflux disease (GERD) continue to experience symptoms that disrupt daily life. see PPIs, page 28

Flex Sig Prevents Deaths From Distal Colorectal Cancers

BY CHRISTINA FRANGOU SAN DIEGO—Colorectal cancer screening with flexible sigmoidoscopy reduces the incidence of colorectal cancer (CRC) in the proximal and distal colon, and prevents deaths from CRC in the distal colon, according to a landmark randomized trial involving nearly 155,000 Americans. see Flexible Sigmoidoscopy, page 22

BY CAROLINE HELWICK SAN DIEGO—According to David Lieberman n, MD, chief of gastroenterology and hepatology at Oregon Health & Science University, in n Portland, improved detection of adenomas does not depend on having better “tools and gadgetss” but on better endoscopy techniques.

“Technological improvements have noot made a big impact on adenoma detection rates [ADRs]—so what has?” he asked in a state-offthe-art lecture at the 2012 Digestive Diseasee Week (DDW) meeting.

“The answer is having an extra set of eyes on the procedure, having supervision, knowing you will be audited. This improves ADRss, which tells me the technique probably trumps gadgets.”

Although it’s not that simple, quality indica-tors will need to focus on ways that individual endoscopists can improve on their performance, he said.

“As we go forward and try to improve colonoscopy, we need to set standards, identify quality indicators,

Stormy Forecast: Seven Changes That Will Affect Your Practice

demonstrate that they are linked to outcomes, develop tools for measuring performance and quality of the bowel preparation and then use all this information to see Colonoscopy 2012, page 20

I N S I D E EXPERTS’ PICKS Best of Digestive Disease Week (DDW): Part 1 Experts share their favorite abstracts from the 2012 DDW meeting ..................................page 6

BY CAROLINE HELWICK SAN DIEGO—Navigating the emerging value-based health care environment will prove to be far more difficult for endoscopists than traversing the colon, according to John I. Allen, MD, MBA, who delivered an unsettling forecast for private practitioners at the 2012 Digestive Disease Week meeting. see Forecast, page 24

Alan Buchman, MD, MSPH

Amy Foxx-Orenstein, DO

Mark Pimentel, MD

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Effective cleansing in all bowel segments, including the right colon Percent of patients with NO RESIDUAL STOOL by colon segment1* Colon Segment

Cecum Ascending Descending Transverse Sigmoid/Rectum

SUPREP Bowel Prep Kit split-dose regimen (n=63) 91%† 91%† 92% 92% 94%

4-Liter Prep same-day regimen‡ (n=66)§ 67% 69% 84% 82% 81%

*This clinical trial was not included in the product labeling. †P≤0.02 vs 4-Liter Prep. Statistically significant difference. ‡ Standard 4-Liter Prep (sulfate-free PEG electrolyte lavage solution). § One patient was excluded who took the preparation but refused colonoscopy. Three patients had one or more segments that could not be evaluated because the procedure was stopped for poor preparation before cecal intubation.

SUPREP Bowel Prep Kit achieved “excellent” bowel cleansing in patients based on investigator grading1,2 • Split-dose regimens of SUPREP Bowel Prep Kit and MoviPrep®|| were equivalent in colon cleansing2 • Significantly more patients had “excellent” preps with SUPREP Bowel Prep Kit compared to MoviPrep (63% vs 53%, respectively; P=0.043¶)2 MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution) is a registered trademark of Salix Pharmaceuticals, Inc. ¶ Statistically significant difference. ||

Important Safety Information SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.

Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes.

Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance.

Please see brief summary of Prescribing Information on adjacent page.

3

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

From the Literature

Colonoscopy Under Pressure: Survey of Endoscopists Underscores Difficulty in Balancing Procedure Volume, Quality

BY MARGARET W. CRANE A thriving medical practice. A busy schedule. A stream of referrals. Most physicians welcome these hallmarks of professional success. But sometimes, successful doctors can be blessed with too much of a good thing.

“There are limits to how much any physician can do on any given day and continue to do well,” said Lawrence Cohen, MD, associate clinical professor of gastroenterology at Mount Sinai School of Medicine, New York City.

In a survey of physicians, published in the March issue of

Gastrointestinal Endoscopy (Whitson MJ et al. 2012;75:641-648), Dr. Cohen and colleagues queried more than 5,000 endoscopists and found that many are feeling the pinch of the rising demand for colonoscopy services.

Although screening colonoscopy has become much more widespread,

there has not been a commensurate increase in the numbers of specialists trained to administer the procedure, and reimbursements have continued to shrink—a scenario that makes for a “perfect storm of trying to do more with the same or less.”

A whopping 92.3% of the survey’s participants reported that a variety of production pressures are affecting the quality of their performance.

Here, “production pressure” is defined as any condition that pushes an individual practitioner to give priority to volume, rather than to quality or safety.

‘There are limits to how much any physician can do on any given day and continue to do well.’

—Lawrence Cohen, MD

SUPREP Bowel Prep Kit. Because the quality of cleansing matters.

• Effective bowel cleansing2,3 in all bowel segments1

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

References: 1. Rex DK, DiPalma JA, Rodriguez g R, McGowan J, Cleveland M. A randomized clinical studyy comparing p g reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage g solution as ppreparation p for colonoscopy. py Gastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez g R, McGowan J, Cleveland MvB. A randomized clinical study evaluatingg the safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenteroll. 2009;104:2275-2284. 3. SUPREP Bowel Prep Kit [package insert].

Braintree, MA: Braintree Laboratories, Inc; 2010.

BRIEF SUMMARY: Before pprescribing, g please p see full Prescribing Information and Medication Guide for SUPREP® Bowel Prepp Kit (sodium sulfate, ppotassium sulfate and magnesium g sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. CONTRAINDICATIONS: Use is contraindicated in the followingg conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allergies g to components p of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prepp Kit is an osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. Use is contraindicated in the followingg conditions: ggastrointestinal (GI) obstruction, bowel pperforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allerggies to components of the kit. Use caution when pprescribingg for patients p with a historyy of seizures, arrhythmias, y impaired p ggagg reflex, regurgitation g g or aspiration p , severe active ulcerative colitis, impaired p renal function or ppatients takingg medications that mayy affect renal function or electrolytes. y Pre-dose and post-colono p scopy ECG’s should be considered in ppatients at increased risk of serious cardiac arrhythmias. y Use can cause temporary p y elevations in uric acid. Uric acid fluctuations in ppatients with ggout mayy pprecipitate p an acute flare. Administration of osmotic laxative products p mayy pproduce mucosal aphthous p ulcerations, and there have been reports of more serious cases of ischemic colitis requiring q g hospitalization. p Patients with impaired p water handlingg who experience p severe vomitingg should be closelyy monitored includingg measurement of electrolytes. y Advise all patients p to hydrate y adequately q y before, during, g and after use. Each bottle must be dilutted with water to a final volume of 16 ounces and ingestion g of additional water as recommended is important p to patient p tolerance. Pregnancy: g y Pregnancy g y Category g y C. Animal reproduction p studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive p capacity. p y Pediatric Use: Safetyy and effectiveness in ppediatric ppatients has not been established. Geriatric Use: Of the 375 ppatients who took SUPREP Bowel Prepp Kit in clinical trials, 94 (25%) were 65 years of age g or older, while 25 (7%) were 75 years of age g or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose p (2-day) y regimen g were observed between geriatric g patients p and yyounger g patients. p DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP mayy not be absorbed completely. p y ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal ppain, nausea, vomitingg and headache. Oral Administration: Split-Dose p (Two-Day) y Regimen: g Earlyy in the eveningg pprior to the colonoscopy: ppy Pour the contents of one bottle of SUPREP Bowel Prepp Kit into the mixingg container pprovided.

Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume onlyy a light g breakfast or have onlyy clear liquids q on the dayy before colonoscopy. py Dayy of Colonoscopy py (10 to 12 hours after the eveningg dose): Pour the contents of the second SUPREP Bowel Prepp Kit into the mixingg container provided. p Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy.y Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F).

Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.suprepkit.com ©2012 Braintree Laboratories, Inc.

SU-13280T

January, 2012

“An emphasis on quantity can have negative consequences not only for patients but for physicians, in the form of stress, fatigue and even burnout,” said Dr. Cohen.

There are no real data on the quality of endoscopic services in the United States, much less whether production pressures have been eroding that quality. But the survey responses point to a small problem that could become a much bigger one if it remains unacknowledged and unaddressed, Dr. Cohen believes. see Survey, page 5

4

LETTER TO THE EDITOR

Performing Endoscopy With Propofol And an Anesthesiologist: No Sweat!

Re: “ESA Retraction Triggers Backlash,� by Monica J. Smith.

Gastroenterology & Endoscopy News May 2012;63:1,32; “Use, Cost of Anesthesia for Endoscopy Increasing,� by Monica J. Smith.

Gastroenterology & Endoscopy News May 2012;63:1,26-27.

To the Editor: When I started my practice 25 years ago, Demerol and Versed were the sedatives of choice. I had to concentrate on the monitor, respond to the patient’s feedback, watch the vitals and react to arrhythmias as they occurred. Was it stressful? That is an understatement!

About 10 years ago, the anesthesiologist arrived on the scene armed with propofol and kept an eye on the patient, and I could concentrate purely on endoscopic findings and

handle any complications that arose “without sweating.�

In my opinion, the addition of the anesthesiologist and propofol to the picture has enhanced both the quality of the procedure and the comfort of the patient. I underwent my own colonoscopy [with propofol] and woke up to find out that it was all over, not a trace of after effects or grogginess. I walked out of the endoscopy suite after sleeping off the propofol for about half an hour.

We should be addressing the issue of the availability of propofol and trying to find the lowest possible dose with the minimal sedative effect, thus shortening recovery time even further.

Chakrapani Prakash, MD, FACP Board-certified gastroenterologist Toms River, New Jersey

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Maintenance of Certification Is Discriminatory (Not To Mention Expensive and Irrelevant) Re: “Maintenance of Certification: The ‘Grandfather’ Clause,� by Tania Haddad, MD, DMD. Gastroenterology & Endoscopy News May 2012;63(5):30-31.

Although performance in groups may decline with age, there certainly are no data that maintenance of certification in age-matched physicians produces any measurable improvement in care.

Your argument is clearly one-sided and incomplete. Although physicians may not be able to assess and evaluate themselves, the ABIM [American Board of Internal Medicine] shows no ability to assess and evaluate its performance.

Many feel the MOC [maintenance of

certification] process, in addition to being irrelevant and too expensive, is discriminatory in that older physicians are forced to compete with younger physicians. It is important to note that there is really no evidence that the whole MOC process improves care in participating physicians in any group. There is likely to be a shortage of all physician specialtiess, with increases in insurance coverage. Sh Should we really con nsi sider a mandatory retirement age for ph physicians? I think it is highly likely that a well-trained, active 68-year-old physician could provid de more complete care than a mid-level provider. “marcs�

Via Web site on June 5, 2012

Web Comment

Vol. 63, No. 7 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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Sacramento, California

PETER R. MCNALLY, DO

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

From the Literature

Survey continued from page 3

Survey Results Deconstructed “When you take a closer look at the numbers, they are not as dramatic as they might seem,” said Douglas Rex, MD, Chancellor’s Professor and Distinguished Professor of Medicine at Indiana University School of Medicine and director of endoscopy at Indiana University Hospital, both in Indianapolis. “For example, 7.2% of the respondents said they’ve sometimes taken less than the optimal amount of time for a procedure because of production pressures. But that means 92.8% did nott compromise on time.

That’s about what you’d expect, and it’s also a pretty positive result.”

Similarly, only 5.3% of respondents said that production pressures caused them to terminate a difficult colonoscopy prematurely.

But there are times when it’s appropriate to abort a procedure, says Dr. Rex: “The decision around when to stop is very subjective. If you’re having difficulty passing the scope to the cecum, stopping the procedure may be the right thing to do.”

In itself, then, 5.3% is a reasonable “failure” rate. And again, 94.7% of respondents report that they have not been forced to abort a colonoscopy because of production pressures.

Although 78.5% of the survey’s participants reported more workrelated stress compared with three years ago, 97% consider the medical care they provide to be at least as good or better than in the recent past.

and improve outcomes on a regular basis,” Dr. Rex added.

“Did I reach the cecum in more than 90% of procedures? What is my adenoma detection rate? Have my patients achieved adequate bowel cleansing? Are they satisfied with my services? Am I observing appropriate guidelines for patient recall?”

In summary, Drs. Cohen and Rex agreed that physicians should do the following to raise the bar on quality: • Know the appropriate benchmarks.

The Big Picture With the growth and aging of the American population, the demand for colonoscopy has surged in recent years, but the supply of trained specialists has held steady. Clearly, the pool of trained endoscopists needs to grow in order to keep pace.

Questions remain, however, around the source of such a striking increase in demand. Is colonoscopy being

used because of legitimate public concerns about colon cancer risk, or overused because of public anxiety?

“According to all available guidelines, patients with no family history of colon cancer should be screened every 10 years,” says Dr. Rex. “The desire of some patients to be checked more often might be contributing to the cycle of overuse and production pressure. It is our responsibility to manage patients’ expectations within the guidelines that govern the way we practice medicine.”

■

YOUR NEW PARTNER IN ULCERATIVE COLITIS

So What’s the Problem?

The survey results may not be alarming, but they could serve as an early warning to help forestall the “perfect storm” scenario that Dr. Cohen describes, at the interface of rising demand, fixed supply and dwindling reimbursements. The best way to do that, he believes, is to balance quality and quantity.

“Every industry has to address the need for quality control at some point in its development if it is to succeed,” Dr. Cohen said. “Our specialty has reached that point.”

Dr. Rex wholeheartedly agreed.

“We need to embrace the quality movement in colonoscopy as the best way to ensure the continuing success of our colon cancer screening and prevention programs. Payers, too, are starting to recognize that they need to incentivize quality.”

Quality control is all about benchmarking.

“Providers need to track, monitor

• Track and measure outcomes.

• Focus on improving performance.

© 2012 Santarus, Inc.

1UCE12149

July 2012

Printed in the USA

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DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Experts’ Picks:

The Best of Digestive Disease Week 2012: Part 1 Gastroenterology & Endoscopy News asked the experts: What were your favorite abstracts presented at this year’s Digestive Disease Week (DDW) meeting? Following is a collection of selected abstracts and comments on the meeting as provided to us by three experts in the field. Stay tuned for more expert commentary on this year’s DDW meeting in Gastroenterology & Endoscopy News in the coming months.

Alan Buchman, MD, MSPH Professor of Medicine and Surgery Feinberg School of Medicine at Northwestern University Chicago, Illinois Dr. Buchman reported no disclosures.

Modified Release Phosphatidylcholine LT-02 in Active Ulcerative Colitis—A Randomized, Placebo-Controlled Multicenter Study (Karner M et al)

1157.

European investigators continued a thread of research examining the therapeutic potential of phosphatidylcholine (PC) in ulcerative colitis (UC) given the role a mucosal deficit of PC is thought to play in the pathogenesis of the disease (Ehehalt R. Biochim Biophys Acta 2010;1801:983-993).

Across 24 centers in several European countries, researchers randomized 156 patients with UC who had failed treatment with mesalamine to receive 0.8, 1.6 or 3.2 g of colonic-released PC or a placebo for 12 weeks. Subjects had Simple Clinical Colitis Activity Index (SCCAI) scores of 5 or greater, and bloody diarrhea for at least six weeks prior to treatment. The four groups had similar demographic and clinical traits at baseline and were permitted to continue using 5-aminosalicylic acid (5-ASA), corticosteroids and thiopurines during the study.

The researchers found 31.4% of high-dose (3.2 g) PC recipients achieved remission, defined as a significant drop in SCCAI scores, after six weeks of treatment, compared with 22% of mid-dose (1.6 g), 27.5% of low-dose (0.8 g) and 15% of placebo recipients (P not available). High-dose recipients experienced a mean 4.3-point drop in their SCCAI scores, compared with a P Midmean 3-point reduction with placebo (P=0.029). and low-dose recipients saw a mean 3.4-point and 3.9point reduction in SCCAI scores, respectively, but these improvements did not reach statistical significance when compared with placebo.

When the investigators specifically examined the subgroup of patients who did not continue with 5-ASA treatments during the study, they found “remarkable dose-dependent treatment effects in all end points.”

There were no adverse events associated with PC, the researchers said.

Dr. Buchman: PC is a constituent of all cell membranes and colonic mucus. Previous studies have shown the concentration of PC is substantially reduced during UC flares. This is the first multicenter trial to examine the efficacy of PC. The study found substantially decreased disease activity in UC patients who received PC, although only one-third achieved complete remission.

Although the investigators did not report on rates of mucosal healing, this would have been a critical piece of information to know and would have added strength to the rationale for using the product. Nevertheless, PC is basically innocuous and the choline moiety is listed on the FDA’s GRAS [generally recognized as safe] list. Therefore, PC can be added as an adjunct to current therapies, and the potential exists for the use of PC as an adjunct to other therapies in future trials.

Although it is available in the United States as a supplement in health food stores, PC-based products tend to have very low concentrations of between 15% and 30% of the active ingredient. Earlier studies used a concentration of 30% but the compound used in this study was close to 100% pure. Relatively pure PC, with a concentration of approximately 85%, can be purchased with a prescription (PhosCol, Nutrasal Inc., Portland). However, this product is released in the small intestine, not the colon, and would unlikely to be effective in patients with UC.

‘The study found substantially decreased disease activity in UC patients who received PC, although only one-third achieved complete remission.’

—Alan Buchman, MD, MSPH

Patients With Ulcerative Colitis Hospitalized With Clostridium difficile Infection (CDI) Should Be Treated With Vancomycin Regardless of CDI Severity (Horton H et al) Despite higher rates of morbidity and mortality in patients hospitalized for inflammatory bowel disease (IBD) and concurrently infected with Clostridium difficile, treatment in these patients follows general guidelines that recommend vancomycin only for severe infections (for general guidelines, see Cohen SH et al. Infect Control Hosp Epidemioll 2010;31:431-455).

To compare outcomes with metronidazole and vancomycin among patients with IBD who have severe or non-severe C. difficile infection (CDI), investigators at Cedars-Sinai Medical Center retrospectively examined data from all hospitalized patients with IBD who developed such infections between 2005 and 2011. The study population included 67 patients with UC and 58 with Crohn’s disease (CD). Thirty-four percent of patients with UC and 19% of those with CD met criteria for severe infection. Forty-nine percent of patients had

626.

received antibiotics within the two months prior to hospitalization and 38% were receiving corticosteroids at the time of admission, the researchers noted.

Treatment regimens consisted of metronidazole alone in 62% of patients, vancomycin following initial treatment with metronidazole in 14%, vancomycin alone in 10% and a combination of the two drugs in 9%.

According to the researchers, 90% of metronidazolealone recipients were readmitted to the hospital within 30 days of discharge with recurrent CDI, which they defined as a positive C. difficile test upon readmission or diarrhea as the predominant symptom. In contrast, 57% of those treated with vancomycin at any point were readmitted for recurrent infection within 30 days (P<0.01).

Patients with UC having both severe and non-severe C. difficile infection who were treated with vancomycin either alone or in combination with metronidazole had significantly lower rates of readmission for recurrent infection and significantly shorter hospital lengths of stay than did patients with UC who were treated with metronidazole alone, the researchers found (P≤ P 0.05 for both).

However, the choice of antibiotic did not affect outcomes in patients with CD who did not have severe infection.

Dr. Buchman: These findings make a strong case for using vancomycin as a first-line treatment for C. difficile infection in the IBD population regardless of the severity of infection. The retrospective design of the study is almost as strong as a prospective study. The researchers did not control for variables that might have impacted length of stay and readmission, but one would expect that most patient characteristics were similar among those treated with metronidazole or vancomycin.

Clinically, it is often the case that sicker patients receive vancomycin, such as those in the intensive care unit, those with very low serum albumin and the elderly.

Although the authors did not indicate whether this was the case, those treated initially with vancomycin may have presented with more severe disease. If vancomycin recipients were indeed sicker and that is why they were given the drug rather than metronidazole, the results would be biased in favor of metronidazole because metronidazole recipients would have been less sick. Thus, despite the relatively small number of patients who received vancomycin as first-line therapy, the actual results are more impressive. Additionally, it would have been interesting to know whether diarrhea, as well as the IBD flare, resolved faster in patients treated with vancomycin, but that was left undetermined by this study.

Immunomodulators, but Not Anti-TNF Monotherapy, Impair Pertussis and Tetanus Booster Vaccine Responses in Adults with Inflammatory Bowel Disease (IBD) (Dezfoli S et al);

Su2081.

Efficacy of Hepatitis B Vaccination and ReVaccination and Factors Impacting on the Response in IBD Patients (Gisbert et al)

Sa1932.

Researchers at Cedars-Sinai set out to examine the effects of immunosuppressive agents on cellular and humoral vaccine response in the IBD population, which is a particularly timely topic given that California recently

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

has experienced its worst pertussis epidemic in half a century (Dezfoli S et al; abstract Su2081). To this end, the investigators prospectively examined 59 consecutive adults with IBD who received a booster vaccination for tetanus, diptheria and acellular pertussis.

Outcomes for patients administered anti-TNF monotherapy (n=15), immunosuppressant monotherapy (n=16) or combination therapy (n=9) were compared with a control group of IBS patients receiving mesalamine (n=19).

Similar numbers of subjects in the four groups were also being treated with corticosteroids.

The investigators found subjects receiving either an anti-TNF or an immunosuppressant alone achieved protective tetanus titers, whereas only 78% of combination-treatment recipients responded to the vaccinations (P=0.01 P for all groups vs. combination). Response rates to pertussis toxoid were 68% in the mesalamine group, 67% in the biologic monotherapy group and 44% in both the immunosuppressive monotherapy and combination therapy groups. Similarly, 84%, 87%, 69% and 67% of the four groups, respectively, achieved response to pertussis filamentous hemagglutinin.

‘These abstracts are important because there are very little data documenting response rates to common vaccinations in the IBD patient population.’

—Alan Buchman, MD, MSPH

A prospective study also highlighted the muted immune response of IBD patients receiving immunomodulators (Gisbert et al; abstract Sa1932). The investigators found that in 149 patients with CD and 92 patients with UC, only 59% achieved adequate response to double-dose hepatitis B virus (HBV) vaccination. Individuals receiving anti-TNF treatment had a lower response rate of 46% compared with 62% among those who received other treatments, including immunosuppressants (P<0.05). Revaccination of nonresponders only led to a 42% response rate, the researchers found.

Dr. Buchman: These abstracts are important because there are very little data documenting response rates to common vaccinations in the IBD population. As the studies indicate, one needs to consider whether vaccinations in our patients are less effective than in other groups of patients. Further studies will need to determine whether, and how frequently, booster vaccinations are required.

The published vaccination response criteria used in both studies should be tracked in our patients. These include a post-vaccination pertussis antibody titer of 20 endotoxin units (EU)/mL or greater in those with a baseline titer less than 5 EU/mL, a fourfold rise in antibody titers in those with a baseline titer between 5 and 20 EU/mL, and a twofold rise in those with a baseline titer of 20 EU/mL or greater. For tetanus, response is a post-vaccination tetanus titer at least 0.4 international units (IU)/mL if prevaccination levels are less than 0.1 IU/mL, or a greater than fourfold increase in titers if baseline titers are at least 0.1 IU/mL. In HBV vaccine recipients, response is defined as an anti-HBs titer greater than 10 IU/L.

Amy Foxx-Orenstein, DO Associate Professor Department of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Dr. Foxx-Orenstein reported no disclosures.

Evidence for Post-Diverticulitis Irritable Bowel Syndrome (Pdv-IBS): Longitudinal Analysis Reveals Higher Incidence of IBS in DV Cases vs. Controls (Cohen ER et al)

1363.

A growing body of research suggests diverticulitis (DV) may lead to long-term impairments in bowel function, including patient-reported functional bowel disorder (FBD) and irritable bowel syndrome (IBS).

In this retrospective, longitudinal study, researchers analyzed data from 1,102 patients with DV who had been treated at the Los Angeles Veterans Affairs Medical Center between 1996 and 2011. The investigators compared rates of FBD and IBS among this population with rates of FBD and IBS in 1,102 age- and gender-matched controls without DV who also were seen at the VA Medical Center. DV, IBS and FBD were identified according to International Classification of Diseases (ICD)-9 codes included in patient medical charts. Medical records also were individually reviewed for clinical, radiographic or surgical confirmation of ICD-9-identified disease. Patients with evidence of FBD and IBS prior to DV diagnosis were excluded.

The subjects (mean age, 64 years) were mostly men and were followed for a mean 35 months following DV diagnosis.

The researchers found patients with DV were 4.6 times more likely than matched controls to have an ICD-9 code indicating IBS (hazard ratio [HR], 4.6; 95% confidence interval [CI], 1.6-13.6; P P=0.005). Furthermore, they were 2.4 times more likely than controls to have an FBD diagnosis subsequent to their DV diagnosis (95% CI, 1.6-3.4; P<0.0001).

“These data corroborate previous cross-sectional data and support the hypothesis that DV might trigger long-term IBS symptoms,” the investigators concluded.

‘The study supports the idea that an acute inflammatory condition can trigger IBS.’ —Amy Foxx-Orenstein, DO “Future research will identify demographic and clinical predictors of post-DV IBS and evaluate its incidence in prospective patient registries to better determine whether this link is causal or merely associative.”

Dr. Foxx-Orenstein: These are interesting findings based on a very well-designed study with large numbers. The results seem to fall in line with previous studies showing IBS can be a post-infectious complication with symptoms remaining prolonged over years (Spiller R. Gastroenterology 2009;136:1979-1988).

7

The study supports the idea that an acute inflammatory condition can trigger IBS. Although the study’s design was strong overall, there are some weaknesses and some things we don’t know from the abstract. The study population was mostly male but we don’t know much more than that about their characteristics. Furthermore, because the design was retrospective and IBS is not the first diagnosis one would consider for a male presenting with abdominal pain and bloating, there is the possibility that some cases of pre-DV IBS went undiagnosed.

Effects of 26 Weeks of Linaclotide Treatment on Adequate Relief and IBS Severity in Patients with Irritable Bowel Syndrome with Constipation (Chey W et al) In this Phase III, extension trial researchers randomized 403 adults with ROME II-defined IBS with constipation (IBS-C) to receive 290 mcg daily of linaclotide, a 14-amino acid peptide, and 401 IBS-C

1381.

‘Given that treatment for IBS typically involves a multidrug approach, including antidepressants, to treat the pain and a separate drug for bloating, the efficacy of this drug in improving both symptoms is very promising.’

—Amy Foxx-Orenstein, DO

patients to receive a placebo, both for 26 weeks. Patients rated their abdominal pain on a daily basis using an 11-point Likert scale, with a score of 0 indicating no pain. Patients also noted the frequency of complete spontaneous bowel movements (CSBMs), rated their IBS severity on a five-point scale and reported whether or not they experienced “adequate relief ” of symptoms.

Participants who reported adequate relief for at least 13 of the 26 weeks of treatment were considered to be treatment responders.

The data showed 49.1% of linaclotide recipients said they achieved adequate relief for at least 13 weeks compared with 25.1% of placebo patients (P<0.0001).

Among drug recipients, 48% said their symptoms were nonexistent or mild at week 26, whereas 20.3% said their symptoms were moderate and 31.7% said they were severe or very severe. In contrast, 25.8% of placebo responders reported nonexistent or mild symptoms after 26 weeks; 38.7% said their IBS was moderate; and 35.5% reported they had severe or very severe symptoms (P P not available). Reductions in abdominal pain and increases in CSBMs were correlated with adequate relief, the researchers said.

Dr. Foxx-Orenstein: This was a large study and the results are, therefore, reliable. Although researchers used ROME II rather than ROME III criteria, patients were evaluated over a prolonged period of time. What is so intriguing about linaclotide is that this therapy is associated with significant reductions in abdominal pain, which is often the most difficult disease component to treat. Such significant improvements with respect to abdominal pain have not been demonstrated with other IBS treatments, including tegaserod and alosetron. see Best of DDW, page 8

8

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GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JULY 2012

Best of DDW continued from page 7

Given that treatment for IBS typically involves a multidrug approach, including antidepressants, to treat the pain and a separate drug for bloating, the efficacy of this drug in improving both symptoms is very promising.

A Longitudinal Study of Clinical Parameters and Cytokine Profiles in IBS (Craig OF et al)

1432.

In light of prior research demonstrating an inflammatory component to IBS (Keohane J et al. Am J Gastroenterol 2010;105:1788-1794), Irish researchers set out to understand changes in IBSrelated cytokine activity over time. To this end, they prospectively examined data from 58 patients with IBS treated at their institution. Patients underwent cytokine profiling using enzyme-linked immunosorbent assays (ELISA) at baseline and

two and six months subsequently. Participants also completed disease activity questionnaires.

The investigators found that compared with a control group of 19 healthy individuals who underwent single assessments, IBS patients had significantly higher levels of interferon (IFN)-γγ and TNF-ι (P=0.03 P and 0.04, respectively).

They found significant variations in IFN-γγ levels over time but no changes in

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the activity of six other cytokines. Patients with constipation-predominant IBS had significantly lower levels of IFN-γγ and TNF-ι than did individuals with diarrhea-predominant or mixed-type IBS. Among the 14 patients who completed the six-month study and consistently met IBS criteria, six experienced changes in IBS subtype. The data also showed that only patients with IBS who reported depressive symptoms had significantly higher levels of interleukin (IL)-6 than did healthy controls (P=0.0003).

P â&#x20AC;&#x153;The cytokine profile of IBS sufferers is for the most part stable over time and differs from healthy controls but does not appear to be exclusively pro-inflammatory,â&#x20AC;? the researchers concluded. â&#x20AC;&#x153;Depressive symptoms in IBS are characterized by higher levels of IL-6.â&#x20AC;?

Dr. Foxx-Orenstein: IBS is a fascinating disease. After so many years, we still know so little about it. Weâ&#x20AC;&#x2122;re only now teasing out information about the role inflammation and immunity play in its pathogenesis, but weâ&#x20AC;&#x2122;ve got a way to go in understanding the disease. In this study, Craig et al found significant variations in IFN levels over time, specifically in those with mixed-subtype IBS or diarrheapredominant disease. Although these are interesting results, it is difficult to draw any conclusions given that the authors failed to highlight what the next steps of this line of research might be. In light of the small number of patients examined here, I would like to see these analyses repeated prospectively, in a larger study population and solely in diarrhea-predominant and mixed-type IBS patients. A prospective study would also help address the question of whether there is a true association between depressive symptoms and IL-6 levels.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Mark Pimentel, MD Director of the Gastrointestinal Motility Program and Laboratory Cedars-Sinai Medical Center Los Angeles, California Dr. Pimentel is a consultant for Asubio Pharmaceuticals and for Salix Pharmaceuticals.

Effect of Gender on Prevalence and Subtype of Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis (Lovell R et al)

Su1016.

Although research has demonstrated a higher prevalence of irritable bowel syndrome (IBS) among women than men, there have not been meta-analyses of existing studies examining the topic.

In light of this literature gap, British researchers searched MEDLINE, EMBASE and EMBASE Classic for population-based studies published through October 2011 that included data on gender-based IBS prevalence.

The studies included at least 50 adult subjects with IBS defined by Manning and ROME I, II or III criteria.

were less likely than men to have diarrhea-predominant IBS (IBS-D), the data revealed (OR, 0.45; 95% CI, 0.32-0.65).

The prevalence of mixed-type IBS was similar among women and men (OR, 1.07; 95% CI, 0.84-1.38).

Gender-based prevalence differed according to diagnostic criteria used, the investigators also found. Specifically, studies using ROME II criteria yielded the lowest odds ratio for IBS in women

compared with men, whereas publications using ROME I criteria showed the highest odds ratio among women.

Dr. Pimentel: The dogma is that IBS is more common in women. As this study demonstrates, if you pool the results, that dogma holds true. However, if you look at extreme ends, such as more severe IBS-D, the prevalence is greater among men. The finding of gender differences

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‘The finding of gender differences in the prevalence of IBS subtypes guides us to look at the disease’s pathophysiology in a different way.’

—Mark Pimentel, MD

Among the 55 studies included in the analysis, the pooled prevalence of IBS in women was 14% compared with a prevalence of 8.9% among men (odds ratio [OR], for women: 1.67; 95% confidence interval [CI], 1.53-1.82).

In a subset of nine studies that also reported IBS subtype-specific prevalence data according to gender, the researchers found constipation-predominant IBS (IBS-C) was significantly more prevalent among women than men (OR, 2.38; 95% CI, 1.45-3.92). However, women

➢ Scan this QR code with your iPad and download the App from iTunes.

9

in the prevalence of IBS subtypes guides us to look at the disease’s pathophysiology in a different way. For example, studies looking at menstrual cycle–related hormonal changes in IBS patients (see Heitkemper MM et al. Gend Med 2009;6:152-167) have shown no obvious relationship overall, but it may be that hormonal differences are found in subjects with extreme IBS-C, where women see Best of DDW, page 10

10

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Best of DDW continued from page 9

dominate men almost 8 to 1, as a recent study we published demonstrated (Herman J et al. Gend Med 2010;7:240-246).

Systematic Review of Diagnostic Criteria for IBS Demonstrates Poor Validity and Utilization of ROME III (Dang J et al) Dr. Pimentel and his group conducted

Mo1053.

this systematic review of validation and utilization studies including ROME criteria for IBS diagnosis. Their analysis included two stages: the first was a literature review of validation studies published since 1978 in PubMed, EMBASE and the Cochrane database.

The review included nine publications that used Manning criteria, three that used Kruis criteria, and three each that examined the sensitivity and specificity

of ROME I and II criteria. The investigators did not find any ROME III validation studies.

Analyses of these studies revealed a range of sensitivity and specificity rates with each of the four sets of criteria.

Sensitivity and specificity when using the Manning criteria reached 94% and 93%, respectively, whereas the highest sensitivity and specificity rates for Kruis, ROME I and ROME II criteria were

for con nsistently mak kin ng

81% and 99%, 85% and 100%, and 89% and 73%, respectively. The “most appropriately designed” validation studies examined Manning criteria, the investigators said.

In a second stage of the review, Dr. Pimentel and his colleagues set out to document the adoption of ROME criteria in clinical trials as they were introduced between 1992 and 2011.

They divided the 20-year period into three segments, which they designated as the ROME I era (1992-1999), the ROME II era (2000-2006) and the ROME III era (2007-2011). Given the lengthy duration of some randomized controlled trials and the possibility that they spanned more than one of the time periods examined in the analysis, the investigators excluded these studies to avoid skewing their findings.

the best-read pu ublication in the ‘One issue these findings raise

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is that IBS is a moving target, depending on the different iterations of ROME used.’

More than 17,000 readers* every month:

—Mark Pimentel, MD

♦ ♦ 1,532 colon and rect ctal al sur urge geon onss

They found 53.1% of studies during the ROME I era in fact used ROME I criteria for IBS diagnosis. Similarly, 59.8% of studies published during the ROME II era used ROME II criteria.

However, only 25.7% of studies published during the ROME III era used ROME III criteria. ROME III criteria, they wrote in their abstract, “are disappointing.”

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Dr. Pimentel: With three versions of the ROME criteria now in use, what this review determined was that ROME III has not been validated and also is poorly used even in the research setting. One explanation for the low utilization rates may be that studies published during the ROME III era were possibly conducted partly during the ROME II era, so that there may have been a lingering effect of use of ROME II. However, we did not see this happen during the transition to ROME II from ROME I. Rather, ROME II was widely and rapidly adopted. One issue these findings raise is that IBS is a moving target, depending on the different iterations of ROME used.

Although the lack of validation studies for ROME III is problematic, the most troublesome aspect of these latest

DDW 2012

criteria is that bloating, which is often considered to be the most bothersome symptom of IBS, is not even included in the criteria.

Impact of Concurrent Use of PPIs or Antidepressants on Efficacy of Rifaximin for IBS Without Constipation (Lembo A et al) Although some patients treated with rifaximin for non-constipation IBS also use proton pump inhibitors (PPIs) and antidepressants concurrently, the effects of these drugs on rifaximin’s efficacy has not been studied. To understand the possible effect of this combination drug regimen on rifaximin’s efficacy, investigators conducted a subgroup analysis of data from two double-blind, placebocontrolled, Phase III trials of 14 days of rifaximin 550 mg twice daily for the treatment of global IBS symptoms and daily bloating in patients with non-constipation IBS. The two studies included nearly 1,000 patients who did not receive PPIs or antidepressants, as well as 288 subjects administered a PPI concurrently and 303 subjects who received an antidepressant. There were similar numbers of PPI and antidepressant users in the rifaximin and placebo groups.

The analysis revealed that significantly more rifaximin recipients not administered a PPI experienced improvements in daily global IBS symptoms and daily bloating than placebo recipients not receiving a PPI (40.25% vs. 29.7% for global symptoms and 41.5% vs. 32.6% for bloating; P<0.05 for both). Among participants also administered a PPI, 40.8% of rifaximin recipients experienced significant improvements in daily bloating compared with 28.8% of combination placebo and PPI recipients (P<0.05). Although there were more patients reporting improvements in daily global symptoms in the rifaximin and PPI group than in the placebo and PPI group, this was not statistically significant (40.1% vs. 28.8%).

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Conversely, in the subgroup of antidepressant recipients, significantly more rifaximin patients than placebo subjects reported improvements in daily global symptoms (32.2% vs. 21.3%; P<0.05).

Although more rifaximin patients also using an antidepressant experienced reductions in daily bloating than placebo subjects using an antidepressant, the difference did not reach statistical signifiFullPageAds-FINAL_v1.ai 1 6/18/12 cance (34.3% vs. 25.6%).

Dr. Pimentel: This is the second study to examine the effects of PPI use in the context of the bacterial hypothesis in IBS. In 2009, the bacterial concept of IBS was criticized on the basis that PPIs could cause bacterial overgrowth. The opinion was that because many IBS patients take PPIs, the resulting acid reduction could cause bacterial overgrowth 11:46 AM to bloating. Since then, three and lead

11

published studies have proven this criticism incorrect (see e.g., Ratuapli et al. Am J Gastroenterol 2012;107:730735, and Shah ED et al. Dig Dis Sci 2010;55:2441-2449). In fact, positive breath tests are less common in patients taking a PPI. This abstract is the final evidence against PPIs having an influence on antibiotic effectiveness in IBS. Rifaximin was effective irrespective of PPI use.

■

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DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Vedolizumab a ‘Major Advance’ for Moderate to Severe UC Novel Compound a ‘First-Out-of-Class Biologic’ for IBD

BY DAVID WILD SAN DIEGO—Vedolizumab, a novel selective α4β7 integrin inhibitor, is significantly more effective in inducing and maintaining clinical remission in patients with moderate to severe ulcerative colitis (UC) than placebo, findings from a randomized, double-blind study presented at the 2012 Digestive Disease Week (DDW) meeting revealed (abstract 943b). Furthermore, this “first-out-ofclass” biologic agent led to sustained clinical remission in up to 37% of patients who had failed prior biologic therapies, with many able to discontinue corticosteroid treatment after one year of treatment.

“I believe this is a potentially major advance in the management of patients with moderate to severe UC,” said Asher Kornbluth, MD, clinical professor of medicine, Mount Sinai School of Medicine, New York City, who helped enroll several patients in the study. “In those UC patients who do not respond fully to infliximab, vedolizumab will be an important option to proceed to early on.”

Lead investigator Brian Feagan, MD, director of clinical trials at Robarts Research Institute in London, Ontario, Canada, presented findings at the DDW meeting. The study, called GEMINI 1, was conducted at several international centers and included 895 patients with UC who had failed prior treatment with corticosteroids, thiopurines or anti-tumor necrosis factor (TNF) agents.

Subjects had baseline Mayo scores of 6 or greater and endoscopic subscores of 2 or greater and were randomized to receive two induction doses of IV vedolizumab 300 mg two weeks apart. One month after the second induction dose, 373 patients (41.7%) who met clinical response criteria, defined as a reduction in Mayo score of three or more points and a reduction in Mayo score of

30% or greater compared with baseline, as well as a significant reduction in rectal bleeding, were randomized to receive a placebo (n=126) or vedolizumab 300 mg every four weeks (n =125) or every eight weeks (n=122), all for 46 weeks.

In an intent-to-treat analysis of data 52 weeks after the initial dose, Dr. Feagan’s team found that 44.8% (56 of 125) of patients who received the monthly dose of the drug and 41.8% (51 of 122) of bimonthly drug recipients achieved clinical remission, which they defined as a Mayo score of 2 or lower and no individual subscores greater than 1. Remission rates in both groups were significantly higher than the 15.9% (20 of 126) rate of remission at 52 weeks among clinical responders randomized to receive placebo following the initial induction phase (P<0.0001).

‘We ‘W e be beliiev eve e vedo ve dolizu uma mab bc ca an be us u sed e eit ithe herr as a fi firrst st-liine tre reat atme ment ntt or in cas ase e o ant of n ii-TN TNF F fa f il ilur ure. e’

Rates of mucosal healing, defined as a Mayo endoscopic subscore less than or equal to 1, also were significantly higher in both treatment arms than in the placebo group (56% and 51.6% for monthly and bimonthly groups, respectively vs. 19.8% for placebo; P<0.0001).

Although 52-week remission rates were lower in absolute terms in the subgroup of patients who had failed prior anti-TNF therapy, they remained significantly higher than in the placebo group, and were in fact more pronounced, the investigators reported (35% and 37.2% for monthly and bimonthly drug recipients, respectively, vs. 5.3% for placebo; P value not available).

Dr. Feagan also told DDW attendees that 45.2% and 31.4% of monthly and bimonthly drug recipients, respectively, who had been receiving corticosteroids at study outset achieved steroid-free remission at 52 weeks compared with 13.9% in the placebo group (P≤ P 0.133 for both treatment groups vs. placebo).

Rates of adverse events (AEs), serious AEs and serious infections were similar in all three groups, Dr. Feagan said.

The absence of any instances of progressive multifocal leukoencephalopathy (PML) in this study was a particularly important finding, Dr. Feagan told Gastroenterology & Endoscopy News. He noted vedolizumab’s mechanism of action is similar to that of natalizumab (Tysabri, Biogen Idec), a drug that increases the risk for PML, however, “whereas natalizumab targets α4β7 integrin nonselectively, vedolizumab specifically targets T-cell trafficking in the gut.

“We believe vedolizumab can be used either as a first-line treatment or in case of anti-TNF failure,” he concluded.

■ Drs. Feagan and Kornbluth have consulted for Millennium Pharmaceuticals, Inc.

—Bri —B rian an Fea eaga gan, n MD

New Anti-TNF, Golimumab, Effective in Moderate to Severe UC Subcutaneous Dosing of Golimumab May Offer Advantage Over Infliximab

BY DAVID WILD SAN DIEGO—A new study reveals that subcutaneously injected golimumab (Simponi, Janssen Biotech Inc.), an antitumor necrosis factor (TNF) agent indicated for several arthritic conditions, is effective in inducing remission in patients with moderate to severe ulcerative colitis (UC), according to findings presented at the 2012 Digestive Diseases Week meeting (abstract 943d).

Results from the placebo-controlled PURSUIT SC (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment) study showed that between 52% and 55% of patients with UC who received two subcutaneous

injections of the drug experienced clinical response within six weeks compared with 29.7% of placebo recipients.

healing and response and remission rates all look promising. These induction data are impressive and I’ll be

‘This is quite exciting. The mucosal healing and response and remission rates all look promising.’

—Vijay Yajnik, MD, PhD

“This is quite exciting,” said Vijay Yajnik, MD, PhD, attending physician at the Massachusetts General Hospital Crohn’s and Colitis Center and assistant professor of medicine at Harvard Medical School, Boston, who was not involved in the study. “The mucosal

waiting for follow-up data for up to one year to see whether response can be sustained.”

PURSUIT SC was conducted by lead investigator William Sandborn, MD, chief of the Division of Gastroenterology and director of the University of

California San Diego Inflammatory Bowel Disease Center at the University of California, San Diego Health System, as well as colleagues in several internationally based centers. The team randomized 759 anti-TNF–naive UC patients with moderate to severe disease (defined as a Mayo score between 6 and 12 and an endoscopic subscore of 2 or greater) to one of three study arms: placebo (n=256); 200 and 100 mg golimumab at weeks 0 and 2, respectively (n=257); or 400 and 200 mg golimumab at weeks 0 and 2, respectively (n=258).

Participants previously had failed or were intolerant to treatment with one or more of the following: 6-mercaptopurine, azathioprine, corticosteroids see Golimumab, page 16

14

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

IBD Medications Appear Safe During Pregnancy Some Complications Associated With Biologics for UC; Disease Activity Is ‘Biggest Risk’

BY CAROLINE HELWICK SAN DIEGO—Medical treatment for inflammatory bowel disease (IBD) during pregnancy does not increase the rate of congenital abnormalities, according to

an analysis of the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry, presented at the 2012 Digestive Disease Week meeting.

“The use of azathioprine [AZA] and biologic therapy during pregnancy is not associated with increased birth defects,”

DIFICID™ (fidaxomicin) tablets Brief Summary of Prescribing Information 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile.

1.1 Clostridium difficile-Associated e Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD).

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections.

5.2 Development of Drug Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice.

The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.

Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.

Table 1. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials

System Organ Class Preferred Term

DIFICID (N=564)

Vancomycin (N=583)

n (%)

n (%)

Blood and Lymphatic System Disorders Anemia

14 (2%)

12 (2%)

Neutropenia

14 (2%)

6 (1%)

said study author Uma Mahadevan, MD, associate professor of clinical medicine, University of California, San Francisco, Center for Colitis and Crohn’s Disease.

“This is the largest study to prospectively follow these patients, and this is comforting information.”

7 DRUG INTERACTIONS Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.

7.1 Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp.

When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range [see Clinical Pharmacology (12.3) in the full prescribing information].] Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials.

Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers It is not known whether fidaxomicin is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

8.5 Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.

In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age) [see Clinical Pharmacology (12.3) in the full prescribing information].] However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

10 OVERDOSAGE No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.

Manufactured for Optimer Pharmaceuticals, Inc., San Diego CA 92121 by Patheon, Inc. DIFICID™ is a trademark of Optimer Pharmaceuticals, Inc.

Gastrointestinal Disorders Nausea

62 (11%)

66 (11%)

Vomiting

41 (7%)

37 (6%)

Abdominal Pain

33 (6%)

23 (4%)

Gastrointestinal Hemorrhage

20 (4%)

12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash

Product protected by US Patent Nos. 7,378,508; 7,507,564; 7,863,249; and 7,906,489 Optimer Pharmaceuticals, Inc. 10110 Sorrento Valley Road, Suite C San Diego, CA 92121 (858) 909-0736 © 2011 Optimer Pharmaceuticals, Inc. All rights reserved.

The data presented included 896 patients with IBD in four groups based on medication exposure: patients not exposed to medication (n=326); thiopurine-exposed patients (including 6-mercaptopurine, AZA; n=204); biologic-exposed patients (including infliximab, adalimumab, natalizumab; n=291) and combination therapy–exposed patients (including thiopurines and biologics; n=75). Exposure was defined as any use of agents between three months prior to the last menstrual period and the end of pregnancy. Women were evaluated at each trimester, at delivery and at infant age 4, 9 and 12 months.

Disease activity was more severe during pregnancy in patients with ulcerative colitis (UC) than in patients with Crohn’s disease (CD). Disease was inactive during pregnancy in 80% to 90% of patients with CD and in 65% to 75% of those with UC. Overall, 55 malformations were observed in 49 births (unexposed patients, 19; thiopurine-exposed patients, 12; biologics-exposed patients, 17; combination-exposed patients, seven). The rate of abnormalities overall was 6% compared with a rate of 3% nationally (based on data from the Centers for Disease Control and Prevention) and compared with 7% in the Kaiser Permanente database (Mahadevan U et al. Gastroenterologyy 2007;133:1106-1112). Compared with unexposed patients and adjusted for disease activity, women exposed to biologics alone experienced more spontaneous abortions (relative risk [RR], 2.56; P<0.05) and cesarean deliveries (RR,

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

‘The use of azathioprine and biologic therapy during pregnancy is not associated with increased birth defects.’

—Uma Mahadevan, MD

patients who are in remission on AZA or a biologic agent should be maintained on that drug; if AZA is added to a biologic solely to prevent antibody formation, she eliminates it. For treatment-naive patients who want to become pregnant, she recommends certolizumab.

“Remember, the biggest risk during pregnancy is disease activity,” she emphasized.

Jerrold R. Turner, MD, PhD, the Sara and Harold Lincoln Thompson Professor at the University of Chicago, who served as moderator during the press

briefing where these results were presented, said the data are “very reassuring.

“We have had concerns that these agents might lead to birth defects,” Dr. Turner said. “There has been the calculation, based on fewer data than we would like, that having active disease is even worse than what the drugs might do during pregnancy. Now we have data.

“The infection risk is somewhat concerning and we need to look further at that. Meanwhile, for complicated IBD patients, we have information to guide treatment, which is as much an art in

15

this disease as a science,” Dr. Turner concluded.

■ The PIANO registry is 100% funded by the Crohn’s & Colitis Foundation of America.

Dr. Mahadevan serves on advisory committees or review panels and receives grant/ research support or teaching honoraria from Abbott Laboratories, Centocor, Elan Pharmaceuticals, GlaxoSmithKline, Merck & Co., Prometheus Laboratories, Sucampo Pharmaceuticals, Takeda Pharmaceuticals and UCB. Dr. Turner reported no relevant conflicts of interest.

CO2 instead of room air for GI endoscopy?

It’s about comfort.

1.23; P<0.05), whereas those on combination therapy had an increased risk for preterm births (RR, 1.83; P<0.05).

“Limiting the analysis to CD, we saw no increase in adverse events based on drug exposure; but when we looked at UC, although we adjusted for disease activity, there was an increase in spontaneous abortions in the biologics group [RR, 4.85; P<0.05],” Dr. Mahadevan noted. In patients with UC who were on combination therapy, the rates of complications were increased threefold, preterm births nearly fourfold, low birthweight more than threefold and neonatal intensive care unit stays fourfold (P<0.05 for all).

Combination therapy raised the risk for infections at 12 months of age by 36% (P<0.05) when the analysis excluded certolizumab, which has minimal placental transfer. Breastfeeding, reported by 75% of women, was not associated with an increased risk for infection or height/ weight deficiencies.

Putting the findings into context at a press briefing, Dr. Mahadevan said that patients with IBD are expected to have more complications than the general population, even with inactive disease, and that those treated with combination therapies may be sicker to begin with.

“Also, we are not capturing malnutrition, anemia and other factors that could impact pregnancy outcomes,” she said.

Reporting bias also may be a factor, as patients on strong therapies for IBD are more likely to call their gastroenterologist when pregnant than women with IBD on no medications or on mesalamine agents.

Dr. Mahadevan suggested that IBD

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DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Serologic Monitoring of Inflammato o ory ry Biomarkers May Be Used To Predict Relapse in Crohn’s Disea ase

BY CAROLINE HELWICK SAN DIEGO—Clinical relapse after infliximab withdrawal in patients with Crohn’s disease (CD) can be predicted by close monitoring of C-reactive protein (CRP) and fecal calprotectin, according to a subanalysis of the STORI (Stop Infliximab in Patients with Crohn’s Disease) study, presented at the 2012 Digestive Disease Week meeting.

“After infliximab withdrawal, a sudden increase of CRP and/or fecal calprotectin may predict the occurrence of a clinical relapse within the next four months,” said senior author of the study, Edouard Louis, MD, of the Centre Hospitalier Universitaire de Liège, in Belgium. “Serum CRP and fecal calprotectin are easy to measure, reasonably cheap and correlate with intestinal inflammation,” he added.

The study assessed 113 patients with CD who were in stable remission without steroids or infliximab for six months or longer in the prospective multicenter STORI trial. After their last infliximab infusion, patients were followed every two months, for a median of 10 months.

CRP and fecal calprotectin levels were compared between patients who relapsed and those who did not at each time point, with a median of four measures per marker per patient. Median CRP level at the beginning of follow-up was 1.9 mg/L; median fecal calprotectin level was 57 mcg/g.

“We found the evolution of CRP and fecal calprotectin levels was significantly different between relapsers and non-relapsers,” Dr. Louis reported. Among the 51 patients who relapsed, significant changes over baseline were observed at four months for both CRP (P<0.0001) and fecal calprotectin (P=0.001).

P In non-relapsers, a slight but significant increase in CRP and fecal calprotectin levels was observed throughout follow-up; however, in relapsers, after a slight and progressive increase, a sudden, pronounced increase in CRP and fecal calprotectin levels occurred during the four months preceding relapse (Table).

“Using the ROC [receiver operating characteristic]

Golimumab continued from page 12

or 5-aminosalicylic acid. Some study participants also were corticosteroiddependent. Participants were permitted concomitant use of other UC drugs throughout the six-week study, with a similar distribution of medication use in the three groups.

Dr. Sandborn and his team examined rates of clinical response, remission and mucosal healing, as well as changes in the inflammatory bowel disease questionnaire (IBDQ) at week 6, four weeks after the second dose of the drug. They defined clinical response as a Mayo score decrease of 30% or more and three points or more relative to baseline, with a significant decrease in rectal bleeding.

curve, the best compromise betw ween sensitivity and specificity to predict relapse was 6.1 mg/L for CRP (sensitivity, 71%; specificity, 66%)) and 305 mcg/g for fecal calprotectin (sensitivity, 70%; specificity, 74%),” Dr. Louis said.

‘If these results are valid, this gives us a window to intervene when the slope starts rising, to put patients back on therapy before they experience a clinical flare.’

—Peter D. Higgins, MD The odds for relapse were deteermined to be 5.3 for patients with CRP greater than n 5 mg/L (P<0.001) and 5.5 for fecal calprotectin greater than 250 mcg/g (P<0.001). Multivariate analysis showed strong colinearity between CRP and fecal calprotectin (r=0.56; P<0.0001).

Peter D. Higgins, MD, assistan nt professor of medicine at the University of Michigan School of Medicine, Ann Arbor, said, “If these results are valid, this gives us a window to intervene when the slope starts rising, to put patients back on therapy before they experience a clinical flare.”

His group made similar findings in patients who discontinued thiopurines (Higgins PD. Am J Gastroenterol 2011;106:556-558).

“We saw that we could intervene before the flare, but this was a small sample compared with STORI,” he said.

“We now have funding from Abbott to conduct a larger prospective study with adalimumab.” The CADHUM (Calprotectin Directed HUMira therapy) study will enroll 54 patients and monitor fecal calprotectin levels every 12 weeks for 48 weeks. Dr. Higgins believes CRP also is a valid biomarker, but the trigger for retreatment in CADHUM will be rising fecal calprotectin levels.

Dr. Higgins called for even larger prospective trials to validate this approach to noninvasive monitoring, “to determine if we really can take a therapeutic drug

Clinical remission was defined as a Mayo score of 2 or lower with no individual subscores greater than 1. Mucosal healing was defined as a Mayo endoscopy subscore of 0 or 1.

The investigators found that 55% (142 of 258) of patients in the high-dose group and 51.8% (133 of 257) in the lowdose group achieved clinical response at week 6 compared with 29.7% (76 of 256) of placebo recipients (P<0.0001 for both treatment groups vs. placebo).

Furthermore, 45.3% (117 of 258) of the high-dose and 43.2% (111 of 257) of the low-dose groups experienced mucosal healing after two injections of the drug compared with 28.5% (73 of 256) of placebo patients (P≤ P 0.0005 for treatment vs. placebo). Approximately 18% (46 of

Table. M Median di L Levels l off S Serologic l i Inflammatory Biomarkers Among Inflammatory Crohn’s Disease Patients Nonrelapsers (n=62)

Relapsers (n=51)

P Value

CRP

2.9 mg/L

4.9 mg/L

0.0218

Fecal calprotectin

58 mcg/g

302 mcg/g

0.0002

CRP, C-reactive protein

holiday and monitor biomarkers closely to intervene before clinical flares occur.”

■ Dr. Louis reported financial relationships with Abbott Laboratories, AstraZeneca, Chiesi, Falk Pharma, Ferring Pharmaceuticals, Menarini Ricerche spa, Millennium Research Group, MSD, Schering-Plough, Shire Pharmaceuticals and UCB. Dr. Higgins reported research support from Abbott Laboratories and Bühlmann Laboratories.

258) of high-dose golimumab recipients and 18.7% (48 of 257) of low-dose drug recipients met clinical remission criteria at week 6 compared with 6.3% (16 of 256) of placebo recipients (P<0.0001).

Treatment recipients also experienced significantly greater improvements in IBDQ scores than did those receiving placebo, the researchers found.

Safety data showed similar overall rates of adverse events (AEs) in all three groups but higher rates of serious AEs in the placebo arm, likely reflecting the effects of continued active disease, Dr. Sandborn said. However, one patient receiving high-dose golimumab died from infection and another experienced demyelination, a well-described complication of anti-TNF therapy.

In an interview with Gastroenterology & Endoscopy News, Dr. Sandborn said he believes that golimumab will ultimately find its place in the clinician’s toolbox for the treatment of patients with moderate to severe UC. “I expect that severely ill, hospitalized patients will be treated with intravenous infliximab, but that in the outpatient setting some patients will choose the convenience of subcutaneous dosing,” Dr. Sandborn said. “This is what we’ve seen happening in the Crohn’s disease population, where more than half of patients choose subcutaneous dosing.”

■ Dr. Sandborn is a consultant for Janssen Biotech Inc. Dr. Yajnik is a consultant for UCB Pharma.

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18

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Enterography-based IBD Risk-Prediction Calculator Helps Predict Benefit of Surgery in Patients With Stricturing Crohn’s Disease

BY DAVID WILD Researchers at the Cleveland Clinic are developing a risk-prediction calculator to help clinicians identify Crohn’s disease (CD) patients with stricturing disease who are more likely to benefit from early surgical intervention. The calculator will

incorporate specific disease and imaging findings that the investigators have identified as most predictive of surgery.

“The risk-prediction calculator will allow providers to use patient findings and classify them into risk categories [to help] predict the need for bowel resection surgery within two years,” lead investigator Ashish Atreja, MD, MPH, staff member

at the Digestive Diseases Institute at the Cleveland Clinic in Ohio, told attendees at the Crohn’s & Colitis Foundation of America’s 2011 Advances in IBD meeting (abstract 0-3). “This will allow both providers and patients to make informed decisions about whether to proceed with earlier surgical consultation, an aggressive medical regimen or watchful waiting.”

The choice of medical therapy, endoscopic dilation or surgical intervention for bowel strictures is not always clear, Dr. Atreja explained. Clinicians need to consider the length, location and number of strictures and whether they are due to edema or fibrosis. Although surgery “is the only definitive treatment for severe strictures,” it brings risks for postoperative complications and recurrence.

When it comes to hemorrhoid removal, there’s good news for you and your patient.

‘The risk-prediction calculator will allow providers to use patient findings [to help] classify them into risk categories and predict the need for bowel resection surgery within two years.’

—Ashish Atreja, MD, MPH

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In light of the clinical challenge of deciding on the most appropriate treatment, Dr. Atreja and his team set out to identify patient traits that correlated with future surgical intervention. They retrospectively examined data from a cohort of 164 patients with stricturing CD who had undergone computed tomography enterography (CTe) and magnetic resonance enterography (MRe) at their institution in 2009.

The investigators conducted statistical analyses to determine any correlations between surgery and the presence of imaging and disease characteristics, which included Montreal classification, disease duration, stricture length, number and location of strictures, previous

19

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

surgeries, presence and extent of proximal bowel dilation, fistulae, inflammatory masses or abscesses, mesenteric stranding, mucosal hyperenhancement and degree of bowel wall thickening.

The researchers found that 54% of the patients ultimately required surgery within a median of 607 days of follow-up.

Early onset of disease, presence of fistulae, masses, abscesses, mesenteric strand-

to make optimal decisions at the point of care and identify patients who will benefit from early referral to a surgeon,” Dr. Atreja said.

The researchers also presented data on validation of the tool with an independent cohort of patients who underwent enterography in 2008 at this year’s Digestive Disease Week meeting. Once

validated in other centers, the investigators hope to make the tool available online.

Richard MacDermott, MD, director of the Inflammatory Bowel Diseases Center at Albany Medical College, in Albany, N.Y., was enthusiastic about the potential to identify patients who would benefit from early surgery.

“The ability to recognize situations in

which medical therapy will most likely not be helpful is of critical importance in order not to expose patients to the potential side effects of ineffective treatments,” said Dr. MacDermott, who was not involved in the study.

■ Drs. Atreja and MacDermott reported no conflicts of interest.

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS 75% of patients develop HE recurrences, even on lactulose.1 Protect your patients with Xifaxan 550 mg continuously from the moment they experience their first overt episode.

58% 50%

ing and proximal bowel dilation greater than 3 cm were significantly correlated with the need for surgery.

Individuals who had strictures but did not have these factors had a 30% likelihood of requiring surgery within two years, whereas 49% of those with one risk factor ultimately underwent surgical resection. If two of these factors were present, the chance of surgery rose to 73.5%, and if three of these factors were present, the likelihood of surgery increased to 84%. All patients who had all the risk factors required surgery, the researchers found.

“Once we validate these findings prospectively, we believe clinicians will be able to make use of the stricture severity score

proven reduction in the risk of overt HE breakthrough2† proven reduction in the risk of HE-related hospitalizations2‡§

Prescribe. Protect. Repeat.

*HE=hepatic encephalopathy. † Over a 6-month period; P<0.0001 vs placebo.2 ‡ Over a 6-month period; P=0.0129 vs placebo.2 § HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.2

IMPORTANT SAFETY INFORMATION XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age. In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly.

XIFAXAN has not been studied in patients with MELD scores >25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of Web site: www.salix.com 1700 Perimeter Park Drive, Morrisville, NC 27560 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16

C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

The most common adverse reactions occurring in >8% of patients in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), ascites (11%), muscle spasms (9%), pruritus (9%), and abdominal pain (9%).

Xifaxan550 is not available for sale outside the U.S. Xifaxan550 is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see adjacent brief summary of Prescribing Information.

References: 1. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017. 2. Xifaxan [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.

www.Xifaxan550.com

20

DDW 2012

Colonoscopy 2012 continued from page 1

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

‘Having an extra set of eyes on the procedure, having supervision, knowing you will be audited. This improves

assess individual performance. This will then lead us to develop additional quality indicators,” Dr. Lieberman said.

adenoma detection rates, which tells me the technique probably trumps gadgets.’

—David Lieberman, MD

Quality Is Critical to Success Earlier this year, Zauber et al published research showing the value of polypectomy in preventing colorectal cancer (CRC) and in reducing mortality from CRC by more than 50% (N Engl J Medd 2012;366:687-696). These findings

validated advanced adenomas as an appropriate target of screening, Dr. Lieberman said. “Therefore, we need to think about how well we are detecting them.”

But there are problems with

colonoscopy—mainly that the procedure offers less protection against cancers in the proximal colon and that interval cancers occur. Although the true rate of interval cancers is unknown—studies

indicate a range of approximately 1% to 9% within three years of a negative exam—clearly, quality issues underlie their occurrence, Dr. Lieberman said.

“We know these are happening, but we don’t know, within individual practices, how often,” he said.

Aggressive biology and rapid growth of the lesions is a suspected cause of interval cancers, as is quality of the polypectomy, Dr. Lieberman said. Polyps are incompletely removed in 19% to 27% of polypectomies.

“But missed lesions are the elephant in the endoscopy suite,” he noted.

Studies have shown that 17% of polyps larger than 1 cm are missed, especially in the proximal colon, and Dr. Lieberman believes the rates may be even higher.

“These are issues related to quality,” he emphasized.

Especially with flat lesions, the addition of chromoendoscopy or narrow-band imaging (NBI) enables better visualization. “I certainly have started using this in my practice,” he said.

Issues related to biology also are becoming clearer, Dr. Lieberman noted.

A study of 1,323 CRCs found 63 (4.8%) to be interval cancers (Arain MA et al.

Gastroenterologyy 2010;105:1189-1195).

Compared with noninterval cancer controls, interval cancers were more likely to occur in the proximal colon and to have more aggressive phenotypes. Interval cancers were more likely to be positive

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

• Make split-dosing regimens the standard. Research shows that split dosing increases the odds for having a satisfactory bowel preparation by fourfold (Kilgore TW et al. Gastrointest Endoscc 2011;73:1240-1245).

Have patients take the second dose of bowel preparation within six hours of the colonoscopy.

• Record and monitor bowel preparation quality in your practice (using

‘Missed lesions are the elephant in the endoscopy suite.’

—David Lieberman, MD

for CpG island methylator phenotype and microsatellite instability. These features are characteristic of serrated polyps, which are thought to be associated with approximately 20% of CRCs. “So, biology is playing a role, but so is our ability to find these lesions,” Dr. Lieberman stressed, noting that studies have shown high variability in identifying serrated polyps. For example, at this year’s DDW meeting, a Dutch study showed that in a five-person practice, the rates of detecting proximal serrated polyps ranged from 6% to 22%; the authors attributed the variability to differences in colonoscope withdrawal time (de Wijkerslooth TR et al., abstract 912).

How Can We Do Better?

Full examination of the colon improves detection rates, Dr. Lieberman emphasized. With complete colonoscopy, the risk for interval cancers is reduced by 27%, according to a study of 14,064 patients in a Canadian registry who underwent colonoscopy (Baxter NN et al. Gastroenterologyy 2011;140:65-72).

But simply reaching the cecum is not enough, Dr. Lieberman said, suggesting several simple factors that will improve technique and adenoma detection: • Predict which patients will have inadequate bowel preparation and intervene early, perhaps with a more intensive regimen—“anticipate and mitigate,” he said.

the Ottawa or Boston Bowel Preparation Scale) and use this information to improve the quality of future preparations.

• Prolong colonoscope withdrawal time; mean ADRs should increase linearly, accordingly (Lee RH et al. Gastrointestinal Endosc 2011;74:128-134).

• Take a comprehensive look at technique; good technique doubles

21

ADRs (Lee RH et al. Gastrointest Endoscc 2011;74:128-134).

• Apply technological innovations, such as chromoendoscopy, highdefinition white-light endoscopy and NBI, appropriately, but do not depend on them.

“The good news is we can improve quality, and hopefully make cancer screening and surveillance more effective by doing so,” he concluded.

■

22

DDW 2012

Flexible Sigmoidoscopy continued from page 1

The results of the trial—part of the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial project (PLCO)—were presented at the 2012 Digestive Disease Week meeting and published online the same day, May 21, in The New England Journal of Medicine (Schoen RE et al. [Epub ahead of print]).

Overall, flexible sigmoidoscopy was associated with a 21% reduction in CRC incidence, with the effect most pronounced for cancers of the distal colon. Screening by flexible sigmoidoscopy also was associated with a reduction in mortality, but the benefit was limited to the distal colon, where there was a 50% reduction in mortality.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Flexible sigmoidoscopy proved effective in preventing cancers in both the distal and proximal colon, but more so for distal cancers. In the distal colon, the cancer incidence was 5.6% in the screening group compared with 7.9% in the usual-care group, representing a reduction of 29% (95% confidence interval [CI], 0.64-0.80; P<0.001). For cancers of the proximal colon, screening by flexible sigmoidoscopy resulted in a cancer incidence of 7% and 6% for the screening and usual-care groups, respectively, representing a 14% decrease in incidence (95% CI, 0.76-0.97; P=0.01).

P There was, however, one glaring omission in terms of the benefit of flexible sigmoidoscopy: Mortality from proximal CRC in the intervention versus the usualcare group was unaffected by screening (143 and 147

‘I believe this study provides the strongest evidence yet for endoscopic screening of both the proximal and distal colon, and it confirms colorectal cancer screening as a

‘The real question for U.S. clinicians is whether we are prepared to refocus attention on a

public health

screening strategy

imperative.’

—Robert E. Schoen,

that has been likened

MD, MPH

to performing mammography on one breast.’

—John M. Inadomi, MD

“I believe this study provides the strongest evidence yet for endoscopic screening of both the proximal and distal colon, and it confirms colorectal cancer screening as a public health imperative,” said principal investigator Robert E. Schoen, MD, MPH, professor of medicine and epidemiology at the University of Pittsburgh.

These findings build on recent large studies from Italy and the United Kingdom that demonstrated the efficacy of flexible sigmoidoscopy in reducing CRC incidence and, in one of the two studies, mortality (Segnan N et al. J Natl Cancer Instt 2011;103:1310-1322; Atkin WS et al. Lancet 2010;375:1624-1633).

In the PLCO study, investigators randomly assigned 154,900 men and women to screening with flexible sigmoidoscopy, with a repeat screen at three or five years, or to usual care. Of 77,445 participants assigned to screening, 83.5% underwent a baseline flexible sigmoidoscopy and 54% were screened again after three or five years. Participants were referred to their primary care physicians for decisions regarding diagnostic follow-up.

When participants had an abnormal screening result, 80.5% underwent a diagnostic intervention within a year; of these, 95.6% had a colonoscopy.

With a median follow-up of 11.9 years, the incidence of CRC was 11.9 per 10,000 person-years among participants in the screening group, markedly lower than the 15.2 per 10,000 person-years in the usual-care group.

deaths, respectively; relative risk, 0.97; 95% CI, 0.771.22; P P=0.81). In contrast, mortality from distal CRC was reduced by 50% in the intervention group (95% CI, 0.38-0.64; P<0.001).

Dr. Schoen said the study investigators could not determine why screening did not improve survival in individuals who developed cancers of the proximal colon. But, he said, the answer may lie in the biology of the polyps of the proximal colon.

“We’re learning that there is a difference in the propensity of polyps in the proximal colon to advance into cancer,” he said. “If we’d done a colonoscopy, would we have seen something different? I don’t know that. I’m impressed by the fact that the lines—tracking mortality in patients who developed proximal cancers in the screening and usual-care groups—basically superimpose on one another.”

The results did not surprise David F. Ransohoff, MD, professor of medicine and epidemiology, University of North Carolina at Chapel Hill. Sigmoidoscopy inspects only the distal colon and could provide a benefit proximally if a distal sentinel lesion that then necessitates a colonoscopy accompanies the proximal lesions.

“Also, in this study, some protection occurred (decreased incidence proximally) probably because of a coincidental distal polyp,” Dr. Ransohoff said.

“In PLCO, 22% of people got a colonoscopy because

sigmoidoscopy found a polyp, even if it was a tiny adenoma or hyperplastic polyp with no CRC risk.”

Commentators also noted that the PLCO study had a high degree of contamination between the two groups, which may have skewed the results. Almost half of the participants in the usual-care and the intervention groups underwent routine colonoscopy after the screening phase.

In a commentary accompanying the study (N Engl J Medd 2012 May 21. [Epub ahead of print]), John M. Inadomi, MD, professor of medicine, University of Washington, said the findings raise the question of what rationale could be used to expand the use of flexible sigmoidoscopy as a screening tool. Currently, most national guidelines, with the exception of those from the American College of Gastroenterology, include flexible sigmoidoscopy as a recommended screening strategy.

Still, the test is not commonly used in the United States.

“The real question for U.S. clinicians is whether we are prepared to refocus attention on a screening strategy that has been likened to performing mammography on one breast,” Dr. Inadomi wrote.

Dr. Inadomi offered several potential reasons for increasing the use of flexible sigmoidoscopy: 1. The quality of evidence supporting the effectiveness of screening colonoscopy is inferior to the quality of data supporting flexible sigmoidoscopy.

2. Screening colonoscopy alternatives should be available in order to maximize adherence to CRC screening.

3. The changing health care climate in the United States would suggest that effective strategies that are less resource-intensive will be viewed more favorably by payers and accountable care organizations.

Dr. Inadomi added that more research is needed to help define the role of flexible sigmoidoscopy as a screening tool.

“High-quality evidence must show the superiority of colonoscopy over other screening tests before we dismiss the use of flexible sigmoidoscopy and fecal occult blood testing.”

The lack of a mortality effect on cancers of the proximal colon gives colonoscopy a strong edge over flexible sigmoidoscopy as a screening tool, said Sidney J. Winawer, MD, Paul Sherlock Chair in Medicine, Memorial Sloan-Kettering Cancer Center, New York City.

“This study, in fact, makes a very good case for colonoscopy.”

Dr. Winawer pointed out that data from the National Polyp Study and case–control studies suggest that the overall expected mortality reduction from screening colonoscopy is between 50% and 70% and that the proximal effect would be significantly larger than from flexible sigmoidoscopy. Randomized controlled trials and large case–control studies initiated recently will provide more precise data on the effect of screening colonoscopy several years from now, he added.

Dr. Ransohoff suggested that there might be a screening role for periodic sigmoidoscopy in combination with other tests.

“Some modeling analyses have shown that a strategy of periodic sigmoidoscopy in combination with other tests like highly sensitive fecal immunochemical testing can be more effective than a strategy of periodic colonoscopy. This sort of role for sigmoidoscopy can be addressed by ongoing research and by modeling,” Dr. Ransohoff concluded.

■

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DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Forecast continued from page 1

“The next decade will be all about cost,” said Dr. Allen, of Minnesota Gastroenterology and the University of Minnesota School of Medicine, Minneapolis.

“Although we strive for quality and value, cost will be 98% of what affects your practice.”

As health care costs rise, risk will be shifted to physicians in the form of accountability and value-based reimbursement and to patients in the form of high deductibles. Entities will consolidate to gain efficiency and power, and the emergence of large, integrated delivery networks will have profound implications for colorectal cancer (CRC) screening and other aspects of gastroenterology care, Dr. Allen said.

“The cost of an independent practice will drive many physicians out of ownership positions,” he predicted. “In small practices that don’t have the capital of large practices, this is becoming crushing. For the first time in history, the number of hospital-owned medical practices exceeds physician-owned. We are about to see tremendous change in how our specialty care is delivered.”

Seven Things That Will Change The Practice of Colonoscopy Within one to three years, seven key changes will affect the practice of colonoscopy, Dr. Allen predicted: 1. Pay-for-performance will become an established payment model.

2. Colonoscopy codes will be revalued.

3. Quality and cost transparency will occur.

4. Reference or fixed pricing will affect incomes.

5. Accountable care organizations (ACOs) will emerge.

6. Population metrics will guide CRC prevention.

Numerous factors are positioning colonoscopy for a possible reckoning, according to Dr. Allen, who noted that many health care analysts call colonoscopy “a target for price controls and quality improvement.”

The decision by the Centers for Medicare & Medicaid Services (CMS) to cover screening colonoscopy was modeled on an assumed 90% CRC risk reduction and a procedural price of less than $700. But the risk reduction is closer to 60%, and the cost exceeds $5,000 in some settings.

Plus, fees and surveillance patterns are highly variable, and detailed analyses of CMS databases demonstrate that some physicians alter coding from screening to diagnostic codes to accrue higher reimbursement for screening colonoscopy.

“These data are known, and we may bear the consequences,” he suggested.

The impending revaluing of colonoscopy codes, completion expected by 2015, portends for even lower reimbursement fees. Changes will be based on surveys of work time, now calculated at 39 to 55 minutes per colonoscopy, although “obviously, it takes us more like 15 to 17 minutes,” Dr. Allen said. “In 2015, this will hit, and hit big. We are anticipating a 10% to 20% professional fee at risk.”

Get Ready for PQRS In 2013, commercial payers will start rolling out programs that will be compatible with the Physician Quality Reporting System (PQRS). In fact, the American Gastroenterological Association (AGA) recently contracted with UnitedHealthcare to support data collection through the AGA Digestive Health Outcome Registry. Data collected will be used by UnitedHealthcare to design its “premium designation program.” Based on 24 months of analyzed data, the program awards one star to practices that meet or exceed quality criteria and two stars to those meeting efficiency standards. The program, called “My Healthcare Cost Estimator,” is designed for patients when they are selecting providers.

One Web site takes the concept even further: www.CheapColonoscopy.com contracts with board-certified gastroenterologists assumed to be “quality performers” in 50 metropolitan areas. These physicians offer colonoscopies at the set price of $950.

“This is relatively brilliant, frankly,” Dr. Allen offered, “but it sets a disturbing bar. … This type of granular price transparency clearly irritates every one of us, but it is the reality that we are dealing with.”

The Next Step: Accountable Care Organizations ACOs comprise capitation plus risk adjustment plus good data analytics, Dr. Allen said.

Although providers are “financial targets,” they also can share in the savings.

Shared risk means that clinical integration and management are a must.

Three levels are evolving: fee-forservice (the old model), the “bundled” episode of care model, and the total cost of care model. In this integrated delivery network, hospitals, primary care, specialty networks and ambulatory services will be “rolled into one,” and one wonders if independent gastroenterology groups can survive in this type of environment, Dr. Allen said.

Treatment and screening settings will look very different tomorrow than

‘The cost of an independent practice will drive many physicians out of ownership positions. In small practices that don’t have the capital of large practices, this is becoming crushing.’

—John I. Allen, MD, MBA

they look today, he added. Ambulatory endoscopy, which constitutes about 70% of a typical practice’s income, will “shift downward”; bundled payments will occur; clinicians will be paid according to “value”; and alternatives to colonoscopy for CRC screening will be offered.

Colorectal Cancer Screening: Today Versus Tomorrow Large employers and health care plans will try to set the price for colonoscopy at about $500 to $700, based on rumblings heard in the community, Dr. Allen said. Also, higher CRC screening rates

will be expected based on success with programs such as Kaiser Permanente’s, which improved screening rates among its participants from about 40% to 85%.

Additionally, in an effort to increase screening rates, more weight will be given to patient preference, even if those preferences include fecal occult blood testing and immunohistochemical testing.

These and other changes are inevitable, Dr. Allen said, concluding his presentation with a challenge: “Wouldn’t you want to get ahead of all this and manage the changes to make them beneficial to all of us?”

■

AAAHC Tailors Accreditation Program For Office-Based Surgery Centers On May 24, the Accreditation Association for Ambulatory Health Care (AAAHC) announced the launch of an accreditation program specifically for practices that provide office-based surgery (OBS).

“As more and more surgical procedures are being performed in doctors’ offices, accreditation

by AAAHC reassures patients, third-party payers and others that OBS providers are delivering care based on nationally recognized standards,” said John Burke, PhD, AAAHC president and CEO, in a statement.

The AAAHC defines an OBS center as an organization that has no more than four physicians/dentists and no more than two operating/procedure rooms. AAAHC has created the Accreditation Handbook for Office-Based Surgery with

Review Guidelines, which contains policies, procedures and current standards as well as guidelines for how to apply them. The handbook provides OBS organizations a clearer understanding of how compliance with each of the standards will be assessed.

The program is designed to be cost-effective for smaller pra actices. The AAAHC has reduc uced accreditation fees for OBS organizations to reflect their sma maller size.

The total cost is $3,5 ,500, which includes a $775 ap application fee and a $2,725 fee e for the on-site survey and rel ela ated activities. All subsequent surveys cost $3,500.

For more re information, visit www. aaahc.or org g.

—B Based on a press release from the Accreditation Association for th Ambulatory Health Care

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Decreased Risk for Upper, Lower GI Events With Celeco oxib Compared With Other NSAIDs Study Confirms Data From Landmark CONDOR Trial

BY TED BOSWORTH NATIONAL HARBOR, MD.—A large randomized, “real-world” study demonstrated that celecoxib (Celebrex, Pfizer) is associated with a reduced risk for upper

and lower gastrointestinal (GI) events compared with nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs).

The study “demonstrates the improved GI safety profile of celecoxib throughout the GI tract,” said senior investigator Byron Cryer, MD, professor of medicine

in the Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, in Dallas. The results of the trial, called GI-REASONS (GI Randomized Event and Safety Open-label NSAID Study), were presented at the 2011 annual meeting of the

for con nsistently mak kin ng

the best-read pu ublica ation in the U.S. gasttro oenterolog gy market More than 17,000 readers* every month: ♦ ♦ 1,532 colon and rect ctal al sur urge geon onss ♦ 982 pediatric ga ast stro roen ente tero rolo logi gist gi sts ♦ 798 physician n as assi sist stan ants ts ♦ 21 19 nu n rse prrac a titiion ner erss ♦ 109 hepato olo ogists

1

# * BPA Worldwide, July 2011 † Kantar Media, December 2011

in readership†, including: ♦

high re eaders

♦

averag ge issue readers s

♦

4/4 (monthly) reade e rs

♦

cover-to-c cover re e a d e rs

American College of Gastroenterology.

Data from GI-REASONS confirm the conclusions of two earlier landmark studies in the field. More than 10 years ago, CLASS (Celecoxib Long-term Arthritis Safety Study) demonstrated that celecoxib was associated with a lower risk for upper GI events compared with ibuprofen or diclofenac in adult patients with osteoarthritis or rheumatoid arthritis (Silverstein FE et al. JAMA 2000;284:1247-1255). CLASS was one study among a series of large randomized trials that demonstrated that selective inhibitors of cyclooxygenase-2 (COX2), like celecoxib, are associated with a reduced risk for GI events compared with classical nsNSAIDs, like ibuprofen.

More recently, the CONDOR (Celecoxib versus Omeprazole and Diclofenac in patients with Osteoarthritis and Rheumatoid arthritis) trial examined GI risk in adult patients with osteoarthritis or rheumatoid arthritis who were taking celecoxib or diclofenac slow release in combination with the proton pump inhibitor (PPI) omeprazole (Chan FK et al. Lancett 2010;376:173-179). Patients included in the CONDOR trial had an increased risk for GI events: They were aged 60 years and older, or 18 years and older with previous gastroduodenal ulceration. The CONDOR trial demonstrated that risk for clinical outcomes throughout the GI tract was lower in patients treated with celecoxib than in those receiving an nsNSAID plus a PPI. Angel Lanas, MD, an expert on NSAID use and GI risk and a co-author of the CONDOR study, said that the current study, GI-REASONS, “provides confirmatory evidence of data obtained from CONDOR.” The initial focus of study of COX-2 inhibitors was on relative protection from gastric ulcers. But a newer emphasis on events in the lower GI tract as well in studies of COX-2 inhibitors may be meaningful for patients at risk for GI bleeding, Dr. Lanas added.

In GI-REASONS, like the CONDOR trial, investigators examined

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

Ulcerative Colitis: Optimizing Mesalamine Strategies ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

ARUN SWAMINATH, MD Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

BRIAN BOSWORTH, MD Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center, New York, New York b Weill Cornell Medical College, New York, New York c Columbia University College of Physicians and Surgeons, New York, New York

T

he greatest challenge for clinicians who treat patients with

inflammatory bowel disease (IBD) is to move from symptom-oriented (step-up) strategies toward prevention-oriented (early intervention) strategies aimed at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of IBD using 5-aminosalicylic acid (5-ASA) agents.

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immuno-inflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease.

One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to classify CD. Three distinct manifestations of CD have been described—inflammatory, fistulizing, and fibrostenotic.1-3 However,

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Crohn’s colitis has not been well defined in the literature.4 Some patients present with CD-like features—such as UC with rectal sparing or UC with nonepithelial granulomas.

Other manifestations of the heterogeneity of colitis are a superficial mucosal CD involving left-sided refractory colitis with rectal involvement (which may actually represent a type of mixed collagenous colitis or vascular collagen disorder still undefined), rectal disease with cecal patch, and a form of UC with posttreatment alterations.4 The many forms of UC (eg, ulcerative proctitis, left-sided colitis, universal colitis) led Brooke5 to suggest that, rather than a single disease entity, UC represents a pathologic state with many etiologies. Indeterminate colitis (IC) might represent part of an immunologic continuum, rather than a well-defined clinical subset of UC and CD.6,7

G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S • J U LY 2 0 1 2

1

IBD is a dysregulated immune response to luminal microbial antigens. Serologic markers may provide a window for observing an abnormal antibody–antigen response and may help identify patients at risk for rapid progression of disease who may benefit from early intervention.8 Molecular diagnostics, such as antibody serology, biomarkers, and genotyping hold the promise of enhancing the understanding of IC and stratifying patients with IBD on the basis of immunophenotypes and immunogenotypes.9 Differential diagnosis is increasingly recognized as important in distinguishing active inflammation from medication–pseudo-refractory IBD—which may include infections (eg, Clostridium difficile, cytomegalovirus), overlap with irritable bowel syndrome, celiac disease, lactose and/or fructose intolerance, dietary indiscretion, bile acid diarrhea, and obstructive stricturing or fistulizing CD requiring surgery—and in stratifying optimal therapeutic response to biologics and immunosuppressives.10 In selected patients with moderate to severe active IBD, early intervention with effective therapy is associated with significant improvement in mucosal healing and reduction in the progression of disease.11-13

Molecular Classification of IBD IBD nomenclature does not accurately reflect the complexity of clinical phenotype. Although the role of serum antibody markers remains controversial, using a combination of markers enhances accuracy and specificity in classifying IBD-related aberrant immunophenotypes. The emerging role of molecular diagnostics is vital in characterizing the immunologic heterogeneity of IBD, and will be a bridge linking clinical immunophenotypes with genotypes.14,15 Over 100 genes associated with IBD have been identified using genome-wide association studies (GWAS), but account for only 25% of the heritability.16 At present, common gene variants identified by GWAS will be too insensitive and nonspecific to predict disease in unaffected patients. New genes continue to highlight host microbial interactions,17,18 and serologic markers indicate dysregulated antibody–antigen immune responses.

Differentiation between types of IBD becomes important in stratifying therapeutic strategies. Poor therapeutic response is an indication for surgery in nearly one-third of patients with UC and approximately 50% to 70% of patients with CD. Patients with refractory left-sided colitis or IC may benefit from serologic testing, in addition to documentation of clubbing and oral aphthae.15 Serologic signatures have proven helpful in patient stratification. Although controversial, high levels of perinuclear antineutrophil cytoplasmic antibodies (pANCA) have consistently correlated with postoperative pouchitis.19 Anti-CBir1 is an antibody to flagellin of the Clostridium species; anti-CBir1 is associated with an increased incidence of chronic pouchitis in patients who have high pANCA levels, and with acute pouchitis in those with low pANCA levels.20 Expression of anti–Saccharomyces cerevisiae antibody (both immunoglobulin [Ig]

2

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

subtypes A and G) correlates with a younger age of onset and more aggressive fibrostenotic disease.21,22 Additionally, antibodies against the CD-related bacterial sequence I2, Escherichia coli outer membrane porin C, and CBir1 flagellin identify a unique subset of immunologically vulnerable patients with complicated/aggressive CD.23,24 The incorporation of validated biomarkers, such as fecal calprotectin, which has been shown to correlate with endoscopic disease severity in both CD and UC,25 into clinical decision making can also help identify patients with active disease.

Serologic diagnostic and biomarker testing provides a molecular snapshot of patients with IBD. New markers and prospective trials are required to correlate immunologic, molecular, and clinical patterns of IBD, and will advance the risk assessment of patients, the selection of prevention-oriented therapies, and the science of IBD.

Epidemiology of IBD Epidemiologic data on IBD are fractionated into the pigeonholes of separate diagnoses, with an incidence of 7 to 9 per 100,000 and a prevalence of 200 to 250 per 100,000 for UC; the incidence and prevalence of CD are 6 to 8 per 100,000 and 130 to 200 per 100,000, respectively.26-28 Although there are patients who fall more clearly into one category than another, the concept of IC is poorly defined and therapeutic guidelines are lacking.

Treatment of IBD Subtypes The majority of patients with IBD have moderate disease. Three-fourths of patients have active UC,29 and two-thirds of patients with CD have moderate to severe disease that requires alternatives to treatment with mesalamine therapies.30 The treatment goals for patients with IBD are universal: Induce remission as quickly as possible, maintain remission as long as possible, facilitate mucosal healing, improve quality of life, minimize toxicity, and minimize cost.

For patients with UC, oral and rectal 5-ASA agents (including free 5-ASA and 5-ASA prodrugs), corticosteroids (IV [eg, hydrocortisone] or oral [eg, prednisone, methylprednisolone]), immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP]), and cyclosporine are used to induce remission. For maintenance of remission of UC, 5-ASAs and 6-MP or AZA may be used.

Additionally, infliximab is approved for the reduction of signs and symptoms, induction of clinical remission and mucosal healing, and elimination of corticosteroid use in patients with moderately to severely active UC who have had an inadequate response to conventional therapies.31 For patients with CD, 5-ASAs, antibiotics (eg, metronidazole, ciprofloxacin [alone or in combination]), corticosteroids (including topically active, rapidly metabolized budesonide), immunomodulators (eg, 6-MP, AZA, methotrexate), and infliximab are used to induce remission. For maintenance of remission, 5-ASAs, antibiotics, immunomodulators, and infliximab can be used. More recently, the anti-TNF agents

adalimumab and certolizumab were approved for the induction and maintenance of clinical remission in adult patients with moderate to severe CD who have had an inadequate response to conventional therapies and for the induction of remission in those patients who also have lost response to or are intolerant to infliximab.32-37 Probiotics and novel antibiotics (eg, rifaximin) have the potential to revolutionize the treatment of patients with IBD.38,39 For example, anti-inflammatory interleukin (IL)-10 levels have been associated with Bifidobacterium infantis.40 A greater understanding of gut microecology and the gut microbiome is emerging and further clinical trials are warranted.41 Colitis-associated arthritis42 responds best to sulfasalazine and this may be related to the antibiotic properties of sulfapyridine rather than the anti-inflammatory properties of 5-ASA.43,44

5-ASA: First-Line Therapy MECHANISMS

OF

ACTION

The specific goals of 5-ASA therapy are to quickly induce complete remission, facilitate mucosal healing, and minimize steroid use and toxicity. The effectiveness of the compound is related to its mucosal concentration,45 and systemic dosages remain low after oral sulfasalazine and rectal 5-ASA administration.46 The putative anti-inflammatory actions of 5-ASA include modulation of inflammatory cytokine production, decreased transcriptional activity of nuclear factor-kappa B (NF-κB) by modulating RelA/p65 phosphorylation, and inhibition of the biosynthesis of prostaglandins and leukotrienes.47 One proposed mechanism of action of 5-ASA is the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase pathways of arachidonic acid metabolism, resulting in a decrease of proinflammatory prostaglandins and leukotrienes.48 The role of the COX pathway and prostaglandin biosynthesis in IBD remains to be elucidated. Attention has shifted from the arachidonic acid cascade to NF-κB. The discovery of the role of nucleotide-binding oligomerization domain 2 in the activation of NF-κB emphasizes the importance of NF-κB in the inflammatory signaling cascade and its interaction with luminal bacterial antigens and genetic susceptibility. In vitro studies demonstrate that sulfasalazine inhibits NF-κB, which provides evidence in support of the direct biologic efficacy of 5-ASA. Recently, it has been postulated that 5-ASA leads to peroxisome proliferator–activated receptor-gamma (PPAR-γ) transcription and protein expression.49 The PPARs are members of the nuclear receptor superfamily. They are activated by fatty acids and are involved in the complex interplay of metabolic and nutritional signals leading to transcriptional responses. They are expressed in high levels in the colonic epithelium and their ligands are involved in regulation of inflammation.

A randomized placebo-controlled trial of rosiglitazone (a PPAR-γ ligand) demonstrated efficacy in treating

mild to moderate UC.50 However, despite these numerous experimental studies, the mechanism of action of 5-ASA remains elusive.

Clinicians should question whether the site of 5-ASA release is a determinant in optimizing and individualizing therapy. Two therapeutic strategies expose jousting views: One is that all 5-ASA preparations are equivalent and that dose escalation leads to optimization; the other is that differences in the mode of 5-ASA delivery translate into differences in clinical efficacy.

Often overlooked is the distribution of UC—more than 50% of patients have left-sided disease51—as well as the variability in colonic pH. Colonic pH may be lower in patients with UC than in those without IBD; thus, employing 5-ASA formulations that release at a lower pH (eg, granulated mesalamine [Apriso, Salix Pharmaceuticals]) may improve drug delivery to the colon while avoiding release in the small intestine.52 Both mesalamine (free, unconjugated 5-ASA) and mesalamine prodrugs (azo-bonded 5-ASA) have similar modes of action. Sulfasalazine, the archetypal azobonded 5-ASA designer drug, is engineered to release free 5-ASA in the colon, protecting it from proximal absorption.43,44 Intolerance and hypersensitivity to the sulfapyridine moiety limit the dose of sulfasalazine and have led to the development of new 5-ASA– containing analogs. The newer topical and oral 5-ASA agents are delivered to different anatomic sites, ideally corresponding to the distribution of active disease (Table). Although these agents are less toxic than sulfapyridine, mesalamine allergies (eg, high fevers, allergic pneumonitis) and intolerance (eg, worsening IBD symptoms) may occur and discontinuation of 5-ASA therapy my be required. Interstitial nephritis has been reported with the 5-ASA moiety alone53 and mandates periodic renal function monitoring.

TREATMENT

OF

UC

Until the introduction of balsalazide, all of the newer 5-ASA agents had been shown to induce and maintain remission of UC nearly as well as sulfasalazine and usually as well as one another. The advantage of some of the newer 5-ASA preparations is that patients can tolerate higher doses. Recently, novel dual-delivery systems (delayed- and extended-release) allow for effective dose de-escalation, with lower doses of active 5-ASA delivered to the site of active colitis.54-56 In the first head-to-head trial comparing an equimolar dose of balsalazide (6.75 g) with pH-dependent mesalamine (2.4 g), balsalazide showed superior efficacy in patients with new-onset left-sided UC (62% vs 37%) and shorter time to response (10 vs 25 days); response rates also were higher in patients with right-sided UC, although the difference was less significant compared with patients with left-sided disease.57 A stratification study confirmed that among patients with new-onset left-sided UC, more than 60% of those treated with balsalazide were in remission at 1 month compared with 40% of those treated with pH-dependent mesalamine.

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Table. Mechanisms of Release of 5-ASAâ&#x20AC;&#x201C;Containing Drugs Type of 5-ASA

Mechanism of Action

Advantage

Indication

Time-released, moisturedependent ethylcelluloseencapsulated mesalamine travels in solution and allows free 5-ASA mesalamine to diffuse out of the ethylcellulose beads and begin releasing in the upper intestines and continue throughout the small and large intestines.

Independent of pH or bacteria; mucosal delivery of mesalamine is less affected by rapid intestinal transit time (ie, diarrhea)96

Free 5-ASA (mesalamine) is indicated in patients with proximal disease activity, severe diarrhea, strictures (1-mm ethylcellulose microspheres offer advantages), pouchitis (the constant, moisture-dependent release may provide advantages), and postoperative anastomosis.

The pH-dependent mesalamine preparations are coated with an acrylate resin and are released at variable pH levels, between 6.0 and 7.0 in the distal ileum and colon. (The pH in the ileum and ascending colon is 7.0.)

Free 5-ASA (mesalamine) A pH-dependent delivdosage can be maximized ery system is indicated to 4.8-6 g daily, equivalent in ileocolonic disease. to a triple dose of sulfasalazine (12 g) with significantly less toxicity. Lialda is a 1.2-g tablet that is a highdose, delayed-release, pHdependent mesalamine formulation.54,56,57 Once-daily dosage is between 2.4 and 4.8 g (2-4 tablets). Apriso once-daily 1.5-g granulated delayed- and extendedrelease mesalamine (4, 0.375-g capsules) travels in solution.36-38

Diffusion-Dependent Mesalamine, controlledrelease (Pentasa, Shire)

pH-Dependent Mesalamine, delayedrelease, pH 7.0 (Asacol, Warner Chilcott) MMX mesalamine, pH 7.0 (Lialda, Shire) Mesalamine, delayedrelease, pH>6.0 (Eudragit-L, Evonik) Mesalamine delayedand extended-release, pH 6.0 (polymer core of slow-release mesalamine; Apriso, Salix)

Colonic floraâ&#x20AC;&#x201C;dependent, azo-bonded Sulfasalazine (Azulfidine, Pfizer) Sulfasalazine, delayedrelease (Azulfidine EN-Tabs, Pfizer) Balsalazide disodium (Colazal, Salix) Olsalazine sodium (Dipentum, Pfizer)

There are currently 3 variations of colonic-releasing, azo-bonded 5-ASA drugs: 1) Sulfasalazine consists of 5-ASA bonded to sulfapyridine; 2) Balsalazide links an inert polymer of 4-aminobenzoylB-alanine to 5-ASA; 3) Olsalazine consists of 2 molecules of 5-ASA linked to each other.

In these azo-bonded 5-ASA forms, the molecule reaches the colon primarily intact and the azo bond is cleaved by colonic bacterial azo-reductase, thereby releasing free, unconjugated 5-ASA (mesalamine). A highdose, 1.1-g balsalazide tablet allows for lower pill burden and twice-daily dosing.41,42

This formulation is indicated for patients with universal and distal colitis.

Advantages of topical preparations include direct exposure to diseased mucosa.

These agents are indicated for patients with left-sided colitis and proctitis.

Topical/rectal formulations Mesalamine suppository Rectal preparations include (Canasa, Aptalis) 5-ASA suspensions (4-g mesalamine enema and 500Mesalamine enema mg mesalamine suppository) (Rowasa, Meda that are instilled directly into Pharmaceuticals) the rectum.

5-ASA, 5-aminosalicylic acid; MMX, MMX Multi Matrix System

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Additionally, patients with right-sided UC who were treated with balsalazide had less rectal bleeding, better sigmoidoscopic-evident healing, and improved stool frequency.58 A new twice-daily balsalazide dosing regimen (3, 1.1-g tablets bid, for a total of 6.6 g/d) has been shown to be well tolerated and effective in relieving signs and symptoms of mild to moderate UC.59,60 This new regimen reduces pill burden and should improve adherence and convenience for patients.

Levine et al61 conducted a randomized, double-blind study comparing 2 doses of balsalazide (6.75 and 2.25 g) and mesalamine (2.4 g) in patients with active, mild to moderate UC. At week 8, rates of remission were similar for all 3 treatment groups, as were safety profiles.

The primary difference between balsalazide (6.75 g) and mesalamine appeared to be the time to symptom resolution (10 vs 25 days, respectively). Kornbluth et al62 compared the colonic mucosal concentration of 5-ASA in patients treated with a mean of 6.75 g per day of balsalazide with those treated with a mean of 3.74 g per day of pH 7–dependent mesalamine and demonstrated that patients who received balsalazide had significantly higher mean mucosal concentrations of 5-ASA than patients who received mesalamine.

Because of the predominance of left-sided disease, the combination of oral and topical aminosalicylates is critical in inducing and maintaining remission.63,64 Safdi et al elegantly demonstrated that although topical mesalamine was more effective than oral in patients with left-sided UC, the combination of 2.4 g of oral mesalamine and mesalamine enemas produced earlier and more complete cessation of rectal bleeding.63 For maintenance of remission, D’Albasio et al found that a combination of 1.6 g of oral mesalamine with twice-weekly mesalamine enemas produced higher rates of remission compared with oral therapy alone (61% vs 31%, respectively).64 Topical mesalamine (enema and suppository formulations), used as infrequently as twice per week, is effective in maintaining remission in patients with distal colitis. A systematic review compared the efficacy of combined oral and topical 5-ASA with oral therapy alone and found a significant increase in remission rates in mild to moderate UC with combined therapy, and intermittent topical therapy was superior to oral therapy in maintaining remission in quiescent UC.65 Biddle et al established that 75% of patients (9 of 12) randomized to receive mesalamine enemas remained in remission at 1 year compared with 85% of patients (11 of 13) on placebo who had relapsed by week 16.66 Similarly, mesalamine suppositories were associated with longterm remission in patients with ulcerative proctitis67; at 12 and 24 months, 86% and 89% of patients on placebo had relapsed compared with 32% and 46% of patients treated with mesalamine suppositories, respectively.

A meta-analysis established that in patients with leftsided UC and ulcerative proctitis, topical mesalamine showed greater efficacy and fewer side effects than oral therapies and topical steroids.68 Additionally, Campieri et al demonstrated that mesalamine suppositories were

effective in inducing remission in patients with ulcerative proctitis (distal colitis up to 20 cm).69 In that study, 74% of patients who received mesalamine suppositories (1.5 g) achieved clinical remission at week 4 compared with 39% of patients who received placebo.70 The pH-sensitive 5-ASAs were evaluated in a placebo-controlled trial in patients with active mild to moderate UC.71 In contrast to a 71% maintenance of remission rate,72 complete remission was induced in 24% of patients on mesalamine 4.8 g, 9% of patients on mesalamine 1.6 g, and 5% of patients on placebo.71 Partial response was achieved in 50% of patients in the high-dose mesalamine group compared with 18% in the low-dose group and 13% in the placebo group.71 The ASCEND II trial found 4.8 g of delayed-release mesalamine (Asacol) to be superior to 2.4 g in patients with moderate UC, with response rates of 72% and 59%, respectively; remission rates were similar in both groups at 24%.73 ASCEND I and II were the first head-to-head— although non–placebo-controlled—comparisons of 2.4 versus 4.8 g of Asacol in patients with mild to moderate UC. In ASCEND III, the response rate at 6 weeks was 70% for patients taking 4.8 g of Asacol (6 tablets, 800 mg each) compared with 66% for those taking 2.4 g of Asacol (6 tablets, 400 mg each).74 A high-strength pH–dependent formulation of 5-ASA—MMX Multi Matrix System (MMX) mesalamine (Lialda, Shire), taken once or twice daily, has been shown to be well tolerated and to induce remission in patients with mild to moderate UC. The formulation is a 1.2-g tablet and has been evaluated for twice-daily (1, 1.2-g tablet, bid; 2.4 g/d) and once-daily (4, 1.2-g tablets, once daily; 4.8 g/d) administration. Lichtenstein et al showed that after 8 weeks of treatment, rates of clinical and endoscopic remission were significantly higher for patients taking MMX mesalamine compared with patients taking placebo (34.1% and 29.2% for 2.4 g/d and 4.8 g/d, respectively, vs 12.9% for placebo; P<0.01).75,76 Increasing the dose to 4.8 g per day for an additional 8 weeks resulted in clinical and endoscopic remission and symptom resolution for nearly 60% of patients in a median time of 15 days.77 In a separate study by Kamm et al, once- or twice-daily MMX mesalamine resulted in maintenance of clinical and endoscopic remission.78 A granulated pH 6 delayed and extended releasing formulation of 5-ASA (Apriso) with a polymer matrix core has been approved by the FDA for the maintenance of remission at 1.5 g per day. Lichtenstein et al79 demonstrated maintenance of remission in nearly 79% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo. In a European dose-ranging study that evaluated this pH 6–releasing granulated formulation of 5-ASA in patients with mildly to moderately active UC, remission rates were 66% for patients taking 3 g per day (1 g, tid), 50% for those taking 1.5 g per day (0.5 g, tid), and 55% in those taking 4.5 g per day (1.5 g, tid).54 Although there was no placebo arm in the study, clinical remission rates in all 3 treatment groups were

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high. With the exception of endoscopic improvement, which was better in the 3-g per day group than in the 1.5-g per day group, no significant differences among the 3 groups were observed. These findings suggest that the novel delivery mechanism of granulated mesalamine may lead to release of active drug at the site of active disease allowing for effective dose de-escalation.

In another study, 2 doses of mesalamine granules—a 3-g dose given once daily and a 1-g dose given 3 times per day—were similarly safe and effective in producing clinical and endoscopic remission in patients with mildly to moderately active UC.55 This provides evidence that decreasing the dosing frequency may improve adherence to medication while maintaining efficacy.

Once-daily, 1.5-g granulated mesalamine delayedrelease (Eudragit-L, Evonik; dissolving at pH>6.0) and extended-release (polymer matrix core, containing slowly eluting mesalamine) have been shown to maintain remission in nearly 80% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo.56 Dose de-escalation with granulated mesalamine 1.5 g per day may improve long-term adherence to medication and remission. Mesalamine granules also have demonstrated higher rates of induction of remission of UC compared with budesonide (54.9% vs 39.5%).80 And in a comparison of MMX mesalamine and Asacol, patients with UC who took MMX mesalamine maintained remission longer than those on Asacol (Warner Chilcott).81 A recent meta-analysis confirmed the benefit of 5-ASA for inducing and maintaining remission in UC.82 The optimal dose appeared to be 2.4 g per day, with no apparent benefit from increasing the dose. Similarly, the optimum dose to prevent relapse was 2.0 to 2.4 g per day. These recommended doses are expressed in mesalamine or equivalent.

Initial mesalamine dosing strategies followed the divided dosing paradigm utilized with sulfasalazine, which was developed to minimize sulfapyridine-related adverse effects. Several studies have assessed the safety and efficacy of once-daily mesalamine administration.

The PODIUM study assessed the use of pH-sensitive mesalamine (Pentasa, Shire) 2 g per day taken as a single daily dose versus two divided doses over 1 year in left-sided UC. For once-daily dosing and divided dosing, remission rates were 69% vs 61%, respectively, and mucosal healing rates were 84% vs 78.6%, respectively, and there was no difference in adverse events.83 The QDIEM study, a large, randomized controlled trial conducted by Sandborn et al,84 assessed Asacol 1.6 and 2.4 g per day in once-daily or twice-daily divided doses for maintenance of remission in 1,023 patients with mild to moderate UC in clinical remission. More than 90% of patients in both dosage groups at 6 months, and 85.4% at 12 months, remained in remission without differences in adverse events or treatment withdrawal rates. An active-control randomized trial of 824 patients with UC in clinical remission by D’Haens et al85 demonstrated non-inferiority of MMX-mesalamine 2.4 g once daily compared with

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pH-sensitive mesalamine 0.8 g twice daily. The aforementioned studies were not placebo-controlled but did demonstrate similar efficacy and safety profiles for the assessed end points. Furthermore, a meta-analysis of 10 randomized controlled trials in UC demonstrated no difference in the rates of maintenance of remission in patients with quiescent UC treated with once-daily mesalamine and also showed a mild but significant benefit in induction of remission in patients with mildly active UC, with improved adherence and a similar adverseevent profile.86 A recent cost–benefit analysis suggested that inflammation-targeted treatment utilizing 5-ASA therapy for patients with stool samples positive for inflammation may cost less than continuous treatment for all UC patients.87 Further studies correlating tight inflammation control and inflammatory biomarker monitoring are warranted.

MESALAMINE THERAPY DURING PREGNANCY In pregnant patients, 5-ASA and its metabolite, acetyl-5-ASA clearly cross the placenta and thus are found in both maternal and fetal plasma in women on mesalamine therapy.88 Currently, per FDA recommendations, all mesalamine therapies, except for olsalazine and Asacol/Asacol HD, are considered pregnancy safety classification B. In 2010, Asacol and Asacol HD were switched to a classification of C for safety in pregnancy by the FDA. Prior studies of mesalamine performed during organogenesis in rats and rabbits at oral doses up to 480 mg per kilogram per day showed no evidence of fetal malformations. These doses represented approximately 1.6 and 3.2 times the recommended human dose (based on body surface area). The class transition was based on more recent animal studies showing that the inert ingredient of Asacol’s enteric coating, dibutyl phthalate (DBP), is associated with adverse reproductive aberrations when given in very high doses.

The maximum daily human intake of DBP is about 48 g. Published reports in rats exposed to DBP in utero at doses 17 times the human dose showed reproductive anomalies in male offspring, specifically an injury to androgenic-dependent development. Even higher doses of DBP, approximately 84 times the human dose, resulted in worse outcomes for these male rat offspring, including cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, reduced daily sperm production, and permanent retention of nipples.

The female offspring appeared to remain unaffected by these same doses. Exposure to DBP at doses equivalent to 106 times the human dose resulted in increased incidences of cleft palate and skeletal abnormalities in both female and male offspring.

It is important to note that the dosage of Asacol/Asacol HD appears to be the critical component in causing these adverse pregnancy outcomes in rats. Before this pregnancy reclassification of Asacol, gastroenterologists had been using this particular mesalamine preparation in varying doses (the maximum dose being 4.8 g daily) for the past decade in pregnant women with IBD

without any adverse effects observed in the mothers or offspring. It appears that Asacol and Asacol HD can be used during pregnancy when administered in the appropriate doses as suggested by studies in human patients and the vast clinical experience of many IBD specialists.

The PIANO registry is a prospective cohort of pregnant women with IBD that has enrolled more than 1,000 patients to date. The analysis of the effect of mesalamine on pregnancy outcomes is pending. Early results have confirmed data from earlier studies which suggest no increase in congenital malformations in children born to mothers exposed to immunosuppressants or anti-TNF drugs compared with mothers who were not exposed to either group of medications. Notably, there was an increase in the number of infections in infants born to mothers exposed to the combination of thiopurines and anti-TNF agents during pregnancy, which merits closer investigation. Developmental milestones were similar among all exposure groups and will be followed in children up to age 4 years.89

OPTIMIZING ORAL 5-ASAS Although there are no prospective studies evaluating combinations of oral 5-ASA drugs, combination therapy may be considered in patients who fail to respond to mesalamine monotherapy or 5-ASA prodrug monotherapy. 5-ASA nonresponders may benefit from a combination of pH-dependent polymer-coated mesalamine, moisture-dependent mesalamine, and azobonded 5-ASA preparations (eg, sulfasalazine, olsalazine, balsalazide). A flexible dosing schedule in which the patient actively modifies the combination therapy based on clinical response may shorten the duration to response. Lastly, a flexible dosing schedule that combines oral and topical 5-ASA agents is an effective therapeutic strategy that should not be overlooked. With the variety of 5-ASA preparations available, optimization of 5-ASA therapy may be viewed as a dynamic rather than a static process. In a patient not responding to an initial 5-ASA therapeutic choice, dosage may be optimized (ie, escalated, de-escalated), and oral preparations may be combined with each other, as well as with topical agents, in an attempt to optimize delivery of 5-ASA to the site of active disease.

Personalizing IBD Therapies In selected patients with moderate to severe UC, an earlier aggressive treatment approach is indicated.13,90 Some patients with mild to moderate disease may benefit from a decrease in medication dosage, adherence to therapeutic regimens, and in some cases, a reevaluation of the diagnosis. Identification of immunologically vulnerable patients through the use of emerging serologic markers, biomarkers, and genotyping may allow for individualized treatment that improves outcomes.

A greater understanding of the human genome is redefining the science of individuality. Less than 0.1% of our DNA is responsible for IBD susceptibility and therapeutic response.91-94 We are at the threshold for

genotyping patients and bacteria, which will lead to a greater understanding of the pathobiology of IBD and its treatment.95 Until genomics can be applied to individualized medicine, predicting IBD progression may be achieved through risk assessment, emerging biomarkers, and optimizing mesalamine therapeutic strategies.

In selected patients with moderate to severe UC, early intervention with immunosuppressive or biologic therapies—and limited use of steroids—may slow the progression of IBD, and treatment may move from a symptom-oriented, step-up strategy to a preventionoriented, early intervention approach.

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2010;32(8):990-999.

80. Gross V, Bunganic I, Mikhailova TL, et al. Gastroenterology. 2009;136 (5 suppl 1):A15. Abstract 83.

81. Kohn A, Prantera C, Caprilli R, et al. Gastroenterology. 2009;136 (5 suppl 1):A65. Abstract 390.

82. Ford AC, Achkar JP, Khan KJ, et al. Am J Gastroenterol.

2011;106(4):601-616.

83. Bokemeyer B, Hommes D, Gill I, et al. J Crohn Colitis.

2012;6(4):476-482.

84. Sandborn WJ, Korzenik J, Lashner B, et al. Gastroenterology.

2010;138(4):1286-1296.

85. D’Haens G, Sandborn WJ, Barrett K, Hodgson I, Streck P. Am J Gastroenterol. 2012 May 8; doi:10.1038/ajg.2012.103. [Epub ahead of print].

86. Tong JL, Huang ML, Xu XT, Qiao YQ, Ran ZH. J Dig Dis. 2012;13(4):200-207.

87. Saini SD, Waljee AK, Higgins PD. Clin Gastroenterol Hepatol. 2012 May 18 [Epub ahead of print].

88. Christensen LA, Rasmussen SN, Hansen SH. Acta Obstet Gynecol Scand. May 1994;73(5):399-402.

89. Mahadevan U, Martin CF, Sandler RS, et al. Gastroenterology.

2012;142(5 suppl 1):S-149. Abstract 865.

90. Scherl EJ. The changing world of inflammatory bowel disease management: the impact of new therapies on old strategies. In: The Changing World of Inflammatory Bowel Disease: Impact of Generation, Gender, and Global Trends. Scherl EJ, Dubinsky, M, eds.

Thorofare, NJ; Slack, Inc; 2009.

91. Cho JH. Nat Rev Immunol. 2008;8(6):458-466.

92. Lander ES, Linton LM, Birren B, et al. Nature.

2001;409(6822):860-921.

93. Venter JC, Adams MD, Myers EW, et al. Science.

2001;291(5507):1304-1351.

94. Jasny BR, Roberts L. Science. 2003;300(5617):277-296.

95. Kevles D, Hood L, eds. The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge, MA: Harvard University Press; 1992:3-363.

96. Dignass AU, Bokemeyer B, Adamek HE, et al. Gastroenterology.

2008;134(4 suppl 1):A-494. Abstract T1146.

AUTHOR DISCLOSURE—Dr. Scherl has served as a consultant or advisory board member for Abbott Laboratories, AstraZeneca, Axcan Pharma, Berlex, Centocor, Cerimon Pharmaceuticals, Cerium, Crohn’s & Colitis Foundation of America (CCFA), PDL BioPharma, Procter & Gamble, Prometheus Laboratories, Questcor, Salix Pharmaceuticals, Shire, Sigma Tau, Solvay Pharmaceuticals, TAP Pharmaceuticals, and UCB. She has received grants or research support from Abbott Laboratories, Centocor, Cerimon Pharmaceuticals, Elan, Millennium, Osiris Therapeutics, Prometheus Laboratories, Salix Pharmaceuticals, and UCB. She has received honoraria from Abbott Laboratories, AstraZeneca, Axcan Pharma, Centocor, Cerimon Pharmaceuticals, PDL BioPharma, Procter & Gamble, Prometheus Laboratories, Salix Pharmaceuticals, Shire, Sigma Tau, Solvay Pharmaceuticals, TAP Pharmaceuticals, and UCB. She has received other financial or material support from Abbott Laboratories, CCFA, Centocor, PDL BioPharma, Prometheus Laboratories, Salix Pharmaceuticals, and UCB. DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the author(s). Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright © 2012, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

27

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

among patients who received celecoxib than nsNSAIDs. CV events, which included unstable angina, revascularization and transient ischemic attacks, were recorded in 17 patients in the celecoxib group versus 13 patients in the nsNSAID group, which Dr. Cryer described as “a slight imbalance.” Serious adverse events were uncommon in both groups.

The results of the study suggest that for patients with moderate GI risk and relatively low CV risk (i.e., <10% estimated likelihood for having a CV event in the next 10 years), treatment with

NSAID use and the risk for events throughout the GI tract, including lower GI bleeding, as detected by changes in hemoglobin or hematocrit. The study employed a prospective, randomized, open-label, blinded, end point design, with exclusion and inclusion designed to reflect “real-world” practice, Dr. Cryer said.

A total of 8,067 patients with osteoarthritis and moderate risk for GI events were enrolled in GI-REASONS; 4,035 were randomized to receive celecoxib and 4,032 received an nsNSAID (meloxicam, 42%; naproxen, 21%; diclofenac, 20%; and nabumetone, 14%). Aspirin use was not permitted in either group; patients in whom aspirin was indicated because of cardiovascular risk factors were excluded from the study. The use of gastroprotective agents (GPAs), including PPIs, was permitted regardless of treatment assignment. GPAs were used by approximately 25% of patients in each treatment group.

Testing for Helicobacter pylorii was conducted, and the presence of H. pylori was used as a stratification factor in the analysis of the results.

At six months of treatment, a GI event occurred in almost twice the proportion of patients receiving an nsNSAID as in those who received celecoxib (2.4% vs. 1.3%; odds ratio [OR], 1.82; 95% confidence interval [CI], 1.31-2.55; P=0.0003). When stratified by the presence or absence of H. pylori, the relative advantage of celecoxib was greater for those who were H. pylori-negative (2.4% vs. 1.1%) than for those who were H. pylori-positive (2.5% vs. 1.8%). Moderate to severe abdominal symptoms occurred in 2.3% of patients who received celecoxib and in 3.4% of those randomized to an nsNSAID (P=0.0035).

P According to Dr. Cryer, the difference in the rates of GI events could be attributed largely to GI bleeding, as revealed by changes in hemoglobin (defined as a >2 g/dL reduction) or hematocrit.

Dr. Cryer noted that there was a numerically, but not statistically, greater number of cardiovascular (CV) events

celecoxib is safer than treatment with an nsNSAID. The study did not require that patients taking nsNSAIDs take a concomitant GPA; it was designed to reflect “real-world” risks. The results indicated that much of the risk protection offered by the COX-2 inhibitor takes place in the lower GI tract, where a GPA would not be expected to provide much benefit.

“When considering the entire GI tract, celecoxib is superior to the other accepted alternative of a traditional NSAID plus a PPI in patients with increased GI risk,” concluded Dr. Lanas,

professor of medicine, University of Zaragoza, Spain, who was not an investigator in GI-REASONS. “The difference is particularly relevant for hemoglobin or hematocrit drops of either confirmed or presumed GI origin,” he said.

■ Dr. Cryer has served as a consultant to AstraZeneca, Cogentus Pharmaceuticals, Inc., Horizon Pharma, NicOx, Pfizer Inc., PLx Pharma, Pozen and TAP Pharmaceuticals. Dr. Lanas is an adviser for and has received research funds from AstraZeneca, Bayer, NicOx and Pfizer.

L A S AR E : H N O E R ISSI Y M HER VER N: E E R ION SIO S I E H M E S R N S YOU TAI MIS IN RE MA UC

Maintain ulcerative colitis (UC) remission with once-daily APRISO so your adult patients can experience what they love, for longer* Proven to maintain remission in 2 clinical trials for up to 6 months1 INTELLICOR delayed- and extended-release delivery initiates at pH ≥6, providing coverage throughout the colon1,2 1.5-g once-daily dose (4 capsules) can be taken with or without meals1 The most common adverse reactions (incidence ≥3% and >placebo) are headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, influenza and influenza-like illness, and sinusitis1

APRISO is the fastest-growing once-daily 5-ASA in the United States2 APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. *The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials.

References: 1. APRISO [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 2. Data on file. Salix Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information, including Important Safety Information.

Please see full Prescribing Information available at AprisoRx.com.

APRISO™ and INTELLICOR™ are trademarks of Salix Pharmaceuticals, Inc. ©2012 Salix Pharmaceuticals, Inc. All rights reserved. GM 11/45-2

28

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

PPIs continued from page 1

“More than 55% of the respondents who reported taking PPIs to control GERD symptoms met the definition of inadequate symptom control,” reported Neil Gupta, MD, who led the study while associated with the University of Kansas. He has since moved to Washington University, St. Louis. The definition of inadequate control among patients taking PPIs in this survey was a positive response to the statement GERD

symptoms “disrupt my life.”

The AGA survey was intended to assess the benefit of PPIs in a general population and was undertaken by telephone interviews conducted through random dialing. Those who met the criteria for symptoms of heartburn underwent structured telephone interviews lasting approximately 12 minutes in which they were questioned about medication use, symptom relief and the effect of symptoms on daily life.

In the survey, 1,004 individuals met the definition for persistent heartburn, which

BRIEF SUMMARY Please consult package insert for full prescribing information.

INDICATIONS AND USAGE APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older.

DOSAGE AND ADMINISTRATION The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO. CONTRAINDICATIONS APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules.

WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine.

It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease.

In animal studies, the kidney was the principal organ for toxicity.

Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine.

Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease.

ADVERSE REACTIONS APRISO was studied in two placebo-controlled trials (n=367 treated with APRISO) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study.

In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%).

The most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).

was defined as troublesome symptoms two or more times per week. Of those taking a PPI, 55.3% reported that they continued

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/ kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Mesalamine is known to cross the placental barrier.

Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman.

Pediatric Use Safety and effectiveness of APRISO capsules in pediatric patients have not been established.

Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. (see WARNING AND PRECAUTIONS) Phenylketonuria Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 0.56 mg of phenylalanine.

CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis.

Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity.

Patients were randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six months.

In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for placebo. In study 1 (N=305), 68% of subjects taking APRISO were relapse-free at 6 months EOT vs 51% with placebo (P<0.001). In study 2 (N=257), 71% of subjects in the APRISO group were relapse-free at 6 months EOT vs 59% for placebo (P=0.046).

HOW SUPPLIED APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule.

NDC 65649-103-02 NDC 65649-103-01

Bottles of 120 capsules Bottles of 4 capsules

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature.

Reference: 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987;92:1894-1898.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GM 08/22-1

MANUFACTURED FOR:

to experience heartburn or other symptoms of GERD that significantly disrupted their life. When compared with respondents on PPIs who had adequate control of symptoms, those who did not were nearly twice as likely to report limitations of occupational activities (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.08-3.03) or physical activity (OR, 1.98; 95% CI, 1.10-3.31).

Patients who did not have adequate control of GERD symptoms also were about twice as likely to express concern that their health care provider did not fully empathize or appreciate the extent of their symptoms (OR, 1.95; 95% CI, 1.22-3.13). Interestingly, those with inadequate symptom control were almost half as likely to agree with the statement that GERD symptoms can be eliminated with current therapy (OR, 0.54; 95% CI, 0.36-0.81).

Based on the results of this study, “the impact of inadequate control of GERD is substantial in the general population,” Dr. Gupta reported. The study was not designed to evaluate how this problem can be addressed but it does support other evidence that a large proportion of individuals on PPI therapy are not reaching treatment goals.

However, the findings do need perspective because they were drawn from a population not diagnosed as having GERD by standard criteria, according to Michael Vaezi, MD, PhD, professor of medicine, Vanderbilt University, Nashville, Tenn., who was not involved in the study. Asked to comment on the study, Dr. Vaezi said the findings are provocative but need context.

“One of the main issues in so-called refractory GERD is whether it was GERD to begin with. Many patients are treated with PPIs for various symptoms that may or may not be GERDrelated. Lack of a symptomatic response to PPIs suggests either poor compliance with the correct dosing or timing of the medication [or] volume reflux, such as in those with regurgitation or non-GERD causes,” Dr. Vaezi explained.

“Thus, when patients report poor response to PPI therapy, as was the case in this report, one must ask the most important question of all: Why was the patient treated with PPIs reflux to begin with?”

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29

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

From the Literature

Gastroprotective Adherence Important To Prevent Upper GI Events in Arthritis Patients

BY GABRIELLE N. ROSEN A study published online in Arthritis & Rheumatism (Valkhoff VE et al.

2012 Apr 16 [Epub ahead of print]) showed that arthritis patients who do not adhere to their gastroprotective agent (GPA) regimen while taking cyclooxygenase-2 (COX-2) inhibitors have an increased risk for upper gastrointestinal (GI) complications, such as stomach ulcers and internal bleeding.

‘T Thi his stu study co onfi nfirrm ms s the he ben be enefits s of GP PA ad adhere ence in n red edu uciin uc ng ri risk for upp risk pper er GI comp mplic mp catiion ons s fr fro om use om se of CO OX-2 bloc cke k rrs s.’ .’

—V —Ver Ver e a Va Valk lkho lkho hoffff, f, MD M

Investigators, led by Vera Valkhoff, MD, research physician, Erasmus University Medical Center, Rotterdam, The Netherlands, constructed a case–control study with arthritis patients (aged ≥50 years) from the United Kingdom, the Netherlands and Italy, who were already using both COX-2 inhibitors and GPAs (N=14,416). The researchers analyzed the subjects’ medical records from 1996 to 2008 to determine if and when the patients took their

prescribed medications. They calculated GPA adherence as the proportion of COX-2 inhibitor treatment days covered by a GPA prescription. Cases with an upper GI event (bleeding or symptomatic ulcer) were matched to event-free control subjects based on age, sex, database and calendar date.

The investigators identified 16,442 episodes of overlapping

prescriptions for COX-2 inhibitors and GPAs. Most patients used their COX-2 inhibitors for less than 30 days. A total of 74 patients reported an upper GI event during or shortly after these treatment episodes, resulting in an annual incidence rate of 11.9 per 1,000 COX-2 user-years (95% confidence interval [CI], 9.414.8). Low GPA-adherers (defined as subjects who took their prescribed

GPAs for one out of every five days) had a higher risk for upper GI events compared with full GPA-adherers (those who took GPAs for four out of every five days; odds ratio, 1.97; 95% CI, 0.84-4.60).

“This study confirms the benefits of GPA adherence in reducing risk for upper GI complications from use of COX-2 blockers,” Dr. Valkhoff concluded in a press release.

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30

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Recent Analysis Finds No Significant Association Between PPI Use and Fractures

BY MONICA J. SMITH NATIONAL HARBOR, MD.—Although she said. “So this could be an issue proton pump inhibitors (PPIs) have of confounding, where people who been reported to be associated with an have other risk factors for BMD also increased risk for fracture, an analyhave risk factors for being prescribed sis of a Canadian database did not a PPI; this could explain the baseline find a decrease in bone mineral dendifference.” sity (BMD) in long-term PPI users, Confounders include taking overaccording to research presented at the the-counter calcium supplementation 2011 American College of Gastroenor other medications, hormonal status terology annual meeting. and exercise participation, explained “Over the years, there have been David Metz, MD, professor of medi‘After we published that paper it close to a dozen studies looking at the cine, Division of Gastroenterology, association between PPIs and fracPerelman School of Medicine, Uniwent viral, and the whole world tures. When these are meta-analyzed, versity of Pennsylvania, Philadelphia. has decided that PPIs should be we find current use of PPIs associated “This is an epidemiological study stopped because they’re deadly with approximately a 25% increase limited to a large extent by potential in risk for fracture,” said Laura Tarconfounders, and there are all sorts and dangerous. The problem is gownik, MD, assistant professor of of variables here that are not meathat people who need the PPIs gastroenterology at the University of surable,” Dr. Metz said. “You try and Manitoba in Winnipeg, Canada, who do the best you can with appropriate are being denied them.’ recently published a review on the topic modeling, but the bottom line is there —David Metz, MD (Targownik LE, Leslie WD. Expert are always questions about residual Opin Drug Saff 2011;10:901-912). confounding.”

But the degree of risk varies from The story goes back, Dr. Metz study to study in terms of magnitude, said, to a study he published that dose response and duration response. showed an association with PPI “So even though there’s a consistently use and increased hip fracture risk positive message, the type of positive ( (JAMA A 2006;296:2947-2953). “After message we get is somewhat inconsiswe published that paper it went viral, tent,” Dr. Targownik said. and the whole world has decided Also, no causal mechanism has been that PPIs should be stopped because identified that would explain why PPI they’re deadly and dangerous,” Dr. increases the risk for fracture. “This Metz said. “The problem is that ‘The conclusion we’re drawing from this is that PPIs do not raises the suspicion that a lot of what people who need the PPIs are being appear to have a clinically significant effect on BMD over time, we’re seeing is not a truly causal reladenied them.” tionship, that it’s a spurious relationPeople with conditions that clearly and therefore do not explain the increased fracture risk seen in ship,” Dr. Targownik said. indicate PPI use should take the other studies.’

Given that decreased BMD is a drugs at the lowest dose effective for —Laura Targownik, MD surrogate for fracture risk, Dr. Tarmaintenance, Dr. Metz suggested. gownik and colleagues analyzed the “But if you don’t have an indication Canadian Multicentre Osteoporosis or you’re on a dose that’s too high, study for an association between PPI use and BMD. “Over time, the effects of PPIs on change in BMD you should try to reduce it to limit potential long-term “We were able to prospectively look at people who said were negligible. Depending on the type of the analysis effects, including ambulating pneumonia, vitamin B12 they were PPI users and determine whether there was and how we define PPI use, there were some effects deficiency, Clostridium difficile colitis, and the most an association between PPI use over time and changes that were associated with BMD loss over time, but well-studied possible association, osteoporosis and in BMD,” Dr. Targownik said. only marginally,” Dr. Targownik said. “The conclusion fractures.”

The population-based sample of participants aged we’re drawing from this is that PPIs do not appear to Although there are no definitive mechanisms to 25 years and older, recruited from nine different cities have a clinically significant effect on BMD over time, explain the association between PPI use and fracture in Canada, underwent BMD testing with dual-energy and therefore do not explain the increased fracture risk, there are many different possibilities, such as parax-ray absorptiometry at baseline, five and 10 years. Sub- risk seen in other studies. This suggests that if there is thyroid hormone abnormalities, vitamin D deficiency, jects also filled out questionnaires throughout the course truly a fracture risk associated with PPI use, it may be calcium malabsorption and others, Dr. Metz said. of the study and were assessed yearly for fractures. occurring by some mechanism that is not dependent “I think this is probably a true association [between PPI use was reported in 2.7% of the 8,219 partici- on BMD.” PPI use and fracture risk], and I think it’s something pants at baseline; of the 4,436 who underwent BMD In an epidemiologic study, however, it is difficult, if to be considered in patients who truly need PPIs longtesting at year 10, 11.5% were using PPIs. At baseline, not impossible, to specify the factors that could explain term; however, I don’t think it should be a reason to deny PPI users had significantly lower BMD: about 3% lower why patients on PPIs have lower BMD in the first place, the use of PPIs,” Dr. Metz said.

BMD in total hip and 3.5% lower BMD at femoral Dr. Targownik explained. “While you can easily adjust “I tell everyone who needs a PPI to use the lowest neck. PPI users, however, did not appear to lose further for age and sex, it’s hard to quantify whether a person is effective dose depending on the indication, make sure BMD. BMD remained stable even up to 10 years, the frail or generally ill. We do know, however, that people they have a good calcium intake, and that they will be caveat being that only 0.9% of patients recorded con- who are frail are more likely to be hospitalized, more followed in due course. If they don’t need a PPI, they tinuous PPI use over 10 years. likely to see physicians and more likely to receive PPIs,” shouldn’t be on it in the first place.”

■

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ND NOTT FOR ORA RAL OPHTHALMIC OR INTRAVA AGINA GI AL US USE E Please see brief summary ry of US Pre r sccri r bing ng Information for REC ECTIIV on the following n page.

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32

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Three Studies of Eosinophilic Esophagitis Reach Similar Conclusion: More Data Needed

BY TED BOSWORTH NATIONAL HARBOR, MD.—Despite the numerous studies published on eosinophilic esophagitis (EoE) during the past decade, questions still outnumber answers. Two natural history studies of EoE, presented at the 2011 American

College of Gastroenterology (ACG) meeting, reached different conclusions about the chronicity of the disease. And in a third study presented at the same meeting, which compared an inhaled corticosteroid and a proton pump inhibitor (PPI) for the treatment of patients with EoE with or without gastroesophageal reflux disease (GERD), neither treatment

RECTIV (nitroglycerin) Ointment 0.4%, for intra-anal use Rx Only Initial U.S. Approval: 1955 Brief summary of Prescribing Information. Please consult package insert for full Prescribing Information.

INDICATIONS AND USAGE: RECTIV™ (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.

CONTRAINDICATIONS: PDE5 inhibitor use - Administration of RECTIV is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see DRUG INTERACTIONS]. Severe anemia - RECTIV is contraindicated in patients with severe anemia. Increased intracranial pressure - RECTIV is contraindicated in patients with increased intracranial pressure. Hypersensitivity - RECTIV is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites.

Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

WARNINGS AND PRECAUTIONS: Cardiovascular disorders - Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly. Headache - RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction of RECTIV (nitroglycerin) Ointment 0.4% applied to the anal canal is headache. Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment. In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1): Table 1: Incidence of Adverse Reactions (≥ 2%) in Study REC-C-001 RECTIV Placebo N = 123 N = 124 System Organ Class Patients Events Patients Events Preferred term n (%) n n (%) n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0

Hypotension: Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Allergic Reactions: Flushing, allergic reactions and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely.

Methemoglobinemia: In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia (see OVERDOSAGE).

DRUG INTERACTIONS: PDE5 inhibitors - Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of RECTIV within a few days of PDE5 inhibitors is contraindicated. Antihypertensives - Patients receiving antihypertensive drugs, betaadrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.

Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with RECTIV in patients with angina pectoris, additional hypotensive effects may occur. Aspirin - Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of RECTIV may be enhanced by concomitant administration of aspirin. Tissue-type Plasminogen Activator (t-PA) - Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving RECTIV during t-PA therapy. Heparin - Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and RECTIV concurrently, the anticoagulation status of the patient must be checked. Ergotamine - Oral administration of nitroglycerin

was effective for control of EoE symptoms. These studies of EoE appear to come to the same conclusion so often reached before: More data are needed.

Natural History Studies The inconsistency of results from two natural history studies of EoE presented at the ACG meeting, although conducted

markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris.

Therefore the possibility of ergotism in patients receiving RECTIV should be considered. Alcohol - The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C - Animal reproduction and teratogenicity studies have not been conducted with RECTIV. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. RECTIV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin. Nursing Mothers - It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECTIV is administered to a nursing woman. Pediatric Use - The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established. Geriatric Use - Clinical studies of RECTIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting.

Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSAGE: Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of RECTIV overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemia g : Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information and Instructions for Use) in the full prescribing information. Interaction with PDE5 inhibitors - Advise patient not to use RECTIV with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of RECTIV and other nitrate drugs. Hypotension - Advise patients that treatment with RECTIV may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly. Headaches - Advise patients that headaches sometimes accompany treatment with RECTIV. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops.

Advise patients that if they experience headache they should not alter the schedule of their RECTIV treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches. Dizziness - Advise patients that dizziness has been reported as a side-effect of treatment with RECTIV. Advise patients not to drive or operate machinery immediately after applying RECTIV.

Aptalis Pharma US, Inc, 22 Inverness Center Parkway, Birmingham, Alabama 35242 USA, Tel (800) 472-2634, Fax (205) 991-8426, www.aptalispharma.com Revised: June 2011

‘E EoE diagn gnos o ed os ed dur urin ing g chilldh ch dhoo ood oo d re rem main main ns a sign si gn nifi ific can nt me edica call is issu s e duri duri du ring ng ear a ly adulltho ood od.’ .’’

—Pau —P ul Me M nard d-Kat -K Kat atch cher ch err, MD e D in very different populations, provided little clarification of the nature of the disease. In one study, researchers evaluated the course of EoE in children who were followed into adulthood. The other study focused on EoE in adults. Although the adult study indicated that symptoms of EoE usually resolve over the course of long-term follow-up, the study of those initially diagnosed as children suggested that they usually do not.

“The vast majority of young adults diagnosed with EoE during childhood continue to require pharmacologic treatment and/or dietary modification for EoE,” reported study author Paul Menard-Katcher, MD, of the Hospital of the University of Pennsylvania, Philadelphia.

He emphasized, “EoE diagnosed during childhood remains a significant medical issue during early adulthood.”

The data on children were drawn from a registry that now includes 1,400 patients. Of 140 patients who were enrolled as children and were evaluated at age 18 years or older, 53 who were contacted by telephone answered all of the questions designed to capture information about current status. The mean age of the patients was 20 years, and the mean age at diagnosis of EoE was 13 years. Notably, 90% of these respondents had a history of atopic airway disease, and 79% had a history of food allergy.

Of these patients, 85% were on at least one therapy that may treat EoE: allergydirected diets (76%), PPIs (49%), topical steroids (6%), and investigational therapy (8%). Of eight patients (15%) who were not on any therapy for EoE, one

33

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

rates of complete symptom relief.

Investigators enrolled 42 patients with EoE (defined as >15 eosinophils per high-power field [HPF]) with the presence of symptoms, such as dysphagia and food impaction. All patients underwent 24-hour pH impedance monitoring to identify concomitant GERD. Patients were then randomized to receive inhaled fluticasone 440 mcg twice daily or esomeprazole 40 mg once daily for eight weeks. The primary outcome was resolution of eosinophilia, defined as less than seven eosinophils per HPF. Symptom

resolution, assessed with the Mayo Dysphagia Questionnaire (MDQ), was a secondary outcome.

Resolution of eosinophilia was achieved in 19% of patients who received fluticasone compared with 35% of those who received esomeprazole, a difference that was not statistically significant (P=0.027).

P Compared with baseline scores, the MDQ symptom scores improved significantly among patients in the PPI group (P<0.001) but not in the fluticasone group (P=0.162).

P There were no significant changes in eosinophil counts or

other histologic markers in either group.

In a subgroup of eight patients (19%) who had concomitant GERD, symptom resolution was achieved in four patients who received esomeprazole (P=0.029) P but not in the four who received fluticasone.

“There were no significant changes in endoscopic findings, eosinophil counts or other histologic markers observed with either treatment,” said Fouad Moawad, MD, of the Walter Reed Army Medical Center, Washington, D.C., at the ACG meeting. see EoE, page 39

Gas Relief!

reported recent swallowing difficulties.

Dysphagia scores overall were positive in 4% of patients and indeterminate in 8%, but 34% of patients reported swallowing difficulties in the past 30 days. GERD symptoms were reported by 62% of patients, which likely accounted for the high rate of PPI use among the group.

Sahil Khanna, MD, of Mayo Clinic College of Medicine, Rochester, Minn., and colleagues conducted a separate study of 60 adult patients with EoE. In this retrospective study, the median age of patients was 50 years; 42% were women; and 69% were on no specific treatment for EoE. Although 33% of patients had severe dysphagia when initially diagnosed, in a follow-up telephone interview at least five years later, 71% reported no dysphagia in the previous four weeks.

Additionally, although almost one-third of patients reported symptoms of food impaction, none had required endoscopic treatment for this complication in the previous four weeks. Half of the patients reported that they could tolerate an unlimited diet.

Based on these findings, Dr. Khanna concluded, “The natural history of EoE may be more benign than previously reported.” Although a minority of patients reported significant symptoms, the majority was off therapy with mild or no symptoms.

Treatment Study In a single-blind, randomized treatment study, also presented at the 2011 ACG meeting, neither therapeutic approach that was tested achieved high

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37

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

From the Literature

Studies Link Composition of Gut Microbiome to Childhood IBS, Long-term Dietary Patterns

BY CAROLINE HELWICK Two teams of investigators have identified new patterns of gut microbes as they relate to irritable bowel syndrome (IBS) in children and to longterm dietary patterns. The techniques involve using 16S rRNA metagenomics microarray hybridization and 454 DNA pyrosequencing.

Gut Bacteria and IBS in Children In a study by investigators at Baylor College of Medicine, Houston, using limited sets of discriminant bacterial series, researchers were able to use different microbial subtypes as a way to discriminate pediatric patients with IBS from healthy children 96% of the time. The study was recently reported in Gastroenterologyy (Saulnier DM et al. 2011;141:1782-1791).

Among 71 samples from 22 children with IBS, microbiomes associated with IBS were characterized by a significantly greater percentage

‘T ‘This does not necessarily mean that the bacteria cause the pain, but that children with IBS have certain species of bacteria that are less likely to be found in the intestines of healthy children.’

—R Rob o er ertt Shul ullma man,, MD

of the class γγ-proteobacteria than microbiomes of 22 healthy children (0.89% vs. 0.07%; P<0.05). At the genus level, the IBS microbiome was characterized by greater percentages of Haemophilus and Dorea (P ( <0.05).

The species Haemophilus parainfluenzae was a prominent component

within the group of Haemophilus sequences, and taxa of the genus Veillonella were abundant as well.

In the study, children kept diaries of abdominal pain and bowel function for two weeks and submitted stool samples for microbiome analyses. In addition to pyrosequencing,

most samples also were hybridized to a microarray that can detect more than 8,000 bacterial types (16S rRNA PhyloChip, Affymetrix Corporation).

Comparisons between the IBS and healthy groups showed that 44 taxa were more abundant in the group of see Microbiome, page 38

38

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

From the Literature

Microbiome continued from page 37

children with IBS. Bacteria taxa also may be associated with protective microbiomes, and the researchers detected 12 taxa that were less abundant in the group with IBS, including several Bacteroides species. The researchers also identified a novel Ruminococcus-like microbe in association with IBS. A greater severity of pain, which was reported in the children’s diaries,

correlated with an increased abundance of several bacterial taxa from the genus Alistipes. Additionally, individual taxa belonging to the genera Akkermansia and Parabacteroides, and a member of the family Ruminococcaceae, were more common in children reporting greater pain frequency.

Senior study author Robert Shulman, MD, professor of pediatrics at Baylor College of Medicine, explained that “this does not necessarily mean that the bacteria cause

the pain, but that children with IBS have certain species of bacteria that are less likely to be found in the intestines of healthy children.”

Although microbial dysbiosis has been described in adults with IBS, data have been lacking for pediatric patients. The finding of microbiome profiles in children provides a more objective assessment of the IBS than clinicians can obtain through subjective reports by the young patients and their parents, Dr. Shulman said.

“The findings make it possible to

characterize the patients by their intestinal bacteria,” he said. “Two children who appear to have the same type of chronic pain may actually need two different treatments.”

‘The findings make it possible to characterize the patients by their intestinal bacteria.

Two children who appear to have the same type of chronic pain may actually need two

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different treatments.’

—Robert Shulman, MD

Yehuda Ringel, MD, associate professor of medicine at the University of North Carolina School of Medicine, Chapel Hill, and co-investigator on the Rifaximin TID for Non-constipation Irritable Bowel Syndrome (TARGET 1 and 2) trials, which evaluated the role of intestinal microbiota in IBS (Pimentel M et al. N Engl J Med d 2011;364:22-32), commented on the findings.

“Using the two molecular techniques of pyrosequencing and microarray enabled Dr. Saulnier and his colleagues a deep and comprehensive look into the composition of the intestinal microbiota in children with IBS. The finding of differences in specific bacterial groups in children with IBS, and their association with the severity of certain IBS symptoms (e.g., pain), are important in supporting the hypothesis of dysbiosis in this condition,” he said.

“At this point, we need similar studies in adult patients and in a larger population to enable the investigation of differences between the different clinical subtypes of IBS,” he added. “We also need further research to clarify whether these observed alterations in the intestinal microbiota are, or can be considered, contributing etiological factors in the pathogenesis of the IBS or a result of the altered intestinal function associated with this condition.”

Gut Microbial Enterotypes and Dietary Patterns

E A R LY B I R D D E A D L I N E

AUGUST 3

Diet can affect health by modulating gut microbiome composition, and University of Pennsylvania researchers reported that certain microbial enterotype states are associated with long-term dietary patterns (Wu GD et al. Science 2011;334:105-108).

Gary D. Wu, MD, and colleagues

39

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

used dietary inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals.

“We investigated the association of dietary and environmental variables with the gut microbiota,” he explained.

A controlled feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/ low-fiber or a low-fat/high-fiber diet, but that enterotype identity remained stable during the 10 days.

In the interventional study, changes were significant and rapid, but the magnitude of the changes was modest and not sufficient to switch subjects to another enterotype. In comparing short- and long-term diets, the investigators found that only long-term diets were correlated with enterotype clustering.

Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. All subjects started in the Bacteroides enterotype (high protein and fat), and none switched stably to the Prevotella (carbohydrate) enterotype over the course of the study.

“Our data indicate that long-term diet is particularly strongly associated with enterotype partitioning,” Dr. Wu said. “If an enterotype is ultimately shown to be causally related to disease, then long-term dietary interventions may allow modulation of an individual’s enterotype to improve health.”

Dr. Ringel said that the study “illustrates the profound effect of diet on the structure of the intestinal microbiota. Although the clinical relevance of these findings, i.e., the diet–microbiota–disease association, needs to be demonstrated, the study

‘The study indicates another potential mechanism by which diet may contribute to the pathogenesis of certain systemic and gastrointestinal disease.’

statistical analyses in advancing the understanding of the intestinal microbiota as a functional organ and its etiologic role in the pathogenesis of disease conditions.

■

—Yehuda Ringel, MD

indicates another potential mechanism by which diet may contribute to the pathogenesis of certain systemic and gastrointestinal disease conditions such as diabetes, obesity, metabolic syndrome and inflammatory

and functional bowel diseases.”

Taken together, Dr. Ringel concluded, the two studies emphasize the importance of high-quality research using advanced molecular biology techniques and sophisticated

Dr. Shulman has received consulting fees from Gerson Lehrman Group.

Dr. Ringel reported no financial conflicts of interest. Dr. Wu has served as a member of an advisory committee and review panel, and has received consulting fees from Advinus Therapeutics and Pfizer.

Think of Enterography as a GPS for Crohn’s disease.

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

EoE continued from page 33

“In patients with coexisting EoE and GERD, PPI therapy was associated with significantly greater resolution of most symptoms. In patients without GERD, symptom resolution was better in the PPI group, although the resolution of eosinophils on histology was no different.”

For dysphagia symptoms, PPI therapy was significantly better than steroids for clinical response and MDQ symptom scores in the total population and in the 34 patients without GERD who were compared separately.

■ Drs. Menard-Katcher, Khanna and Moawad reported no conflicts of interest.

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery.

Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

40

BOOK REVIEWS

GAST A ROEN AS OENT OEN T EROLOGY & ENDOSCOPY NEWS • JULY 2012

Recommended Reads in Gastroe enterolo ogy and Hepatology

By Nirmal S. Mann, MD, BSc, MS, PhD, DSc Professor of Medicine and Gastroenterology Senior Consultant in Gastroenterology–Hepatology UCDMC Sacramento Director of Gastroente erology–Hepatology UCDMC Folsom Folsom, California

Hepatocellular Carcinoma: Diagnosis and Treatment Carr BI, 2nd ed. New York, N.Y.: Springer Science+Business Media; 2010: 416 pp. Price: $219.00

In Hepatocellular Carcinoma: Diagnosis and Treatment, leading experts in the field of hepatocellular carcinoma (HCC) update and expand on the latest developments in the diagnosis and treatment of primary liver cancer detailed in the first edition of the book.

This second edition discusses the diagnostic and therapeutic value of neoadjuvant chemotherapy, intra-arterial versus IV therapy, as well as the importance of portal vein thrombus. The new chapters explore the clinical practice of cell cycle growth inhibitors, new research on genomics and proteomics and novel ways of delivering intrahepatic chemotherapy. The figures and pictures are first rate, and diagnostic and therapeutic modalities for HCC are well presented. Of note was

Esophageal Pain Mittal RK, ed. San Diego, CA.: Plural Publishing; 2010: 180 pp. Price: $138.66

Esophageal Pain provides in-depth coverage of all aspects of this problem. Divided into five sections, the book addresses a range of topics from the basic science of how neural pathways work and how receptors sense pain, as well as diagnostic and treatment strategies, including recent pharmacologic treatments currently in clinical trials. Section I introduces the problem of heartburn and esophageal pain; Section II deals with the basics of esophageal pain receptors; Section III addresses the issue of stimuli of esophageal pain, including longitudinal muscle spasm as a mechanism for esophageal pain; Section IV is devoted to peripheral and central mechanisms of sensitivity and hypersensitivity; and Section V concludes the book with a discussion of diagnosis and management of esophageal pain.

The list of contributors is impressive. I particularly enjoyed Chapter 4, “Vagal and Spinal Distension Sensitive Primary Afferents of the Esophagus,” because it denotes the depth of knowledge and clear analysis of its author, Raj Goyal, MD. I recommend this small book for faculty members who are interested in learning and teaching the mechanism and management of esophageal pain.

Copyright © 2009 Plural Publishing, Inc. All rights reserved.

Used with permission.

Chapter 10, “Clinical Features and a Clinician’s Approach to Hepatocellular Carcinoma,” as well as Chapter 13, “MRI for Detection and Evaluation of Hepatocellular Carcinoma.”

This comprehensive book on HCC will be useful for experts in pathology, clinical pharmacology, interventional radiology, hepatology, liver transplant, and surgical and medical oncology who are involved in teaching and managing patients with HCC.

Chronic Liver Failure: Mechanisms and Management Gines P, Kamath PS, Arroyo V, eds. New York, N.Y.: Springer Science+Business Media; 2011: 590 pp.

Price: $239.00

Chronic Liver Failure: Mechanisms and Managementt covers all aspects of chronic liver failure, including new developments in the field. Part I of this three-part book delves into liver physiology, splanchnic circulation, liver fibrosis, genomics and the future use of stem cells in chronic liver failure. Part II is devoted to the effects of liver failure on organ systems, including the important problem of hepatic encephalopathy. Part III addresses problems related to the management of chronic liver failure.

Each chapter is written by a renowned expert and provides the latest knowledge in the field. The list of contributors is impressive. The diagrams, tables and figures are high quality and informative, and the lists of references following each chapter also are helpful. This book is recommended for faculty and students from a range of specialties, including clinical gastroenterologists, hepatologists, internists and nephrologists, who are caring for patients with chronic liver failure.

PREPARE For a new partner in GI care

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42

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Investigational Agent, Teduglutide, Reduces Parenteral Volume Needs in Patients With Short Bowel Syndrome

BY MONICA J. SMITH NATIONAL HARBOR, MD.—Phase III data confirm that teduglutide, a novel analog of glucagon-like peptide 2 (GLP-2), can reduce demand for parenteral support in patients with short bowel syndromeintestinal failure (SBS-IF). The benefit is attributed to the ability of teduglutide to increase villous height and crypt depth, increasing the structural integrity and function of intestinal mucosa.

“Reductions in parenteral support volume continue to be observed [in an extension of a 24-week Phase III study],” said Lauren Schwartz, MD, Division of Gastroenterology, Mount Sinai Medical Center, New York City. “A small number of patients have been completely weaned off parenteral support after six or more months of exposure to teduglutide.”

Presenting one of several sets of data at the 2011 annual meeting of the American College of Gastroenterology (ACG), Dr. Schwartz reported that teduglutide therapy does come with side effects, but there have been no new or unexpected safety signals in the extended follow-up.

The data represent interim results from STEPS2, an open-label extension of the 24-week double-blind, multinational Phase III trial called STEPS (Study of Teduglutide in PN-Dependent Short-Bowel Syndrome). In the initial STEPS study, teduglutide was associated with a statistically and clinically significant reduction in parenteral support volume relative to placebo (4.4 vs.

2.3 L per week by study end; P=0.001).

P In STEPS, 86 SBS-IF patients dependent on parenteral support for at least one year were randomized to 0.05 mg/ kg per day of subcutaneous teduglutide or placebo; 78 patients completed the study. The primary end point was at least a 20% reduction in the parenteral support volume requirement from baseline.

The difference between the teduglutide and placebo groups was highly significant (63% vs. 30%; P=0.002).

P “Significantly more teduglutidetreated subjects were able to reduce the number of infusion days per week by one or more days compared with placebo [54% vs. 23%; P P=0.0047],” reported Stephen J. O’Keefe, MD, medical director, Small Intestine Rehabilitation & Transplant Service, University of Pittsburgh.

He observed that significant response was seen in the teduglutide-treated patients as early as eight weeks with an increasing degree of response through the 24 weeks of observation.

By 24 weeks, only eight patients discontinued treatment for an adverse event (AE), but three of these were in the placebo group. The most common AEs in STEPS were gastrointestinal (GI)-related. Based on the 24-week data, Dr. O’Keefe said teduglutide was well tolerated.

STEPS2 enrolled 76 of the 78 patients

who completed STEPS, 37 from the active treatment group and 39 from the placebo group. In STEPS2, the placebo patients were switched to active therapy, whereas those on teduglutide were maintained on treatment. The interim STEPS2 results included data from patients who had completed at least six months on therapy.

Largely focused on safety, the interim results indicate that the most common AEs have not changed from those encountered in STEPS. GI complaints, including abdominal pain, distension, nausea and vomiting, were the most common type AEs, occurring in 22% of patients. Non-GI AEs, such as edema and injection-site reactions, were experienced

Inadequate Bowel Preps: A Problem With Potentially Serious Consequences

Colonoscopic view of cecum in patient using a split-dose bowel prep1

Colonoscopic view of cecum in patient using a single-dose bowel prep1

In Bowel Cleansing, Location Matters Inadequate bowel cleansing can compromise detection of lesions in the right colon,2 where cancer often develops3

43

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

by 13%. Infection, both catheter-related and urinary tract-related, were recorded in 12%. Most of the discontinuations during the extension study, approximately 10% of patients, were due to AEs. Although “no unexpected safety signal has been observed to date,” Dr. Schwartz also reported that the efficacy in regard to reduced parenteral volume observed

in the 24 weeks of the blinded study has persisted. Although further reduction in parenteral volume has not been common, three patients in this series were completely weaned off parenteral support, which indicates that improvement in the utility and structure of intestinal function does continue to advance with prolonged therapy in some patients.

In another teduglutide analysis presented at the 2011 ACG meeting, histologic examinations of biopsy specimens from 77 patients on active therapy or placebo were compared (abstract P949).

The specimens were retrieved at baseline and again at the end of 24 weeks of therapy. Measurements were taken of villous height, crypt depth, mid-villous width

How Common Are Inadequate Bowel Preps?

• In a review of over 236,000 outpatient colonoscopies, bowel preparation was inadequate in almost 24% of procedures4 • In another review of over 93,000 colonoscopies, bowel preparation was inadequate in 23% of procedures5

The Impact of Inadequate Bowel Preps on Colonoscopy: • Liquid residues remaining in the colon4 • Incomplete cleaning of right side of colon2 • Longer mean cecal intubation time6

‘A small number of patients

• Higher rate of difficult colonoscopies6

have been completely weaned

• Greater likelihood of aborted examination6

off parenteral support after six or more months of exposure to 6

Figure 1. Association of bowel cleansing quality with difficulty of colonoscopy (% of patients) Colonoscopy Quality

50

Intermediate*

40 % of Patients

—Lauren Schwartz, MD

Low*

49.1

30 20

teduglutide.’

High*

34.2

33.1

20.0 15.4

10 0

Easy†

12.4

Difficult† Difficulty of Colonoscopy

* Cleansing quality was determined by endoscopist grading using a 5-point scale. High = completely clean (score 5) or clear liquid present (score 4); Intermediate = liquid plus solid stool present that can be aspirated (score 3); Low = liquid and solid stool present that cannot be totally aspirated (score 2) or solid stool preventing visualization (score 1). † Degree of difficulty of procedure was determined by endoscopist grading with a 6-point scale: extremely easy, easy, fairly easy, fairly difficult, difficult, extremely difficult.

The Impact of Inadequate Bowel Preps on Diagnosis: • In a survey of patients with poor/fair bowel preps (N=3047), 42% of adenomas found in a follow-up colonoscopy had not been detected in the first colonoscopy7 • 27% of advanced adenomas, which have a greater premalignant potential, were missed in the first colonoscopy7 • Smaller adenomas (<10 mm) were missed nearly twice as often as adenomas ≥10 mm when the prep was poor7 References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Baxter N, Rabeneck L. ICES report: new findings about the risks and limitations of colonoscopy used in the early detection of colorectal cancer. Healthcare Quarterly. 2009;12:24-25. 3. Cappell MS. The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. Med Clin N Am. 2005;89:1-42. 4. Crispin A, Birkner B, Munte A, Nusko G, Mansmann U. Process quality and incidence of acute complications in a series of more than 230 000 outpatient colonoscopies. Endoscopy. 2009;41:1018-1025. 5. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58:76-79. 6. Froehlich F, Wietlisbach V, Gonvers J-J, Burnand B, Vader J-P. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc. 2005;61:378-384. 7. Lebwohl B, Kasinos F, Glick M, Rosenbaum AJ, Wang T, Neugut AI. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc. 2011;73:1207-1214. ©2012 Braintree Laboratories, Inc.

SU-12873RV

March, 2012

Brought to you as an educational service by

and villous surface area. The biopsies also were examined for dysplastic changes over the course of treatment.

Relative to placebo (P=0.02) P or baseline (P=0.015), P the increases in crypt depth were significant in those treated with teduglutide. The increase in villus height also was significant compared with placebo (P=0.007).

P No dysplasia was observed in any the specimens, according to the lead author of the analysis, Kelly Tappenden, PhD, RD, University of Illinois at Urbana-Champaign.

Although these data confirm that the GLP-2 analog improves villous height and crypt depth, the outcome data indicate that the changes are clinically meaningful. According to the investigators who presented these data, the efficacy of teduglutide in the context of a benign, but still significant side-effect profile, suggests that this drug will have a role in patient management if it is granted regulatory approval.

■ Drs. Schwartz and O’Keefe received funding for the STEPS2 study from NPS Pharmaceuticals, Inc. Dr. Tappenden has no conflicts of interest to disclose.

44

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Boston Scientific Announces Expanded Indication for CRE Wireguided Balloon Dilator On May 29, Boston Scientific Corporation announced that the FDA had cleared an expanded indication for the CRE Wireguided Balloon Dilator for endoscopic dilation of the sphincter of Oddi after sphincterotomy.

place and is consistent and reliable for inflation size and pressure. I am very comfortable with this balloon for the DASE application as I’ve been using it for many years for esophageal and gastric stenosis.”

The CRE Wireguided Balloon Dilator is made of Pebax for durability and flexibility, and can open strictures gradually by delivering three pressure-controlled diameters in a single balloon. The rounded-shoulder

design of the balloon facilitates endoscopic visualization or balloon endoscopy and provides more usable balloon surface area during dilation.

“The CRE Wireguided Balloon Dilator for the DASE procedure provides a new and alternative endoscopic therapy for the more than 60 million people worldwide affected by the presence of stones in the common bile duct,” David Pierce, president of the endoscopy division at Boston

Scientific, said in a statement. “The CRE Wireguided Balloon Dilator is a core product in our endoscopy portfolio, and it underscores our ongoing commitment to advancing treatments that meet the needs of patients and physicians.”

For more information, visit www.bostonscientific.com/endoresources.

■ —Based on a press release from Boston Scientific

Improving GI outcomes in critically ill patients.

That’s the

The new indication offers physicians the ability to perform dilationassisted stone extraction (DASE) with the CRE Wireguided Balloon Dilator.

The CRE Wireguided Balloon Dilator also is indicated to dilate strictures in the digestive tract.

“Since becoming available, the DASE procedure with the CRE Wireguided Balloon has significantly changed my approach to the endoscopic removal of large common bile duct stones,” Kenneth Sigman, MD, physician at Birmingham Gastroenterology Associates, and chief of the GI Division and director of the Endoscopy Lab at Trinity Medical Center in Alabama, said in a statement. “The CRE Wireguided Balloon is easy to

The only 100% whey peptide-based family of tube-feeding formulas shown to improve patient tolerance and promote absorption in GI-compromised patients1,2 Backed by over 20 years of clinical experience and 50 clinical studies, the PEPTAMEN® family of formulas:

FDA Update & Product News column is compiled by the editors based on press releases from manufacturers and the U.S. Food and Drug Administration.

Please send product news to: cgordon@ mcmahonmed.com

References: 1. Donald P et al. Nutr Res. 1993;14:3-12. 2. Borlase BC et al. Surg Gynecol Obstet. 1992;174:181-188.

3. Dylewski ML et al. A.S.P.E.N. Clinical Nutrition Week 2006;NP72.

4. Flack S et al. J Hum Nutr Diet.

2003;16:367. 5. Fried MD et al.

J Pediatr. 1992;120:569-572. 6. Shea JC et al. Pancreatology. 2003;3:36-40.

vomiting, abdominal pain, loose stools, and other signs of intolerance2-6 3

which may help facilitate gastric emptying5 Nutrition. The factor that can make a difference.TM For more information, visit www.NestleHealthScience.us or call 1-800-422-ASK2 (2752).

USE UNDER MEDICAL SUPERVISION All trademarks are owned by Société des Produits Nestlé S.A., Vevey, Switzerland or used with permission. © 2012 Nestlé. All rights reserved.

Florham Park, NJ 07932-1521 U.S.A. PPTM-11838-0112

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

45

Covidien Introduces HALO(90)ULTRA Ablation Catheter for Barrett’s Esophagus On May 17, Covidien announced the launch of the HALO(90) ULTRA Ablation Catheter, the latest addition to the HALO family of catheters for the endoscopic treatment of Barrett’s esophagus (BE).

The HALO(90) ULTRA is double the length of the original HALO(90) focal device and features an electrode mounted on the end of an

endoscope. The HALO(90) ULTRA shortens BE focal ablation treatment times because it can treat twice as much area per energy application as the HALO(90) catheter, and thus is able to safely and effectively remove more diseased tissue and facilitate the growth of new, healthy tissue.

“The HALO(90) ULTRA is an exciting development for patients with Barrett’s esophagus, as well as for those suffering from a condition commonly referred to as ‘watermelon stomach,’ where chronic bleeding occurs,” Vafa Jamali, vice president and general manager of Covidien GI Solutions, said in a statement.

The new device can be used independently or with the available HALO(90) and HALO(60) Ablation Catheters, and the HALO(360+) Ablation Catheter, a balloonbased endoscopic ablation system for treating larger areas of BE. The HALO(90) ULTRA Ablation Catheter has received the CE mark and is currently available in the United States and Europe.

For more information, visit www.covidien. com.

■ —Based on a press release from Covidien

The HALO90 (top) and the HALO(90) ULTRA (bottom)

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W E N

US Endoscopy Announces Full Market Release of InStream Polyp Trap

Introducing the power of prebiotics in a proven, calorically dense peptide-based formula

of PEPTAMEN® 1.5 formula helps to promote absorption and tolerance in GIcompromised patients1,2 PREBIO1™, that promotes the growth of

On May 15, US Endoscopy announced the release of the InStream polyp trap, a cost-effective method to retrieve endoscopically removed polyps via suction. The InStream polyp trap minimizes exposure to biomaterial and is a valuable alternative to single specimen and mucous traps. The InStream polyp trap includes several notable features: • Specimen screen to easily isolate and remove the polyp • Luer lock connector to flush the polyp from the screen with a syringe • Removable screen for flow-through capability

digestive health3,4 Tetra Prisma® or

with

®

To receive samples for patient trialing, visit www.NestleNutritionSamples.com and enter registration code PP003 References: 1. Donald P et al. Nutr Res. 1993;14:3-12. 2. Borlase BC et al. Surg Gynecol Obstet. 1992;174:181-188.

3. Gibson GR et al. Gastroenterology. 1995;108:975-982. 4. Bouhnik Y et al. J Nutr. 1999;129:113-116.

USE UNDER MEDICAL SUPERVISION All trademarks are owned by Société des Produits Nestlé S.A., Vevey, Switzerland or used with permission. © 2012 Nestlé. All rights reserved.

Florham Park, NJ 07932-1521 U.S.A. PPTM-11838-0112

“Sifting through biomaterial to locate and retrieve a tissue specimen is a frustrating process for clinicians,” said Gulam Khan, US Endoscopy CEO, president and co-chairman. “The InStream polyp trap eliminates this step in an easy and cost-effective way.”

For more information, visit www.usendoscopy.com.

■ —Based on a press release from US Endoscopy

46

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Medspira Receives FDA 510(k) Clearance for mcompass Anorectal Manometry Device On May 21, Medspira received FDA 510(k) clearance for its mcompass anorectal manometry device, which is designed to evaluate pelvic floor function in patients with constipation or fecal incontinence. Medspira plans to market the device to colorectal surgeons and gastroenterologists, as well as primary care physicians, gerontologists,

urogynecologists and obstetricians/ gynecologists (OB/GYNs).

“Anorectal testing is crucial to appropriate diagnosis and efficient treatment of fecal incontinence and related problems,” said Jim Quackenbush, CEO of Medspira, in a statement. “mcompass has broken down all the barriers to testing.” mcompass comprises three

Download the FREE

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intuitive and userfriendly parts—a disposable catheter, mobile tablet PC and wireless portable manometer.

Unlike the more complicated anorectal devices, mcompass is portable, compact and

light, weighing only three pounds; mcompass does not require a dedicated room like other products and can be set up anywhere in minutes.

Built-in software prompts users through the simple testing process, and results display in real time on the device’s tablet PC workstation.

The encrypted data packet can be emailed to specialists for interpretation, if needed, using the device’s built-in Wi-Fi connectivity. mcompass features a disposable catheter for enhanced testing accuracy and a single-connector to simplify setup. The catheter includes a central rectal balloon and four radial anal canal balloons at 90 degrees relative to each other, which provide independent measurement. The device’s anal canal balloon is 20 mm long, allowing one or two positioned full anal canal measurements.

Urogynecologists also can use this device to treat women with pelvic floor damage in childbirth who often suffer from fecal incontinence, and OB/GYNs will now be able to conduct a quick test to determine whether a woman’s sphincter muscles remain intact after vaginal birth.

“Most manometry devices on the market today handle a range of motility exams in addition to anorectal testing, making them costly and complicated for anorectal use,” explained Mr. Quackenbush. “Therefore, anorectal testing is typically performed by gastroenterologists or colorectal specialists, when it is performed at all. Because mcompass is dedicated to this one function, Medspira is able to offer the device for a far more affordable purchase price and to simplify the design.”

For more information, visit www.medspira.com.

■ —Based on a press release from Medspira

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JULY 2012

SRS Endoscopic System Receives FDA Clearance for Treatment of GERD Medigus Ltd., recently received FDA 510(k) marketing clearance for its SRS endoscopic system.

The SRS device is intended for minimally invasive endoluminal treatment of gastroesophageal reflux disease (GERD). The SRS device met safety and efficacy criteria during an international prospective trial of otherwise healthy patients with moderate to severe GERD and hiatal hernia of up to 3 cm. The trial, presented at the 2012 Digestive Disease Week (poster 135), showed that 74% of patients (50 of 67) met the primary success criterionâ&#x20AC;&#x201D;50% reduction in GERD health-related quality of life scoresâ&#x20AC;&#x201D;as well as a low complication rate of 6%.

The study authors concluded, â&#x20AC;&#x153;This study shows for the first time an effective endoscopic treatment for GERD patients. The new developed Medigus stapling device can endoscopically create an anterior fundoplication.â&#x20AC;?

The endoscope combines a miniature video camera, ultrasonic sights and a stapling device that allows the

47

operator to perform an anterior fundoplication. The SRS endoscope is inserted into the esophagus through the mouth with no required incisions in the abdominal cavity. The procedure is performed under general anesthesia and takes approximately 45 to 60 minutes in total.

Medigus has already received CE mark approval for the SRS system.

For more information, visit www. medigus.com. â&#x2013; â&#x20AC;&#x201D;Based on a press release from Medigus

NestlĂŠ Introduces Next-Generation Food and Liquid Thickener To Improve Swallowing Safety On June 11, NestlĂŠ Health Science announced the availability of Resource ThickenUp Clear, a nonâ&#x20AC;&#x201C;starch-based thickening powder designed to decrease the risk for aspiration in people with dysphagia.

Dysphagia, which affects nearly 25 million people in the United States, may require that liquids and foods be thickened to help these individuals swallow safely and to prevent foods and liquids from entering the lungs.

Resource ThickenUp Clear has no taste, mixes and dissolves easily in a variety of foods and beverages, and remains clear when mixed with water.

This product contains mostly maltodextrin and xanthan gum, and has only five calories per scoop.

A recent study showed a significant reduction in the incidence of penetration and aspiration in patients with dysphagia who consumed Resource ThickenUp Clear compared with thin liquid, as well as improvement in airway closure time for gum-thickened barium compared with thin liquid barium (Leonard R et al. Poster at 1st Congress of the European Society for Swallowing Disorders).

NestlĂŠ Health Science also has developed the Swallowing Assessment Tool (EAT-10), a symptom-specific 10-question survey that can help see NestlĂŠ, page 49

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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

Cook Expands Line of Endoscopic Ultrasound Needles: EchoTip ProCore Cook Medical has added a 25-gauge needle to its EchoTip ProCore line of fine-needle biopsy histology needles.

The EchoTip ProCore is a singleuse, disposable needle designed for sampling submucosal lesions, mediastinal masses, lymph nodes and intraperitoneal masses during endoscopic ultrasound (EUS).

Gastrointestinal (GI) cancers are notoriously difficult to detect and diagnose in the early stages. Although a fine needle often is needed to obtain samples from hard-to-reach areas, such as the pancreas, fine-needle aspiration can have limited yield and sensitivity for certain kinds of tumors or in certain locations.

“The 25-gauge EchoTip ProCore and our entire fine-needle biopsy line have changed the landscape of EUS globally, providing clinicians with the latest innovations to improve patient care,” Barry Slowey, global business unit leader for Cook Medical’s Endoscopy division, said in a statement.

The ProCore 25-gauge needle allows pathologists to achieve a quicker and more accurate diagnosis

by grabbing intact tissue samples in remote areas in the GI tract. ProCore uses a modified slow-pull technique for tissue acquisition that yields complete biopsies, which are easier to diagnose. The core trap at the tip of the needle receives the tissue sample and the reverse bevel collects the

core sample by shaving material from the target lesion during retrograde movement of the needle.

In a poster presentation at the 2012 Digestive Disease Week meeting, investigators reported that the 25-gauge biopsy needle enabled a single-pass diagnosis of 88% (or

91% when including subsequent passes) in suspected pancreatic tumors after examining the histologic and cytologic yields, with no complications observed in any patients (Iwashita T et al., poster Sa1530).

“The 25-gauge EchoTip ProCore has a unique advantage because physicians are able to obtain histological and cytological samples on a single-pass or limited-pass basis,” said Kenneth Chang, MD, executive director, H.H. Chao Comprehensive Digestive Disease Center at the University of California-Irvine, who is a paid consultant for Cook Medical.

“Since the single-pass yield is so high with the 25-gauge ProCore, the needle streamlines the EUS procedure for physicians and may require fewer patients to return to their doctors for further sampling.”

The 25-gauge EchoTip ProCore needle is now available to physicians in most major markets internationally.

For more information, visit www.cookmedical.com.

■ —Based on a press release from Cook Medical

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

F D A U P D AT E & P R O D U C T N E W S

49

Pernix Therapeutics Introduces Omeclamox-Pak To Treat H. pylorii Infection On May 15, Pernix Therapeutics Holdings, Inc., announced the release of Omeclamox-Pak, a new 10-day triplecombination oral therapy to eradicate Helicobacter pylorii and treat duodenal ulcer disease. The Omeclamox-Pak therapy, which is expected to launch

the addition of a new branded product that will be launched by our newly established gastroenterology sales force,” Cooper Collins, president and CEO of Pernix Therapeutics, said in a statement. “We are pleased to offer patients suffering from H. pylorii infection and duodenal ulcers with a new treatment option that we expect will be available by prescription in July 2012.”

Omeclamox-Pak consists of the

protein pump inhibitor omeprazole, which decreases the amount of acid the stomach produces, as well as the broad-spectrum antibiotics clarithromycin tablets and amoxicillin capsules, which inhibit the growth of bacteria and allow the stomach lining to heal.

Omeclamox-Pak is contraindicated in patients with a history of hypersensitivity to omeprazole, a macrolide antibiotic or penicillin. The safety and

effectiveness of Omeclamox-Pak in the pediatric population has not yet been established.

“We anticipate physicians and their patients will welcome the short, 10-day dosing regimen, especially when compared with other treatments,” said Chuck Hrushka, vice president of sales and marketing at Pernix Therapeutics.

■ —Based on a press release from Pernix Therapeutics

“The need to directly visualize small bowel diseases led to our solution... officially this month, includes omeprazole delayed-release capsules (20 mg), clarithromycin tablets (500 mg) and amoxicillin capsules (500 mg).

The FDA approved Omeclamox-Pak in 2011.

“The introduction of OmeclamoxPak is an important milestone for Pernix as the company’s prescription portfolio continues to broaden with

which changed my treatment decision...

which made my Crohn’s management right for me.”

Nestlé continued from page 47

physicians identify patients at risk for dysphagia.

“We’re thrilled to introduce a new solution to modify food and beverage consistency that is meaningful for both the dysphagia patient and the hospital,” Juan Ochoa, U.S. medical and scientific director of Nestlé Health Science, said in a statement.

“Resource ThickenUp Clear offers a clear, consistent and easy-to-use option to help people manage their swallowing difficulties.”

For more information, visit www.nestlehealthscience.us or www.thickenupclear.com.

■ —Based on a press release from Nestlé

75% of your Crohn’s patients have lesions in their small bowel.1 Within 3 months of using PillCam® SB, 62% of patients had their Crohn’s therapy changed. 2 What PillCam SB reveals could change your treatment decisions, which could improve your patients’ lives. And that’s what we’re all focused on.

To learn more, contact us at 1.800.448.3644 or visit givenimaging.com

1. Engstrom PF, Goosenberg EB, Diagnosis and Management of Bowel Diseases. Caddo, OK: Professional Communications Publisher; 1999.

2. Long MD, Barnes E, Isaacs K, Morgan D, Herfarth HH. Impact of capsule endoscopy on management of inflammatory bowel disease: a single tertiary care center experience. Inflamm Bowel Dis. 2011;17(9):1855-62.

The risks of PillCam® capsule endoscopy include capsule retention, aspiration, or skin irritation. The risks of the PillCam patency capsule include capsule retention and aspiration. After ingesting the PillCam capsule and until it is excreted, patients should not be near any source of powerful electromagnetic fields, such as one created by an MRI device. Endoscopic placement may present additional risks. Medical, endoscopic, or surgical intervention may be necessary to address these complications, should they occur. Please consult the product user manual or refer to www.givenimaging.com for detailed information.

Copyright ©2001-2012 Given Imaging Ltd. GIVEN, GIVEN & Design, PILLCAM, and PILLCAM & Logo are trademarks and/or registered trademarks of Given Imaging Ltd., its subsidiaries, and/or affiliates in the United States and/or other countries. All rights not expressly granted are reserved.

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Acing the Hepatology Questions on the GI Board Exam: The Ultimate Crunch-Time Resource

Brennan Spiegel, MD, MSHS Slack, August 1, 2011 This book is truly the ultimate crunch-time resource for acing the often vexing liver section of the examination, taking recertifying examinations, looking good on clerkship rounds or for just challenging yourself with interesting and entertaining vignettes.

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Atlas of Endoscopic Ultrasonography

Frank G. Gress; Thomas J. Savides John Wiley/Blackwell Publishing, October 18, 2011 This atlas provides a large collection of excellent images obtained from both diagnostic and therapeutic procedures to give readers a preview of practice. It includes a CD-ROM with video clips and searchable database of images.

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Evaluation of Inflammatory Bowel Disease, An Issue of Gastroenterology Clinics

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Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

John Dibaise McGraw-Hill, April 20, 2012 This book is a unique question-and-single-answer review for gastroenterology in-service and board exams. The book features about 3,500 questions with only the correct answer provided, reinforcing the answer students need to remember on exam day. Emphasis is placed on distilling g key y facts and clinical pearls p essential for exam success.

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Oxford Handbook of Gastroenterology and Hepatology Stuart Bloom; George Webster; Daniel Marks

Oxford University Press, January 15, 2012 Fully revised and updated for the new edition, the Oxford Handbook off Gastroenterology and Hepatology y comprises a unique A-Z compendium of the specialty and a dedicated section detailing 30 of the most common problems in GI medicine, which can be used as a quick reference.

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Lippincott Williams & Wilkins Lippincott Williams & Wilkins, October 15, 2010 Understanding Irritable Bowel Syndrome Anatomical Chartt provides a simple, visual overview of the digestive system and manifestations of the disease. This chart also discusses symptoms, risk factors and manage e t techniques. agement tec ques GEN0712

51

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2012

FDA Fast Tracks ACH-3102 for the Treatment of Chronic HCV The FDA has given Fast Track designation to Achillion Pharmaceuticals’ second-generation NS5A inhibitor, ACH-3102, as part of an interferon (IFN)-free regimen to combat chronic hepatitis C (HCV). ACH-3102 was discovered by Achillion Pharmaceuticals and currently is being evaluated in a Phase I clinical trial.

Few therapeutic options currently exist for the treatment of HCV infection. Current options are limited by their specificity for certain types of HCV, side-effect profiles and expense. ACH-3102 is a unique compound that has demonstrated strong inhibition of the NS5A protein across all genotypes of HCV in preclinical studies, as well as in vitro against mutants resistant to first-generation NS5A inhibitors.

“We are very pleased with the granting of a Fast Track designation for ACH-3102, which we believe highlights this second-generation NS5A inhibitor’s attributes that include pan-genotypic coverage of HCV and potential for maintained activity against NS5A mutant strains of HCV,” Michael Kishbauch, president and CEO of Achillion, New Haven, Conn., said in a statement.

“We are excited to leverage the

MoviPrep®

USE IN SPECIFIC POPULATIONS

(PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information.

Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed.

INDICATIONS AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

CONTRAINDICATIONS

MoviPrep is contraindicated in patients with the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep.

WARNINGS AND PRECAUTIONS Use with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities (such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), patients with known or suspected hyponatremia), patients at increased risk of cardiac arrhythmias, patients with a history of seizures or at increased risk of seizures such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, ARBs, or non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or inflammatory bowel disease, patients with impaired gag reflex or patients prone to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization.

Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease.

If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate.

Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

MoviPrep contains phenylalanine (233 mg per treatment).

ADVERSE REACTIONS

Fast Track designation was requested for ACH-3102 for its potential to provide the following: • Improved safety compared with the current standard of care; • Potential for development in a once-daily, IFN-free fixed-dose combination; • Potent antiviral activity in vitro against HCV genotypes 1 to 6; and • Low potential for drug–drug interactions, thus greater prospects for treating HCV patients with comorbidities, coinfected with HIV or pre- or post-liver transplantation.

superior profile of ACH-3102 in combination with our Phase 2 protease inhibitor, ACH-1625, as we seek to create an optimized, potentially bestin-class potent, well-tolerated, oncedaily regimen to treat HCV, which will enter combination studies during the third quarter of this year.”

For more information, visit www.achillion.com.

■ —Based on a press release from Achillion Pharmaceuticals, Inc.

In clinical trials, the most common adverse reactions for split dosing regimen (incidence 5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence 5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions.

Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age.

These adverse events included upper gastrointestinal bleeding from a MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation.

In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration.

DRUG INTERACTIONS Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate.

Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman.

Pediatric Use: The safety and effectiveness of MoviPrep in pediatric patients has not been established.

Geriatric Use: Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep.

STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

When reconstituted, store upright and keep solution refrigerated. Use within 24 hours.

PATIENT COUNSELING INFORMATION Advise patients to read the Medication Guide included in the full prescribing information.

Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine.

Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration.

Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions.

Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep.

Tell patients not to take other laxatives while they are taking MoviPrep.

Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy.

Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

Rx only

Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 2011 Salix Pharmaceuticals Inc. July 11

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive Raleigh, NC 27615 Tel. 866-669-SLXP (7597) All rights reserved.

MoviPrep® #1 prescribed branded purgative in the United States

1

Seeing is believing MoviPrep has proven 89% excellent or good cleansing when used as a split dose2 ° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° FDA approved for PM|AM Split Dosing™ ° Osmotic laxative with electrolytes ° In clinical trials, no differences in safety and tolerability between younger and geriatric patients -Most common adverse reactions for split dosing (incidence ⱖ5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence ⱖ5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Please see Brief Summary of full Prescribing Information on reverse.

References: 1. Medi-Span® Price Rx® [database online]. Indianapolis, IN: Wolters Kluwer Health. http://www.medispan.com/drug-pricing-analysis-pricerx.aspx. Accessed July 18, 2011. 2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2011.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597) MoviPrep® is a registered trademark and PM | AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2011 Salix Pharmaceuticals, Inc. All rights reserved. MOV11/41-2

www.MoviPrep.com