1978 —
35th Anniversary — 2013
gastroendonews.com
The Independent Monthly Newspaper for Gastroenterologists
Volume 64, Number 1 • January 2013
ACG 2012
IBS No Longer Only Functional Disorder
Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search
BY DAVID WILD BY CHRISTINA FRANGOU LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8
Mesalamine Elicits Response in IBS BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9
If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search. The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training. With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy Newss summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25
Experts’ Picks
I N S I D E
Best of the American College e Of Gastroenterology: Part 2 COMPILED AND WRITTEN BY DAVID WILD Gastroenterology & Endoscopy Newss asked several experts to select their favvorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scien ntific Meeting. Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the Decemberr 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14
MDs and DOs Plan Unified Accreditation System For Graduate Medical Education ............... page 5
EXPERT REVIEW: Sexual Misconduct by Professionals: A New Model of Understanding BY GREGORY E. SKIPPER, MD, AND STEPHEN SCHENTHAL, MD..................... page 29
EXPERT REVIEW: Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD .................................................................. page 33
PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37
The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11
Clean Freak
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 • JANUARY 2013
Investigational Aspirin–PPI Combination Tablet Posts Positive Phase III Results BY MEGAN BLOCK, MPH Patients receiving an investigational compound containing a combination of aspirin and omeprazole reported fewer gastric ulcers than patients who received enteric-coated aspirin alone, according to new data. The findings are particularly
noteworthy for the millions of patients at risk for cardiovascular disease who are taking preventative daily aspirin therapy. “Enteric-coated aspirin is not an absolute way to appropriately protect patients from gastric ulcers,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, who was not
involved in the research. “We can diminish this risk by the coadministration of aspirin and a proton pump inhibitor.” The investigational drug, called PA32540, is being developed by Pozen Inc., and consists of a coordinateddelivery tablet with immediate-release omeprazole (40 mg) layered around pHsensitive aspirin (325 mg).
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 study comparingg 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 studyy 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 pplease 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 ppatients 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 ppost-colonoscopy 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 pproducts 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 ppatient 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 ggeriatric ppatients and yyounger g ppatients. 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 provided. 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 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. 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
“This product would be helpful in patients who need cotherapy, and it would increase compliance because patients are taking one medication instead of multiple medications,” Dr. Johnson noted. Findings from two Phase III trials of PA32540, presented at the 2012 annual meeting of the American Heart Association (poster 12057), were favorable. “The results of these Phase III pivotal studies are promising and report the important role that PA32540 may play in the long-term management of cardiovascular protection,” said senior study author, Chris O’Connor, MD, director of Duke Heart Center at Duke University Hospital in Raleigh, N.C. Dr. Connor and his colleagues presented combined data from two doubleblind, randomized, multicenter studies that included 1,049 patients. Patients enrolled in the studies required 325 mg of aspirin for the secondary prevention of cardiovascular events and were at risk for aspirin-associated upper gastrointestinal (GI) ulcers. Patients were randomized in a 1:1 ratio to receive once-daily treatment with PA32540 or enteric-coated aspirin 325 mg, and were evaluated at one-, three- and six-month intervals. The primary end point of the study was the cumulative incidence of endoscopically confirmed gastric ulcer, defined as a mucosal break of no less than 3 mm in diameter with depth. Investigators also assessed rates of treatment emergent adverse events (AEs), discontinuation of therapy due to prespecified upper GI events, and cardiovascular AEs, including cardiovascular-related death, acute coronary syndrome, ischemic stroke or unplanned coronary artery bypass graft or percutaneous coronary intervention. The researchers found that patients who received PA32540 had fewer endoscopically confirmed gastric ulcers than those who received aspirin alone at six months (3.2% vs. 8.6%, respectively; P<0.001). AEs occurred in 71.8% of patients who received PA32540 compared with 85.1% of patients who received aspirin alone. The most commonly reported AEs in patients who received PA32540 or aspirin alone included dyspepsia (11.3% vs. 30.2%, respectively), erosive gastritis (11.5% vs. 26.3%, respectively) and gastritis (17.5% vs. 16%, respectively). Discontinuation of therapy due to prespecified upper GI events occurred less frequently in patients who received PA32540 than in those who received aspirin alone (1.5% vs. 8.2%, respectively; P<0.001). The incidence of major cardiac AEs was similar between see Aspirin–PPI Combo, page 7
4
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Sedation Not for Everyone
PIMs Not Proven
Re: “Sedationless Colonoscopy Preferred for Some Patients, Experts Say,� by Monica J. Smith. Gastroenterology & Endoscopy News October 2012;63:49.
Re: “Maintenance of Certification: The ‘Grandfather’ Clause,� by Tania Haddad, MD, DMD. Gastroenterology & Endoscopy News May 2012;63:30-31.
an ACG Visit d AA bo us SL oth at D bo #1 oth 614 #1 13
As a patient who has had a colonoscopy with sedation, I can say that, for me, the sedation was the worst part. I have spoken with many people who agree with me, so it definitely isn’t for everyone. I disagree that sedationless colonoscopy only should be offered to the “rightâ€? patient. ‌ My doctor did not explain anything to me in advance, even after I specifically requested to be awake [for the procedure]. I was given a large amount of Versed, with no mention of amnesia, which in my case lasted 10 times longer than the procedure. [This was] extremely upsetting and frightening to me. If you don’t have time to explain anything to the patient, why not mail the information to him or her in advance? It’s called informed consent. roseF Via website on Oct. 17, 2012
.
gastroendonews.com
The Independent Monthly Newspaper for Gastroenterologists
40 th ANNIVERS ARY 1 972–2012
H E PAT O L O G Y IN F O C U S
‘Astonishing’ Data on Metformin for HCC
By Christina Frangou San Diego—One of the most widely used diabetes drugs in the world appears to have an unexpected secondary benefit: reducing the risk for hepatocellular carcinoma (HCC) by more than 50%, according to two new studies. Results from an American case–control study and a see Metformin, page 26
First Guideline on NAFLD Published By Christina Frangou
Three leading American gastroenterology societies have published a new guideline on the diagnosis and management of non-alcoholic fatty liver disease (NAFLD). Prompted by the fact that physicians are seeing a growing number of patients with the disease, this is the first time that any of these professional societies have developed
Studies Attempt To DeďŹ ne Patient Preferences for CRC Screening By Caroline Helwick
Despite its clear benefits, colorectal cancer (CRC) screening rates in the United States have stalled at around 50% of those eligible for screening. Acceptance of screening recommendations might be enhanced if certain barriers could be overcome. Some believe that computed tomographic colonography (CTC) might be one way to improve adherence to screening recommendations. This topic has been the aim of several recent clinical research surveys. What do these surveys reveal? Are they accurate reflections of what patients truly desire? And why bother asking: Does patient preference really matter? “The patient’s input and preferences have to be regarded as an absolutely central component of highquality care,� said David Weinberg, MD, MSc, chairman and professor of medicine at Fox Chase Cancer Center in Philadelphia, who spoke on the subject at
the 2012 Digestive Disease Week meeting in a lecture entitled, “What Will Be Competing with Colonoscopy in 5 years?� “Clearly, patients who are well versed at an appropriate level, understand their treatment options and see Patient Preferences, page 7
see NAFLD Guideline, page 28
I N S I D E
GI Roundtable Rou und 2012
Gasttroente enterologists Discuss Challenges, Chan nges, Fu Future of GI Health Care Compiled and written by Monica J. Smith
Knoxville, Tenn.—The GI Roundtable conference evolved as a collaboration between Bergein Overholt, MD, of Gastrointestinal Associates in Knoxville, Tenn., and Klaus Mergener, MD, PhD, MBA, of Digestive Health Specialists in Tacoma,
EXPERT’S PICKS Best of Digestive Disease Week (DDW): Inammatory Bowel Disease (IBD)
Ellen J. Scherl, MD, provides an overview of IBD research presented at the DDW meeting Ellen J. Scherl, ............................................ page 10 MD
Complications of Biologic Therapy for IBD
Four IBD experts discuss common risks and complications associated with anti-TNF therapy for IBD ............................................ page 14
see GI Roundtable, page 50
PRODUCT ANNOUNCEMENT
PRODUCT ANNOUNCEMENT
see page 67 for product information
see page 67 for product information
Pylo Plus, From Gulf Coast Medical, Inc., Offers Improvement Over Older CLO Test H. pylori Assays
Introducing VSL#3 JUNIOR Medical Food Probiotic, the Newest Addition to the VSL#3 Brand
As an endocrinologist and having just missed the grandfather clause cutoff, I have enjoyed studying the knowledge modules and taking the tests for [maintenance of certification in] both internal medicine and endocrinology now twice in my career. However, the American Board of Internal Medicine [ABIM] has gone [too
Web Comments far]—like our federal government with Medicare—with the requirement for Practice Improvement Modules (PIMs), which, as the above article implies, have no proven validity in either testing quality or improving quality. In my experience within large institutional teaching hospitals for most of my career, in the context of regular Joint Commission inspection “dog and pony showsâ€? and institutional Quality Assurance Activities, ‌ the numerous PIM options that ABIM offers cannot possibly be fair tests of quality or
False-Positives Questioned gastroendonews.com
The Independent Monthly Newspaper for Gastroenterologists
4 0th ANNIVERSARY 1 972–201 2
Adenoma Detection Rate an ‘Imperfect’ Measure of Quality
Re: “Novel Test Identifies IBD Subtypes,� by David Wild. Gastroenterology & Endoscopy News September 2012;63:1,14,16.
BY CAROLINE HELWICK
New Drugs, Policy Changes Offer Gastros Ways To Help Patients Manage Obesity BY CHRISTINA FRANGOU
SAN DIEGO—Are adenoma detection rates (ADRs) the best way to measure the quality of colonoscopy? “The ADR is imperfect but better than some proposed replacements,� said Douglas K. Rex, MD, in a lecture at the 2012 Digestive Disease Week (DDW) see ADR, page 12
Novel Test IdentiďŹ es IBD Subtypes BY DAVID WILD SAN DIEGO—A new diagnostic test incorporating 17 serologic, genetic and inflammatory markers is 87% accurate in identifying inflammatory bowel disease (IBD) and 93% accurate in differentiating ulcerative colitis (UC) from Crohn’s disease (CD), according to research presented at the 2012 Digestive Disease Week (DDW) meeting. see IBD Test, page 14
After a series of national policy changes and drug approvals this summer, gastroenterologists have new tools to help their patients who struggle with obesity. In late June, the U.S. Preventive Services Task Force (USPSTF) recommended that all adults be screened for obesity during their checkups—a directive geared to primary care physicians, but all physicians are asked to heed the recommendations. The USPSTF also called on clinicians to refer patients with a body mass index (BMI) of 30 kg/ m2 or greater to intensive multicomponent behavioral interventions, or to offer these patients interventions. Several days later, the FDA approved Belviq (lorcaserin hydrochloride; Eisai Pharmaceuticals) as an addition to a reduced-calorie diet and exercise for chronic weight management. Belviq was the first anti-obesity drug to be approved in the past 13 years,
and marked a significant shift in FDA policy. For the past decade, the agency has been reluctant to approve new diet drugs, largely because of a history of product withdrawals and serious side effects. Weeks after endorsing Belviq, the FDA also approved Qsymia (Vivus Pharmaceuticals), which combines the anti-seizure/migraine drug topiramate and the appetite-suppressant phentermine. “Obesity threatens the overall well-being of patients and is a major public health concern,� said Janet Woodcock, MD, director of the FDA’s
The Future of Gastroenterology Practices: Is Bigger Better?
Do we know how patients with other associated conditions, such as psoriasis, atopy or sundry other
see Obesity, page 18
I N S I D E EXPERTS’ PICKS Best of Digestive Disease Week (DDW): Part 3 Experts share their favorite abstracts from the 2012 DDW meeting....................page 8
BY MONICA J. SMITH KNOXVILLE, TENN.—A common refrain at the 2012 GI Roundtable, a meeting that explored strategies to help medical practices remain successful in a rapidly changing health care environment, was “bigger is better.� But more than half of gastroenterology practices today are small, with no more than five physicians and most with less than 10. Staying small and independent may take some innovative thinking as demand grows for lower-cost, high-quality health care services, said experts who spoke at the meeting.
Frank G. Gress, MD
Edward Loftus Jr., MD
see Gastro Practice, page 20
Corporate Spotlight Covidien Acquires BĂ‚RRX Medical, Launches GI Solutions Initiative see pages 6 & 7
PRODUCT ANNOUNCEMENT see page 47 for product information
Prometheus Launches Anser™ IFX To Help Guide Management of IBD Patients Using Infliximab
lead to improved quality because they are not standardized and are largely Brownian motion efforts that for some, perhaps many of us, are onerous, if not invasive, new requirements to “maintain� certification. In summary, please keep the knowledge modules and certification exams, but leave PIMs to the federal and state bureaucrats. Perhaps then some of our grandfathered colleagues would be more willing to participate. franc Via website on Oct. 26, 2012 immunologic conditions, test on the newest, fourth-generation Prometheus panels—i.e., might some patients test positive for inflammatory bowel disease (IBD), when in fact they don’t have IBD. How many false-positives might there be? gorli Via website on Nov. 18, 2012
Vol. 64, No. 1 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD
GARY R. LICHTENSTEIN, MD
Houston, Texas
Philadelphia, Pennsylvania
ALAN F. CUTLER, MD
NIRMAL S. MANN, MD, BSC, MS, PHD, DSC
Farmington Hills, Michigan
FREDRIC DAUM, MD
Sacramento, California
Mineola, New York
PETER R. MCNALLY, DO
STEVEN M. FABER, MD Elizabeth City, North Carolina
RONNIE FASS, MD Cleveland, Ohio
BARBARA B. FRANK, MD Philadelphia, Pennsylvania
FRANK G. GRESS, MD Brooklyn, New York
Fort Carson, Colorado
TARUN MULLICK, MD St. Charles, Illinois
JOEL E. RICHTER, MD Tampa, Florida
DAVID ROBBINS, MD New York, New York
ELLEN J. SCHERL, MD New York, New York
CHRISTOPHER JOLLEY, MD
PRATEEK SHARMA, MD
Gainesville, Florida
Kansas City, Kansas
MYRON LEWIS, MD
JEROME H. SIEGEL, MD
Memphis, Tennessee
New York, New York
January 2013
EDITORIAL STAFF
SALES STAFF
DAN RADEBAUGH, Director of Production and Technical Operations
CYNTHIA J. GORDON, PHD, Managing Editor, cgordon@mcmahonmed.com
BRIAN J. HIGGINSON, Publication Director, bhigginson@mcmahonmed.com
BRANDY WILSON, Circulation Coordinator
MATTHEW SPOTO, Senior Account Manager, mspoto@mcmahonmed.com
MCMAHON PUBLISHING
ALINA DASGUPTA, Junior Sales Associate, Classified, adasgupta@mcmahonmed.com
VAN VELLE, President, Partner
MAUREEN SULLIVAN, Associate Editor, msullivan@mcmahonmed.com DAVID BRONSTEIN, KEVIN HORTY, ADAM MARCUS, GABRIEL MILLER, DONALD M. PIZZI, SARAH TILYOU, Contributing Editors JAMES PRUDDEN, Group Editorial Director
ART AND PRODUCTION STAFF
DONALD M. PIZZI, Editorial Director
MICHELE MCMAHON VELLE, Creative Director
ROBIN B. WEISBERG, Manager, Editorial Services
JEANETTE MOONEY, Y Senior Art Director
ELIZABETH ZHONG, Associate Copy Chief
JAMES O’NEILL, Senior Systems Manager
RAYMOND E. MCMAHON, Publisher and CEO, Managing Partner
MATTHEW MCMAHON, General Manager, Partner LAUREN SMITH, MICHAEL P. MCMAHON, MICHELE MCMAHON VELLE, ROSANNE C. MCMAHON, Partners
Subscription to Gastroenterology & Endoscopy News Gastroenterology & Endoscopy Newss obtains its mailing list from the American Medical Association (AMA) and the American Osteopathic Association (AOA). You do not have be a member of the AMA or AOA to receive the publication, but you do need to be correctly listed on the appropriate organization’s file, with a designated specialty of “gastroenterology,� “hepatology� or “colon and rectal surgery.� All U.S. gastroenterologists, hepatologists and colorectal surgeons should receive Gastroenterology & Endoscopy News
McMahon Publishing is a 41-year-old family-owned medical publishing and medical education company. McMahon publishes monthly clinical newspapers, annual and semi-annual Special Editions, and continuing medical education and custom publishing pieces.
free of charge. If you are a U.S. gastroenterologist, hepatologist or colorectal surgeon and you are not receiving Gastroenterology & Endoscopy News, or if you are changing your name, address or professional specialty, contact the AMA at (800) 262-3211 or the AOA at (800) 621-1773 and notify them of your name, address and professional specialty.
check payable to Gastroenterology & Endoscopy Newss to:
If you are not a U.S. gastroenterologist, hepatologist or colorectal surgeon and would like to subscribe, please send a
may be addressed to the Circulation Coordinator at (212)
Circulation Coordinator, Gastroenterology & Endoscopy News, 545 West 45th Street, 8th Floor, New York, NY 10036. Annual subscription: $70.00 (outside U.S.A., $90.00). Single copies: $7.00 (outside U.S.A., $10.00). Please allow 8-12 weeks for delivery of the first issue. Further questions 957-5300, ext. 362, or bwilson@mcmahonmed.com.
GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,100 gastroenterologists, colorectal surgeons, and hepatologists, and GI-speciďŹ c physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2012). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing oďŹƒces. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036.
Educational & Commercial Reprints Reprints of articles appearing in Gastroenterology & Endoscopy Newss are available in minimum quantities of 500. Reprints can be ordered in black and white or four-color versions and are printed on 80-lb. glossy stock paper. Standard turnaround time is 4 weeks. For specific price quotes, contact Brian J. Higginson at (212) 957-5300, ext. 241, or bhigginson@mcmahonmed.com.
INFECTIOUS DISEASE SPECIAL EDITION
1CAB=; ;327/
5
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
MDs and DOs Plan Unified Accred ditation System For Graduate Medical Education BY GEORGE OCHOA The Accreditation Council for Graduate Medical Education (ACGME) and two osteopathic organizations—the American Osteopathic Association (AOA) and the American Association of Colleges of Osteopathic Medicine (AACOM)—have agreed to pursue a single, unified accreditation system for graduate medical education programs in the United States beginning in July 2015. According to an ACGME press release, the three organizations will work toward developing a process, format and timetable for ACGME to accredit all the osteopathic graduate medical education programs that AOA currently accredits. AOA and AACOM would become organizational members of ACGME. “ACGME’s motivation [for the plan] is the desire to have a single model of graduate medical education in the United States, with a single set of standards, accountable to the public, to achieve the ACGME’s mission of improvement in the health of the public through improvements in graduate medical education using the lever of accreditation,” Thomas Nasca, MD, chief executive officer of ACGME, Chicago, told Gastroenterology & Endoscopy News.
“The big picture is that it benefits patients to have a uniform pathway for physicians,” said Boyd R. Buser, DO, vice president for health affairs and dean, University of Pikeville Kentucky College of Osteopathic Medicine, and a member of AOA’s Board of Trustees. ACGME accredits more than 9,000 programs in graduate medical education, with more than 116,000 resident physicians, compared with the AOA’s accreditation of more than 1,000 programs with about 6,900 resident physicians, according to the press release. But the plan is not to merge the organizations into one, Dr. Buser pointed out. “AOA and AACOM would become organizational members of ACGME. It’s not a merging of our professional organizations, but we would become members,” explained Dr. Buser. “AOA will clearly remain autonomous and independent. The proposal is limited strictly to accreditation of graduate medical education. “What we think is important in the osteopathic model will remain distinct,” Dr. Buser added. “AOA and ACGME share six competencies. AOA has a seventh competency, osteopathic principles and osteopathic manipulative treatment,
implemented throughout the other six competencies. It’s an important component and will remain.” The unification plan is expected to improve quality and efficiency. “We seek to use a single set of standards to foster and evaluate quality and that the profession can use to assure quality,” Dr. Nasca said. Furthermore, Dr. Buser said, “A lot of graduate medical education programs are dually accredited by ACGME and AOA. Now these programs will not have to respond to different organizations. It is more efficient from an administrative and cost perspective.” The transition to a unified system is planned to be seamless so that residents in current AOA-accredited residency programs would be eligible to complete residency or fellowship training in ACGME-accredited programs, according to the press release. But there will be
some obstacles on the path to a unified accreditation system. “There are a number of challenges still to face, some of them logistic, many philosophical, some political in nature,” said Dr. Nasca. “2015 is the target date for implementation, if it is to occur,” he continued. “Over the next 12 months we will know whether we’ll be able to proceed. There will be a series of votes to accept key elements of the plan and work out something that can be presented to the ACGME and its member organizations, the AOA Board and AACOM Board, for their decision(s). This implementation is contingent on all parties accepting the proposed plan for a single graduate medical education accreditation process.” ■
Drs. Buser and Nasca reported no relevant financial conflicts of interest.
Guest Editorial
Unification in Graduate Medical Education Col. (R) Peter R. McNally, DO Chief of Gastroenterology Evans Army Hospital Colorado Springs, Colorado Thank you for the opportunity to offer an opinion concerning the Accreditation Council for Graduate Medical Education (ACGME) and American Osteopathic Association (AOA) announcement that MDs and DOs are moving toward a single, unified accreditation system for graduate medical education. It was my great opportunity to participate in the original MD and DO integrated graduate medical education system—military medicine. In the post-Vietnam era, it was difficult to recruit physicians into military service. The Health Professions Scholarship Program (HPSP) was created to attract the finest of medical students, by offsetting the tremendous financial burden of medical school. HPSP indiscriminately accepted medical students from allopathic and osteopathic medical schools from across the country. All allopathic and osteopathic interns and residents wore either scrubs or identical
the great opportunity to work with outstanding physicians from all over the world, and continued to train both original MD and DO integrated graduate medical allopathic and osteopathic physicians. All of the physicians wore scrubs or education system—military medicine. white coats and all were addressed as doctor. Faculty and trainee evaluations military uniforms. They were all addressed as were again objectively based on knowledge, dedication, doctor or by their military rank. In this envi- compassion and commitment to academic excellence. ronment, physicians were not judged by the In the United States, we judge men and women by medical school they graduated from, but by the content of their character, not the color of their skin their knowledge, dedication, compassion for patients or religious creed. In the 21st century, we judge doctors and commitment to excellence and teamwork. Selection not by the medical school they attended, but by their for residencies, fellowships and postdoctoral training in knowledge, compassion and dedication to make new the military was, and continues to be, decided solely on medical discoveries. I am confident that the graduate merit. Each of the military residency programs accom- medical education unification process will make medimodated the unique requirements of both allopathic cal education better for all U.S. doctors. It is with great and osteopathic trainees. From my generation forward, respect that I congratulate the leaders of the ACGME most osteopathic physicians have taken both the allo- and AOA for their courage to find common ground pathic and osteopathic board examinations. that will make the next generation of doctors even After my retirement from the military, I served as greater healers. ■ professor of medicine and director of the gastroenterology fellowship training at the University of Colorado Dr. McNally reported no relevant financial Health Sciences in Denver. During my tenure, I had conflicts of interest.
It was my great opportunity to participate in the
6
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
From the Literature
PPIs Superior to H2RAs To Prevent Stress-Related Mucosal Bleeding PPIs More Effective, but Cost Still a Question BY ROSEMARY FREI, MSC Proton pump inhibitors provide effective prophylaxis in critically ill patients at high risk for stressrelated mucosal bleeding, concluded a meta-analysis of the literature on the topic.
The study showed that prophylactic use of proton pump inhibitors (PPIs) reduces the probability of a gastrointestinal (GI) bleed by 70% compared with prophylaxis using histamine-2 receptor antagonists (H2RAs; Barkun AN et al. Am J Gastroenterol 2012;107:507-520). “I’m already recommending PPI
prophylaxis for high-risk patients, but I’m not using it universally at this point—that requires a separate study,” said David Wolf, MD, assistant professor of gastroenterology at the University of Texas Health Science Center at Houston Medical School, who was not involved in the study.
Save when you register by April 10
PHOTO © VISIT ORLANDO
“Universal PPI use would be quite expensive for the system, without clear gain,” Dr. Wolf noted. The meta-analysis by Barkun et al did not include a cost-effectiveness component. Tanvi Dhere, MD, who also was not involved in the meta-analysis, concurred with Dr. Wolf: “The cost–benefit gained from the prevention of GI bleeding with the use of PPI therapy, despite its significant cost, compared with H2RAs requires further study,” said Dr. Dhere, assistant professor, Division of Digestive Disease, Emory University School of Medicine, Atlanta.
‘Universal PPI use would be quite expensive for the system, without clear gain.’ —David Wolf, MD ORANGE COUNTY CONVENTION CENTER ORLANDO, FLORIDA
2 0 1 3 A S G E A N N U A L P O S T G R A D U AT E C O U R S E
May 20, 2013 Orange County Convention Center Orlando, Florida Held in conjunction with DDW®
Back to the popular one-day format! Course Directors
Todd H. Baron, MD, FASGE Mayo Clinic Rochester, MN
An International and Multidisciplinary Approach to Gastrointestinal Diseases: Patient Care at its Best In today’s healthcare environment, understanding the role endoscopy plays in the multidisciplinary, team-based setting is essential. This course will demonstrate how gastrointestinal endoscopy integrates with specialists in various fields to provide excellent, state-of-the-art care for gastrointestinal diseases. The 2013 ASGE Annual Postgraduate course will feature: lectures and expert * Evidence-based opinion about common issues in daily practice from internationally renowned endoscopic experts and leaders in surgery, oncology and radiology. fic panel discussions and * Topic-specifi breakout sessions for individualized, practice-specifi fic learning.
Vanessa M. Shami, MD, FASGE University of Virginia Health System Charlottesville, VA
If endoscopy is your practice, this is your course!
symposia on a variety of * Thematic gastrointestinal problems, including Barrett’s esophagus, treatment of gastrointestinal bleeding, endoscopic screening, surveillance and treatment of upper and lower luminal neoplasia as well as pancreaticobiliary diseases.
Course Objectives
*
Identify current and emerging technologies in gastrointestinal endoscopy and their applicability to practice.
how respected experts integrate * Describe scientific fi evidence with experience to diagnose and treat gastrointestinal disorders most effectively. the state-of the-art management * Discuss of important gastrointestinal issues in a multidisciplinary manner. current trends in quality assurance * Integrate with effective and costeffective endoscopic interventions. current controversies in the * Characterize utilization of novel endoscopic techniques to screen, detect and treat gastrointestinal luminal and pancreaticobiliary neoplasia.
* Plus much more! For additional information, visit www.ddw.org
“If we are able to identify those ICU patients who are at high risk for GI bleeding [and for whom PPIs are optimal], regular use of PPI therapy in these patients may prove to be not only clinically beneficial but also costeffective,” she said. This is a high-stakes area because, although only a small proportion of ICU patients experience a GI bleed, these critically ill individuals are at risk for mortality from the additional insult of GI bleeding. Studies have shown that both PPIs and H2RAs can reduce the risk for stress-related mucosal bleeding, however, randomized controlled trials (RCTs) of PPIs have yielded conflicting results. Hence, Alan Barkun, MD, MSc, who is the Douglas G. Kinnear Chair in Gastroenterology and professor of medicine at McGill University, in Montreal, and his colleagues conducted this meta-analysis of studies published between 1950 and September 2011 to determine which agent is best for patients at risk for bleeds. The investigators identified eight fully RCTs and five abstracts that met inclusion criteria for their study. The studies included 1,587 patients, of whom 967 were given active treatment with omeprazole (Losec, Prilosec, AstraZeneca), rabeprazole (AcipHex, Janssen-Cilag), pantoprazole or lansoprazole (Prevacid,
7
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Takeda), and 620 were given ranitidine, famotidine or cimetidine. There was no significant heterogeneity between the studies, although Dr. Barkun’s team found that one study had a high risk for bias and nine others had indeterminate bias risk status. The researchers found that prophylactic PPI administration significantly decreased the incidence of clinically significant bleeding, the primary outcome of the meta-analysis (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.17-0.54). The number needed to treat to avoid one episode of an upperGI bleed was 39. The team conducted four sensitivity analyses, the first of which showed that PPIs significantly decreased the incidence of clinically significant bleeding in six trials that had bleeds as a primary outcome (OR, 0.39; 95% CI, 0.19-0.77) and also in several trials where bleeding was not a primary outcome (OR, 0.17; 95% CI, 0.06-0.52). Sensitivity analysis of the eight
full publications also showed that PPIs significantly reduced bleeding compared with H2RAs (OR, 0.35; 95% CI, 0.18-0.68), and an analysis of the five abstracts revealed a similar outcome (OR, 0.18; 95% CI, 0.05-0.63). When the researchers focused on the 11 trials that included patients receiving enteral feeding or a naso/orogastric tube, PPIs also significantly reduced bleeding incidence (OR, 0.33; 95% CI, 0.18-0.60). In the two remaining studies, however, PPIs did not decrease bleeding. PPIs were not associated with significant changes in the secondary outcomes of the metaanalysis, nosocomial pneumonia and mortality: The investigators observed that PPIs did not lower the risk for nosocomial pneumonia compared with H2RAs in seven studies (OR, 1.05; 95% CI, 0.69-1.62) and did not lower all-cause mortality risk in eight trials (OR, 1.19; 95% CI, 0.841.68). Among the three studies that examined total mean ICU stay, PPIs and H2RAs were
associated with a similar length of stay. “PPI prophylaxis significantly decreased rates of clinically significant bleeding compared with H2RAs, without affecting the development of nosocomial pneumonia or mortality rates,” the researchers concluded. The use of PPIs to prevent stressrelated mucosal bleeding “is superior to prophylaxis with H2RAs,” they said. Dr. Barkun noted that he and his team also have completed a cost-effectiveness analysis of PPIs versus H2RAs in this population and have submitted it for peer review. “These data, within the limitations of the adopted assumptions of costs and probabilities of outcomes, will help further guide clinicians and third-party payers in optimal decision making in the management of these patients,” he said. ■
Aspirin–PPI Combo continued from page 3
the two treatment groups: Nine patients taking PA32540 experienced major cardiac AEs compared with 13 patients taking aspirin alone. “Discontinuation of aspirin therapy is often due to the adverse GI effects of aspirin,” Dr. Connor noted. “In these pivotal studies, PA32540 was associated with a significantly lower rate of treatment discontinuation than aspirin alone. Patient adherence to aspirin therapy saves lives, as aspirin discontinuation increases the likelihood of potential adverse cardiovascular events,” he added. Dr. Johnson noted that it is important to appropriately select patients who might be candidates for a combined therapy such as PA32540. “Not everybody who takes aspirin needs a proton pump inhibitor, so where a product like this would be of significant benefit is in patients identified at incremental risk. Evaluation of risk stratification factors such as age, nonsteroidal antiinflammatory drug [NSAID] use, history of ulcers and complications from ulcers can help determine appropriate patient selection.” NSAID complications frequently present without preceding symptoms, so risk stratification is important, he said. In a press release, Pozen Inc., said the company plans to pursue an indication for PA32540 for the secondary prevention of cardiovascular disease in patients at risk for aspirin-induced ulcers. ■
Dr. Barkun is a consultant for AstraZeneca and Takeda Canada. Drs. Wolf and Dhere did not report any relevant conflicts of interest.
Montefiore Einstein Center for Transplantation
A World-Class Center of Excellence Dedicated to Liver Disease The Comprehensive Liver Program at Montefiore Medical Center in New York City is a multidisciplinary integrated practice bringing experts together in hepatology, advanced hepatobiliary surgery and liver cancer. One-Year Adult Patient Survival Rate The Marion Bessin Liver Research Center at Albert Einstein College of Medicine is one of the oldest continuously funded National Institutes of Health Liver Centers in the United States and has 40 faculty investigators. More than 200 adult and pediatric patients have been evaluated in Montefiore’s new liver transplant program.
90%
93%
Montefiore 89%
85
%
U.S. National Average
The Children’s Hospital at Montefiore has a dedicated hepatology and transplant program and is ranked among America’s top pediatric hospitals by U.S. News & World Report.
80%
To refer or discuss an outpatient, please call 888-RX-LIVER (888-795-4837) or 718-920-2800 for inpatient transfers.
Scientific Registry for Transplant Recipients, www.srtr.org
To watch our vignette on stem cell research or to learn more about the Montefiore Einstein Center for Transplantation, visit www.montefiore.org/transplant
8
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
IBS continued from page 1
American College of Gastroenterology annual meeting (abstract 52). ‘Given the visible structural lesions in the small bowel “Given the visible structural lesions in the small bowel of IBS of IBS patients, I think it is accurate to say that we can patients, I think it is accurate to no longer call IBS a functional bowel disorder.’ say that we can no longer call IBS —Julia Liu, MD a functional bowel disorder,” said principal investigator Julia Liu, MD, assistant professor at the University of Alberta’s Center of Excellence for Gastrointestinal patients during routine endoscopy and prospectively Inflammation and Immunity Research in Edmonton, documented epithelial gap density—an indicator of epiAlberta, Canada. thelial cell loss—in the small intestine. Two independent Using probe-based confocal laser endomicroscopy and blinded investigators reviewed the pCLE images (pCLE) in 17 patients with IBS and 18 healthy con- and quantified epithelial gap densities. Researchers also trols, Dr. Liu and her colleagues found that small bowel examined random biopsies of the patients to exclude epithelial cell loss was five times higher in patients other underlying pathologies. Baseline demographics in with IBS. They conducted fluorescein-aided pCLE in the two groups were similar.
One patient with IBS was found to have microscopic colitis on biopsy and was excluded from the analysis, the researchers reported. Of the remaining 16 patients with IBS, 12 had diarrhea-predominant IBS and four had constipation-predominant IBS. All met the Rome III diagnostic criteria for functional gastrointestinal disorders. According to Dr. Liu, pCLE images revealed a median of 32 epithelial gaps per 1,000 cells among patients with IBS compared with a median of six gaps per 1,000 cells in healthy controls (P<0.001). Apart from the paradigm-shifting nature of the findings, Dr. Liu believes the structural epithelial abnormalities that her team documented can be used to diagnose IBS. Statistical analyses her team conducted showed that quantifying epithelial gaps with pCLE images could yield a diagnostic sensitivity of 62% and
MuDelta Reduces Symptoms of Frequency and Urgency in IBS Promising Phase II Data Lead to Phase III Development of New IBS Drug BY CAROLINE HELWICK Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) experienced a significant reduction in frequency and urgency of bowel movements (BMs) while being treated with MuDelta, a µ-opioid agonist/δ-opioid antagonist being developed by researchers at Furiex Pharmaceuticals, Wilmington, N.C. “Our results indicate that MuDelta provides statistically significant and clinically meaningful efficacy in improving bowel movement frequency and urgency in patients with IBS-D,” said Paul Covington, MD, of Furiex Pharmaceuticals Inc. Explaining the rationale for the study, Dr. Covington said, “Simultaneously targeting µ- and δ-opioid receptors in the gastrointestinal tract may provide symptom relief for sufferers of diarrhea-predominant irritable bowel syndrome without the constipating effects of a pure µ-opioid agonist.” A recently published study supports the idea that the activity of MuDelta at two different opioid receptors controls gastrointestinal function and decreases pain, and potentially mitigates the
constipating effect of an unopposed µ-agonist (Wade PR et al. Br J Pharmacol 2012;167:11111125). Furiex completed Phase II studies of the drug last year; the drug is currently in Phase III development.
BM frequency over a period of 84 days, using a responder definition of at least 50% of days. The percentage of UE-free days, of at least 75% of days, also was improved among recipients of MuDelta compared with those
‘Our results indicate that MuDelta provides statistically significant and clinically meaningful efficacy in improving bowel movement frequency and urgency in patients with IBS-D.’ —Paul Covington, MD
In the double-blind, placebocontrolled, Phase II trial of MuDelta, 807 patients who met Rome III diagnostic criteria for IBS-D received twice-daily treatment with MuDelta at doses of 5, 25, 100 or 200 mg, or placebo, for 12 weeks. In the most recent analysis of data from the Phase II trial, researchers evaluated data on frequency of BMs and urgency episodes (UEs) based on patientreported daily calls to an interactive voice-response system. At baseline, patients averaged 4.5 to five BMs per day and approximately three UEs per day. In patients with three or more BMs per day, MuDelta improved
who received placebo, according to Dr. Covington. “These patients were having a lot of BMs, and many of them were planning their days around this,” he said. “They experienced a 10% to 20% reduction in BM frequency with 100 and 200 mg of MuDelta.” In a comparison of the 100-mg dose of MuDelta with placebo, mean BM frequency was significantly lower with MuDelta over the course of 28 days of treatment (relative risk [RR], 0.90; P=0.032), 56 days of treatment (RR, 0.91; P=0.042) and 84 days of treatment (RR, 0.85; P=0.002). Mean UE frequency also was significantly
lower for the 100-mg treatment group compared with placebo at 28 days (RR, 0.77; P=0.021), 56 days (RR, 0.79; P=0.032) and 84 days (RR, 0.75; P=0.012). Gianrico Farrugia, MD, of Mayo Clinic in Rochester, Minn., said he found it interesting that a drug combining an opioid agonist and an opioid antagonist “appears to confer some advantage in IBS-D.” However, Dr. Farrugia pointed out that “it is also clear that the placebo had a significant effect as well, and this is typical for patients with this condition.” MuDelta currently is being studied in Phase III trials being conducted in centers in the United States, Canada and the United Kingdom. “The Phase III program is designed to capture the 12-week composite end points as specified in the FDA 2012 guidance on IBS, while also collecting longer term global outcomes and pain data that could support registration in the European Union,” according to Furiex. ■ Dr. Covington is an employee of Furiex Pharmaceuticals, which provided research funding for the study. Dr. Farrugia reported no relevant conflicts of interest.
9
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
a specificity of 89%, with a positive predictive value of 83% and a negative predictive value of 73%. However, Dr. Liu acknowledged that, “this was a pilot study, and we need to confirm the diagnostic potential of pCLE-detected epithelial gaps in a large, prospective, multicenter study with many more patients.” She added that “although we only looked at the terminal ileum, I suspect that similar findings are present throughout the intestine.” Lucinda Harris, MD, associate professor of medicine in the Department of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minn., an IBS expert who was not involved in the study, cautioned that the results need to be replicated before conclusions can be drawn. “[CLE] is a relatively new technique of uncertain
Mesalamine continued from page 1
(IBS), according to research presented at the 2012 American College of Gastroenterology (ACG) annual meeting. “[Other] single-center observational studies have suggested a significant response to mesalamine in all forms of IBS,” said primary investigator, Jeffrey Aron, MD, of California Pacific Medical Center, in San Francisco, referring to a study in which mesalamine reduced the activation of immune cells and mast cells in patients with IBS (Corinaldesi R et al. Aliment Pharmacol Ther 2009;30:245-252). “The primary objective of the study,” he explained, “was to determine the optimal daily dose that provides adequate relief from the symptoms of IBS with diarrhea. The secondary objective was to evaluate the safety of the 12-week course of the two dosing regimens in these patients,” Dr. Aron told attendees of the ACG meeting. Dr. Aron and his colleagues conducted a multicenter, randomized, placebo-controlled, double-blind trial of 148 patients who were given 750- or 1,500-mg daily doses of mesalamine granules or placebo for 12 weeks. Patients were eligible for the study if they met Rome III diagnostic criteria for gastrointestinal functional disorders and experienced diarrhea during the seven- to 13-day eligibility period; scored an average of at least 3 for abdominal pain and bloating and at least 5 for stool consistency; and experienced no adequate relief from symptoms during screening and randomization. The investigators monitored patients beginning on day 5 of treatment. Patients were identified as responders if they improved at least 30% from baseline in
‘The role of barrier function and the meaning of this difference in epithelial gap may certainly fit as another physiologic explanation, particularly in IBS patients with a post-infectious etiology with diarrhea, but may not explain the disorder in all subtypes.’ —Lucinda Harris, MD
significance for this indication,” Dr. Harris said. She also pointed out that most of the study subjects had diarrhea-predominant IBS, meaning the findings may not be generalizable to all IBS subtypes. “IBS is a diverse disorder with several different theories of pathogenesis,” she said. “The role of barrier
function and the meaning of this difference in epithelial gap may certainly fit as another physiologic explanation, particularly in IBS patients with a post-infectious etiology with diarrhea, but may not explain the disorder in all subtypes. However, it certainly does warrant further study.” ■
Dr. Liu reported no conflicts of interest. Dr. Harris is a consultant for Dyax, Forest Laboratories Inc., GastroIntestinal Health Foundation, Ironwood Pharmaceuticals, Inc., and Takeda Pharmaceuticals.
their average weekly abdomi- ‘Many experts in the field believe there is nal pain score, and if the number of days per weekk some overlap between IBS and IBD with with stool consistency of type respect to etiology and pathophysiology.’ 6 or 7 was halved. Weeklyy —Brian E. Lacy, MD, PhD responders needed to respond for at least two of four weeks, and monthly responders forr at least two of three months. Overall response for ab bdominal pain and stool consistenccy was significantly greater in the mesalamine 1,500-mg dose group than in the placebo group (47.1% vss. 28%, respectively). There was no significant difference between thee 750mg mesalamine dose and placebo groups. “Looking at monthly ressponders, in the first month on ne can see a significant improvem ment in the 1,500-mg group; 43.11% versus 23% in placebo,” Dr. Arron noted. “What’s exciting about this data is that this response is maintained over three months: 45.1% at two monthss and 45.1% at three months, with the usual increase in the placebo response over time.” i ” The researchers concluded that mesa- etiology and pathophysiology,” Dr. Lacy lamine granules at a dose of 1,500 mg per noted. “There are some studies showing day for 12 weeks provided a statistically that microscopic inflammation may be significant improvement in abdominal present in IBS patients. Thus, mesalapain and stool consistency in patients mine might make sense in some patients.” with diarrhea-predominant IBS. No difDr. Lacy also pointed out some caveats: ferences were recorded in adverse events The number of participants was small; 12 observed in the mesalamine group com- weeks was a good, but insufficient, length pared with the placebo group. of time to achieve FDA acceptance; and Brian E. Lacy, MD, PhD, professor colonoscopy was not required. of medicine at Dartmouth-Hitchcock “This is very important, since IBD can Medical Center, in Lebanon, N.H., be confused with IBS and microscopic found the study an interesting and novel colitis also can mimic IBS,” he said. “The approach to IBS treatment. low dose did not work, but the higher “Many experts in the field believe there dose did. Was that a true effect, or is it is some overlap between IBS and IBD due to the fact that the numbers are low? [irritable bowel disease] with respect to “I believe this warrants further
‘There are some studies showing that microscopic inflammation may be present in IBS patients. Thus, mesalamine might make sense in some patients.’ —Brian E. Lacy, MD, PhD investigation; it’s intriguing,” Dr. Lacy concluded. l d d “Th “The next study d needs d to be b larger and longer, and patients need to have colonoscopy with random biopsies.” Dr. Aron noted that the decision not to conduct colonoscopies for this study was based on the findings of previous IBS trials that support the robust nature of Rome II diagnostic criteria (Chey WD et al. Am J Gastroenteroll 2010;105:859-865 and Ozdil K et al. BMC Gastroenterol 2011;11:96). He also said that a larger, Phase III trial that addresses Dr. Lacy’s points will be undertaken. ■ This study was supported by Salix Pharmaceuticals, Inc. Dr. Aron receives consultant fees and research support from Salix.
THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES
The Gastric Cancers: Targeted for Personalized Medicine The blunt instrument of cancer chemotherapy, as wielded against gastric cancer, is likely to get considerably more precise and effective. There are many to thank for this development, not least of which are researchers at NewYork-Presbyterian Hospital, who have advanced our understanding of the family of oncologic disorders whose group name—gastric cancer—belies significant variability. The emerging understanding of gastric cancer as a group of subtypes whose susceptibility to chemotherapeutic intervention is not monolithic is set to have a significant effect on clinical drug trials and cancer therapy.
Additionally, a rising tide of research on biomarkers has begun to differentiate susceptibilities to chemotherapy.
Faculty Manish A. Shah, MD Director of Gastrointestinal Oncology Co-director of Research Center for Advanced Digestive Care NewYork-Presbyterian/Weill Cornell Medical Center Associate Professor of Medicine Weill Cornell Medical College New York, New York
Timothy C. Wang, MD Division Chief, Digestive and Liver Diseases NewYork-Presbyterian/Columbia University Medical Center Silverberg Professor of Medicine Columbia University College of Physicians and Surgeons New York, New York
Introduction The Lauren classification scheme,1 the nearly half century–old system that separates gastric adenocarcinomas into either intestinal or diffuse type based on histopathology, does not adequately reflect the latest understanding of gastric cancer. Manish A. Shah, MD, Director of Gastrointestinal Oncology at NewYork-Presbyterian/Weill Cornell Medical Center, where he is also Co-director of Research at the Center for Advanced Digestive Care, noted that chemotherapy for gastric cancer has been poorly defined for decades. “Whether the patient had diffuse- or intestinal-type gastric cancer didn’t really matter too much in these studies; the patient would receive the chemotherapy that was available for gastric cancer as a whole.” Dr. Shah, who is also Associate Professor of Medicine at Weill Cornell Medical College, added, “In clinical trials, a chemotherapy’s effectiveness was reported generally, not broken down into subtypes. The patients had stomach cancer, and this trial showed how well the chemotherapy worked against it. This is how research on gastric cancer has been performed for decades.” Two major factors have converged to change this. First, there is a greater understanding of the varieties of gastric cancer that exist, as well as the factors that influence them.
10
Mouse Models Timothy C. Wang, MD, Division Chief, Digestive and Liver Diseases, NewYork-Presbyterian/Columbia University Medical Center, who is the Silverberg Professor of Medicine at Columbia University College of Physicians and Surgeons, is a world leader in the creation of mouse models for gastric cancer. The mouse models from Dr. Wang’s laboratory help further understanding of how these cancers develop, including their genetic requisites. The mouse models are crucial because a fuller picture of how these gastric cancers develop will offer the opportunity to intervene at an earlier stage, or perhaps prevent the cancer entirely. Dr. Wang has extensive experience with mouse models of Helicobacter felis and H. pylorii infection, and his lab was the first to fully describe a murine model of Helicobacterdependent gastric carcinogenesis.2 “What we have been doing over the past several decades is combining Helicobacterr infection with genetic modifications in transgenic mice that overexpress growth factors or cytokines, or with various diets, or with other types of infections. We are trying to determine what are the important cofactors that bring about the induction of stomach cancer. Only about 1% of individuals infected with Helicobacterr go on to develop stomach cancer, so why is that? We are researching genetically determined host factors that predispose to stomach cancer.” Dr. Wang has found that certain coinfections can accelerate, whereas others can impede, the development of cancer. Surprisingly, helminth worms slow gastric cancer in those infected with H. pylori,3 a fact that is likely reflected in the low prevalence of these cancers in low-lying, wet areas of Africa where the worm is common, despite the locally high rate of H. pylorii infection. Dr. Wang has used his mouse models to confirm human observations. A report by El-Omar et al in Nature found that specific genetic polymorphisms in the gene for the cytokine interleukin-1beta (IL-1β) seemed to correlate with the susceptibility of gastric cancer in the presence of infection with H. pylori.4 Dr. Wang’s lab was able to overexpress IL-1β in the stomach of mice, which went on to spontaneously develop stomach cancer. When infected with H. felis, the mice developed stomach cancer very rapidly, suggesting that Helicobacterr infection together with high amounts of IL-1β create
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
FROM THE BENCH TO an excellent environmental milieu in which stomach cancer THE BEDSIDE develops. These findings validated the human observations of El-Omar et al.5 “What we have learned from our H. pylorii mouse modsee pages 10-11 els is that the particular type of immune response is what drives the development of cancer. But it is clear that other infectious agents or bacteria can modulate the response. In the gut there are trillions of bacteria—in fact, there are more bacteria in the gut of a mammal than there are cells in its body. For that reason this is a complicated question.”
Heterogeneity The more one explores the differences in gastric cancers, the more variations present themselves. Most obvious, perhaps, are the geographical differences in prevalence. In the United States, and in the developed West generally, proximal tumors, cancers of the gastroesophageal (GE) junction, distal esophagus, and cardia tumors are significantly more prevalent than in Korea, where middle and lower gastric cancers predominate.6 Staging at diagnosis differs, too, with earlier staging more likely in Korea, which enjoys higher overall survival. Gastric cancer is most common in China and Japan, where intestinal-type cancer predominates. Epidemiologies vary. Cardia and GE junction cancers, more common in the industrialized West, are 5 times more likely in men than women and twice as likely in blacks than whites. Distal noncardia cancers are twice as likely in men than women and 4 times more likely in blacks than whites. The main risk factors for gastric cancers are H. pylori, tobacco use, and genetic predisposition. But the relationships are not straightforward. “Stomach cancer is in part disappearing because of the decline in H. pylori, but there is a disconnect between its prevalence in some countries and the rate of cancer. For one thing, it seems that there are differences in bacteria strains, so researchers talk about the African, Asian, and European strains, for example,” Dr. Wang said. “Stomach cancer is most common per case of H. pylorii infection in Japan, so it might be that the Japan strain is the most virulent. There are regions in China and Korea that nearly match Japan in terms of virulence.” Diet may be another factor, although dietary studies have been difficult to replicate. The role of H. pylorii varies among subtypes of gastric cancer. The pathogenesis of noncardia gastric cancer is initiated by chronic inflammation (eg, from H. pylori), progressing from chronic gastritis, intestinal metaplasia, to dysplasia.7-9 And yet the presence of H. pylorii gastritis may be protective against proximal adenocarcinomas.10,11 Thus, as H. pylori infection has decreased in the industrialized West, a “proximal shift” has been noted, with more proximal GE junction tumors, as well as esophageal cancers, occurring. “There is this idea that gastric cancers are decreasing when, in fact, if you look at individual subtypes, you see quite a lot of variation,” Dr. Shah said. These geographic differences affect clinical trials. “If you look at a clinical trial done in Europe or North America, perhaps 25% of the patients with stomach cancer will have GE
Supported by
A
microtubules (the drug target) may be subtype-dependent (Figure). This finding is now being pursued in a prospective clinical trial in gastric cancer. In the future, oncologists treating patients with gastric cancer will note the subtype of gastric cancer and treat accordingly, using a drug or drugs that are specifically effective for that group. “By doing this we will be able to increase survival for the whole group of gastric cancers,” Dr. Shah said. “It is still a very deadly disease. This type of research will improve patient outcomes.”
B
References 1. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31-49, PMID: 14320675. 2. Wang TC, Dangler CA, Chen D, et al. Synergistic interaction between hypergastrinemia and Helicobacterr infection in a mouse model of gastric cancer. Gastroenterology. 2000;118:36-47, PMID: 10611152. 3. Fox JG, Beck P, Dangler CA, Whary MT, Wang TC, Shi HN, Anderson CN. Concurrent enteric helminth infection modulates inflammation, gastric immune responses, and reduces Helicobacter-induced gastric atrophy. Nat Med. 2000;6:536-542, PMID: 10802709.
Figure. Drug-target engagement in gastric cancer. Intestinal-type (A) and diffuse-type (B) gastric cancer cell lines following treatment with docetaxel. Arrows (A) show presence of mitotic arrest, whereas B shows no abnormalities of the microtubule network.
junction tumors, maybe 30% will have diffuse cancers, and the rest will be intestinal antral tumors,” Dr. Shah explained. “If you did the same clinical trial in Japan, 5% would have GE junction tumors, and the rest would be evenly split between diffuse and intestinal antral tumors. “And the question is,” Dr. Shah added, “does that matter?”
Tomorrow’s Therapy Increasingly, as targeted pharmacologic intervention for gastric cancer is tested in clinical trials, the heterogeneity of gastric cancer will indeed matter. “There are many new drugs for gastric cancer being tested now or that will be soon,” Dr. Shah said. “There are MET inhibitors, antiangiogenic agents, EGFR [epidermal growth factor receptor] inhibitors, and others. The more targeted the drug and specific the effect, the greater the chance the drug is subtype-specific.” Dr. Shah offered an example. “Trastuzumab (Herceptin, Genentech) is approved for HER2-positive gastric cancer, for instance, but diffuse gastric cancer is rarely HER2-positive, GE junction tumors are HER2-positive about 30% of the time, and distal intestinal gastric cancers are HER2-positive about 20% of the time. So the target differs among subtypes,” thereby demonstrating their relevance.
Dr. Shah and his colleagues participated in a trial of bevacizumab (Avastin, Genentech/Roche) when added to capecitabine plus cisplatin for first-line treatment of gastric cancer; the primary end point was overall survival.12 Results showed that bevacizumab, while increasing progressionfree survival and overall response rate, did not improve overall survival. A follow-up study evaluated the efficacy of bevacizumab using a comprehensive prospective biomarker analysis, and found that baseline plasma levels of vascular endothelial growth factor A (VEGF-A) and tumor expression of neuropilin-1 are candidate biomarkers of efficacy.13 It also was noted that plasma VEGF-A levels were predictive of efficacy in non-Asian patients. In a separate study, Dr. Shah and his colleagues found that when bevacizumab was added to chemotherapy in patients with metastatic GE adenocarcinoma, intriguing differences according to gastric cancer subtype were revealed.14 The response rate was 85% in patients with proximal/GE junction tumors, 56% in patients with distal/intestinal tumors, and only 38% in patients with diffuse tumors. Dr. Shah and his colleagues are now examining the influence of gastric cancer subtype on taxane sensitivity, with preliminary data suggesting that the ability of the drug to engage with
4. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404: 398-402, PMID: 10746728. 5. Tu S, Bhagat G, Cui G, Takaishi S, et al. Overexpression of interleukin1beta induces gastric inflammation and cancer and mobilizes myeloidderived suppressor cells in mice. Cancer Cell. 2008;14:408-419, PMID: 18977329. 6. Strong VE, Song KY, Park CH, et al. Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Ann Surg. 2010;251:640-646, PMID: 20224369. 7. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylorii infection and the development of gastric cancer. N Engl J Med. 2001;345:784-789, PMID: 11556297. 8. Correa P, Shiao YH. Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res. 1994;54(suppl):1941s-1943s, PMID: 8137316. 9. Shah MA, Ajani JA. Gastric cancer—an enigmatic and heterogeneous disease. JAMA. 2010;303:1753-1754, PMID: 20442394. 10. Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter Pylori seropositivity. J Natl Cancer Inst. 2006;98:1445-1452, PMID: 17047193. 11. Abbrederis K, Bassermann F, Schuhmacher C, et al. Erythropoietin-alfa during neoadjuvant chemotherapy for locally advanced esophagogastric adenocarcinoma. Ann Thorac Surg. 2006;82:293-297, PMID: 16798232. 12. Ohtsu A, Shah M, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-3976, PMID: 21844504. 13. Van Cutsem E, de Haas S, Kang Y-K, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30:2119-2127, PMID: 22565005. 14. Shah MA, Jhawer M, Ilson DH, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011;29:868-874, PMID: 21189380.
Disclosures: Dr. Shah reported that he has received research funding from Genentech and Sanofi. Dr. Wang reported no relevant disclosures. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, NewYork-Presbyterian Hospital, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. BB132
Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
11
12
OPINION
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Food for Thought Lauren Kosinski, MD Assistant Professor of Surgery Medical College of Wisconsin Milwaukee, Wisconsin
Frederick L. Greene, MD General Surgeon Surgical Oncologist Charlotte, North Carolina It was intriguing to hear the news last year that the Disney Company was beginning an initiative to promote good nutritional choices by only accepting food product advertisers that promoted healthful options. We should applaud the company’s initiative to combat the obesity epidemic by encouraging its young audience to associate the magic of Disney with healthful foods. A slew of other initiatives have tried to encourage better eating habits among young people. Sixteen years ago, Alice Waters, the celebrity chef founder der of Chez Panisse Restaurant credited with introduciing nouvelle cuisine to American diners, established an Edible Schoolyard Project and School Lunch Inittiative in Berkeley, Calif. These programs were bu uilt on the nouvelle cuisine concept emphasizingg eating fresh, locally grown and seasonally available foods prepared in uncomplicated ways that enhanced d the natural flavors of the base ingredients. The Edible Schoolyard engages middle school children in gardening and recycling projects that not only help them appreciate connections between food and culturee, but also allow them to participate in the harvvest, which ultimately contributes to the luncches 10,000 children receive each day. In a sim milar venture, celebrity chef Jamie Oliver aiired a reality television series in 2010 intended d to help combat obesity by educating and inspirring young people, who previously could not iden ntify common fruits and vegetables, to grow and prepare fresh food. His work continues through h the Jamie Oliver Foundation. And we can’t foorget Michelle Obama’s campaign to improve school lunches, which prompted the U.S. Departm ment of Agriculture to make some major revisioons to nutritional standards for school lunches. In the same week as Disney’s annoouncement, New York City Mayor Michael Blooomberg was advocating banning the sale of large sweetened drinks—an intriguing approach to reducin ng the consumption of sugar and addressing problemss of diabetes and obesity. It may, however, be very difficult to have appropriate oversight and sanctions to assure that this soft drink ban or the Disney initiative have the anticipated outcome. All around us, there is growing commitment to improving eating habits to prevent obesity, heart disease and diabetes in order to live more sustainably and have a better quality of life. But even with these changes, Congress deemed pizza a vegetable in 2011 to keep it as an option on school cafeteria menus, and special interest groups that represent virtually every pizza ingredient marshaled their forces to resist alterations in pizza composition. No wonder children are confused! So where do we as physicians stand? Some of us
are the worst offenders. Coke and Mountain Dew are considered the “breakfast of champions” among surgical residents and staff. The last time most of us had a real breakfast on a weekday was probably when we were home sick: a long time ago. We rarely stop for 15 minutes to eat during the day. Needing to eat (or drink) has been seen as a sign of weakness among surgeons. In fact, one department chairman was famous for never being seen eating. At best, coffee and a high-glycemic-index donut comprise the morning offerings at most of our conferences. Our hard-working cafeteria staff endeavor to make healthy meals, but we still have ice cream bars
All of us, and especially those who serve in medical staff leadership positions, should make it known to our nonmedical administrative colleagues that foods with unacceptable nutritional value have no place in an environment that is promoting good health.
instead of juice bars and an abundance of fried foods on the breakfast, lunch and dinner lines. If you’re hungry or thirsty after a late case in the operating room, the vending machines in the lounge and the rest of the hospital usually are fully stocked with candy, chips and soda. In most of the hospitals in the United States, the food offered to patients, visitors, support staff, nurses and physicians has no place in institutions whose sole purpose is promoting good health. Once the diner gets past the salad bar (which also often has an abundance of canned foods or vegetables sliced, diced and packaged in ways that reduce their value), most of what can be found is the antithesis of nutritional well-being. Perhaps the time has come for us to reconsider our eating habits and relearn how preparing,
enjoying and sharing food can help us be healthier and happier. Health care providers, however, may face many obstacles on the road to healthier living. Just as eliminating tobacco products within hospitals encountered great resistance from within our own ranks, instituting better food practices may cause similar opposition. There are many ways we can positively affect the nutritional landscape in our own hospitals. While making rounds, we often have the occasion to cast a glance at our patients’ trays. We should take opportunities to look at the foods our patients are eating as they recover and talk to them about good nutrition. We can each be positive forces for change if we see that our hospital dining facilities are guilty of serving fatty and starchy foods rather than fresh or organic produce, grains and caffeine-free and sugar-free beverages. We also can make sure that the impulse-buy choices at the cafeteria are healthier. We can ask for different kinds of foods at our conferences and try to encourage work breaks throughout the day to eat. We also should be sure our residents and students are eating during the day, perhaps by providing thermoses or insulated lunch bags as thank yous for good work instead of coffee coupons. The difficulties legislating lifestylle changes are obvious. The thirsty New Yorker wanting a Big Gulp can simply substitute two regular size sod das for the prohibited ginormous one. It is less obvioous to discern whether savvy advertising camp paigns reflect corporate values. Will Disney practice what it preaches? E Efforts to capitalize on consumeer approval by restricting ad dvertising contracts to nuttritionally reputable prroducts may have no bearing on what is b aactually serviced at Disney Enterprises. It is reported that 30 ttons of fruits and vegetables grown at Epcot Ceenter are served in Disneey World restaurants, but appaarently each year visitors consum me nearly six Cokes for every bottle of water, and 10 million hamburgers, 6 millioon hot dogs and 9 million pounds of french fries are serveed. Likewise, we must consider whetther we physicians will embrace the behaviors we advocate. We have a real opportunity in our health care centers to take a leadership role to create an environment that prom motes good nutritional concepts for patients, patients visitors and health h care personnel. Institutions should be highlighted for their best practices and serve as examples of good nutritional approaches to health. Reducing obesity and preventing gastrointestinal cancer and heart disease begin in our hospitals and health care facilities. All of us, and especially those who serve in medical staff leadership positions, should make it known to our nonmedical administrative colleagues that foods with unacceptable nutritional value have no place in an environment that is promoting good health. In meeting this challenge on behalf of the patients we serve, we also have the chance to take care of ourselves, perhaps even to redefine the admirable surgeon as the one who works hard but lives well too. ■
13
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Expert Calls Diet ‘Next Big Thing’ in IBS BY TED BOSWORTH A large body of evidence suggests that diet modification can contribute to a substantial reduction in or elimination of symptoms associated with irritable bowel syndrome (IBS), according to an expert in the field.
of foods they eat influence the risk for worsening of their IBS symptoms. He noted that physicians often counsel their patients with IBS to avoid caffeine, chocolate and junk food, despite the very limited evidence that reduced intake of these items makes a difference, but he recommended a more systematic approach.
Physicians often counsel their patients with IBS to avoid caffeine, chocolate and junk food. Dr. Chey recommends a more systematic approach.
“It is starting to become more and more apparent that diet really should play a central and very early role in the management of patients with IBS,” said William D. Chey, MD, professor of gastroenterology at the University of Michigan Health System, in Ann Arbor. “We have completely changed the way we run our program,” said Dr. Chey of the functional bowel clinic at his institution. “Dietary therapy is now front and center as first-line therapy in virtually every patient we see.” According to Dr. Chey, a majority of patients report that the amount and type
Celiac Screening Specifically, Dr. Chey recommended screening all patients with IBS for celiac disease. He acknowledged that the diagnostic yield may be low but cited several studies demonstrating that gluten-free diets can reduce symptoms of IBS substantially. For IBS patients who test negative for celiac disease, Dr. Chey considers a low carbohydrate diet. Although lactose intolerance has not been reported to be more prevalent in patients with IBS, emerging evidence suggests that IBS patients who are deficient in lactase—and who often have
underlying abnormalities in motility and visceral sensation—are more likely to develop symptoms in response to fermentation of lactose in the colon. Dr. Chey also cited evidence that food hypersensitivities are more common in patients with IBS, and that elimination diets may be useful for personalizing a dietary approach to control symptoms.
Low FODMAP Diet Dynamic health care speakers sharing with GI leaders the latest on reform, change and the future of gastroenterology.
St. Patrick’s Day weekend
March 15-17, 2013 Boston Park Plaza Hotel s Boston, MA View the program & register online at www.giroundtable.com or call: 865-686-4637
Dealing with
Disruptive Change Keynote Speakers X X X
Donald M. Berwick, MD MPP M. Bridget Duffy, MD Regina E. Herzlinger, PhD
Conference Directors X X
Klaus Mergener, MD, PhD, MBA Bergein F. Overholt, MD
The so-called low FODMAP (fermentable oligo-, di- and monosaccharide and polyol) diet also may be beneficial for patients with IBS. The concept of the FODMAP diet is that poorly absorbed carbohydrates are fermented by colonic bacteria, which leads to the production of gas and short-chain fatty acids; this creates an osmotic load in the colon, leading to symptoms of bloating, flatulence, cramping, urgency and diarrhea. The components of the FODMAP diet are prebiotics, and thus exert effects on the gut microbiota. According to Dr. Chey, several studies, including one published last year (e.g., Staudacher HM et al. J Hum Nutr Diet 2011;24:487-495), have contributed evidence to the premise that a diet low in FODMAPs may relieve symptoms of IBS, particularly in patients with symptoms of bloating, abdominal pain and flatulence. There also is evidence that diet influences colonic transit time. The premise that IBS is associated with changes in
colonic transit time was substantiated by Dr. Chey’s father in a study published a decade ago (Chey WY et al. Am J Gastroenteroll 2001;96:1499-1506). Dr. Chey said that clinicians at his center are now using a systematic approach to diet modification to reduce symptoms of IBS. He predicted this approach will spread. “It is very clear to me that diet is the next big thing in IBS,” Dr. Chey said.
Diet an ‘Extremely Complex Subject’ Asked to comment, Michael Camilleri, MD, of Mayo Clinic, Rochester, Minn., called the concept both interesting and important, but he cautioned that data supporting diet modification for IBS—including the low FODMAP diet and gluten-free diets—should be interpreted conservatively “given the small size of studies to date, unclear mechanism to explain effects and incorporation of subsets of patients, such as those who already have been demonstrated to be sensitive to gluten.” Overall, Dr. Camilleri characterized the relationship of diet and IBS as “an extremely complex subject,” and said that the effects of diet, other than fiber, on colonic transit and the gut microbiome “require much more formal and detailed, prospective studies.” Ultimately, Dr. Camilleri said that diet and IBS is a promising area of study, but the current data appear to offer limited guidance for management at the present time. ■
14
ACG 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Experts’ Picks
Best of the American College of Gastroenterology: Part 2 continued from page 1
Michel Kahaleh, MD Professor of Clinical Medicine Chief of Endoscopy Medical Director of the Pancreas Program Division of Gastroenterology & Hepatology Department of Medicine Weill Cornell Medical College New York, New York
6.
POEM (PerOral Endoscopic Myotomy): Effective NOTES (Natural Orifice Transluminal Endoscopic Surgery) Accessible to the Gastroenterologist, 3 Year Experience at a U.S. Center (Stavropoulos S et al) This abstract included data from 37 patients with achalasia who were treated with peroral endoscopic myotomy (POEM) at a single institution between 2009 and 2012. All of the procedures were conducted by a gastroenterologist. The majority of patients had non-sigmoid–type esophageal dilations, with preprocedure dilations measuring a mean of 5.1 cm (range, 2.1-11 cm). Of these patients, 35% had failed prior therapies, including botulinum toxin injections, pneumatic dilations and/or laparoscopic Heller myotomy. The patients’ mean age at time of treatment was 52 years. The investigators compared Eckardt Scores among patients—an index measure of dysphagia frequency, regurgitation, chest pain and extent of weight loss— before and after POEM. They observed that scores dropped from a mean 7.8 at baseline to a mean 0.4 three months after the procedure (P<0.0001). Mean lower esophageal sphincter (LES) pressure decreased from 45 mm Hg at baseline to 15.2 mm Hg at three months (P<0.0001). Two patients experienced symptom recurrence after the procedure, and both responded well to subsequent pneumatic dilation. No significant complications occurred, and most patients did not require postprocedure analgesia. Mean procedure time was 145 minutes (range, 43-240 minutes); mean myotomy length was 8.6 cm (range, 3-14 cm); and mean postprocedure hospital length of stay was 2.2 days (range, one to five days). Dr. Kahaleh This abstract summarizes data from the largest U.S. study on POEM and adds to the current literature that points to POEM as an emerging alternative to Heller myotomy. If long-term results of this new technique show that POEM does as well as Heller myotomy in terms of safety and efficacy, it will be difficult to continue to defer offering this novel therapy to patients. Questions that remain to be determined are how to achieve competency in this novel procedure, and how to bill for it.
26.
Fullyy-covered Self-expandable Mettal Stents are More Effic cacious than Plastic Stents as First-lin ne Therapy in Treating Extrahep patic Benign Biliary Strictures Following Liver Transplantation (S Shrode CW et al) Investigators review wed retrospective data from 39 patients who were treated for extrahepatic benign biliary strictures foollowing orthotopic liver transplantation. Fourteeen patients were implanted with fully covered self--expandable metal stents (FCSEMS) and 25 patients received plastic biliary stents. Both stent varieties were used as a first-line treatment for this complication. Benign biliary sttricture was defined as total bilirubin or alkaline ph hosphatase levels higher than two times the upper limit of normal, as well as extrahepatic bile duct narrowingg documented on endoscopic retrograde cholangiop pancreatography (ERCP). Stricture resolution was deteermined using repeat laboratory values and ERCP. Plastic stent reciipients had multiple stents of increasing size imp planted sequentially after balloon dilation, whereas patients receiving FC-SEMS had a single 8- or 10-mm m device implanted. Patients were a mean age of 56 years. Findings showed d that 71.5% of FC-SEMS recipients experienced stricture resolution l i within i hi a median di off 94 days. In contrast, strictures resolved in 32% of those who received plastic stents within a median of 142 days after initial stent placement.
‘Unfortunately, this retrospective study does not provide enough data to support the use of metal stents for benign biliary strictures.’ —Michel Kahaleh, MD
All four patients whose strictures did not resolve with placement of FC-SEMS underwent subsequent placement of plastic stents; three of these patients subsequently experienced stricture resolution. Seven patients with persistent benign biliary strictures after initial plastic stent placement underwent placement of FC-SEMS, and five of these patients subsequently experienced stricture resolution. Statistical analysis controlling for patients’ age and gender revealed that first-line treatment of benign biliary strictures using FC-SEMS increased the odds for stricture resolution by 6.4 times compared with the use of plastic stents (P=0.019). P FC-SEMS recipients required a mean 0.6 stent exchanges per patient to achieve stricture resolution
compared w with a mean 1.3 exchan nges among plastic stent recipients. Two pattients who received plaastic stents and one who recceived FCSEMS developed post-ERCP p pancreatitis. Dr. Kahaleh Unfortunately, this retrospective study does n not provide enough data to supp port the use of metal stents for benign b biliary strictures. The exxact number and size of plastic sten nts used and the number of sessioons needed in each group to reacch complete resolution are unclearr. Additionally, another multiccenter trial examining the use of m metal stents in the same patientt population showed poor resultts (Brijbassie A et al. Gastrointest Endosc 2011;73[4 suppl]:AB115. Abstract 170). Therefore, this abstract needs to be taken with a lot of circumspection.
55.
R t l NSAID Rectal NSAIDs are more E Effective than Pancreatic Stents in Preventing Post-ERCP Pancreatitis among High-Risk Patients: A Systematic Review and Network Meta-Analysis (Akshintala VS et al) Investigators at Johns Hopkins Medical Center, in Baltimore, conducted a meta-analysis of randomized controlled trials (RCTs) included in the MEDLINE, EMBASE and Cochrane Library databases that examined the efficacy of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) and pancreatic stents in preventing post-ERCP pancreatitis in high-risk patients. Their analysis included one trial comparing NSAIDs to placebo, five trials comparing pancreatic stents to placebo and one trial comparing NSAIDs to pancreatic stents. The trials included data from 1,168 patients at high-risk for post-ERCP pancreatitis. Results from the trial directly comparing NSAIDs with pancreatic stents showed that patients who received rectal NSAIDs were 61.7% less likely than those who received pancreatic stents to experience post-ERCP pancreatitis. Statistical analysis of the pooled data from all seven studies revealed that rectal NSAIDs decreased the risk for post-ERCP pancreatitis in high-risk patients by 47% compared with pancreatic stents. Moreover, a Bayesian mixed-treatment comparison of pooled data confirmed that rectal NSAIDs were significantly more effective than pancreatic stents in preventing PEP. Dr. Kahaleh This abstract supports the findings of a trial recently published in The New England Journal of Medicine that
ACG 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
showed rectal indomethacin decreased post-ERCP pancreatitis (Elmunzer BJ et al. N Engl J Med 2012;366:1414-1422). The current results provide crucial information that suggests NSAIDs might be even better than pancreatic stents for post-ERCP pancreatitis. An RCT is required to confirm this finding. Dr. Kahaleh is a consultant for Boston Scientific and Xlumena, and has received grants from Boston Scientific, EMcision, Mauna Kea Technologies, M.I.Tech, Pinnacle Biologics and Xlumena.
David T. Rubin, MD
There was a significantly greater decrease in the use of abdominal and computed tomography (CT) imaging, as well as a significantly greater reduction in the cumulative exposure to radiation from pre- and post-initiation of treatment in the anti-TNF group compared with the corticosteroid group (–10.7 vs. –6.9 mSv, respectively; P=0.002). Furthermore, imaging-related cost reductions were estimated at $275,090 per 1,000 patient-years in the anti-TNF group compared with $121,960 in the corticosteroid group (P=0.036).
‘This study did a very nice job of comparing groups of patients with CD on anti-TNF therapy with those on steroids, and the findings demonstrate that, not surprisingly, those on the anti-TNF treatments are less likely to need imaging studies.’ —David T. Rubin, MD
15
Dr. Rubin This study measured the indirect downstream effects of drug therapy in patients with CD and asked whether use of antiTNF agents reduces the need for more intensive diagnostic studies and, therefore, exposure to ionizing radiation. The general principle is that if you provide an effective therapy and the disease is well controlled, there will be fewer complications and less of a need for diagnostic imaging. This principle stems from the idea that effective treatments not only see Best of ACG, page 18
New
Assistant Professor of Medicine Section of Gastroenterology MacLean Center for Clinical Medical Ethics University of Chicago Chicago, Illinois
P942.
Use of Anti-TNF Agents in Crohn’s Disease is Associated with Larger Reductions in Diagnostic Imaging and Radiation Doses Compared with Systemic Steroids in the Year Following Initiation of Therapy (Cross R et al) This database analysis compared the use of abdominal imaging and exposure to radiation in 742 patients with Crohn’s disease (CD) receiving anti-tumor necrosis factor (TNF) agents and 2,002 patients with CD who were treated with corticosteroids between 2005 and 2009. The researchers examined a one-year period before, and at least a one-year period after, initiation of treatment. The two groups of patients had similar types of health insurance. The proportion of male and female patients was similar between the two groups, and there were significantly fewer patients between the ages of 56 and 65 years in the anti-TNF treatment group. Additionally, 54% of patients in the anti-TNF group were receiving immunosuppressant medications at the time of anti-TNF treatment initiation compared with 16% of patients in the corticosteroid group (P<0.001). Anti-TNF recipients also had lower mean scores on the Charlson comorbidity index (P<0.001).
9410 Carroll Park Drive San Diego, CA 92121 ĉĉĉġąĂăġĆĂĂĈƫđƫĉĆĉġĉĂąġĀĉĊćƫ" 4
www.prometheuslabs.com
NOW AVAILABLE! A NEW BOWEL PREP OPTION
Indication and Important Safety Information Prepopikâ„¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH or signs of dehydration after taking Prepopik r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT (>1%) following Prepopik administration 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU
New Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a flexible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t Superior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 – 84% vs 74%, respectively, achieving “excellent or good” visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1
To learn more, scan this code with your smartphone, or go to www.prepopik.com.
Reference: 1. Prepopik™ Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.
© 2012 Ferring B.V. PREPOPIKTM is a trademark of Ferring B.V. PREP_LJAD_001_0912
18
ACG 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Best of ACG continued from page 15
make patients feel better but also reduce other potential hazards, in this case exposure to ionizing radiation, and also are more cost-effective in other ways. This study did a very nice job of comparing groups of patients with CD on anti-TNF therapy with those on steroids, and the findings demonstrate that, not surprisingly, those on the anti-TNF treatments are less likely to need imaging studies. The effects of exposure to
‘It is a general principle that we want to avoid imaging using ionizing radiation in young patients unless it is absolutely necessary, and only if it is likely to change the clinical management of that patient.’ —David T. Rubin, MD ionizing radiation have been well documented, and models of radiation exposure have shown that exposure to a single
Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHÀH[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ RU DVSLUDWLRQ VKRXOG EH REVHUYHG GXULQJ WKH DGPLQLVWUDWLRQ RI PREPOPIK. Use with caution in these patients. Not for Direct Ingestion (DFK SDFNHW PXVW EH GLVVROYHG LQ RXQFHV RI FROG ZDWHU DQG administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. LQJHVWLRQ RI WKH XQGLVVROYHG SRZGHU PD\ LQFUHDVH WKH ULVN RI QDXVHD YRPLWLQJ GHK\GUDWLRQ DQG HOHFWURO\WH GLVWXUEDQFHV INDICATIONS AND USAGE PREPOPIK™ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV CONTRAINDICATIONS DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW PREPOPIK is contraindicated in the following conditions: EH GLUHFWO\ FRPSDUHG WR UDWHV LQ FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ ‡ 3DWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ FUHDWLQLQH FOHDUDQFH QRW UHÀHFW WKH UDWHV REVHUYHG LQ SUDFWLFH less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium DQG YRPLWLQJ ZHUH WKH PRVW FRPPRQ DGYHUVH UHDFWLRQV ! ‡ *DVWURLQWHVWLQDO REVWUXFWLRQ RU LOHXV IROORZLQJ 35(323,. DGPLQLVWUDWLRQ 7KH SDWLHQWV ZHUH QRW EOLQGHG WR ‡ %RZHO SHUIRUDWLRQ WKH VWXG\ GUXJ 6LQFH DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ ‡ 7R[LF FROLWLV RU WR[LF PHJDFRORQ and watery diarrhea are known to occur in response to colon cleansing ‡ *DVWULF UHWHQWLRQ SUHSDUDWLRQV WKHVH HIIHFWV ZHUH GRFXPHQWHG DV DGYHUVH HYHQWV LQ ‡ $Q DOOHUJ\ WR DQ\ RI WKH LQJUHGLHQWV LQ 35(323,. WKH FOLQLFDO WULDOV RQO\ LI WKH\ UHTXLUHG PHGLFDO LQWHUYHQWLRQ VXFK DV a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS GLDJQRVWLF SURFHGXUHV PHW WKH FULWHULD IRU D VHULRXV DGYHUVH HYHQW Serious Fluid and Serum Chemistry Abnormalities RU VKRZHG FOLQLFDOO\ VLJQL¿FDQW ZRUVHQLQJ GXULQJ WKH VWXG\ WKDW ZDV $GYLVH SDWLHQWV WR K\GUDWH DGHTXDWHO\ EHIRUH GXULQJ DQG DIWHUU WKH QRW LQ WKH IUDPH RI WKH XVXDO FOLQLFDO FRXUVH DV GHWHUPLQHG E\ WKH XVH RI 35(323,. 8VH FDXWLRQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW LQYHVWLJDWRU IDLOXUH ZKHQ UHSODFLQJ ÀXLGV ,I D SDWLHQW GHYHORSV VLJQL¿FDQW YRPLWLQJ 35(323,. ZDV FRPSDUHG IRU FRORQ FOHDQVLQJ HIIHFWLYHQHVV ZLWK or signs of dehydration including signs of orthostatic hypotension D SUHSDUDWLRQ FRQWDLQLQJ WZR OLWHUV / RI SRO\HWK\OHQH JO\FRO SOXV after taking PREPOPIK, consider performing post-colonoscopy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compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were GRFXPHQWHG RXW WR VHYHQ GD\V SRVW FRORQRVFRS\ Table 1: Treatment-Emergent Adverse Reactions observed in at )OXLG DQG HOHFWURO\WH GLVWXUEDQFHV FDQ OHDG WR VHULRXV DGYHUVH HYHQWV Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** DQG HOHFWURO\WH DEQRUPDOLWLHV VKRXOG EH FRUUHFWHG EHIRUH WUHDWPHQW ZLWK 35(323,. ,Q DGGLWLRQ XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen IRU SDWLHQWV ZKR KDYH FRQGLWLRQV RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW Reaction LQFUHDVH WKH ULVN IRU ÀXLG DQG HOHFWURO\WH GLVWXUEDQFHV RU WKDW PD\ PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* LQFUHDVH WKH ULVN RI DGYHUVH HYHQWV RI VHL]XUH DUUK\WKPLD DQG UHQDO (N=296) with 2 x (N=305) with 2 x 5-mg impairment. n (% = n/N) bisacodyl n (% = n/N) 5-mg Seizures 7KHUH KDYH EHHQ UHSRUWV RI JHQHUDOL]HG WRQLF FORQLF VHL]XUHV ZLWK WKH XVH RI ERZHO SUHSDUDWLRQ SURGXFWV LQ SDWLHQWV ZLWK QR SULRU KLVWRU\ RI VHL]XUHV 7KH VHL]XUH FDVHV ZHUH DVVRFLDWHG ZLWK HOHFWURO\WH DEQRUPDOLWLHV H J K\SRQDWUHPLD K\SRNDOHPLD K\SRFDOFHPLD DQG K\SRPDJQHVHPLD DQG ORZ VHUXP RVPRODOLW\ 7KH QHXURORJLF DEQRUPDOLWLHV UHVROYHG ZLWK FRUUHFWLRQ RI ÀXLG DQG HOHFWURO\WH DEQRUPDOLWLHV 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK D history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or EHQ]RGLD]HSLQHV SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG K\SRQDWUHPLD Use in Patients with Renal Impairment $V LQ RWKHU PDJQHVLXP FRQWDLQLQJ ERZHO SUHSDUDWLRQV XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK LPSDLUHG UHQDO IXQFWLRQ or patients taking concomitant medications that may affect renal IXQFWLRQ VXFK DV GLXUHWLFV DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQJLRWHQVLQ UHFHSWRU EORFNHUV RU QRQ VWHURLGDO DQWL LQÀDPPDWRU\ GUXJV 7KHVH SDWLHQWV PD\ EH DW LQFUHDVHG ULVN IRU UHQDO LQMXU\ $GYLVH WKHVH SDWLHQWV RI WKH LPSRUWDQFH RI DGHTXDWH K\GUDWLRQ EHIRUH GXULQJ DQG DIWHU WKH XVH RI 35(323,. &RQVLGHU SHUIRUPLQJ EDVHOLQH DQG SRVW FRORQRVFRS\ ODERUDWRU\ WHVWV HOHFWURO\WHV FUHDWLQLQH DQG %81 LQ WKHVH SDWLHQWV ,Q SDWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.
tablets (N=298) n (% = n/N)
bisacodyl tablets (N=302) n (% = n/N) 1DXVHD 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) / 3(* ( WZR OLWHUV SRO\HWK\OHQH JO\FRO SOXV HOHFWURO\WHV VROXWLRQ DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ DQG ZDWHU\ GLDUUKHD QRW UHTXLULQJ DQ LQWHUYHQWLRQ ZHUH QRW FROOHFWHG
DUUK\WKPLDV DQG SURORQJHG 47 LQ WKH VHWWLQJ RI ÀXLG DQG HOHFWURO\WH DEQRUPDOLWLHV 7KLV LQFOXGHV SDWLHQWV UHFHLYLQJ GUXJV ZKLFK PD\ EH associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used LQ SDWLHQWV RQ QRQVWHURLGDO DQWL LQÀDPPDWRU\ GUXJV 16$,'6 RU GUXJV NQRZQ WR LQGXFH $QWLGLXUHWLF +RUPRQH 6HFUHWLRQ 6,$'+ VXFK DV WULF\FOLF DQWLGHSUHVVDQWV VHOHFWLYH VHURWRQLQ UH XSWDNH LQKLELWRUV DQWLSV\FKRWLF GUXJV DQG FDUEDPD]HSLQH DV WKHVH GUXJV PD\ LQFUHDVH WKH ULVN RI ZDWHU UHWHQWLRQ DQG RU HOHFWURO\WH LPEDODQFH &RQVLGHU DGGLWLRQDO SDWLHQW HYDOXDWLRQV DV DSSURSULDWH Potential for Altered Drug Absorption Oral medication administered within one hour of the start of DGPLQLVWUDWLRQ RI 35(323,. VROXWLRQ PD\ EH ÀXVKHG IURP WKH *, WUDFW DQG WKH PHGLFDWLRQ PD\ QRW EH DEVRUEHG 7HWUDF\FOLQH DQG ÀXRURTXLQRORQH DQWLELRWLFV LURQ GLJR[LQ FKORUSURPD]LQH DQG SHQLFLOODPLQH VKRXOG EH WDNHQ DW OHDVW KRXUV EHIRUH DQG QRW OHVV WKDQ KRXUV DIWHU DGPLQLVWUDWLRQ RI 35(323,. WR DYRLG FKHODWLRQ ZLWK PDJQHVLXP Antibiotics 3ULRU RU FRQFRPLWDQW XVH RI DQWLELRWLFV ZLWK 35(323,. PD\ UHGXFH HI¿FDF\ RI 35(323,. DV FRQYHUVLRQ RI VRGLXP SLFRVXOIDWH WR LWV DFWLYH PHWDEROLWH %+30 LV PHGLDWHG E\ FRORQLF EDFWHULD USE IN SPECIFIC POPULATIONS Pregnancy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needed. Nursing Mothers ,W LV QRW NQRZQ ZKHWKHU WKLV GUXJ LV H[FUHWHG LQ KXPDQ PLON %HFDXVH PDQ\ GUXJV DUH H[FUHWHG LQ KXPDQ PLON FDXWLRQ VKRXOG EH H[HUFLVHG when PREPOPIK is administered to a nursing woman. Pediatric Use 7KH VDIHW\ DQG HIIHFWLYHQHVV RI 35(323,. LQ SHGLDWULF SDWLHQWV KDV QRW EHHQ HVWDEOLVKHG
Geriatric Use ,Q FRQWUROOHG FOLQLFDO WULDOV RI 35(323,. RI SDWLHQWV ZHUH \HDUV RI DJH RU ROGHU 7KH RYHUDOO LQFLGHQFH RI WUHDWPHQW HPHUJHQW DGYHUVH HYHQWV ZDV VLPLODU DPRQJ SDWLHQWV • \HDUV RII DJH DQG SDWLHQWV \HDUV RI DJH $PRQJ DOO SDWLHQWV • years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities ZDV JUHDWHU LQ WKH 35(323,. JURXS WKDQ LQ WKH FRPSDUDWRU In general, PREPOPIK was associated with numerically higher rates JURXS RI DEQRUPDO HOHFWURO\WH VKLIWV RQ WKH GD\ RI FRORQRVFRS\ FRPSDUHG WR WKH SUHSDUDWLRQ FRQWDLQLQJ / RI 3(* ( SOXV WZR [ PJ ELVDFRG\O 5HQDO ,QVXIÀFLHQF\ WDEOHWV 7KHVH VKLIWV ZHUH WUDQVLHQW LQ QDWXUH DQG QXPHULFDOO\ VLPLODU Patients with impaired renal function or patients taking concomitant EHWZHHQ WUHDWPHQW DUPV DW WKH 'D\ YLVLW medications that may affect renal function (such as diuretics, DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQJLRWHQVLQ UHFHSWRU Postmarketing Experience EORFNHUV RU QRQ VWHURLGDO DQWL LQÀDPPDWRU\ GUXJV PD\ EH DW 7KH IROORZLQJ IRUHLJQ VSRQWDQHRXV UHSRUWV KDYH EHHQ LGHQWL¿HG GXULQJ LQFUHDVHG ULVN IRU IXUWKHU UHQDO LQMXU\ $GYLVH WKHVH SDWLHQWV RI WKH XVH RI IRUPXODWLRQV VLPLODU WR 35(323,. %HFDXVH WKHVH HYHQWV DUH LPSRUWDQFH RI DGHTXDWH K\GUDWLRQ EHIRUH GXULQJ DQG DIWHU WKH XVH UHSRUWHG YROXQWDULO\ IURP D SRSXODWLRQ RI XQFHUWDLQ VL]H LW LV QRW DOZD\V RI 35(323,. &RQVLGHU SHUIRUPLQJ EDVHOLQH DQG SRVW FRORQRVFRS\ SRVVLEOH WR UHOLDEO\ HVWLPDWH WKHLU IUHTXHQF\ RU HVWDEOLVK D FDXVDO ODERUDWRU\ WHVWV HOHFWURO\WHV FUHDWLQLQH DQG %81 LQ WKHVH SDWLHQWV relationship to drug exposure. ,Q SDWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ FUHDWLQLQH FOHDUDQFH P/ PLQ DFFXPXODWLRQ RI PDJQHVLXP LQ SODVPD PD\ RFFXU 7KH Allergic reactions VLJQV DQG V\PSWRPV RI K\SHUPDJQHVHPLD PD\ LQFOXGH EXW DUH QRW &DVHV RI K\SHUVHQVLWLYLW\ UHDFWLRQV LQFOXGLQJ UDVK XUWLFDULD DQG OLPLWHG WR GLPLQLVKHG RU DEVHQW GHHS WHQGRQ UHÀH[HV VRPQROHQFH SXUSXUD KDYH EHHQ UHSRUWHG K\SRFDOFHPLD K\SRWHQVLRQ EUDG\FDUGLD PXVFOH UHVSLUDWRU\ SDUDO\VLV FRPSOHWH KHDUW EORFN DQG FDUGLDF DUUHVW Electrolyte abnormalities 7KHUH KDYH EHHQ UHSRUWV RI K\SRNDOHPLD K\SRQDWUHPLD DQG OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation 7KH SDWLHQW ZKR KDV WDNHQ DQ RYHUGRVH VKRXOG EH PRQLWRUHG FDUHIXOO\ prior to colonoscopy. and treated symptomatically for complications.
Cardiac Arrhythmias 7KHUH KDYH EHHQ UDUH UHSRUWV RI VHULRXV DUUK\WKPLDV DVVRFLDWHG ZLWK WKH XVH RI LRQLF RVPRWLF OD[DWLYH SURGXFWV IRU ERZHO SUHSDUDWLRQ 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV DW LQFUHDVHG ULVN RI DUUK\WKPLDV H J SDWLHQWV ZLWK D KLVWRU\ RI SURORQJHG 47 XQFRQWUROOHG DUUK\WKPLDV UHFHQW P\RFDUGLDO LQIDUFWLRQ XQVWDEOH DQJLQD FRQJHVWLYH heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal (&*V VKRXOG EH FRQVLGHUHG LQ SDWLHQWV DW LQFUHDVHG ULVN RI VHULRXV $EGRPLQDO SDLQ GLDUUKHD IHFDO LQFRQWLQHQFH DQG SURFWDOJLD KDYH EHHQ UHSRUWHG ZLWK WKH XVH RI 35(323,. IRU FRORQ SUHSDUDWLRQ cardiac arrhythmias. SULRU WR FRORQRVFRS\ 7KHUH KDYH EHHQ LVRODWHG UHSRUWV RI UHYHUVLEOH Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis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eurologic FRORQRVFRS\ ¿QGLQJV LQ SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG LQÀDPPDWRU\ 7KHUH KDYH EHHQ UHSRUWV RI JHQHUDOL]HG WRQLF FORQLF VHL]XUHV associated with and without hyponatremia in epileptic patients. ERZHO GLVHDVH 8VH LQ 3DWLHQWV ZLWK 6LJQLÀFDQW *DVWURLQWHVWLQDO 'LVHDVH ,I JDVWURLQWHVWLQDO REVWUXFWLRQ RU SHUIRUDWLRQ LV VXVSHFWHG SHUIRUP DSSURSULDWH GLDJQRVWLF VWXGLHV WR UXOH RXW WKHVH FRQGLWLRQV EHIRUH DGPLQLVWHULQJ 35(323,. 8VH ZLWK FDXWLRQ LQ SDWLHQWV ZLWK VHYHUH DFWLYH XOFHUDWLYH FROLWLV
abdominal pelvic CT scan before the age of 35 carries a measurable downstream risk for a subsequent malignancy, which
DRUG INTERACTIONS
0DQXIDFWXUHG E\ Ferring Pharmaceuticals (China) Co., Ltd. 1R +XL/LQJ /X )HUULQJ 5RDG 1DWLRQDO +HDOWK 7HFKQRORJ\ 3DUN =KRQJVKDQ &LW\ *XDQJGRQJ 3URYLQFH &+,1$ 0DQXIDFWXUHG IRU Ferring Pharmaceuticals Inc. 3DUVLSSDQ\ 1 -
www.ferringusa.com )(55,1* Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities ‹ )HUULQJ 3KDUPDFHXWLFDOV ,QF 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK FRQGLWLRQV $OO ULJKWV UHVHUYHG 3ULQWHG LQ 86$ RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW LQFUHDVH WKH ULVN IRU ÀXLG DQG 35(3B%560B B HOHFWURO\WH GLVWXUEDQFHV RU PD\ LQFUHDVH WKH ULVN RI VHL]XUH
is thought to be related to radiation exposure. Therefore, it is a general principle that we want to avoid imaging using ionizing radiation in young patients unless it is absolutely necessary, and only if it is likely to change the clinical management of that patient. The second important finding of the study was that there are greater cost reductions associated with a reduced use of imaging, even when the added costs of biologic therapy are taken into account. In conclusion, when considering the cost-effectiveness of a treatment, we need to factor in the costs of improved clinical outcomes as well as indirect health hazards such as radiation exposure and the costs of resource utilization. These findings provide another piece of information to consider when deciding on a treatment course for patients with CD.
P1499.
Influence of Trough Serum Drug Level and Immunogenicity on the Lack of Response to Adalimumab Therapy in IBD Patients (Wang SL et al) Investigators analyzed the correlation between serum adalimumab and human antibodies against adalimumab levels as measured by a homogeneous mobility shift assay in 100 patients with inflammatory bowel disease (IBD) who had experienced an initial response to adalimumab therapy lasting at least three months, and who subsequently lost response. Analysis of serum samples showed that 40% of patients tested positive for antibodies against adalimumab. Furthermore, among a subset of 36% of patients who had serum adalimumab levels less than 3 mcg/mL, 58.3% were positive for antibodies against adalimumab. In contrast, only 18% of those with adalimumab levels greater than 20 mcg/mL were positive for antibodies against adalimumab. Dr. Rubin It is well established that higher trough levels of infliximab are associated with a greater likelihood for remission, a greater likelihood for mucosal healing and a lower likelihood for loss of response. Although a similar assay for adalimumab has been developed, sufficient research on this assay has not been conducted. Therefore, this study is quite important. This study demonstrated that, as is the case with infliximab, lower trough levels of adalimumab are associated with loss of response. The study supports the general principle that if you have a patient on
ACG 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
adalimumab who has previously responded to therapy but is now losing response, measuring the patient’s drug trough levels can provide valuable information regarding a potential pharmacodynamic explanation for the loss of response. This type of measurement can aid in determining whether to escalate dosing, in the case that drug trough levels are too low in the absence of antibody positivity, or to change to a different drug, or even a different class of drug, if antibodies are present.
‘This study demonstrated that, as is the case with infliximab, lower trough levels of adalimumab are associated with loss of response.’ —David T. Rubin, MD
Our understanding of the role of therapeutic monitoring in patients with IBD is evolving, and these findings bring us one step closer to the general idea that we might measure drug trough levels routinely—not only in patients who are losing response—and preemptively adjust doses to prevent clinical relapse.
P1521.
Immune Response and Safety of Herpes Zoster Vaccine in IBD Patients on Methotrexate or Thiopurines (Wasan SK et al) In light of the increased risk for developing herpes zoster in patients with IBD, researchers at Boston Medical Center set out to examine the safety of administering herpes zoster vaccine to IBD patients and determining whether immunosuppressed individuals with IBD are able to mount an adequate immune response to a single vaccination. This study included data from six patients with ulcerative colitis and 11 individuals with CD who received the herpes zoster vaccine as part of an ongoing, prospective open-label study. At the time of vaccination, two patients were receiving methotrexate and six were undergoing thiopurine therapy. The remaining nine patients were not receiving an immunosuppressant medication at the time of vaccination. The researchers recorded pre- and postvaccination antibody and cytokine responses, and documented the occurrence of adverse events up to 42 days after vaccination. The investigators reported that patients receiving immunosuppressive therapy were able to mount a statistically significant cytokine response after vaccination; however, this response was significantly lower than the response among immunocompetent individuals (P=0.04). P There were no cases of varicella-like rash, and the vaccinations did not affect IBD activity. Four patients reported a transient headache at one-week follow-up. Dr. Rubin An important aspect of treating patients with IBD who are scheduled to begin immunosuppressant treatment is adequately vaccinating against vaccine-preventable illnesses, such as herpes zoster. One challenge in doing
so is determining the optimal timing of vaccination in relation to initiation of immunosuppressive therapy. For other vaccines and other conditions, it is well described that patients who are immunosuppressed are half as likely as those who are immunocompetent to convert to active immunity following vaccination. In this particular study, which was small but nonetheless important, patients with IBD receiving immunosuppressants tolerated herpes zoster vaccination but did not seem to develop the same immune response as those who were not immunosuppressed. There are two things to take away from this study and apply to clinical practice: First of all, we need to remember to vaccinate our IBD patients before we start them on immunosuppressant therapy; secondly, you should not assume that vaccinated immunosuppressed individuals have active immunity against the vaccinated infection. If there is any concern or doubt about their immunity, you should check titers and keep the possibility of an active opportunistic infection in mind when a patient on an immunosuppressive agent presents with a fever or another possible manifestation of infection. Dr. Rubin is a consultant for and has received grant support from AbbVie and Janssen Pharmaceuticals.
Prateek Sharma, MD Professor of Medicine University of Kansas Medical School Kansas City, Kansas
P12.
Influence of Fundoplication on Remission and Recurrence of Intestinal Metaplasia after Ablation of Barrett’s Esophagus (Ragunathan K et al) Researchers set out to determine whether performing fundoplication before radiofrequency ablation (RFA) can increase the likelihood of complete remission of intestinal metaplasia (CRIM) in individuals with Barrett’s esophagus (BE) and lower the rate of recurrence following CRIM.
‘The theory behind this is that if you are able to better control acid and bile reflux, patients undergoing RFA may experience a better response to ablation.’ —Prateek Sharma, MD
Investigators analyzed data from a cohort of 206 patients with BE who were treated with RFA for intestinal metaplasia between 2003 and 2012, including 28 individuals who underwent fundoplication before RFA.
19
All patients received proton pump inhibitors (PPIs) after RFA. Patients were considered to have CRIM if intestinal metaplasia was absent over two consecutive endoscopies with biopsies. Recurrence was defined if, following CRIM, intestinal metaplasia reappeared with any grade of dysplasia.
‘The results tell us that patients who need RFA do not necessarily need to undergo fundoplication prior to ablation for the purposes of improving outcomes.’ —Prateek Sharma, MD
Patients in both the fundoplication and non-fundoplication groups were aged 63.5 years and most were male. Those receiving pre-RFA fundoplication had a mean BE segment length of 6.6 cm compared with a mean of 3.95 cm among non-fundoplication patients (P=not P significant). In fundoplication patients, mean hiatal hernia length was 3 cm compared with 4 cm in the non-fundoplication group (P=not P significant). Fundoplication and non-fundoplication patients received a mean 2.36 and 2.47 RFA sessions, respectively (P=not P significant). The mean follow-up period was 26.7 months in the two groups combined, with no differences in follow-up time between groups. In a multivariate analysis controlling for age, number of RFA sessions, length of BE segment and hiatal hernia length, the investigators found no differences in rates of CRIM or recurrence in the fundoplication and non-fundoplication groups (hazard ratio [HR] for CRIM, 0.93; 95% confidence interval [CI], 0.47-1.65; HR for recurrence, 0.99; 95% CI, 0.15-3.81). Moreover, pre-RFA fundoplication had no effect on the time to recurrence. Dr. Sharma With the proliferation of endoscopic ablation treatments for BE with high-grade dysplasia and early cancer, some have been asking whether performing fundoplication before RFA might improve rates of complete ablation of BE and reduce recurrences. The theory behind this is that if you are able to better control acid and bile reflux, patients undergoing RFA may experience a better response to ablation. This retrospective study from Mayo researchers found that it does not matter how acid is controlled, and that recurrence and remission rates are very similar whether or not fundoplication is performed before RFA. The results tell us that patients who need RFA do not necessarily need to undergo fundoplication before ablation for the purposes of improving outcomes.
P571.
Trends and Outcomes of Hospitalized Patients with Gastrointestinal Bleeds in the U.S.: Data from Nationwide Inpatient Sample Over the Past Decade (20012010) (Parasa S et al) This was an analysis of data from the Agency for Healthcare Research and Quality’s Nationwide Inpatient see Best of ACG, page 20
20
ACG 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Best of ACG continued from page 19
Sample, collected between 2001 and 2010. The Nationwide Inpatient Sample represents 90% of all hospitalizations in the United States. Investigators used International Classification of Diagnoses 9 codes to identify primary diagnoses of gastrointestinal (GI) bleeding, including variceal or non-variceal upper GI bleeding and lower GI bleeding. The analysis found a 4.45% increase in the overall number of hospital
‘These data suggest that an increasing prevalence of liver disease, either from hepatitis C or fatty liver disease, could be a contributing factor to the rise in GI bleeding rates over the past decade.’ —Prateek Sharma, MD admissions due to GI bleeding during the study period (P<0.006). The number of hospital admissions due to variceal
upper GI bleeding increased by 45.9% over the 10-year period, from approximately 25,000 in 2001 to approximately
When it comes to hemorrhoid removal, there’s good news for you and your patient.
™
The CRH O’Regan System is a non-surgical hemorrhoid removal procedure that is fast, painless and 99% effective. The result is improved patient care and increased practice revenue. Join the 1000+ gastroenterologists and surgeons who’ve adopted the CRH O’Regan System™ by calling 866.473.3024 x 1023 to schedule a free training session at your office or ASC. Happiness awaits. Visit GEnews.CRHsystem.com for more information.
37,000 in 2010 (P<0.005), whereas the number of admissions due to non-variceal upper GI bleeding and lower GI bleeding decreased by 16.8% and 4.5%, respectively (P<0.05). In an age-based subanalysis, researchers found a significant increase in admissions for both variceal and non-variceal upper GI bleeding among individuals aged 45 to 64 years, and a significant overall reduction in the number of admissions for individuals aged 65 to 84 years admitted for GI bleeding. Despite the overall increase in admissions due to GI bleeding, the mortality rate in this cohort decreased from 3.99% in 2001 to 2.73% in 2010. Additionally, the average hospital length of stay decreased from 4.58 days in 2001 to 4.29 days in 2010. Dr. Sharma This study used data from the Nationwide Inpatient Sample, a well-validated and representative sample of inpatient care. One important finding was that admissions for GI bleeding have increased over the past decade by about 5%, with the majority of this increase due to a greater number of variceal bleeding cases. Although the etiology of esophageal varices was not known, these data suggest that an increasing prevalence of liver disease, either from hepatitis C or fatty liver disease, could be a contributing factor to the rise in GI bleeding rates over the past decade. Equally significant are the findings that other types of bleeding—including non-variceal bleeding, mainly due to peptic ulcer disease, as well as lower GI bleeding, from causes such as diverticulosis or vascular malformations—have decreased. Finally, the finding that mortality and hospital length of stay have significantly decreased over the past decade reflects improvements in medical and intensive care for these patients.
P581.
Electrical Stimulation Therapy (EST) of the Lower Oesophageal Sphincter (LOS): An Emerging Therapy for Refractory GORD: Preliminary Results of an International Multicenter Trial (Bredenoord AJ et al) This joint Dutch–Chilean study follows prior research that has demonstrated electrical stimulation therapy of the lower esophageal sphincter (LES) improved control of acid and symptoms in patients with gastroesophageal reflux disease (GERD; Rodriguez L et al. ACG 2011. Abstract 28).
ACG 2012
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Investigators of the current study presented data on three-month follow-up (P<0.001). HRQoL scores were 11 patients with GERD with partial response to PPI maintained among the three patients who completed treatment who subsequently had the device implanted. six months of follow-up (P=0.05 P vs. baseline). MorePartial PPI response was defined as a reduction of at over, HRQoL scores at both three and six months were least 5 points on the GERD Health-Related Quality significantly lower than the median preimplant on-PPI of Life (HRQoL) index during PPI therapy. All par- HRQoL score of 22. ticipants had hiatal hernia, LES end-expiratory pressures greater than 5 mm Hg and esophageal ‘These are preliminary results from a study of a new device that pH less than 4.0 for at I believe we will be hearing more about in the next few years as least 5% of a 24-hour pH monitoring period. data from an ongoing, large multicenter study are released.’ —Prateek Sharma, MD Implant recipients were a mean age of 54 years, and seven were male. At the time of the abstract presentation, six patients had completed three months Additionally, the median time of esophageal pH less of follow-up, and three patients had been evaluated six than 4.0 decreased from 11.8% of a 24-hour period at months after device implantation. baseline to 7.8% of a 24-hour period at three months, The investigators reported that HRQoL scores and remained stable at 7.3% over a 24-hour period at six dropped from an off-PPI median of 32 at baseline months. Ninety-one percent of all patients were able to to a score of 9 among patients who had completed discontinue PPI use.
Adverse events included one trocar-related small bowel perforation during device implantation, implant site pain in seven patients and postimplantation nausea in one participant. Dr. Sharma These are preliminary results from a study of a new device that I believe we will be hearing more about in the next few years as data from an ongoing, large multicenter study are released. Findings from this series of a small group of patients show improvements in quality of life and reduced acid exposure with this device, with scores continuing to improve after device implantation. However, as we look forward to future results, we have to keep an eye on the safety of this device. It was troublesome that one patient had a small bowel perforation during device implantation. GERD is a condition in which treatments should not have major complications at all; we have relatively safe medical therapies. So, if we are thinking of using other therapies, they need to be absolutely safe. ■ Dr. Sharma has received grant funding from BARRX Medical, Cook Medical, Olympus and Takeda Pharmaceuticals.
Top Ten Stories of 2012 on GastroEndoNews.com 1.
New Study of Interferon-free HCV Therapy Hailed as ‘Watershed Moment’ in Hep C Research
6.
By Christina Frangou. Gastroenterology & Endoscopy News February 2012 Breaking News [ahead of print]
2.
Use, Cost of Anesthesia For Endoscopy Increasing By Monica J. Smith. Gastroenterology & Endoscopy News May 2012
3.
Novel Test Identifies IBD Subtypes
Bowel Preparation for Colonoscopy: Eschewing the One-Prep-Fits-All Approach By Howard Hampel, MD, PhD. Gastroenterology & Endoscopy News January 2012
5.
IBS Remains Mysterious Disorder, With Few Effective Remedies By Monica J. Smith. Gastroenterology & Endoscopy News April 2012
Small Trial Evaluates New Disease Paradigm, Treatment for Ulcerative Colitis By David Wild. Gastroenterology & Endoscopy News October 2012
8.
By David Wild. Gastroenterology & Endoscopy News September 2012
4.
Stool DNA Test for CRC Is Improving; New Data Show High Accuracy By Caroline Helwick. Gastroenterology & Endoscopy News March 2012
7.
Vedolizumab a ‘Major Advance’ for Moderate to Severe UC; Novel Compound A ‘First-Out-of-Class Biologic’ for IBD By David Wild. Gastroenterology & Endoscopy News July 2012
9.
21
The Use of JCV Antibody Assay in Treating Patients With Crohn’s Disease: How the Test Will Influence Treatment With Natalizumab By Monica J. Smith. Gastroenterology & Endoscopy News June 2012
New Treatment Options for C. difficile 10. Infection Raise More Questions By Christina Frangou. Gastroenterology & Endoscopy News January 2012
Read these and other articles at GastroEndoNews.com. Access to online content and e-Newsletters delivered to your email inbox is FREE! Register for access at GastroEndoNews.com.
Read the No. 1 publication in the
gastroenterology market,
anywhere, anytime!
Explore gastroendonews.com at your convenience, from your iPad, personal computer or smartphone.
gastroendonews.com Read all the articles from each month’s issue online. Search the archive for articles from past issues that you may have missed. Post a comment about an article for your colleagues to see. Share articles you read online with your colleagues via email, Facebook, Twitter and other popular social networking sites. Follow our Twitter feed and keep up with us between monthly issues. View our Digital Edition, which includes articles in the same layout as our print edition.
Download the FREE
iPad App
3 Ways to Download: ➢ Go to the iTunes App Store on your iPad and
search for Gastroenterology & Endoscopy News.
➢ Go to www.gastroendonews.com/apps and click on the "Available on the App Store" icon.
➢ Scan this QR code with your iPad and download the App from iTunes.
for consistently making
the best-read publication in the U.S. gastroenterology market More than 17,000 recipients*† every month: ♦ 13,748 gastroenterologists ♦ 1,588 colon and rectal surgeons ♦ 1,059 pediatric gastroenterologists ♦ 780 physician assistants ♦ 210 nurse practitioners ♦ 120 hepatologists
1
# * Kantar Media, December 2011 †
BPA Worldwide, July 2012
including: ♦
high readers
♦
average issue readers
♦
4/4 (monthly) readers
♦
cover-to-cover readers
25
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Job Search continued from page 1
Brijen Shah, MD Assistant Professor of Medicine (Gastroenterology) Mount Sinai Hospital New York, New York
Dr. Shah joined the faculty at Mount Sinai Hospital in 2011, immediately after finishing his fellowship there.
The job search needs to start before your last year of training. To begin, you need to establish your short- and longterm career goals. Where do you see yourself in the next five years? The next 10 years? Look at the careers of junior and senior faculty around you; this can help you figure out what your career goals might be. It is important that you speak with your spouse and family from the start. These are the people who can make your first job successful. Reflect on the experiences you had in residency and fellowship. Look back and identify the elements of clinical work, teaching and research that were most
exciting to you. Consider the four elements of an academic job—basic and clinical research, teaching, administration and patient care—and the importance you give to each. Sketch out what your ideal job would look like. What are your responsibilities? What will you oversee? What does a typical day look like? A typical week? Within academia, there are three major career tracks for physicians: the physician– scientist or clinician–scientist, the physician–educator and the clinical–scholar. These tracks can help you determine the job responsibilities, opportunities for promotion and tenure, and the funding sources for your salary. After you have identified your career goals, start preparing your resumé. Ask faculty at your institution to show you theirs and use it as a model. Make sure you include any talks you have given and research you have presented, and be prepared to discuss them in an interview. For those interested in the educator track, make sure you reference your teaching experience. Those who are interested in the physician–scientist track may be asked to give a job talk as part of the interview process. These are generally 35-minute talks that cover your area of interest. During the
summer before you finish training, find ideas for that talk. Practice your job talk whenever you can—at fellows’ conferences or internal grand rounds—so you will be at your best by the time interviews start.
‘Finding a job in academia is really about contacts. Most positions are not advertised or posted: You have to rely on other sources to find out about opportunities.’ —Brijen Shah, MD Finding a job in academia is really about contacts. Most positions are not advertised or posted: You have to rely on other sources to find out about opportunities. Seek out mentors and touch base with former faculty and fellows. Let them know what kind of job you are looking for; they can keep their eyes and ears open for you. And do not underestimate the power of networking at national meetings. By the fall, put together a list of programs or institutions where you would like to apply. Reach out with a short and concise cover letter or email to find out what opportunities exist. Mention
the type of position you are looking for, highlight any particular skill set you have developed and explain your research focus. Let prospective employers know if you have secured any grant funding that you could carry over. Most interviewing begins in late fall or early winter when you will typically interview with faculty across a particular division and institution. Keep your mentors in the loop throughout the process as they can help you to evaluate programs. If you succeed in getting a job offer, remember that for academic jobs, negotiations are different from most other fields: Salaries and benefits at most institutions are fixed, especially at the junior level, so negotiations are really about other issues. For example, if you are interested in research, you might want to ask for start-up funds to gather material and personnel. Think about what you need for your professional development and continuing education. Always ask and try to negotiate for the clinical support that the job entails. If you are going to oversee something new, you might want to ask for a title that reflects this responsibility. It may not change your salary but it can be very important in the tenure process. Also keep in mind that board and see Job Search, page 26
OPT IN ➢ ➢ to receive your free monthly e-newsletter at www.gastroendonews.com
➢
Be the first first to get the latest news delivered directly to your compu computer. The new interactive format has embedded Web site links that give you instant access to gastroendonews.com, where you will find additional information as well as unique search features and article printing capabilities. Each installment contains top-line summaries of the most important articles from the current month’s issue and breaking news ahead of the print edition.
26
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Job Search continued from page 25
licensing fees are among the largest costs incurred when you transition from fellow to faculty, so consider this during negotiations. Once you have agreed on the terms and receive the employment contract, give it to your lawyer to review. Make sure that the standard content of the contract is updated to include any negotiated items such as resources, vacation time or professional development time. Examine these terms closely for non-compete agreements, especially if you are in an area with several academic medical centers. You also may want to review the intellectual property clauses associated with the institution. This may be important if you are engaged in research that potentially develops into a new technology or therapy. A few last words of advice: As you go through the process, speak to the junior faculty at the institutions where you are interviewing. It is helpful to get a sense of how the mentoring has been, how the support has been, what pitfalls and strengths they see at the institution. Be sure to think about who will be your mentor. Mentorship is one of the key factors for success of junior faculty in the first three to five years.
‘Make sure you gauge the internal and external politics. Look at physician and staff turnover. If nobody wants to work with the group, there is a problem.’
Anthony A. Starpoli, MD Private Practice Gastroenterologist Greenwich Village Gastroenterology Clinical Instructor New York University Attending Physician Beth Israel Medical Center and Lenox Hill Hospital President, New York Society for Gastrointestinal Endoscopy New York, New York If you want a job in private practice, you have to ask yourself some important questions in that last year of training. Where do you want to live? Do you want to be in an urban environment where you are a fish in an ocean, or in a rural or suburban area where you are a fish in a pond? Next, I cannot emphasize enough the importance of having a top-notch resumé that also is simple and nondistracting. You may want to obtain a professional service to help you with this. The question then arises of where to look for job opportunities. Start with journals, specialty journals and meetings and also use the Internet as there are all kinds of sites that list openings. You will sometimes hear about jobs through recruiters and word of mouth. For any interview, it is important that you describe situations where you show yourself to be a team player, have leadership potential, and demonstrate flexibility and patience. Ask questions and show interest. Listen to what employers have to say. You will need to make a decision about whether you want to pursue a solo or group practice. I am a solo practitioner and have been since 1991. There are plenty of benefits to solo practice. Most importantly, you are your own boss. The disadvantages include the all-consuming nature of the practice and the lack of on-call and vacation coverage. You also will have limited negotiation power with insurance carriers.
—Anthony A. Starpoli, MD
In a group practice, you have the advantages of call coverage, a better lifestyle, mentoring and more power in insurance carrier contract negotiations and purchasing. Some of the disadvantages include lack of the personal touch, dealing with many and varied personalities, and negotiating administrative hierarchy and intra-practice competition. If you are considering starting your own practice, there are some things you need to consider. You need to learn about the community and local industry, including the insurance coverage in your surrounding area. Look at support services. Research the cost of medical real estate and whether you should buy or lease. Assess your staffing needs. I think it helps to contact the local medical society as it can give you some support. Another option is to take over an existing private practice. Again, you need to familiarize yourself with the practice and the community and assess the expenses associated with the process, for example the cost of running the office. Think about whether existing staff will stay, or leave the minute you come in the door? Look at future growth and the patient demographic. And certainly obtain a third-party valuation. If you decide to go ahead with the practice, work out a transition plan. Will the selling practitioner stay with you and guide you through introductions so that the transition is smooth? For a group practice, you need to consider all financial aspects of the offer: Check out the AMA reports to ascertain whether the deal is competitive for that area. Talk to the people in the practice and find out about ancillary income, through initiatives like ambulatory surgery or an endoscopy center, and establish if these are included in your purchase deal. Ask how many shares you will get, and find out the cost per share, the value per share and the revenue generated for those shares. Check the non-competes specific to the ambulatory surgery center independent of your contract or group practice.It
‘Before you sign the contract, clarify expectations. Unmet expectations are probably the main reason for people leaving a practice.’ —Anthony A. Starpoli, MD
is important to look at the demographics of the medical group you are joining. If the practitioners are older, business practices will shift as they retire, which could cause instability down the road. On the flip side, if the partners are younger, you have many hands in the cookie jar. Everybody wants immediate gratification and there can be a lack of business wisdom. Make sure you gauge the internal and external politics. Look at physician and staff turnover. If nobody wants to work with the group, there is a problem. A few other considerations for a group practice: Who leads the organization? How is it governed? What are the values and practice philosophy? How will you get paid? What is the organization’s financial situation? How much cash is on hand, and how much debt does it hold? Where is your office going to be? Will you have to travel from facility to facility? Do they already have all the equipment you need? Get as much information as you can and confirm, in writing, what measures you will need to take to become a partner. This can happen in two ways: sweat equity, where you start at a lower pay rate than the partners but which gradually increases over time; or a lump payment, usually in the six figures, and paid back over three to five years. Once that contract is drawn up, have an attorney review and double-check it. Before you sign the contract, clarify expectations. Unmet expectations are probably the main reason for people leaving a practice. Make sure everybody knows what is expected of them. You do not want to get stuck doing all the work for people who do not want to do on-call shifts, for instance. I think it is important not to accept the first offer right away. If you do, they might think they offered you too good a deal. And be prepared to compromise because at the end of the day, both parties have to be satisfied so that you can get off on the right foot. ■
For the treatment of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) or other conditions
ULTRESA™ helps treat malabsorption* and stool symptoms 1-2 of EPI
Important Safety Information Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement. Exercise caution when doses of ULTRESA exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) To avoid irritation of oral mucosa, do not chew ULTRESA or retain in mouth Exercise caution when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia There is theoretical risk of viral transmission with all pancreatic enzyme products, including ULTRESA In rare cases, patients taking pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have experienced severe allergic reactions including anaphylaxis, asthma, hives, and pruritus
The most common adverse reactions (*7% of patients treated with ULTRESA) were headache, pharyngolaryngeal pain, and epistaxis Use of ULTRESA in pediatric patients is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight ULTRESA is not interchangeable with any other pancrelipase product *Reduction in malabsorption is shown by improvement in coefficient of fat absorption (CFA), primary endpoint, and coefficient of nitrogen absorption (CNA), secondary endpoint.1-2 References: 1. Konstan MW, Liou TG, Strausbaugh SD, et al. Efficacy fi and safety of a new formulation of pancrelipase (Ultrase MT20) in the treatment of malabsorption in exocrine pancreatic insufficiency fi in cystic fibrosis. Gastroenterol Res Pract. 2010. 2. Data on file (UMT20CF05-01), Aptalis Pharma US, Inc., Bridgewater, NJ.
Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin Please read brief summary of full US Prescribing Information on following pages.
ULTRESA (pancrelipase) delayed-release capsules, for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR ULTRESA (pancrelipase) delayed-release capsules: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE ULTRESA™ (pancrelipase) is a combination of porcine-derived lipases, proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions. 2 DOSAGE AND ADMINISTRATION ULTRESA is not interchangeable with other pancrelipase products. ULTRESA is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of ULTRESA should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 2.1 Administration Children and Adults ULTRESA should be taken during meals or snacks, with sufficient fluid. ULTRESA capsules should be swallowed whole. ULTRESA capsules p and capsule p contents should not be crushed or chewed. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on a small amount of applesauce, yogurt and other acidic soft food with a pH of 4.5 or less at room temperature. The ULTRESA-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth to avoid mucosal irritation. Any unused portion of capsule contents should be discarded, and not used for subsequent dosing. The remaining exposed contents may lose potency and become less effective. 2.2 Dosage Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences. ULTRESA should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraphs. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme. Children Older than 12 Months and Younger g than 4 Years and Weight g 14 kgg or Greater Children older than 12 months and younger than 4 years, weighing under 14 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children. Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. Children 4 Years and Older and Weight g 28 kgg or Greater and Adults Children 4 years and older, weighing under 28 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children. Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. Usually, half of the prescribed ULTRESA dose for an individualized full meal should be given with each snack. The total daily dosage should reflect approximately three meals plus two or three snacks per day. Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight. Limitations on Dosing: g Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines. If symptoms and signs of steatorrhea persist, the dosage may be increased by a healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range. Use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight. Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually with use over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age. Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally
recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.2)]. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range. 5.2 Potential for Irritation to Oral Mucosa Care should be taken to ensure that no drug is retained in the mouth. ULTRESA should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and Administration (2.1) and Patient Counseling Information (17.1) in the full prescribing information] For patients who are unable to swallow intact capsules, the contents may be sprinkled on applesauce, yogurt and other acidic soft food with pH 4.5 or less. The ULTRESA-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion. 5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels. 5.4 Potential for Viral Exposure from the Product Source ULTRESA is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that ULTRESA will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported. 5.5 Allergic Reactions Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued ULTRESA treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient. 6 ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions (5.1, 5.3 and 5.5)]. 6.1 Clinical Trials Experience 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 clinical practice. The short-term safety of ULTRESA was assessed in two clinical trials conducted in 40 patients with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). Study 1 was conducted in 31 patients, ages 8 years to 37 years; Study 2 was conducted in 9 patients, ages 7 years to 11 years. Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with EPI due to CF. In this study, patients were randomized to receive ULTRESA at doses not to exceed 2,500 lipase units per kilogram per meal or matching placebo for 6 to 7 days of treatment, followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean daily dose of ULTRESA was 6,270 lipase units per kilogram body weight per day. The mean exposure to ULTRESA during this study was 5.4 days. The most common adverse reactions (≥7%) were headache, pharyngolaryngeal pain, and epistaxis. Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 7%) treated with ULTRESA at a higher rate than with placebo in Study 1. TABLE 1 Adverse Reactions Occurring in at Least 2 Patients (≥ 7%) in Cystic Fibrosis (Study 1) ULTRESA n=30 n (%)
PLACEBO n=31 n (%)
Headache
2 (7%)
1 (3%)
Pharyngolaryngeal Pain
2 (7%)
1 (3%)
Epistaxis
2 (7%)
0
Adverse Reaction
Study 2 was an open-label study of 9 patients, ages 7 years to 11 years, with EPI due to CF. After a screening period of up to 15 days on individually-titrated doses of ULTRESA not to exceed 2,500 lipase units per kilogram per meal, patients entered a washout phase (no treatment) of up to 7 days before returning to a treatment phase of up to 12 days on the same individually-titrated dose of ULTRESA. Two patients discontinued during the washout phase leaving 7 patients in the treatment phase. The mean daily dose of ULTRESA was 6,361 lipase units per kilogram body weight per day during the last 4 days of the screening phase, and was 6,846 lipase units per kilogram body weight per day during the treatment phase. The mean duration of the treatment phase was 5.7 days. Adverse reactions that occurred during treatment with ULTRESA were nasal congestion (14%), neck pain (14%), beta-hemolytic streptococcal infection (11%), ear pain (11%), and lymphadenopathy (11%). 6.2 Postmarketing Experience Postmarketing data for ULTRESA has been available since 2003. The safety data is similar to that described below. Because these reactions are reported voluntarily from a population of uncertain size,
EXPERT REVIEW
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
29
Sexual Misconduct by Professionals: A New Model of Understanding Gregory E. Skipper, MD Director of Professional Health Services, Promises Treatment Centers Malibu and West Los Angeles, California Former Medical Director Alabama Physician Health Program Montgomery, Alabama Stephen Schenthal, MD Founder of Professional Boundaries, Inc. Jacksonville, Florida
[Editor’s Note: This article was originally published in Missouri Medicine, May/June 2012.]
The following are but a few fictional examples drawn from compilations of real cases:
Case 1 An overworked married pediatrician was attracted to a single mom in his practice. They became friendly and one day he offered to help if she ever needed anything fixed around the house. Eventually she called and asked him to come over to fix a leaky faucet. This started an affair that lasted several months. When his wife discovered the affair, he broke it off. The mother became angry, felt exploited and retained an attorney. Comment It’s important to realize that the family of patients can be considered patients too, especially in pediatrics, where the parents are considered patients along with their children. Case 2 A general surgeon kissed an employee, who also was his patient, when she came to him crying about a problem she was having. Word got out in the office and a formal complaint was made to the medical board.
it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pancreatic enzyme products (delayed and immediate-release) with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of preexisting carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash. 7 DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic g effects Pregnancy Category C. Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ULTRESA should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULTRESA is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency. 8.4 Pediatric Use The short-term safety and efficacy of ULTRESA were assessed in two clinical studies in pediatric patients with exocrine pancreatic insufficiency due to cystic fibrosis; one study included patients aged 8 years to 17 years, and the other included patients aged 7 years to 11 years. Study 1 was a randomized, double-blind, placebo-controlled crossover study of 31 patients with exocrine pancreatic insufficiency due to cystic fibrosis including 2 children aged 8 to 11 years, and 12 adolescents aged 12 to 17 years. The safety and efficacy in pediatric patients in this study were similar to that in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information]. Study 2 was an open-label study of 9 pediatric patients, ages 7 years to 11 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Patients showed similar control of fat malabsorption as in the treatment arm of Study 1 [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information].
Comment Treating an employee, neighbor Claiming that an affair was the or anyone else, means that the per- patient’s fault doesn’t work. It’s the son then becomes a patient. doctor’s responsibility to set limits Case 3 A family practitioner finally gave and act professionally. in to a seductive patient who brazenly seduced him. Comment problematic because it strikes at the core Claiming that an affair was the spirit of the profession. The breach of trust patient’s fault doesn’t work. It’s the doc- associated with PSM is damaging to the tor’s responsibility to set limits and act patient, the health professional and the professionally. If you are uncomfortable medical profession at large. It’s damagwith a seductive patient, refer him or her ing to the patient, who is exploited and to another doctor. may never be able to trust another health professional. It’s damaging to health proProfessional Sexual Misconduct fessionals, who often lose their reputaBetrayal and exploitation are among the tions, find their finances plundered and most egregious of human offenses, and their licenses revoked and in more than when they involve a health professional two dozen states, find themselves subject preying on a vulnerable patient, the most to criminal charges and imprisonment. basic of ethical principles are violated. Finally, it’s damaging to the medical proWhen the patient–physician relationship fession at large because of degradation in is exploited and professional sexual mis- the perceived legitimacy of the profession conduct (PSM) occurs, it is particularly see Sexual Misconduct, page 30
The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience. Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences. However, use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight. Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended [see Dosage and Administration (2)]. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use Clinical studies of ULTRESA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE There have been no reports of overdose in clinical trials or postmarketing surveillance with ULTRESA. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2) and Warnings and Precautions (5.1)]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.
Marketed by: Aptalis Pharma US, Inc. 22 Inverness Center Parkway Birmingham, AL 35242 USA Manufactured by: Aptalis Pharma S.r.L. Pessano, Italy 20060 ULTRESA and APTALIS are trademarks. © 2012 APTALIS PHARMA US, INC.
30
EXPERT REVIEW
Sexual Misconduct continued from page 29
each time this happens. Unfortunately, claims of PSM are not rare. A confidential survey found that 8% of physicians admitted committing some degree of PSM with one or more patients, and most physicians acknowledge they’ve been tempted (Bayer T et al. South Med J 1996;89:977-982). Despite this, there is generalized denial in the health professions regarding the risks and/or existence of PSM and a taboo
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
regarding discussing it. Even with the “sexual” nature of the offense, it turns out that health professionals who’ve committed PSM rarely have any type of sexual disorder. Very few are true sociopaths. Most of the time, in fact, these physicians simply lose good judgment and believe they’ve “fallen in love” with the patient. Most physicians who commit PSM do so in times of personal trauma or professional crisis, when judgment is diminished. Unresolved vulnerabilities may arise associated with overwork or professional dissatisfaction. The
turbulent times of midlife often trigger PSM. To flee the pain of parental death, a failing marriage or empty nest issues with the departure of children to college are times when physicians may “act out” inappropriately. All this becomes more relevant by the fact that PSM is preventable. Educating physicians about good boundaries and helping them become more aware of their vulnerabilities and risks and ways of setting up their practice to protect patients and themselves is critical. Not only is PSM preventable, but doctors who commit
WE’RE
CHANGING THE NORM
FOR PATIENTS WITH CROHN’S DISEASE After Crohn’s surgery, it is common for the disease to return within a few months despite anti-inflammatory medicine. At UPMC, our multidisciplinary team developed a new post-op treatment
approach that has reduced the recurrence of Crohn’s disease by nearly two thirds. And now many other hospitals are adopting this novel approach. Because when you make patients feel better, it’s normal to want them to stay that way. Learn more at UPMCPhysicianResources.com/Crohns.
UPMC is affiliated with the University of Pittsburgh School of Medicine.
PSM usually are treatable, and relapses are rare when good treatment and education occurs and precautions are taken. Considering the very damaging reallife consequences of PSM, it is surprising how casually it is depicted on TV and in movies. The discordance between how professional boards and criminal agencies view PSM versus its media portrayal is troubling, and may contribute to the risk for PSM because it creates a false sense of acceptability for inappropriate relationships with patients. Additionally, there are many stories about relationships between doctors and their patients leading to successful marriage, without any apparent harm. These, however, are the exceptions. More typically, the patient eventually becomes aware of a sense of exploitation and becomes very angry. Not uncommon
EXPERT REVIEW
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
of a sexual nature that oversteps or disregards ethical or legal limits of professional behavior. For our purposes, sexual refers to any erotic physical contact, and also may include sexual behavior involving language or gesture. Even the use of sexual humor or informal speech can be deemed misconduct. The somewhat vague concept of “boundary” is made more explicit by reference to professional ethical and legal norms. Ethical prohibition against sexual relations with patients dates back at least as far as the Hippocratic oath of ancient Greece.
An abbreviated version of the passage states: “[I] will abstain from every voluntary act of mischief and corruption; and, further from the seduction of females or males, of free men or slaves.” Most professional societies have a code of ethics that contains clear statements regarding what constitutes appropriate sexual boundaries. The major area in which these codes differ is regarding how long, if ever, it is necessary following termination of the patient– physician relationship before a relationship can be pursued. On the subject of where the lines are drawn inside the professional
31
relationship, they are essentially identical. The Federation of State Medical Boards, in a policy statement in 2007, clearly defines what it considers sexual boundaries, and states that disciplinary action should be taken against any physician who violates them. Here are some salient excerpts from that document: “Physician sexual misconduct is behavior that exploits the physician–patient relationship in a sexual way. This behavior ... may be verbal or physical, and may include expressions of thoughts and feelings or gestures see Sexual Misconduct, page 32
DIFICID® (fidaxomicin) tablets Awarded New Technology Add-on Payment (NTAP)1 Physician sexual misconduct is behavior that exploits the physician–patient
CMS* has granted a NTAP for DIFICID administered in the inpatient hospital setting to treat Clostridium difficile-associated diarrhea (CDAD) CMS will reimburse hospitals an additional amount of up to $868 in fiscal year 2013, not for every case involving DIFICID, but only where the costs of the entire case exceed the MS-DRG† payment amount
relationship in a sexual
The CMS NTAP policy is designed to support timely access to innovative therapies used to treat Medicare beneficiaries in the inpatient setting that provide a substantial clinical improvement over existing therapies
way, whether verbal or
DIFICID is the first oral medication ever approved for a NTAP
physical, or expressions
*Centers for Medicare & Medicaid Services. † Medical severity diagnosis-related groups.
of thoughts and feelings or gestures that are sexual or that reasonably
For more information about DIFICID, please visit DIFICID.com.
For a copy of the CMS final rule regarding FY2013 Add-On Payments, please visit http://federalregister.gov/a/2012-19079.
may be construed by a patient as sexual.
are cases in which a physician–patient marriage ends in divorce, at which time the ex-spouse files a complaint and a lawsuit—and wins. It’s tragic that as terrible and devastating as PSM is, it is essentially a taboo subject; little or nothing is taught regarding PSM in medical schools, and it’s rarely a subject for postgraduate training. To help prevent PSM, it’s important to have a basic understanding of boundary theory and the dynamics that underlie boundary violations, to develop vigilance for early warning signs of potential boundary problems with patients, and to gain insight into professional and personal vulnerabilities and risk factors. Excellent continuing medical education–based courses are available for further in-depth training. PSM (synonymous with “sexual boundary violation”) can be defined as any action
Indications and Usage DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficileassociated diarrhea 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
Important Safety Information DIFICID should not be used for systemic infections Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile. 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 The most common adverse reactions are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%) Please see brief summary of full prescribing information for DIFICID on following page. Reference: 1. Department of Health and Human Services, Centers for Medicare and Medicaid Services, Medicare Program; Hospital Inpatient Prospective Payment Systems for Acute Care Hospitals and the Long-Term Care Hospital Prospective Payment System and Fiscal Year 2013 Rates, 77 Fed. Reg. 53258-53750 (August 31, 2012).
© 2012 Optimer Pharmaceuticals, Inc. San Diego, CA 92121 5124 September 2012
32
EXPERT REVIEW
Sexual Misconduct continued from page 31
that are sexual or that reasonably may be construed by a patient as sexual. … There are primarily two levels of sexual misconduct: sexual violation and sexual impropriety. Behavior listed in both levels may be the basis for disciplinary action by a state medical board. ... Sexual violation may include physician–patient sex, whether or not initiated by the patient, and engaging in any conduct with a patient that is sexual or may be reasonably interpreted as
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
sexual. Sexual impropriety may comprise behavior, gestures or expressions that are seductive, sexually suggestive or sexually demeaning to a patient.” The document goes on to state, “Findings of sexual misconduct are often sufficiently egregious as to warrant revocation of a physician’s medical license, although a lesser action may be considered for cases of sexual impropriety.” It is important to know that most acts of PSM occur following progressive problems with boundaries that precede the PSM. Often these steps are referred to as
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%)
“boundary crossings,” which may be initiated with the best of intentions, but progressively tumble down a “slippery slope” of professional destruction. Although these precedent behaviors are not necessarily unethical in and of themselves, they are major warning signs. In order to prevent sexual boundary violations, it is important to understand this progression and the precedent boundary disturbances. Sometimes these boundary disturbances are limited to one patient or one particular type of patient, and in other cases they may characterize the clinician’s general practice
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.
style. In the context of rehabilitation from sexual boundary violation(s), it is incumbent on the professional to address all of these boundary issues. Precedent boundary problems can include time issues, such as extending the time of office visits (often by scheduling at the end of the day), conducting the visit during non-office hours or by extending the visit from the last appointment of the day into non-office hours (after the staff leave the office). Another category of precedent behaviors includes “concepts of place and space,” for example, making home visits (except when clearly part of regular practice), meeting a patient at a social occasion or agreeing to share a meal with a patient at a restaurant. Another area, giving or receiving gifts, can be a problem if it tends to “deprofessionalize” the relationship, encourage romanticizing of the relationship or interferes with therapeutic aims. In general, it is a good idea to have an office policy that gifts from patients are not accepted (except to the office as a whole). Physical contact is another area of concern. There are times in the course of clinical practice where touching the patient outside of a physical examination is accepted, such as a handshake at the beginning or end of an appointment, or the placing of a hand on the shoulder as a comforting gesture. Some practitioners also feel it is permissible to hug patients at times, although, depending on the characteristics of the patient, this can be very dangerous. Context clearly is important in determining the extent that a hug may be thought of in this way. Hugging can cause serious confusion in the professional relationship, can be interpreted or experienced in a romantic way by the patient and can lead to greater intimacy. An important adage to remember is that when it comes to boundaries, “perception is everything.” The misinterpretation of a therapeutic hug as romantic may be impossible to defend. Boundary issues involving money can precede PSM. Examples include lending or borrowing of money from patients, business activities with patients or even bartering in place of the standard fee. It’s also important to be careful of the language used with patients. Using the title of doctor, for example, helps establish the professional relationship. The use of a too-familiar tone of voice, the use of inappropriate colloquial language or the use of first names can be risky, especially in some settings. Wearing a white coat reinforces the professional image. Informal dress may convey the opposite. Finally, the issue of self-disclosure should be mentioned. Although it is not uncommon for clinicians to occasionally see Sexual Misconduct, page 35
33
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Safeguarding Yourself Against Allegations of Sexual Abuse or Patient Impropriety Harvey Tettlebaum, JD Husch Blackwell, LLP Jefferson City, Missouri Kevin Meyers, JD Associate Husch Blackwell Springfield, Missouri [Editor’s Note: This article was originally published in Missouri Medicine, May/June 2012.]
By drawing boundaries between their personal and professional lives, physicians can protect their practices and themselves while also still achieving their true goal: providing quality care to their patients. As an attorney, I know that lawyers and doctors are frequently strange bedfellows. However, the two professions have one thing squarely in common, and likely always will. No matter where we are or who we’re surrounded by, be it at a church, synagogue or mosque, at a dinner party, having a drink at a pub, or even when simply spending time with extended family over the holidays, the same question always comes up, “Hey, can I ask you something?” The lines between patient and professional are frequently blurred, especially in rural areas, where “the family doctor” can, after knowing a particular family of the common good is still bound by ethical requirements, and it can be tough to tell where the line between the two begins or ends. With allegations of physician sexual abuse of patients continuing to be in the headlines, doctors need to be alert to prevent even the appearance of impropriety. Physicians can safeguard themselves with a few simple suggestions that will ensure that quality care is being provided with a minimum of issues.
1. Use Your Office The simplest line to draw is to always insist that patients be seen in the office whenever possible. This rule frequently can be used to politely brush aside random inquiries that doctors (and I, as a lawyer) frequently get at social occasions. The person saying, “Hey, can I ask you something? I’ve got this issue with my back...” should be politely redirected by merely saying, “Of course you can. Here’s my card. Why don’t you call my office and we can set up an appointment for next week.” By directing patients to
your office whenever possible, you help to maintain the line between friendship and professional practice.
2. Redirect When Necessary If a patient or potential patient behaves in a way that gives you pause or you otherwise feel as though you cannot remain professionally objective with respect to that person’s care, refer the individual to another physician immediately. If someone asks you for your advice on an informal basis, providing that person with the contact information of a doctor who is a specialist in the area of inquiry will help to redirect the conversation away from your own medical expertise. Physicians who field phone calls from their patients at all hours of the day and night are advised in nonemergent situations to politely ask the patient to call again in the morning or refer the individual to the on-call physician (e.g., “You need me at my best and asking me to give an opinion late at night does not fully benefit either of us”).
3. Charge for Your Services Although it may seem difficult to charge friends or family for your services, remember your expertise and knowledge are all you have to sell. Giving away your time devalues your skills. You deserve to be compensated for your services. If you charge for your services, it helps to remove any doubt that your advice and treatment were made in your full capacity as a physician, not “just as a friend.” Finally, in some instances, this practice will likely dissuade some people from coming to you during off-hours with trivial complaints.
4. Always Ask Yourself if Your Objectivity Is Being Compromised Every professional must be vigilant to ask this very question as relationships and issues change. Although you may be comfortable treating your child’s ear infection, objectively as a professional could you perform surgery on your own child? What about the child of a close friend or a co-worker? In those instances, it is not an issue of competence but one of clearly separating personal and professional relationships. As situations change, you may be called on to re-evaluate whether you can objectively treat a patient you have treated for see Safeguarding, page 34
May 18–21, 2013 Exhibit Dates: May 19–21, 2013 Orange County Convention Center Orlando, FL
“I found [DDW sessions] terrifically rewarding, not only professionally but also personally.” — Donald Jensen, MD
Nine out of ten DDW attendees agree that the quality of DDW sessions is excellent. Experience for yourself what your colleagues are saying. Register for DDW 2013 and attend sessions designed to enhance your clinical competency in the fi fields of gastroenterology, hepatology, GI endoscopy py and GI surgery. g y
“If you want to see really good science being presented, you want to be with the experts, this is the place to come.”
Connecting the World of Digestive Disease
— Thomas Tompkins, MD
Members of AASLD, AGA, ASGE and SSAT can take advantage of member-only housing and registration on January 9, 2013.
General registration opens January 16. Get a $100 discount when you register by April 10.
Register online at ddw.org
34
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Safeguarding continued from page 33
several years or decades. As time passes and relationships change, the nature of the physician–patient relationship should be re-evaluated as well.
5. Avoid Charges of Sexual Harassment In today’s world of heightened sensitivity to what may appear to be inappropriate conduct, it is recommended,
especially within the physician’s office, to maintain an atmosphere of political correctness. This requires maintaining the appearance of appropriate, professional distance between yourself and your patients at all times. It may require a staff person of the same sex as the patient be in the room during an examination of patients of opposite sex from the physician. It requires sensitivity to appearances. For example, when patients are close friends of the opposite-sex physician, greeting them with a kiss on the cheek or
a hug may be regarded by staff and colleagues as inappropriate because they may not know of the prior existing relationship. A physician should always be ready for the patient who is sexually forward or otherwise a bit too friendly. This behavior must be immediately and politely deflected with statements that do not embarrass the patient but make clear your position on such conduct (e.g., “I am sorry but professional standards do not allow what may be regarded by others as not appropriate conduct with a patient”). If the behavior does not stop, you
A physician should always be ready for the patient who is sexually forward or otherwise a bit too friendly.
OPT IN to receive your free monthly e-newsletter att www.gastroendonews.com ➢ ➢ ➢
Be the first to get the latest news delivered directly to your computer. The new interactive format has embedded Web site links that give you instant access to gastroendonews.com, where you will find additional information as well as unique search features and article printing capabilities. Each installment contains top-line summaries of the most important articles from the current month’s issue and breaking news ahead of the print edition.
should consider seriously terminating the physician–patient relationship. Of paramount importance, for unmarried physicians, the development of romantic relationships with office staff or patients must be approached with the greatest of caution. It is recommended that the physician refer his or her romantic interest to another physician, ideally not in the same office, for care. Romantic relationships with married patients, married or single staff or minors, is a professional, financial and legal disaster of the gravest order.
Conclusion The key to retaining professional objectivity and to finding the right balance between being a professional and being a person is vigilance. The five suggestions given here easily can be combined into one general principle: Draw boundaries. By drawing boundaries between their personal and professional lives, physicians can protect their practices and themselves while also still achieving their true goal: providing quality care to their patients. ■
35
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
This behavior must be immediately and politely deflected with statements that do not embarrass the patient but make clear your position on such conduct.
affecting a patient also can increase risk. Patients with histories of sexual abuse appear to be particularly vulnerable. It is important for every physician to know that PSM is unethical and can carry harsh consequences. Physicians should recognize inappropriate behaviors and not act inappropriately due to their emotional attractions to patients. Ultimately, it’s best to refer the patient causing concerns to another physician. Before pursuing a relationship with a patient, the physician should contact his or her specialty society for more
guidelines to ensure it is ethical and safe. Consulting a good therapist prior to taking any action also is a good idea. Physicians also are ethically responsible to protect their colleagues. If a physician sees red flags of an evolving boundary problem in another physician, an intervention should be considered. Stepping in can save a professional and protect a patient. Failing to follow these recommendations is very likely to be costly to everyone involved. ■
what is your
opinion?
Gastroenterology & Endoscopy News is now accepting opinion pieces. Send your thoughts to the editor at: mail: fax: email:
545 West 45th Street, 8th Floor New York, New York 10036 212.957.7230
cgordon@mcmahonmed.com
Sexual Misconduct continued from page 32
share a story with a patient or to reveal selective aspects of their personal experience, the injudicious sharing of private information clearly is a boundary crossing, and interferes with the aim of the professional relationship. The disclosure of personal problems is virtually always inappropriate. Sharing by the doctor with the patient that he or she has an unethical attraction to the patient is highly inappropriate. This type of boundary crossing commonly precedes PSM. Preexisting vulnerabilities afflicting the physician, such as psychiatric illness; alcohol and/or substance abuse disorder; paraphilia; personality or mood disorders; sexual compulsivity or addiction; and/or insufficient support, supervision, oversight or accountability make PSM more likely to occur. Other factors that can predispose the physician to PSM include marital/family problems, midlife or late midlife stage-of-life crisis and burnout. Similar preexisting vulnerabilities
RESEARCH Advancing the knowledge of gastric cancers.
Creating more precise and effective treatments.
Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)
36
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
From the Literature
CDC Issues ‘Tour de Force’ on Prevention of Hepatitis And Other Infectious Diseases in Illicit Drug Users BY GEORGE OCHOA The Centers for Disease Control and Prevention (CDC) and the U.S. Department of Health and Human Services (HHS) issued a summary guidance on the prevention of infectious diseases in users of illicit drugs (MMWR Recomm Rep 2012;61[RR5]:1-40). Focusing on integrated prevention services, the report discusses viral hepatitis, as well as HIV infection and other sexually transmitted diseases, and tuberculosis. The document summarizes existing guidelines and recommendations, as of 2011, that have been issued by HHS.
we’ve been preaching for many years, especially integrated care in an addicted population with multiple comorbidities, such as hepatitis C and mental illness, or HIV and medical issues,” said Dr. Sylvestre, who is founder and executive director of OASIS (Organization to Achieve Solutions in Substance Abuse), an inner-city, community-based clinic in Oakland, Calif., known for its work in treating HCV infection in drug users. “With the people we see, the fewer visits they can have, the better,” she said. Underscoring its emphasis on integrated prevention services, the guidance states:
‘This is a fabulous document. It’s comprehensive and will help localities move toward integrated services.’ —Diana Sylvestre, MD
“This is a fabulous document. It’s comprehensive and will help localities move toward integrated services,” said Diana Sylvestre, MD, assistant clinical professor of medicine at the University of California, San Francisco, who was not an author of the guidance. Comorbidities are common in illicit drug users: Among HIV-infected persons who inject drugs illegally, the guidance says, 80% are also infected with hepatitis C virus (HCV). “The new document says things
“Providing multiple prevention services at a single venue or coordinating referrals and linkage to care for services delivered at multiple venues can improve access to quality and comprehensive prevention services. Such coordination can offer the opportunity to address multiple infectious diseases and related health conditions, such as substance use and mental disorders, at one time or at a single facility, thus increasing the likelihood that clients will receive needed services.”
First among the 12 science-based public health strategies for prevention advocated by the guidance is the prevention and treatment of substance use and mental disorders. “SBIRT” (screening, brief intervention, referral, and treatment), the document says, is a way of identifying problematic drug use and reducing substance abuse in primary care settings. Other strategies advocated in the document include: • outreach programs, including peer educators who can help reduce risky behaviors; • risk assessment for illicit use of drugs in patients with infectious diseases; • risk assessment for infectious diseases in persons who use drugs illicitly; • screening, diagnosis and counseling about HCV and other infectious diseases; • vaccination; • prevention of mother-to-child transmission of infectious diseases; • interventions to reduce risky behaviors; • partner services and contact follow-up; • referrals and linkage to care; • medical treatment for infectious diseases; and • delivery of integrated prevention services. Potential barriers to prevention and treatment efforts include contextual factors (e.g., poverty), mental
health needs, fear of criminalization or stigmatization and tension in the patient–provider relationship. Providing integrated infectious disease services for persons who use drugs illicitly requires coordinated and collaborative planning, an integrated service delivery plan, and monitoring and evaluation of delivery, the guidance states. Regarding medical treatment in drug users, the document says: “Most persons who use drugs illicitly are capable of adhering actively to complex medical regimens. … Therefore, past or current illicit use of drugs should not be considered a contraindication to successful treatment for infectious diseases.” “It reaffirms the approach that we’ve been taking,” Dr. Sylvestre noted. “You can and should treat the most challenging patients with hepatitis C if you can address their special needs.” Dr. Sylvestre noted that she would not be changing anything in her medical practice as a result of the guidance, saying that, “they’re preaching to the choir. But here we’re having it come out of the mouth of the CDC.” She called the paper “a tour de force.” “Armed with this document, we might be better advocates for establishing integrated centers in other agencies,” she said. ■ Dr. Sylvestre serves on the speakers’ bureau of Merck & Co., and is involved in three clinical trials for Gilead, Novartis and Vertex.
F D A U P D AT E & P R O D U C T N E W S
Boehringer Ingelheim Launches Hepatitis C Web Portal for Patients, Health Care Providers Boehringer Ingelheim recently launched a website, HepCRedefined.com, to help improve the lives of people with hepatitis C virus (HCV) infection. Created in collaboration with HCV community advocates and health care providers, the portal offers a range of interactive resources that can be shared via social media channels, embedded on other websites or viewed on various smart devices. “The more we empower ourselves to learn about the challenges associated with HCV, the better we will be able to provide patient management and come closer to a cure for this disease,” said Steve Smith, vice president of established brands at Boehringer Ingelheim, in a statement. Some of the tools available on the portal include: • a comprehensive and interactive checklist to help patients manage the care and treatment of their condition;
• a key facts page on HCV mortality; • at-a-glance information cards designed to debunk myths surrounding HCV; and • a community “C-pledge,” where patients, health care providers and caregivers can take an oath to redefine the experience of living with HCV and the way it is perceived. “The entire HCV community is in need of simple tools and resources to talk about the disease in an informed, supportive way,” said Michael Ninburg, executive director of the Hepatitis Education Project, in a statement. “There is information about HCV across the web, but HepCRedefined.com is designed to aggregate straightforward and accurate information in a single, virtual destination.”
According to the Centers for Disease Control and Prevention, an estimated 16,000 cases of acute HCV and an estimated 3.2 million people with chronic HCV infection were recorded in the United States in 2009. For further information, visit www.HepCRedefined.com. —Based on a press release from Boehringer Ingelheim
The bookstore division of
MCMAHONMEDICALBOOKS.COM An Online Bookstore
ORDER BOOKS ONLINE
THE BOOK PAGE PUBLISHER’S TOP PICKS OF THE MONTH ON MCMAHONMEDICALBOOKS.COM These books and thousands more...
1
1
2
3
4
5
6
7
8
Acing the GI Board Exam: The Ultimate Crunch-Time Resource
Brennan Spiegel; Hetal Karsan August 11, 2011 Many board review manuals provide lists and bullet points lacking sufficient background and context. This book presents time-tested and highyield information in a rational, useful and contextually appealing format.
Scan here for our complete catalog of medical books.
ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.
2
Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics
Gerald Friedman January 11, 2013 The authors in this issue provide state-of-the-art reviews on the use of probiotics in care of the gastroenterologic system. Articles are devoted to probiotics as treatment for IBD, chronic diarrhea, C. difficile colitis, functional bowel disease, allergic disorders, necrotizing enterocolitis and obesity.
3
Doctor’s Eyes Only: Exclusive Financial Strategies for Today’s Doctors and Dentists
Thomas Martin; Paul Larson; Jeffrey Larson March 13, 2012 This book is the missing financial guide that physicians need as a supplement to their ongoing professional training. These pages include basic financial wisdom that could end up saving them millions of dollars throughout their medical careers.
4
Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition
John DiBaise April 20, 2012 The book features about 3,500 questions with only the correct answers provided, reinforcing the answers students need to remember on exam day. Emphasis is placed on distilling key facts and clinical pearls essent a for tial o exam e a success. success
5
Gastroenterology Coding Manual, Third Edition
AGA Institute and the Professional Association of Healthcare Coding Specialists May 1, 2011 Published jointly by the AGA Institute and PAHCS, this manual presents the essential elements of gastroenterology coding in a two-part, easyto-use format designed for both the experienced coder and the novice.
6
Helicobacter Species: Methods and Protocols
JeanMarie Houghton September 27, 2012 Identifying Helicobacterr infection as the leading cause of peptic ulcer disease and gastric cancer has dramatically altered the treatment of these disease states. Over the past several decades, scientists have come to understand that the interplay between the bacteria, the host and the environment all contribute to the clinical outcome of infection. In Helicobacter Species: Methods and Protocols, expert researchers in the field detail many of the methods that are now commonly used to study Helicobacterr infection.
7
Hepatology: Diagnosis and Clinical Management
Jenny Heathcote November 13, 2012 This is a highly practical handbook on hepatology, aimed at residents// trainees in gastroenterology, GI nurses and recently qualified consultants for use as a quick reference when managing patients presenting with possible or overt liver disease.
8
The Gastrointestinal System at a Glance, Second Edition
Keshav October 30, 2012 This concise introduction to the gastrointestinal system encapsulates the fundamental facts and principles of this rapidly growing and changing specialty. Written by experienced clinicians and teachers, the text covers the basic concepts of both the science surrounding the gastrointestinal system y and the basics of clinical practice p in an accessible format. GEN0113
38
F D A U P D AT E & P R O D U C T N E W S
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
Ondansetron (Zofran) 32-mg Single IV Dose Discontinued Because of Potential for Cardiac Risks The FDA announced in December that the 32-mg single IV dose of the
antiemetic ondansetron (Zofran and generic versions) will no longer be marketed because of the potential for serious cardiac risks. The single 32-mg IV dose had been used to prevent chemotherapy-induced nausea and vomiting and was sold in premixed solutions of either dextrose or sodium chloride in plastic containers. The agency had warned health care professionals in a Drug Safety
Communication issued in June 2012 that the 32-mg single IV dose should be avoided due to the potential risk for QT interval prolongation, a type of irregular heart rhythm that can lead to Torsades de pointes, which is potentially fatal. The most recent communication from the FDA indicates that this dose now will be discontinued. The FDA continues to recommend
the IV regimen of 0.15 mg/kg administered every four hours for three doses. If the calculated weightbased dose exceeds 16 mg, the potential for prolonged QT interval increases, therefore the FDA stipulates that no single IV dose should exceed 16 mg. Currently, the FDA is working with the manufacturers of all 32-mg dose see Ondansetron, page 39
Linzess, New Drug for IBS and Chronic Constipation, Now Available in Pharmacies
Download the FREE
iPad App Read the latest issue on your iPad 3 Ways to Download: ➢ Go to the iTunes App Store on your iPad and
search for Gastroenterology & Endoscopy News.
➢ Go to www.gastroendonews.com/apps and click on the "Available on the App Store" icon.
➢ Scan this QR code with your iPad and download the App from iTunes.
On Dec. 17, Linzess (linaclotide), which received FDA approval on Aug. 30 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC) in adults who do not respond to standard treatments, became available in U.S. pharmacies. Linzess is being copromoted in the United States by Ironwood Pharmaceuticals and Forest Laboratories, who announced the market availability in a joint press release. According to the companies, Linzess is the first and only guanylate cyclase-C agonist approved by the FDA for the treatment of both IBS-C and CIC in adults. Linzess is a oncedaily capsule that helps relieve the abdominal pain and constipation associated with IBS-C, and the constipation and hard stools associated with CIC, the companies said. The recommended dosage is 290 mcg for patients with IBS-C and 145 mcg for those with CIC. Linzess should be taken at least 30 minutes before the first meal of the day. For more information about Linzess, visit www.linzess.com. —Based on a press release from Ironwood Pharmaceuticals and Forest Laboratories
F D A U P D AT E & P R O D U C T N E W S
GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2013
39
New System Safely Warms Robotic Scopes, Preventing Lens Fogging Ecolab Healthcare recently launched the Scope Pillow Warmer Drape to supplement its Fluid Warming System for robotic scopes. The product includes a foam pillow that is integrated into a sterile drape that is used in a fluid bath system to warm scopes, using sterile water, to a controlled temperature. Warming scope lenses can prevent them from fogging during procedures, thus preventing procedural delays and ensuring the proper care of costly medical equipment. According to research cited by Ecolab Healthcare, “During laparoscopy, vision is likely to be impaired in situations where paradoxically the best vision is required including close-up viewing where lens fogging is more likely to occur. … It must also be stressed that minimal or no (in the case of robot-assisted) haptic feedback in laparoscopy ensures that vision and visual cues become extremely important” (Lawrentschuk N et al. J Endourol 2010;24:905-913). The foam pillow is 44" × 66" in size, and has safeguards on each side that hold scopes securely in place to prevent accidental tipping and falling while in the fluid-warming bath. It also provides superior safety when
Ondansetron continued from page 38
ondansetron injectable products (Zofran and generic versions) to voluntarily recall them from the market. These products are expected to be phased out through early 2013. GlaxoSmithKline, the manufacturer of Zofran, has updated the Zofran drug label to reflect the dosing changes. A complete list of products involved in the recall is available on the FDA’s website at www.fda.gov/ Drugs/DrugSafety/ucm330049.htm. The FDA does not anticipate that the removal of the 32-mg single IV dose from the market will contribute to a drug shortage, as it accounted for less than 1% of the product’s IV sales (e.g., vials and bags) to retail and nonretail channels between June 2011 and June 2012. At this time, there is not enough information available for the FDA to recommend an alternative single IV dose regimen, the agency stated in a press release. Oral formulations of ondansetron are not affected by FDA’s announcement. —Based on a press release from the FDA
The Scope Pillow Warmer Drape includes a foam pillow integrated into a sterile drape used in a sterile fluid bath system that warms scopes to a controlled temperature.
hospital practice includes connecting the camera to the scope before or during a procedure. The pillow can cradle multiple scopes simultaneously, thus providing long-lasting fog prevention during laparoscopic procedures. For more information or to schedule a demonstration, call (800) 824-3027, or visit www.ecolabhealthcare.com.
Photo courtesy of Ecolab Healthcare
—Based on a press release from Ecolab Healthcare
The following is a brief summary; please see complete Prescribing Information at www.Xifaxan550.com.
INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
population studied had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).
Table 1: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo Number (%) of Patients
Hepatic Encephalopathy 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. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed. XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) 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 [see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
CONTRAINDICATIONS Hypersensitivity 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 [see Adverse Reactions (6.2)].
WARNINGS AND PRECAUTIONS Travelers’ Diarrhea Not Caused by Escherichia coli XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered. XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.
Clostridium difficile-Associated Diarrhea 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 C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development of Drug Resistant Bacteria Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Severe (Child-Pugh C) Hepatic Impairment There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].
ADVERSE REACTIONS Clinical Studies Experience 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.
Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The
MedDRA Preferred Term
XIFAXAN Tablets 550 mg TWICE DAILY N = 140
Placebo N = 159
21 (15%) 20 (14%) 18 (13%) 17 (12%) 16 (11%) 13 (9%) 13 (9%) 12 (9%) 11 (8%) 11 (8%) 10 (7%) 10 (7%) 10 (7%) 10 (7%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 7 (5%)
13 (8%) 21 (13%) 13 (8%) 18 (11%) 15 (9%) 11 (7%) 10 (6%) 13 (8%) 12 (8%) 6 (4%) 11 (7%) 8 (5%) 11 (7%) 10 (6%) 8 (5%) 4 (3%) 10 (6%) 10 (6%) 7 (4%) 5 (3%) 6 (4%)
Edema peripheral Nausea Dizziness Fatigue Ascites Muscle spasms Pruritus Abdominal pain Abdominal distension Anemia Cough Depression Insomnia Nasopharyngitis Abdominal pain upper Arthralgia Back pain Constipation Dyspnea Pyrexia Rash
The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure. Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension
Postmarketing Experience The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Infections and Infestations Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)]. General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.
whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium. The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients, based upon plasma AUC comparisons. Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.
Nursing Mothers It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age.
Geriatric Use Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC) of rifaximin was about 10-, 13-, and 20fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)]. Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.
DRUG INTERACTIONS In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use. An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown
Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74
For overt HE* patients
OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS “After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indefinite period of time or until liver transplantation.” —Clinics in Liver Disease, February 20121 73% of recurrences among lactulose patients result in hospitalization 2 Xifaxan 550 mg reduces the risk of HE-related hospitalizations by 50%3†‡ The most common adverse reactions (≥12% incidence) in clinical trials with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.
Prescribe. Protect. Repeat.
*HE=hepatic encephalopathy. † Over a 6-month period; P=0.0129 vs placebo.3 ‡ HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.3
Important Safety Information About XIFAXAN 550 mg XIFAXAN® (rifaximin) 550 mg tablets are 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 C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C). Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74-1
Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother. The most common adverse reactions occurring in ≥10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%). Xifaxan 550 mg is not available for sale outside the U.S. Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see Brief Summary on reverse. References: 1. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis. 2012;16(1):73-89. 2. 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. 3. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2011.
www.Xifaxan550.com
PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM
Approach to Hemorrhoids A Primer for Gastroenterologists HARRY SARLES JR., MD Gastroenterologist Digestive Health Associates of Texas Dallas, Texas
H
emorrhoids are normal vascular structures of the
anal canal. Often, they are the source of a variety of
troublesome symptoms, including bleeding, anal pruritus,
prolapse, and pain due to thrombosis of external hemorrhoids. Patients often mistake other anal or perianal problems for hemorrhoids, such as anal fissures, skin tags, hypertrophied anal papillae, anal cancer, and anal condylomata, as well as other infections. A good medical history and physical examination, including anoscopy or office proctoscopy, should guide the physician to the correct diagnosis; in cases of bleeding, a colonoscopy or sigmoidoscopy in addition to anoscopy is necessary to verify the source of the bleeding. It is the intent of this review to provide gastroentertologists with a general introduction to the nonsurgical management of hemorrhoids.
covers the internal hemorrhoidal cushions (mucosa) and the extremely sensitive squamous epithelium, which extends up into the anus (anoderm). The junction of these 2 epithelial layers is known as the dentate line, and is typically located approximately 3 cm inside the anal verge. This line marks the transition between the columnar epithelial窶田overed internal hemorrhoids and the squamous epithelial窶田overed external hemorrhoidal vessels.4-6
Anatomy Thomson, in his description of hemorrhoidal anatomy, noted a series of 3 cushions in the anal canal, located in the left lateral, right anterior, and right posterior positions. These hemorrhoidal cushions receive their blood supply primarily from the superior and middle hemorrhoidal arteries; the superior, middle, and inferior hemorrhoidal veins provide venous drainage. A sinusoidal pattern of arteriovenous communication is formed within the cushions, which explains why hemorrhoidal bleeding is arterial, rather than venous in nature.1 In addition to the vessels noted above, the hemorrhoidal cushions are also rich in muscular fibers, arising from the internal sphincter and the conjoined longitudinal muscle. These fibers help to anchor the cushions to the underlying muscular layer of the anorectum, and it is the breakdown of these supporting fibers that eventually leads to the changes that can cause hemorrhoidal symptoms.1,2 The cushions play an important role in the maintenance of rectal continence, as they provide 15% to 20% of the resting pressure at the anal verge.3 The epithelial layer of the anorectum is characterized by the relatively insensate columnar epithelium, which
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
Pathophysiology There are a number of proposed mechanisms to explain the development of symptomatic hemorrhoids, including abnormal venous dilatation, abnormal distension of the arteriovenous anastomoses, downward displacement or prolapse of the hemorrhoidal tissue, or a breakdown of the connective tissue anchoring the hemorrhoidal cushions. Prolapse of hemorrhoidal tissue is what appears to lead to the development of symptoms. This prolapse allows for mucous deposition on the perianal skin, which causes itching, and leads to tissue friability and bleeding. Other symptoms include swelling of associated external disease and fecal soiling when the prolapsing tissue precludes complete closure of the anal opening.1,7 Internal hemorrhoids are covered by the mucosa; they reside proximal to the dentate line and are generally painless. External hemorrhoids are located distal to the dentate line and are covered by squamous epithelium; patients who experience pain as a result of hemorrhoids often have a thrombosed external hemorrhoid or an anal fissure.
G AST R O E N T E R O LO GY & E N D O S CO PY N E WS 窶｢ JA N UA RY 2 0 1 3
1
The causes of symptomatic hemorrhoids are not completely clear, but a number of factors, including a lack of dietary fiber, constipation, straining on defecation, diarrhea, pregnancy, obesity, a sedentary lifestyle, spending excess time on the commode, spinal cord injuries, and family history all have been suggested.8
seems to be better tolerated than the prone, “jack-knife” position.14 A digital rectal examination will identify such things scars, small fissures, and the origins of fistulae. These clinical findings will be important in formulating a comprehensive treatment plan for the symptomatic patient.15
Epidemiology
ENDOSCOPIC EXAMINATION
It is difficult to quantify the incidence of hemorrhoidal disease, in large part because many patients do not seek medical care for their condition; additionally, some attribute almost any anorectal symptom to hemorrhoids. Estimates of the prevalence of hemorrhoidal disease in the United States range from 4.4% to 40%.9 Some research suggests that 75% of the population will experience symptomatic hemorrhoid disease at some point in their lives.10 Although these estimates vary widely, it seems clear that symptomatic hemorrhoids have a significant effect on health and well-being.
Anoscopy is an accurate, efficient, inexpensive way to evaluate the anal canal quickly, with minimal discomfort to the patient. Flexible endoscopy frequently is performed to evaluate patients with symptoms of hemorrhoids, however, it is not as accurate as anoscopy. A prospective study showed that anoscopy revealed 99% of anorectal lesions, whereas endoscopy revealed 78% when performed with straight withdrawal of the endoscope, and 54% with retroflexion.16 The limitations of flexible endoscopy, along with increased cost and inconvenience to the patient, stress the need to consider anoscopy in the evaluation of hemorrhoidal disease.
Grading of Hemorrhoidal Disease Banov et al11 developed a grading system for internal hemorrhoids based on the degree of prolapse. The grade of hemorrhoidal disease has some bearing on the treatment options available to a patient with internal hemorrhoids: • grade I: non-prolapsing internal hemorrhoids • grade II: prolapse of internal hemorrhoids during defecation with spontaneous reduction • grade III: prolapse of internal hemorrhoids during defecation that requires manual reduction • grade IV: prolapse and incarceration of internal hemorrhoids; hemorrhoids cannot be reduced
Diagnosis PATIENT HISTORY As previously stated, patients often attribute any anorectal symptom to hemorrhoidal disease, and although this may partly explain symptoms, it is important for the physician to determine whether there are other issues involved as well.5,12 Internal hemorrhoids are associated with painless bleeding, prolapse, mucus discharge, soiling, and symptoms of pruritus ani; these symptoms rarely cause significant pain. External hemorrhoids usually are asymptomatic, unless they become thrombosed. Pain with defecation is commonly due to the presence of an anal fissure, which is found in up to 20% of patients with hemorrhoids.13 The relationship between symptoms, defecation habits, bleeding, and a description of factors that might relieve or exacerbate a patient’s symptoms are important to consider in the medical history.
PHYSICAL EXAMINATION A visual inspection of the perianal area will allow for the discovery and description of rashes, tags, fissures, fistulae, abscesses, neoplasms, condylomata, some cases of prolapse, and so forth. The left lateral decubitus position is preferred for the examination, as this position
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
Treatment CONSERVATIVE MEDICAL TREATMENT There are a number of over-the-counter preparations intended to treat patients with symptomatic hemorrhoids. These compounds contain ingredients such as antiseptics, astringents, topical anesthetics, and corticosteroids. There is not a lot of evidence to support the use of many of these products, and the potential negative effects of the long-term use of topical steroids should be considered.17 Common dietary and behavioral recommendations for patients with hemorrhoids include increasing the intake of dietary fiber, minimizing the amount of time spent on the commode, avoiding straining during defecation, and taking sitz baths several times a day. There is evidence to support these recommendations both for the treatment of symptomatic disease and in limiting the risk for recurrence.18 These measures are a reasonable first-line approach for patients with mild symptoms.
NONSURGICAL TREATMENT Sclerotherapy Sclerotherapy uses the injection of a sclerosant into the submucosa, beneath the hemorrhoid, to create an inflammatory reaction in the soft tissue that affixes the loose hemorrhoidal mucosa back to the underlying musculature. The procedure dates back to the 1800s. Some research shows sclerotherapy to be beneficial in patients with grade I and II hemorrhoids,19 whereas other research shows it to be no more beneficial than bulk laxatives.20 Potential complications of sclerotherapy include pain, urinary retention, abscess, and impotence. Avoidance of these complications depends on precise placement of the injection.21 Rubber Band Ligation Rubber band ligation (RBL) is the most commonly performed nonsurgical procedure used in the treatment of hemorrhoids; it is performed in up to 80% of patients
with hemorrhoids.22,23 Blaisdell first described a ligation technique using a silk suture in 1958,24 with Barron beginning to use rubber bands in 1963.25 Barron treated one column of hemorrhoids per session to minimize pain and post-banding complications. The process causes the banded tissue to necrose and slough, with the resultant inflammatory reaction causing refixation of the mucosa to the underlying tissue, eliminating hemorrhoidal prolapse. This mechanism of action is common among the nonsurgical treatments for hemorrhoids, stressing the importance of hemorrhoidal prolapse in the etiology of symptoms. RBL is a simple, inexpensive procedure, effective for grade I to III hemorrhoids.2 Patients undergoing RBL typically do not require bowel preparation, sedation, narcotics, or a significant recovery period; they are able to return to work immediately.5 One of the disadvantages of earlier RBL procedures was the need for 2 operators to perform the procedure, but this has since been overcome with the development of single-use, disposable devices that do not require an assistant.6,7 RBL leads to reconfiguration and reduction in the size of hemorrhoidal cushions, resulting in symptom resolution. Short-term success rates of up to 99% and longterm success rates of up to 80% have been described; however, there is a large range in the reported incidence of complications. The predominant issue in patients undergoing RBL is significant pain, with the incidence rates ranging from less than 1% to 50%, in some series.6,26 Other reported complications include bleeding, urinary retention, vasovagal reactions, and the very rare complication of sepsis. Based on the literature, the incidence of complications appears to be related to the techniques that are used to perform the banding. Endoscopic RBL has been shown to have excellent results, however, the method is more expensive than the others and requires patient preparation as well as anesthesia.27 Endoscopic RBL also has been reported to be more painful than other banding techniques.28 Other common techniques use an anoscope to gain access to the hemorrhoids. There also is a procedure that allows for a “blind” placement of the band, obviating the need for an anoscope. The literature is confusing when it comes to where the band should be placed, as descriptions vary from “a few millimeters” above the dentate line29 to “at least 2 cm proximal” to the dentate line.30,31 I prefer a technique that involves placing the band at least 2 cm above the dentate line, as this technique has been associated with less pain.6 Controversy exists regarding the number of hemorrhoids to treat during a single session. In the time since Barron’s original work was published,25 most researchers have recommended treating only one column of hemorrhoids per session in order to minimize the rate of complications. Other authors have suggested banding 2 or more columns per session in order to minimize the number of patient visits required; however, complication rates are higher when more bands are placed.32
I recommend banding a single hemorrhoid per session. Endoscopic band placement is effective but is more costly and is associated with higher rates of post-procedural pain compared with in-office band placement.24,33 Personally, I prefer the blind “touch” technique described by Cleator and Cleator.6 This technique allows placement of the band without an anoscope at 2 cm above the dentate line. Using this technique, the researchers demonstrated a 1% complication rate (primarily pain) and successful treatment of up to 99% of patients, with a recurrence rate of 5% at 2 years.5 Infrared Coagulation Neiger first described infrared coagulation (IRC) in 1979.34 The infrared coagulator is placed through an anoscope while infrared light is converted to heat in the hemorrhoidal tissue. The heat produces tissue destruction, protein coagulation, and inflammation, leading to scarring and tissue fixation. During the procedure, 3 to 4 pulses of energy are applied to the mucosa at the apex of the hemorrhoid, and 1 to 2 columns of hemorrhoids are treated at a time. Treatment is repeated every 2 to 4 weeks.24 Advantages of IRC include a relative lack of significant complications. Disadvantages include equipment costs, the need for repeated treatments, higher recurrence rates, and its ineffectiveness in patients with more advanced disease.24,34 Direct Current Electrotherapy Direct current electrotherapy also uses a device that is inserted through an anoscope (Ultroid, Ultroid Technologies, Inc).35 This procedure uses direct current and does not create heat but rather produces sodium hydroxide, creating the submucosal reaction that leads to scarring, which helps to eliminate the hemorrhoidal prolapse.7 Limitations of direct current electrotherapy include the cost of the technology and the amount of time required to treat the involved tissue. The length of the procedure depends on the grade of hemorrhoidal disease and the amount of current that the patient can tolerate, which ranges from 4:45 to 19:45.35 The procedure has been reported to cause significant pain in up to 20% of patients, resulting in termination of therapy; 16% of patients have prolonged post-procedural pain.36 Bipolar Diathermy and “Heater Probe” Coagulation These technologies may be used by way of anoscopy in order to control chronic hemorrhoidal symptoms. Both procedures generate heat, which causes coagulation of the target tissue leading to a fibrotic reaction with fixation of the treated tissue.32 The procedures have similar efficacy for the treatment of bleeding. In one study, the heater probe controlled the bleeding more quickly (76.5 vs 120.5 days) at the expense of more pain.37 The bipolar technology was associated with a higher overall rate of complications (11.9% vs 5.1%), including pain, bleeding, fissure formation, and spasm of the internal sphincter. Another study demonstrated symptomatic mucosal ulceration in 24% of patients treated with bipolar electrocoagulation, significant bleeding in 8%, and prolonged pain in 4%.36
G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • JA N UA RY 2 0 1 3
3
Neither technology was able to reliably eliminate prolapsing tissue.29,36,37 Cryosurgery and Lord’s Stretch Procedure These techniques are mentioned for historical reference only, as neither is recommended. Cryosurgery is associated with significant post-procedure pain, along with foul-smelling discharge and prolonged recovery in several series.36 The “Lord’s Stretch,” a forceful dilatation of the anus in order to reduce elevated sphincter pressures was found to result in incontinence in a significant number of patients.38 Some have recommended that the procedure be abandoned.39
SURGICAL TREATMENT OPTIONS This review is intended to discuss nonsurgical options available for the treatment of symptomatic hemorrhoidal disease, and these approaches have been shown to be effective in 80% to 99% of patients. A number of surgical options are available as well, but because of increased cost, pain, disability, recuperation time, risk for complications, and so on, surgical options should be reserved only for nonresponders and for patients with grade IV hemorrhoids or hemorrhoids with both internal and external components.40
Conclusions Symptomatic hemorrhoids are common and patients frequently visit a gastroenterologist for diagnosis and treatment. A number of effective nonsurgical approaches are available for these patients. RBL is the most commonly used office-based hemorrhoidal therapy. Information is presented here to aid the gastroenterologist in the evaluation and definitive treatment of patients with hemorrhoidal disease.
References 1.
Thomson WH. The nature of haemorrhoids. Br J Surg. 1975;62(7):542-552.
2.
Sardinha TC, Corman ML. Hemorrhoids. Surg Clin North Am. 2002; 82(6):1153-1167, vi.
3. Lestar B, Penninckx F, Kerremans R. The composition of anal basal pressure. An in vivo and in vitro study in man. Int J Colorectal Dis. 1989;4(2):118-122.
15. Beck DE. Evaluation of the anorectum during endoscopic examinations. Tech Gastro Endoscopy. 2004;6:2-5. 16. Kelly SM, Sanowski RA, Foutch PG, Bellapravalu S, Haynes WC. A prospective comparison of anoscopy and fiberendoscopy in detecting anal lesions. J Clin Gastroenterol. 1986;8(6):658-660. 17. Chong PS, Bartolo DC. Hemorrhoids and fissure in ano. Gastroenterol Clin North Am. 2008;37(3):627-644, ix. 18. Moesgaard F, Nielsen ML, Hansen JB, Knudsen JT. High-fiber diet reduces bleeding and pain in patients with hemorrhoids: a double-blind trial of Vi-Siblin. Dis Colon Rectum. 1982;25(5):454-456. 19. Khoury GA, Lake SP, Lewis MC, Lewis AA. A randomized trial to compare single with multiple phenol injection treatment for haemorrhoids. Br J Surg. 1985;72(9):741-742. 20. Senapati A, Nicholls RJ. A randomised trial to compare the results of injection sclerotherapy with a bulk laxative alone in the treatment of bleeding haemorrhoids. Int J Colorectal Dis. 1988;3(2):124-126. 21. Pilkington SA, Bateman AC, Wombwell S, Miller R. Anatomical basis for impotence following haemorrhoid sclerotherapy. Ann R Coll Surg Engl. 2000;82(5):303-306. 22. Kann BR, Whitlow CB. Hemorrhoids: diagnosis and management. Tech Gastro Endoscopy. 2004;6(1):6-11. 23. Corman ML, Veidenheimer MC. The new hemorrhoidectomy. Surg Clin North Am. 1973;53(2):417-422. 24. Blaisdell PC. Prevention of massive hemorrhage secondary to hemorrhoidectomy. Surg Gynecol Obstet. 1958;106(4):485-488. 25. Barron J. Office ligation of internal hemorrhoids. Am J Surg. 1963; 105:563-570. 26. Kumar N, Paulvannan S, Billings PJ. Rubber band ligation of haemorrhoids in the out-patient clinic. Ann R Coll Surg Engl. 2002;84(3):172-174. 27. Jutabha R, Jensen DM, Chavalitdhamrong D. Randomized prospective study of endoscopic rubber band ligation compared with bipolar coagulation for chronically bleeding internal hemorrhoids. Am J Gastroenterol. 2009;104(8):2057-2064. 28. Cazemier M, Felt-Bersma RJ, Cuesta MA, Mulder CJ. Elastic band ligation of hemorrhoids: flexible gastroscope or rigid proctoscope? World J Gastroenterol. 2007;13(4):585-587. 29. Daram SR, Lahr C, Tang SJ. Anorectal bleeding: etiology, evaluation and management (with videos). Gastrointest Endosc. 2012:76(2):406-417. 30. Madoff RD, Fleshman JW, Clinical Practice Committee, American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology. 2004;126(5):1463-1473. 31. Kaidar-Person O, Person B, Wexner S. Hemorrhoidal disease: a comprehensive review. J Am Coll Surg. 2007;204(1):102-117. 32. Lee HH, Spencer RJ, Beart RW Jr. Multiple hemorrhoidal bandings in a single session. Dis Colon Rectum. 1994;37(1):37-41. 33. Cataldo P, Ellis CN, Gregorcyk S, et al. Practice parameters for the management of hemorrhoids (revised). Dis Colon Rectum. 2005;48(2)189-194. 34. Neiger S. Hemorrhoids in everyday practice. Proctology. 1979;2:22-28. 35. Ultroid® Model 3053 Operating & Maintenance Manual. Ultroid Technologies, Inc., Rev 10.5.2010a:17. 36. Yang R, Migikovsky B, Peicher J, Laine L. Randomized, prospective trial of direct current versus bipolar electrocoagulation for bleeding internal hemorrhoids. Gastrointest Endosc. 1993;39(6):766-769.
4. Wexner SD, Jorge JMN. Anatomy and embryology of the anus, rectum, and colon. In: Corman ML, ed. Colon and rectal surgery. 4th ed. Philadelphia, PA: Lippincott-Raven; 1998.
37. Jensen DM, Jutabha R, Machicado GA, et al. Prospective randomized comparative study of bipolar electrocoagulation versus heater probe for treatment of chronically bleeding internal hemorrhoids. Gastrointest Endosc. 1997;46(5):435-443.
5. Guttenplan M, Ganz RA. Hemorrhoids—office management and review for gastroenterologists. Touchgastroentorology.com; December 2011.
38. Lord PH. A new regime for the treatment of haemorrhoids. Proc R Soc Med. 1968;61(9):935-936.
6. Cleator IGM, Cleator MM. Banding hemorrhoids using the O’Regan disposable bander. US Gastroenterology Review. 2005:69-73.
39. The Standards Task Force. Practice parameters for the treatment of hemorrhoids. Dis Colon Rectum. 1990;33(11):992-993.
7.
40. MacRae HM, McLeod RS. Comparison of hemorrhoidal treatments: a meta-analysis. Can J Surg. 1997;40(1):14-17.
Corman ML. Hemorrhoids. In: Corman ML, ed. Colon and rectal surgery. 4th ed. Philadelphia, PA: Lippincott-Raven; 1998:147-205.
8. Loder PB, Kamm MA, Nicholls RJ, Phillips RK. Haemorrhoids: pathology, pathophysiology and aetiology. Br J Surg. 1994;81(7):946-954. 9. Ohning GV, Machicado GA, Jensen DM. Definitive therapy for internal hemorrhoids—new opportunities and options. Rev Gastroenterol Disord. 2009;9(1):16-26. 10. Baker H. Hemorrhoids. In: Longe JL, ed. Gale encyclopedia of medicine. 3rd ed. Detroit: Gale; 2006:1766-1769. 11. Banov L Jr, Knoepp LF Jr, Erdman LH, Alia RT. Management of hemorrhoidal disease. J S C Med Assoc. 1985;81(7):398-401. 12. Halverson A. Hemorrhoids. Clin Colon Rectal Surg. 2007;20(2):77-85. 13. Schubert MC, Sridhar S, Schade RR, Wexner SD. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009;15(26):3201-3209. 14. Alonso-Coello P, Castillejo MM. Office evaluation and treatment of hemorrhoids. J Fam Pract. 2003;52(5):366-374.
4
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
AUTHOR DISCLOSURE—Dr. Sarles is a member of the advisory board of CRH Medical. DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the author. 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 © 2013, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.