July 2015

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 66, Number 7 • July 2015

Governments Face ‘Growing Challenge’ Of Harmful Diet Aids BETHESDA, MD.—A — decade ago, roughly 5% of liver injuries were attributable to herbal and dietary supplements.

Since then, that figure has quadrupled, health officials say. Yet, assessing liver injury related to supplements remains vexing for clinicians around the world, according

Barrett’s Esophagus Appears To Be Spiking in Younger Patients WASHINGTON— —The incidence of Barrett’s esophagus (BE) among relatively young people has surged in recent years, an analysis of a large health care database has found.

see DILI, page 21

Report Card Improves Colonoscopy Quality

T

he use of colonoscopy quality report cards and a minimum institutional standard of practice can dramatically improve adenoma detection rates (ADR), Illinois researchers have found.

After clinicians at Northwestern University started using report cards and an institutional standard of practice, their ADR increased by 11% over a two-year period.

The study is the first published report to examine the impact of institutional minimum standard of practice on ADR. A previous study of veterans in Indianapolis found that, when distributed quarterly, report cards were significantly associated with increased ADRs after

The study, of 50 million unique patient records between 2008 and 2013, showed that while the absolute incidence remaains low among people younger than n age 55 years, the share off cases in that group climbed sharply over the five-yyear period. Meanwhilee, cases of BE among peoplle over age 55 fell, suggessting a demographic shift in n the disease with potentially important i implications for screeening, according to the researchers. As a precancerous condition, BE maay be more dangerous in younger patiients because of the longer time for th he abnormal cells to progress to malignancy. “The in ncrease in the rate of BE was particularrly high in the age group of 25 to 34 yyears,� said Sasan Sakiani, MD, of the Division of see Surge, page 58

see Report Card, page 30

I N S I D E

Hormone Therapy Linked To Increased Risk for GI Bleeds

EXPERTS’ PICKS The Best of Digestive Disease Week (DDW): Part 1

Study in postmenopausal women finds link between HRT and bleeds, particularly in lower intestine

Experts share their favorite abstracts from the 2015 DDW meeting ......................................... page 24

WASHINGTON— —Women who take hormone replacements after menopause are about 50% more likely to experience gastrointestinal (GI) bleeding as those not on the treatment, new research shows. see HRT, page 34

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Role of Positive Practice Management During the Transition to ICD-10 Faculty Kathleen Mueller, RN, CPC, CCS-P, CMSCS, PCS, CCC President and Coding Consultant AskMueller Consulting, LLC Lenzburg, Illinois

Introduction Over the past several years, gastroenterology and endoscopy practices have faced increasing efforts to define and improve standards for quality of care led by agencies such as the American Gastroenterological Association (AGA), the American College of Gastroenterology (ACG), and the American Society for Gastrointestinal Endoscopy (ASGE). Similarly, practices also require efficient management to ensure proper reimbursement, particularly since billing and coding DIBOHFT EVF UP UIF BEPQUJPO PG UIF UI SFWJTJPO PG UIF *OUFSOBUJPOBM $MBTTJGJDBUJPO PGG %JTFBTFT *$%

are imminent. As a standard diagnostic and health NBOBHFNFOU UPPM VTFE CZ DPVOUSJFT it is important for clinicians and practice staff to understand how to CFTU USBOTJUJPO UP XPSLJOH XJUIJO *$% DMBTTJGJDBUJPOT

Transition to ICD-10: Top-Level Changes From ICD-9

During the Transition to ICD-10 see page 8

The 9th edition of the ICD was implemented by the 6OJUFE 4UBUFT JO 3; due to the changing medical landscape, the use of a set of diagnosis and inpatient QSPDFEVSF DPEFT UIBU JT ZFBST PME EPFT OPU QSPWJEF the type of clinical specificity needed to completely describe a patient’s condition and/or ultimate treatment BT IBOEMFE UPEBZ 5IVT *$% XIJDI XBT FOEPSTFE CZ UIF 8PSME )FBMUI 0SHBOJ[BUJPO JO BOE CFHBO XPSMEXJEF VTF JO JT TDIFEVMFE UP CF JOTUJUVUFE JO UIF 6OJUFE 4UBUFT PO 0DUPCFS BOE JT EFTJHOFE to provide more details per code and allow clinicians to better track patient severity and risk as well as overall quality measures.3 5IF BEEJUJPOBM EFUBJM DPOUBJOFE JO *$% DPEFT informs health care providers and health plans of disease characteristics and history, which allows for more effective case management and better coordination of care. From a practical standpoint, this means that the coding options for the typical gastroenterology practice will expand

For example, whereas ICD-9 included markedly (Table).

T DPEFT GPS $SPIO T EJTFBTF *$% JODMVEFT NPSF UIBO codes, and codes can be combined depending on illness and eventual patient diagnosis, leading to more options.

0WFSBMM *$% DPOTJTUT PG BQQSPYJNBUFMZ DPEFT DPNQBSFE XJUI *$% T DPEFT

Specifically addressing these code changes, the VQEBUFE *$% FYQBOET UIF OVNCFS PG EJHJUT JO UIF EJBHOPTJT DPEF GSPN UP BMMPXJOH GPS BEEJUJPOBM TVCEJWJTJPOT GSPN UP EJHJUT JO *$% XIJMF PUIFSXJTF keeping the codes themselves similar to ICD-9.

Additionally, codes for inpatient procedures in the hospital setting previously included in the ICD-9, Clinical .PEJGJDBUJPO *$% $.

BSF HSPVQFE JO UIF *$% 1SPDFEVSF $PEJOH 4ZTUFN *$% 1$4 DBUFHPSZ PGGJDF and outpatient procedures will not be affected by this change.3 "U BMQIBOVNFSJD EJHJUT UIF *$% 1$4 DPEFT are different and more descriptive than those in ICD $. (FOFSBMMZ UIF *$% DPEFT FNQIBTJ[F TQFDJGJDJUZ Factors such as time of patient presentation, side of the body related to illness, and patient follow-up condition all can be coded to ensure that tracking is accurate and payors approve claims quickly and correctly with GFXFS JORVJSJFT BOE EFMBZT 'VSUIFSNPSF *$% DPEFT have been modernized and are constructed with the changing medical field in mind.

"MUIPVHI UIF DPNQMFYJUZ PG *$% QSPWJEFT NBOZ benefits because of the increased level of detail conveyed in the codes, it also underscores the need for QSBDUJDFT UP CF BEFRVBUFMZ USBJOFE PO *$% JO PSEFS to fully understand reporting changes that will come with the new code sets, so that reimbursement can better reflect the intensity of the patient’s condition and diagnostic needs.

The Transition Process: Obstacles and Success Strategies Whether implementing a new laboratory information system or a new coding system, the planning, preparation, education, training, and communication steps taken to prepare for implementation are crucial to the success of any new health information system project. Key obstacles in the way of a successful transition, such as insufficient staff, lack of coordination, and poor communication, should be identified and corrected to mitigate difficulties inherent in the change to a new coding system.

Thus, in order to achieve optimum outcomes in the DPVSTF PG *$% JNQMFNFOUBUJPO JU JT JNQPSUBOU GPS practices to provide most, if not all, of the following NFBTVSFT Senior leadership support: Support from senior leadership is essential for any implementation project.

It is crucial that senior leadership fully supports NPWJOH GPSXBSE XJUI BO *$% JNQMFNFOUBUJPO QMBO as scheduled. Support must be shown throughout the plan’s progress as well as after the project’s completion.

Lack of support may impede changing behaviors and documentation procedures throughout the staff, and decrease transition success.

Multidisciplinary steering committee: The initial step of any implementation plan is to identify key TUBLFIPMEFST BOE IPX UIFZ XJMM CF JNQBDUFE CZ *$% The latest coding system will affect all staff, from schedulers to those who manage preauthorization to clinicians, so it is imperative that the steering committee reflects representation from all areas of the practice.

The steering committee will become the leadership for guiding and planning the implementation.

Development of the implementation plan, identification of goals, and setting of expectations: The steering committee (with senior leadership approval) is responsible for defining the overall implementation plan for the practice. Realistic goals must be outlined, including a timeline that is designed to meet the required deadline. Enacting a plan too late may not leave adequate time to fully train all staff. Thus, the plan should include staffing, technology, and time requirements. It is a critical tool that helps in tracking the progress of the implementation, and should also be used as a tool to manage the budget in addition to providing communication to staff.

Budget: A thorough analysis of the funds required for a successful implementation must be completed to ensure appropriate allocation. According to the American Medical Association, implementation of *$% GPS B TNBMM QSBDUJDF DPVME DPTU GSPN BCPVU UP BCPVU XIFO QVSDIBTFT TVDI BT OFX software are considered. (Other sets such as Current Procedural TTerminology codes will continue to be used BGUFS UIF *$% USBOTJUJPO ) Communication plan: Staff must be kept informed with timely alerts and notifications of all changes and developments in the plan’s progress. Communication is key to reducing confusion and keeping staff involved as changes occur.

Readiness assessments: Review and analysis of workflows and processes must be conducted to determine practice readiness levels and what remains to be done.

Education and training: It is crucial to identify necessary staff and ensure that their knowledge and skill set are qualified to use this new coding system.

Often, coding software will provide users with the option to create a “favorites� or frequently used codes, simultaneously allowing specific providers to use their preferred terminology in their charting. For FYBNQMF BO *$% DPEF GPS iCMPPE JO TUPPMw NJHIU be linked to “melena,� “hematochezia,� or “bright red blood per rectum (BRBPR).� Sometimes designating an enthusiastic and computer-savvy provider “champion� within the practice to set up these favorite-lists can be useful.

Most insurance companies have indicated that they will deny claims that have nonspecific diagnosis codes, and such denials can be costly. Indeed, among UIF WBSJPVT SFBTPOT GPS UIF FYUFOTJPO PG UIF *$% implementation deadline was that most clinical practices did not appear to be fully ready to implement *$% 1SPTQFDUJWF BVEJUT QSFEJDUFE UIBU BQQSPYJNBUFMZ

Educational Review

Update on Endoscopic Eradication Therapy for Barrett’s Esophagus

John Vargo, MD, MPH

Time to end the Barrett’s double standard ................ page 7

Departm ment of Veterans Affairs Medical Center Kansass City, Kansas b Uniiversity of Kansas School of Medicine Kansas City, Kansas Ka Dr. Sharma has received grant support from Barrx Medical, CDX Labs, D Coo ok Medical, Ninepoint Medical, and Olympus Inc. Drs. Saligram and Venna alaganti reported no relevant financial conflicts of interest.

B

arrett’s esophagus (BE) is the precursor lesion to esophageal

Magnets control GERD in long-term study ............ page 18

adenocarcinoma, which in an

inva asive stage causes significant morbidity and mortality. Surgery m was the mainstay of treatment for w pa atients with high-grade dysplasia (HGD)) and adenocarcinoma associated

see insert after page 66

with BE. However, surgery in itself carries substan ntial m morbidity. There has been tremen ndous progress in the minimally invasive ndou treatment of BE in the past decade.

The premise to be aggressive in treating dysplasttic BE and early-stage adenocarcinoma is to prevent pro ogression to an advanced-stage cancer. Most interventionall endoscopists are comfortable treating dysplasia and intramuc cosal esophageal cancer, although recently there have been emerging emer data on the treatment of early submucosal cancer in BE. This article reviews the different modes of and strategies for endoscopic treatment of BE with emphasis on newer techniques.

Barrett’s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (IM; goblet cells) proximal to the gastroesophageal junction. The overall population prevalence is estimated at 1.6%1 with an annual incidence of 62 per 100,000.2 In patients with BE, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12% and 0.5%.3-6 Intestinal metaplasia can have a histologic

G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S • J U LY 2 0 1 5

8 ("4530&/5&30-0(: &/%04$01: /&84 t +6-:

KMarie Reid Lombardo, MD, MS

SHREYAS SALIGRAM, MD, MRCPa,b PRASHANTH VENNALAGANTI, MDa PRATEEK SHARMA, MDa,b a

Update on Endoscopic Eradication Therapy for Barrett’s Esophagus

Marc Ghany, MD, MHSc

1

WHO issues guidance for HBV treatment .............. page 40

1 MOST PRESCRIBED,

#

BRANDED BOWEL PREP KIT1

A CLEAN SWEEP

EFFECTIVE RESULTS IN ALL COLON SEGMENTS >90% no residual stool in all colon segments compared to Standard 4-Liter Prep2*†‡ · These results were statistically significant in the cecum (P=.010)2*§ · Significantly more subjects in SUPREP® group had no residual fluid in 4 out of 5 colon segments2*‡ Help meet Gastroenterology Quality Improvement Consortium (GIQuIC) benchmarks for 85% quality cleansing3 with the split-dose efficacy of SUPREP ® Bowel Prep Kit.4 *This clinical trial was not included in the product labeling. †Standard 4-Liter Prep [sulfate-free PEG electrolyte lavage solution]. ‡Based on investigator grading. §Statistically significant difference.

References: 1. IMS Health, NPA Weekly, March 2015. 2. Rex DK, Di Palma JA, Rodriguez R, McGowan J, Cleveland M. A randomized clinical study comparing reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy. Gastrointest Endosc. 2010;72(2):328-336. 3. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81(1):31-53. 4. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2012.

©2015 Braintree Laboratories, Inc.

16-00590

March 2015

3

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Stop the “Insanity”: The Economic Case for More EMR WASHINGTON—If reimbursement rates are any indication, insurers push surgery over less invasive modalities for polyp removal. Now, a new study suggests that payors are wasting potentially hundreds of millions of dollars in the process—and for inferior patient outcomes.

The study found that patients who undergo endoscopic mucosal resection (EMR) for benign large polyps in the colon stay much shorter in the hospital, have fewer complications and cost

thousands less to treat than those who undergo surgical resection for the same lesions. The researchers, who call their study “a plea for sanity,” say the findings show that both private insurers and the federal government have created perverse incentives when it comes to the removal of large polyps.

“Patients are having surgery for removal of benign large polyps when the skills and expertise are available to remove those endoscopically,” said Ji

Young Bang, MD, MPH, a gastroenterology fellow at Indiana University, in Indianapolis, who led the study.

“Insurance carriers and Medicare value endoscopy services less than surgery, although [EMR] provides better outcomes and is much cheaper,” said Shyam Varadarajulu, MD, medical director of endoscopy at Florida Hospital, in Orlando, who helped conduct the research. “The cost of doing EMR is more than what is being reimbursed,

leading to a huge loss. If the procedure involves shorter hospital stays and fewer adverse events than surgery, then it has to be rewarded with better reimbursements so that a more expensive surgery is not being done. On the contrary, one gets penalized by the current system. Translated nationally, this results in a loss of hundreds of millions of dollars” annually.

Dr. Bang’s group conducted a retrospective case-control study involving 99 patients with polyps at least 2 cm in size.

Of those, 33 patients underwent surgery and 66 underwent EMR. Patients treated with EMR tended to be older than the surgery group (average, 71 vs. 62 years; P=0.0001), but polyp size was similar in P the two cohorts.

‘The cost of doing EMR is more than what is being reimbursed, leading to a huge loss. If the procedure involves shorter hospital stays and fewer adverse events

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.

than surgery, then it has to be rewarded with better reimbursements so that a more expensive surgery is not being done.’

—Shyam Varadarajulu, MD

BRIEF SUMMARY: Before prescribing, please see full Prescribing Information and Medication Guide for SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution.

INDICATIONS AND USAGE: An osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: 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. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prep Kit is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. 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. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. 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. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established.

Geriatric Use: Of the 375 patients who took SUPREP Bowel Prep Kit in clinical trials, 94 (25%) were 65 years of age or older, while 25 (7%) were 75 years of age or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP may not be absorbed completely. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Split-Dose (Two-Day) Regimen: Early in the evening prior to the colonoscopy: Pour the contents of one bottle of SUPREP Bowel Prep Kit into the mixing 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 only a light breakfast or have only clear liquids on the day before colonoscopy. Day of Colonoscopy (10 to 12 hours after the evening dose): Pour the contents of the second SUPREP Bowel Prep Kit into the mixing 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. Complete all SUPREP Bowel Prep Kit and required water at least two hours prior to colonoscopy. 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

©2015 Braintree Laboratories, Inc.

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March 2015

Patients who received EMR had significantly shorter hospital stays than those who underwent surgery, one versus four days, respectively (P<0.0001), and had a significantly lower rate of complications (6% vs. 24%; P P=0.02), according to the researchers.

The cost of EMR was far less than for surgery, at $3,649 per procedure compared with $13,440, the researchers found. However, while the hospital received an average of $31,371 per surgery case, it recouped $3,120 for every EMR—a loss per procedure of $529.

Of course, it’s possible that hospitals are satisfied to have higher-priced surgical resections instead of EMRs—after all, the economics are so much better. Dr. Varadarajulu said it’s something that gastroenterologists should work to change.

“What should not happen is [gastroenterologists] referring all their cases to a surgeon because it is not worth their time,” he said.

The researchers presented their study at Digestive Disease Week 2015 (abstract Sa1616).

—Adam Marcus

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Heard Here See page 70 First

FDA Okays Two Drugs for IBS-D he FDA has approved two therapies, eluxadoline and rifaximin, for irritable bowel syndrome accompanied by diarrhea (IBS-D).

Both drugs are approved to treat men and women with IBS-D, a condition that affects between 10% and 15% of adults in the United States.

Eluxadoline (Viberzi, Actavis) is a new agent. Rifaximin (Xifaxan, Salix Pharmaceuticals) is already approved for the treatment of traveler’s diarrhea from infection with Escherichia coli, as well as overt hepatic encephalopathy (see story, page 56).

According to the FDA, the most frequent side effects in patients taking eluxadoline include constipation, nausea and abdominal pain. The most serious known adverse event of the drug is spasm

in the sphincter of Oddi, which can result in pancreatitis, the agency said. The drug should not be used in patients with a history of bile duct obstruct i o n , p a n c re a t i t i s , severe liver impairment or severe constipation, or in those who report drinking more than three alcoholic beverages daily.

Side effects of rifaximin, when taken for IBS-D, include nausea and an increase in alanine aminotransferase, the FDA said. Patients who do not improve on the drugs should be evaluated for Clostridium difficile enterocolitis. Clinicians should exercise caution when using rifaximin in patients with severe liver impairment or when combined with certain other drugs, health officials said. For more information, visit the FDA website.

—GEN Staff

T

Compared with other solid organ transplants,

immunosuppression in small-bowel transplant is the most challenging to control short- and long-term, because unlike other organs that are placed in a sterile environment, the small bowel is continually exposed to foreign antigens in the food and stool passing through it.

Vol. 66, No. 7 MEDICAL ADVISORY BOARD GARY R. LICHTENSTEIN, MD

PRATEEK SHARMA, MD

Philadelphia, Pennsylvania

Kansas City, Kansas

Houston, Texas

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Sacramento, California

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PETER R. MCNALLY, DO

FREDRIC DAUM, MD

Fort Carson, Colorado

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Tacoma, Washington

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Elizabeth City, North Carolina

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Cleveland, Ohio

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Tampa, Florida

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Gainesville, Florida

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INFECTIOUS DISEASE SPECIAL EDITION

5

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JULY 2015

To Make Money in the Markets, Look for Creativity First

W

hen I am approached for financial advice, my zeal to be helpful is often deflated by the complexity of the situation.

Recently, an acquaintance in his mid-70s asked how he should invest his retirement savings; he would like to retire next year. I callously asked whether his nest egg was over or under $500,000. The amount was closer to $10,000, a challenging premise.

I instinctively responded, â&#x20AC;&#x153;I donâ&#x20AC;&#x2122;t know.

How much does a time machine cost?â&#x20AC;?

Maybe I lack the cool sensitivity of a licensed broker, but I was stumped. I couldnâ&#x20AC;&#x2122;t come up with a safe strategy; his required return was somewhere in the 750% annualized range. To put an end to our conversation, I agreed that his plan to invest in a fighting-robot dinner theater was as good a solution as any.

A misunderstanding about hedge funds (the media is a prime purveyor of this misconception) is that they perform poorly if the stock market is up more than the funds are. This story may sell newspapers, but it completely misses the point.b A well-managed hedge fund simply gives you a chance to make money regardless of the direction of the market.

It takes risks that are diffferent from market risk, thus itss return should be different.

Yoda Versus Shrek How do hedge funds atttempt to achieve market independence?

Letâ&#x20AC;&#x2122;s take a simple examp ple, a so-called see Hedge, page 6

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Transaction costs are boring,

â&#x20AC;˘ Better than bed wedges1

but they are critical.

â&#x20AC;˘ Better than head of bed elevation1,2 â&#x20AC;˘ Better quality of life3

I personally invest more simply: in stocks, bonds and hedge funds, which are relatively liquid things, and in real estate and children, which are less liquid things.

Most people understand stocksâ&#x20AC;&#x201D;buy low, sell highâ&#x20AC;&#x201D;and some understand bondsâ&#x20AC;&#x201D; yields down, price upâ&#x20AC;&#x201D;but few have a solid grasp of the admittedly nebulous body of investments called hedge funds. In this article, Iâ&#x20AC;&#x2122;ll try to clear some of this haze.

Truth in Labeling As the name suggests, hedge funds are meant to hedge other risks in your portfolioâ&#x20AC;&#x201D;that is, to protect against loss in one type of investment by taking balancing risks of another sort. The average investor takes his or her primary financial risk in stocks. Thus, ideally, hedge funds should hedge stocks. Few do.

But as a fan of the football team based in our nationâ&#x20AC;&#x2122;s capital, I have trained myself to temper my expectations. I think of the â&#x20AC;&#x153;hedgeâ&#x20AC;? in hedge funds as stock market independence.a If the market is down today, my hedge funds may be up or down.

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6

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Hedge continued from page 5

long/short hedge fund. Long/short managers try to pick winning and losing companies. Let’s speculate that Disney will do better than the rest of the entertainment industry and that DreamWorks will fare relatively worse. So, we buy $1 million worth of Disney stock and sell short $1 million of DreamWorks stock.c The next morning, blood spurts from your car radio as the market drops 10%.

Bad news for your stock portfolio, but it shouldn’t affect our long/short position.

While Disney is probably down with the rest of the market, so too is DreamWorks, which we had bet against. The next day the broad market is fine, but the entertainment sector was crushed overnight.

(Let’s just say, hypothetically, that all entertainment content could suddenly be downloaded for free from the Internet.)

Again, both stocks are down proportionally on this news, but our Disney losses are offset by the gains on our short position in DreamWorks. What we care about is that Disney improves more or sinks less than DreamWorks.

When I first learned of this approach to investing I was thrilled. It perfectly suited my risk tolerance. Most of the volatility in a stock’s price flows from events in its industry and the market in general. What a wonderful way to free myself from the randomness of markets! But in reality, making money by choosing winners and losers iss incredibly hard, and consistently successful stock pickers are rare. My previous article (Gastroenterology & Endoscopy News May 2015, page 6) goes into some detail about the scarcity of “alpha.”d

Insufferable Managers In 2014, only 14% of large cap—that’s $10 billion or more in market value—stock managers beat the market, according to Standard & Poor’s. Yet those impressive few must live near me because I’ve never met an investment manager who self-identifies as below average. Clearly managers who outperformed last year are special.

But as I said, consistency is rare. As a fairly green associate at Goldman Sachs in the late 1990s, I was curious about how likely it would be for a manager who beat the market in one year to repeat this feat over the next. I had assumed that good

stock, which had soared over the year.

He had managed his position through the options market to keep his market exposure low. But his trader admitted to me that while the idea was a winner, the manager had paid more in option premiums throughout the year than the brilliant pick had made. The investment that the manager was most proud of for the year had lost money. Transaction costs are boring, but they are critical. Winners are inconsistent, but every transaction costs real money.

A Powerful Tool

“Hedge Hedge Funds: Hedge Run for rich people from Geneva, G by rich people from m Greenwich” Gree —Cliff Asness, co-founder of AQR Capital —C tal Man Management managers were consistently good. Upon crunching the entire money manager universe, I was surprised to learn that the top quartile of outperformers over a given period had less than a 25% chance of outperforming in the next. In other words, the chance of repeating a strong performance was worse than random!e I have a friend who ran a multibilliondollar investment fund for a large developed country. He’d say the manager who beat the market for a few years through luck was usually insufferable, but the truly great manager, the one who achieved consistently through skill and process, wasn’t seeking attention.f So, my suggestion that you find a well-managed hedge fund is like the Steve Martin joke advising how to be a millionaire and never pay taxes: “First, get a million dollars …” But those hedge funds are out there and once you’ve found them, you can stay with them for many years.

Hedging … Or Obstructing I mentioned that few hedge funds fully hedge. Staying with the long/short example, there are three primary explanations for this (in order from innocent to annoying), as I see it:

Love. When managers discover one stock out of hundreds that is special, they bond with it. When a stock makes them money, the love is requited, and over time confirmatory bias leads managers to focus on data that validate their feelings. Moreover, finding new great companies is hard and capacity (see my May 2015 column) is diminished whenever a stock is dropped.

Prevailing winds. On average, over time, the market rises. Although the mandate of the hedge fund manager is to eschew the market, collecting a 20% incentive fee on something that just happens is a tempting business model. Clients are to blame as well.

When stocks had ridden a 20% updraft, I hated explaining that our 8% return was terrific, considering we had hedged out the market.

Death, taxes and transaction costs.

Shorting stocks can be painful, and playing out an idea in options markets can be expensive. I’ve witnessed this at many different firms in dozens of subtle ways, but here’s a fun one: A hedge fund manager wrote in his letter to clients that he had correctly chosen XYZ

Hedge funds can be a powerful tool.

They turn experts at selecting great American companies into experts at selecting great German cars. But the best managers are worth it. They demonstrate a repeatable process and are habitually innovative. Still, they don’t expect to win all the time.

As an investor, expect less in terms of performance, but look for the extraordinary in terms of idea generation and process. Creativity and repeatability, more than historical results, are what indicate a hedge fund will perform exceptionally in the future.

—Joe DeLuca Mr. DeLuca is a writer, and former hedge fund executive, in Montclair, N.J. He can be reached at joedeluc@gmail.com.

Footnotes a For the purposes of this article, I’ll refer to the broad stock market as “the market.” b Newspapers are where your parents got their news before Twitter and Facebook. c Sell short: to borrow shares of a stock now, which you pay for later. One would do this when one thinks the shares of the stock are going to go down, thus what you pay in the future would be less than what you are paid for selling them now. d Making money from skill rather than just generating the returns that the broad market gives. e There are many reasons this would be the case, which I cannot go into here. Please feel free to send me an email to discuss. f In my more limited experience, this is true with the exception of new managers.

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COMMENTARY

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Treating Barrett’s Esophagus: Time To End the Double Standard

T

he way we have approached most cancers in the practice of evidence-based medicine has been to remove the precursor lesion before the onset of cancer, thus preventing or minimizing the risk that cancer will develop. We do that for actinic keratosis, cervical dysplasia and colon polyps.

We have not done it for Barrett’s esophagus, which is the immediate precursor to esophageal adenocarcinoma (EAC). The reason is that we did not have a safe or effective means of doing so—until now!

Gastroenterologists have long had a double standard. We approach colon polyps aggresF. Scott Corbett, MD sively, but despite data suggesting that nondysplastic Barrett’s is two to three times more likely to progress to high-grade dysplasia (HGD) or EAC than is an adenomatous colon polyp left in place, we are content to use a “watch and wait” strategy for Barrett’s.

We have followed a policy of surveillance with little or no data to support its utility. In the interest of costeffectiveness, we have spaced out surveillance intervals based on little more than whim and expert opinion. Fortunately, most of us haven’t gotten into too much trouble with surveillance because most Barrett’s patients have a relatively low risk for progression.

However, the risk for progression from nondysplastic Barrett’s to EAC is not as low as some experts may purvey. A meta-analysis of 25 studies by Shaheen et al, in 2000, estimated the annual risk for EAC to be 0.5% per patient per year of follow-up, after correction for study bias (Gastroenterology 2000;119:333-338). Wani et al, in 2009, estimated the risk for progression at 5.98 per 1,000 patient-years (about 0.6% per patient per year; Am J Gastroenteroll 2009;104:502-513). To suggest that the rate of progression has somehow decreased, when the incidence of this disease over the past three decades has soared, seems to defy logic.

One explanation for this lower rate may be that publishers of natural history studies have generally excluded patients from the data pool if they were noted to progress from nondysplastic Barrett’s to EAC in the first year of the study. It is assumed that the endoscopist must have missed dysplasia at the time of inclusion.

Not only is this requirement an admission of the failure of surveillance as a policy, it is potentially removing

a highly important subset from the data—and falsely underestimating risk. No matter how you look at this issue, the first and generally only time you sit down with a patient and explain the risk from this disease is the first time you diagnose it. The risk for patients during that first year includes the risk for that subset of patients with prevalent cancers who have been cut out of the data.

Even when excluding that subset in 1,376 patients with a first-time diagnosis of Barrett’s esophagus, Sharma at al reported data showing that 53% of the patients who developed HGD or EAC had at least two consecutive initial endoscopic surveillances showing only nondysplastic Barrett’s (Clin Gastroenterol Hepatol 2006;4:566572). This disease is variable and unpredictable. It also carries one of the worst prognoses of any human malignancy, and patients know this. A diagnosis of Barrett’s is highly anxiety-provoking, and this subsequently affects the quality of a patient’s life (Clin Gastroenterol Hepatol 2009;7:613-623).

The average patient doesn’t care if the risk for progression to EAC is 0.1% per year or 0.6%. Any risk is too much, especially when there is a saafe, effective, costeffective and durable way to deal witth it. Many of my patients are already survivors of anoth her cancer, or they know someone close to them (other than a blood relative) who suffered or died from the trreatment of EAC. They feel the need to be proactive.

In 2010, Shaheen et al reported th hat radiofrequency ablation (RFA) improved health-relatted quality of life for patients with dysplastic Barrett’ss, apparently due to a perceived reduction in the risk fo for cancer (Endoscopyy 2010;42:790-799). At this year’s Digestive Disease Week, Li et al reported similar observvations from more than 4,000 patients in the United Sttates RFA Registry (abstract Sa1077). Treatment of Barrett’s with RFA markedly improved health-related quaality of life specific to the disease in these patients, especiallly when clearance of all intestinal metaplasia was achieeved. Surprisingly, nondysplastic Barrett’s had a significantly greater negative impact on life than dysplasia. Treattment significantly improved this impact to a similar degrree. Although that effect at that time may have been due to a perception of improved survival, we now have data, pending publication, from the U.S. RFA Registry that su upports a 10-fold risk reduction for nondysplasticc Barrett’s patients receiving RFA (compareed with historical controls).

Anxiety about one’s health is real.

7

It has its own billing code. On Jan. 17, 2014, a Federal Appeals Court in Boston upheld the ruling of a lower court, granting consent for a taxpayer-funded gender change procedure for an inmate serving a life sentence for a murder conviction. The essence of the ruling was that “medically necessary treatment is a constitutional right that must be protected, even if that treatment strikes some as odd or unorthodox.”

In 2010, Fleischer et al outlined the opinion of 16 of the nation’s most respected Barrett’s experts, including gastroenterologists, pathologists and surgeons, in an elegant treatise on why we should offer RFA to those with nondysplastic Barrett’s and low-grade dysplasia. Their conclusion: This treatment is “medically necessary.” The anxiety of an individual with Barrett’s is real, and even surveillance, no matter how frequent or lax, produces anxiety. This anxiety may or may not be comparable to an individual plagued by the perception that they have been born of the wrong sex, and that the only relief is a medical procedure to correct this. Yet, that is not the message of the court’s opinion. What the court implied is that no matter what the circumstance—whether RFA for the patient with nondysplastic Barrett’s, propofol for a colonoscopy patient or a sex change operation for an inmate serving a life sentence—if there is support for medical necessity, a patient has a constitutional right to receive the treatment in question. To withhold treatment from someone desiring RFA is unconscionable.

—F. Scott Corbett, MD Dr. Corbett is medical director of Suncoast Endoscopy of Sarasota, Gastroenterology Associates of Sarasota, LLC, a division of Florida Digestive Disease Health Specialists, in Sarasota, Fla. He is a member of the authoring committee of the U.S.-RFA Barrett’s Registry.

For more on Barrett’s esophagus, see page 58.

Many Problem Drinkers Don’t Seek, Receive Treatment

N

early 30% of Americans will experience problem drinking in their lifetime, but as many as one-third of them will not receive treatment for the condition, new research shows.

Scientists with the National Institute on Alcohol Abuse and Alcoholism surveyed more than 36,000 adults in an effort to update the prevalence of alcohol use disorders (AUD) in the United States. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) includes a broader definition

for problem drinking than the previous iteration, merging abuse and dependence into a single category. It adds craving to the criteria and sets a diagnostic threshold of at least two criteria. The DSM-5 also establishes a severity metric based on the number of criteria met.

According to the latest study, the 12-month prevalence of AUD under DSM-5 was 13.9%, and the lifetime prevalence was 29.1%. These percentages amount to approximately 32.6 million and 68.5 million adults, respectively. However,

only 19.8% of adults sought treatment or help for alcohol abuse in their lifetime; 7.7% of those with a 12-month disorder sought treatment, the study found.

The prevalence figures differ from those determined under the DSMIV criteria, which found 12-month and lifetime rates of 12.7% and 43.6%, respectively.

White men had the highest rates of 12-month and lifetime AUDs. Problem drinking was more common among young people, individuals who had

previously or never been married, and people with a history of substance abuse and mental illness.

The study “highlighted the urgency of educating the public and policy makers about AUD and its treatments, destigmatizing the disorder and encouraging those who cannot reduce their alcohol consumption on their own, despite substantial harm to themselves and others, to seek treatment,” according to the authors. The findings appeared online in JAMA Psychiatry.

—GEN Staff

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Role of Positive Practice Management During the Transition to ICD-10 Faculty Kathleen Mueller, RN, CPC, CCS-P, CMSCS, PCS, CCC President and Coding Consultant AskMueller Consulting, LLC Lenzburg, Illinois

Introduction Over the past several years, gastroenterology and endoscopy practices have faced increasing efforts to define and improve standards for quality of care led by agencies such as the American Gastroenterological Association (AGA), the American College of Gastroenterology (ACG), and the American Society for Gastrointestinal Endoscopy (ASGE).1 Similarly, practices also require efficient management to ensure proper reimbursement, particularly since billing and coding changes due to the adoption of the 10th revision of the International Classification of Diseases (ICD-10) are imminent. As a standard diagnostic and health management tool used by 117 countries,2 it is important for clinicians and practice staff to understand how to best transition to working within ICD-10 classifications.

Transition to ICD-10: Top-Level Changes From ICD-9 The 9th edition of the ICD was implemented by the United States in 19793; due to the changing medical landscape, the use of a set of diagnosis and inpatient procedure codes that is 35 years old does not provide the type of clinical specificity needed to completely describe a patient’s condition and/or ultimate treatment as handled today. Thus, ICD-10, which was endorsed by the World Health Organization in 1990 and began worldwide use in 1994, is scheduled to be instituted in the United States on October 1, 2015, and is designed to provide more details per code and allow clinicians to better track patient severity and risk as well as overall quality measures.3 The additional detail contained in ICD-10 codes informs health care providers and health plans of disease characteristics and history, which allows for more effective case management and better coordination of care. From a practical standpoint, this means that the coding options for the typical gastroenterology practice will expand markedly (Table).4,5 For example, whereas ICD-9 included 4 codes for Crohn’s disease, ICD-10 includes more than 30 codes, and codes can be combined depending on illness and eventual patient diagnosis, leading to more options.

Overall, ICD-10 consists of approximately 68,000 codes compared with ICD-9’s 13,000 codes.6

8

Specifically addressing these code changes, the updated ICD-10 expands the number of digits in the diagnosis code from 3 to 7, allowing for additional subdivisions, from 3 to 5 digits in ICD-9, while otherwise keeping the codes themselves similar to ICD-9.

Additionally, codes for inpatient procedures in the hospital setting previously included in the ICD-9, Clinical Modification (ICD-9-CM) are grouped in the ICD-10Procedure Coding System (ICD-10-PCS) category; office and outpatient procedures will not be affected by this change.3 At 7 alphanumeric digits, the ICD-10-PCS codes are different and more descriptive than those in ICD9-CM. Generally, the ICD-10 codes emphasize specificity: Factors such as time of patient presentation, side of the body related to illness, and patient follow-up condition all can be coded to ensure that tracking is accurate and payors approve claims quickly and correctly with fewer inquiries and delays. Furthermore, ICD-10 codes have been modernized and are constructed with the changing medical field in mind.

Although the complexity of ICD-10 provides many benefits because of the increased level of detail conveyed in the codes, it also underscores the need for practices to be adequately trained on ICD-10 in order to fully understand reporting changes that will come with the new code sets, so that reimbursement can better reflect the intensity of the patient’s condition and diagnostic needs.

The Transition Process: Obstacles and Success Strategies Whether implementing a new laboratory information system or a new coding system, the planning, preparation, education, training, and communication steps taken to prepare for implementation are crucial to the success of any new health information system project. Key obstacles in the way of a successful transition, such as insufficient staff, lack of coordination, and poor communication, should be identified and corrected to mitigate difficulties inherent in the change to a new coding system.

Thus, in order to achieve optimum outcomes in the course of ICD-10 implementation, it is important for practices to provide most, if not all, of the following measures: Senior leadership support: Support from senior leadership is essential for any implementation project.

It is crucial that senior leadership fully supports moving forward with an ICD-10 implementation plan as scheduled. Support must be shown throughout the plan’s progress as well as after the project’s completion.

Lack of support may impede changing behaviors and documentation procedures throughout the staff, and decrease transition success.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Multidisciplinary steering committee: The initial step of any implementation plan is to identify key stakeholders and how they will be impacted by ICD-10.

The latest coding system will affect all staff, from schedulers to those who manage preauthorization to clinicians, so it is imperative that the steering committee reflects representation from all areas of the practice.

The steering committee will become the leadership for guiding and planning the implementation.

Development of the implementation plan, identification of goals, and setting of expectations: The steering committee (with senior leadership approval) is responsible for defining the overall implementation plan for the practice. Realistic goals must be outlined, including a timeline that is designed to meet the required deadline. Enacting a plan too late may not leave adequate time to fully train all staff. Thus, the plan should include staffing, technology, and time requirements. It is a critical tool that helps in tracking the progress of the implementation, and should also be used as a tool to manage the budget in addition to providing communication to staff.

Budget: A thorough analysis of the funds required for a successful implementation must be completed to ensure appropriate allocation. According to the American Medical Association, implementation of ICD-10 for a small practice could cost from about $55,000 to about $225,000 when purchases such as new software are considered. (Other sets such as Current Procedural Terminology codes will continue to be used after the ICD-10 transition.6,7) Communication plan: Staff must be kept informed with timely alerts and notifications of all changes and developments in the plan’s progress. Communication is key to reducing confusion and keeping staff involved as changes occur.

Readiness assessments: Review and analysis of workflows and processes must be conducted to determine practice readiness levels and what remains to be done.

Education and training: It is crucial to identify necessary staff and ensure that their knowledge and skill set are qualified to use this new coding system.

Often, coding software will provide users with the option to create a “favorites” or frequently used codes, simultaneously allowing specific providers to use their preferred terminology in their charting. For example, an ICD-10 code for “blood in stool” might be linked to “melena,” “hematochezia,” or “bright red blood per rectum (BRBPR).” Sometimes designating an enthusiastic and computer-savvy provider “champion” within the practice to set up these favorite-lists can be useful.

Most insurance companies have indicated that they will deny claims that have nonspecific diagnosis codes, and such denials can be costly. Indeed, among the various reasons for the extension of the ICD-10 implementation deadline was that most clinical practices did not appear to be fully ready to implement ICD-10. Prospective audits predicted that approximately

Supported by

ICD-9-CM Diagnosis

ICD-9-CM Code

ICD-10-CM Diagnosis

ICD-10-CM Code

Barrett’s esophagus

530.85

BE without dysplasia BE with low grade dysplasia BE with dysplasia, unspecified BE with high grade dysplasia

K22.7 K22.710 K22.719 K22.711

Benign neoplasm of the rectum/ anus

211.4

Benign neoplasm of the colon

211.3

BN of rectum BN of rectosigmoid junction BN of anus and anal canal BN of cecum BN of ascending colon BN of appendix BN of transverse colon BN of descending colon BN of sigmoid colon BN of colon, unspecified Polyp of colon Polyp of rectum Polyp of anus

D12.8 D12.7 D12.9 D12.0 D12.2 D12.1 D12.3 D12.4 D12.5 D12.6 K63.5 K62.1 K62.0

1st degree hemorrhoids 2nd degree hemorrhoids 3rd degree hemorrhoids 4th degree hemorrhoids Other hemorrhoids (without mention of degree) Unspecified hemorrhoids

K64.0 K64.1 K64.2 K64.3

Internal hemorrhoids without mention of complication

455.0

Other ulcerative colitis

556.8

Ulcerative colitis, unspecified

556.9

K64.8 K64.9

Other UC without complications Other UC with rectal bleeding Other UC with intestinal obstruction Other UC with fistula Other UC with abscess Other UC with other complications Other UC with unspecified complications UC, unspecified UC, unspecified with rectal bleeding UC, unspecified with intestinal bleeding UC, unspecified with fistula UC, unspecified with abscess UC, unspecified with other complications UC, unspecified with unspecified complications

K51.80 K51.811 K51.812 K51.813 K51.814 K51.818 K51.819 K51.90 K51.911 K51.912 K51.913 K51.914 K51.918 K51.919

BE, Barrett’s esophagus; BN, benign neoplasm; ICD, International Classification of Diseases; UC, ulcerative colitis Adapted from references 4 and 5.

20% of billing charges would have been rejected due to incorrect or nonspecific coding from most practices.

Coding experts advise that practices perform an analysis per provider to determine how many nonspecific ICD-9 diagnosis codes the provider has chosen and compare codes with diagnoses in medical

records to determine if a more specific diagnosis choice was applicable.8 A particularly useful strategy is to use the provideraudit data to predict the annual costs of rejected claims if their nonspecific ICD-9 coding habits were to carry over into the ICD-10 system. For example, if the cost associated with a denied claim is $40 per instance, and a provider is filing 40 nonspecific codes weekly over 52 weeks those denied claims would translate into a potential reimbursement loss of $80,000 per year. Such a concrete illustration of loss for the practice may help motivate providers to be more specific in their documentation and coding.

Providers should also expect that a dual system of both ICD-9 and ICD-10 codes will be in use until all payors are compliant.

They should contact payors as to when they will start accepting ICD-10 codes, and create a spreadsheet and begin testing claims transmission when the payor can accept either test or real claims. It is important that providers prepare for delayed claims processing with software glitches, and therefore set aside funds for office payroll expenses and other expenses to prepare for delayed reimbursement.

A useful strategy is to plan on a shorter office visit schedule for at least the first go-live date to allow time for updating diagnosis codes. Some software will make the latter changes automatically; others will not. Lastly, staff should maintain close contact with their software vendor about the status of the transition to ICD-10.

Resources for Improving Practice Management

The Centers for Medicare & Medicaid Services has created a specialty website, Road to 10: The Small Physician Practice’s Route to ICD-10 (www.roadto10.org) to provide a comprehensive resource to help practices successfully navigate the transition to ICD-10.

Furthermore, several major gastroenterological societies have established their own resources for the ICD-10 transition with a focus that is more specific

to the typical gastroenterological and endoscopic clinical practice. These include resources from the AGA (www.gastro.org/practice-management/coding/ icd10), ACG (gi.org/practice-management/), and ASGE (www.asge.org/Practice/).

Conclusion Practices should familiarize themselves with the ICD-9 to ICD-10 network of changes and implement a comprehensive transition plan now in order to be ready by the transition date. Although codes for conditions typically treated by gastroenterologists did not change as much as for other specialties, it is key that all practice staff know how and where to find codes in the new system to ensure that reimbursement is not hindered by error or misidentification.

References 1.

Rex DK, Bond JH, Winawer S, et al; U.S. Multi-Society Task Force on Colorectal Cancer. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2002;97(6):1296-1308.

2.

World Health Organization. International Classification of Diseases (ICD). www.who.int/classifications/icd/en/.

Accessed June 11, 2015.

3.

Centers for Medicare & Medicaid Services. Introduction to ICD-10: a guide for providers. www.cms.gov/eHealth/ downloads/eHealthU_IntroICD10.pdf. Accessed June 11, 2015.

4.

Centers for Medicare & Medicaid Services. 2015 ICD-10-CM and GEMs. 2015 code descriptions in tabular order. www. cms.gov/Medicare/Coding/ICD10/Downloads/2015-codedescriptions.zip. Accessed June 11, 2015.

5.

Centers for Medicare & Medicaid Services. ICD-9-CM Diagnosis and procedure codes: abbreviated and full code titles. Version 32 full and abbreviated code titles– effective October 1, 2014. www.cms.gov/Medicare/Coding/ ICD9ProviderDiagnosticCodes/Downloads/ICD-9-CM-v32master-descriptions.zip. Accessed June 11, 2015.

6.

Medicaid.gov. ICD-10 Changes from ICD-9. http://medicaid. gov/medicaid-chip-program-information/by-topics/dataand-systems/icd-coding/icd-10-changes-from-icd-9.html.

Accessed June 11, 2015.

7.

American Medical Association. ICD-10 code set to replace ICD-9. www.ama-assn.org/ama/pub/physician-resources/ solutions-managing-your-practice/coding-billing-insurance/ hipaahealth-insurance-portability-accountability-act/ transaction-code-set-standards/icd10-code-set.page.

Accessed June 11, 2015.

8.

Kim CY, Muller KA. The American Society for Gastrointestinal Endoscopy (ASGE) practice management: is your practice ready for ICD-10? www.asge.org/assets/0/71550/71568/ c4b6626e-5e76-4788-bc36-bddb51bbb7ed.pdf. Accessed June 11, 2015.

Disclosure Ms. Mueller reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

BB1510

Table. Comparison of ICD-9-CM and ICD-10-CM Codes For Common Gastroenterological Conditions

9

10

COMMENTARY

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

‘Put the Phone Away, You Are Having an Operation’

A

ny visitor to a modern hospital or health facility will quickly observe that patients, families and visitors are looking into the glow of the box in their right hand. They exercise their thumb with rapid motion on the screen, texting and shuttling between social media posts. The press is full of how this now-known addiction has affected the human condition. There are thousands of deaths and injuries attributed to distracted driving and walking, and horrible reports of individuals jumping in front of subways to “rescue the phone.” It is common knowledge that many teens believe their life is on the phone and they could not live without it.

As one who has observed how such uncontrolled technology use affects health care providers and helped coin the term “distracted doctoring,” I have begun to study how this dependency on what I term “personal technology” affects the professional–patient relationship. We all know the complaints that patients have that their provider is too fixated on the electronic health record and is not interacting with the living patient, but with

the so-called i-patient that is in the computer. Medical schools and medical societies are addressing so-called technology–human interactions and professional etiquette, but a new problem looms: the patient who does not interact with the provider. Patients can thus affect their care based on their distraction.

As an illustration, I will give several patient scenarios that I have observed. A young teen struck by a car and awaiting surgery is too busy taking selfies in her hospital bed. Both parents are on their own personal electronic devices, one texting, the other posting on Facebook.

When the anesthesiologist tries to get a preoperative history and share his anesthesia plan with them, he is cut off with the statement, “Do you not see I am texting?

Do not interrupt.” This scenario is becoming more and more common in our society and illustrates a fact, that has been identified by neuroscientists, that the individual is so engaged with the technology that the actual event eludes them. This electronic escapism has been identified many times by texting drivers who have no recall of the accident after th he fact.

This psycholoogical response can truly endanger the professional relatioonship because patients may not remember all-imporrtant information transmitted to them by the bed dside staff—this information is just not processed d. Lack of engagement may also decrease the amoount of medical history or data that the patien nt or their families volunteer. They are too eengaged in hypersocial interactions with distant virtual worlds to think about the importance of the here and now.

Repeatedly, we also see a new phenomenon in which the patient has become the i-patient and depends on teechnology to know their own informatioon. Such interactions can be as simple as the aanswer to the question, “What medications arre you on?” with the now common answer, “I do not know, it’s on the computer.” This would be all fine an nd good if there were a uniform electronic medical recorrd shared by all that is always complete,

but we all know that is not the case. There are other factors, such as spurious information being present in electronic records and incorrect information about medical history and current medications, all of which may greatly affect the care of the patient. As an active clinician, I can tell you I am confronted daily with false information in these records that might have affected patient care if I had not verbally reviewed the information with the patient and corrected it.

How can we, as health professionals, begin the battle to regain the sacred bond between the patient and the practitioner, which has been at the core of medical practice since the ancient Greeks? I believe we need to educate the public about how this dependency on technology has affected them. Physicians should take the lead on how texting and social media addiction affects health.

Trauma and emergency medicine providers should be at the forefront of educating parent and school groups about the dangers of texting and driving and the many other aspects of electronic addiction. Hospitals should clearly post signs noting that patients must put their devices away during exams. Physicians should also educate their patients about the necessity of knowing their medical history and medications. Physicians should support the concept of keeping a hard copy of this data at hand in case of technology failure. Patients should be encouraged and have the ability to go into their record and review and correct any errors on a regular basis.

I believe technology has been a great boon to our society, but in many respects it has been introduced so rapidly that we have not been able to adapt to it and control its many pitfalls. The human brain needs to be trained to become adept with this technology and integrate it to provide humanistic effective care. We must truly understand how to rewire our brains to cope with this technological, hypersocial world.

—Peter J. Papadakos, MD Dr. Papadakos is director of Critical Care Medicine at the University of Rochester Medical Center, in Rochester, N.Y. He writes and lectures on the impact of technology on medical care.

FMT May Block Multidrug-Resistant Pathogens

A

fecal microbiota transplant (FMT) not only cured a case of Clostridium difficilee infection (CDI) in a 66-year-old man, it eliminated populations of multidrug-resistant organisms (MDROs) both in the patient’s gastrointestinal (GI) tract and at several other body sites (J ( Clin Microbiol 2015;53:1986-1989).

The patient suffered from quadriplegia and multiple other conditions, requiring a ventilator, a feeding tube and chronic Foley catheterization. Because of his complex medical needs, he was admitted to the ICU at Scripps Mercy Hospital in San Diego. Within the first week, he was diagnosed with C. difficile colitis and was treated with oral antibiotics. However, whenever the antibiotics were tapered, the C. difficilee rapidly recurred. Concurrently, a number of MDROs were isolated from the

patient, which led to repeated infections.

Ultimately, he received an FMT; the material was injected using a colonoscope, after discontinuation of antibiotics.

After FMT, there was no recurrence of C. difficile for the two years leading up to the patient’s death. Although methicillin-resistant Staphylococcus aureus did recolonize in his urinary tract several months after FMT, the many other antibiotic-resistant microbes did not, despite his ongoing ICU stay.

“The fecal microbiota transplant was successful in replenishing the patient’s gut flora and stopping the releases of C. difficile,” said Nancy Crum-Cianflone, MD, an infectious disease specialist at Scripps Mercy. The normal bacteria replenished his GI tract, she added, thus halting the growth of resistant bacteria.

“Patients, especially those in long-term

facilities, receive numerous courses of antibiotics that almost invariably result in both colonization and infections from multidrug-resistant organisms, and in the end with bacteria resistant to all antibiotics,” said Gonzalo Ballon-Landa, MD, also an infectious disease specialist at Scripps Mercy. Although the report involved just one patient, there is the possibility that replenishing the normal gut flora and keeping these patients off antibiotics can result in the disappearance of MDROs, he explained.

C. difficile causes inflammation of the large intestine, resulting in diarrhea. It is a particular problem in older hospitalized adults and caused an estimated 500,000 infections in 2011, with 29,000 deaths occurring within 30 days after diagnosis, according to the Centers for Disease Control and Prevention.

FMT has been demonstrated to cure C. difficilee at a rate of 90% plus, vastly superior to antibiotic treatment, the researchers explained.

The rationale behind the technique lies in the fact that the healthy, intact human microbiome strongly resists invasion by pathogens because the good bacteria outcompete the bad ones for nutrition, binding sites, alteration of environmental conditions such as pH, and potentially host–microbiome interactions. A number of investigators are testing it against other conditions.

FMT is not new. Evidence exists that “yellow soup” was used against intestinal infections 1,700 years ago, and fecal transplant has been used sporadically for pseudomembranous colitis since the 1950s.

—GEN Staff For more on C. difff see page 42.

NEW

Clinical Evidence Supports a New Approach in Managing IBS Reduction in total IBS symptoms at 24 hours... and trend holds at 4 weeks2 Percentagee Reductionn in TISS Sccore

Study results presented by motility disorder experts at the recent DDW meeting in Washington DC show why this clinically studied non-prescription medical food should be considered a first-line approach for IBS. IBgard® is specially formulated for the dietary management of IBS. IBgard® capsules contain L-menthol,

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precision of Site Specific Targeting (SST®) technology. IBgard® capsules contain individually triple-coated sustained release microspheres that deliver peppermint oil quickly and reliably where it is needed most in IBS—the small intestine.1

24 hours

0

-9.8%

4 Weeks

-18.8%

-25.4%

-39.6%

10

20

P =0.0092

30

Placebo 24 Hours Active

40

P =0.0246

4 Weeks Active 50

Percent Reduction of Total IBS Symptoms Score (TISS)

Clinically Studied •W Works at 24 hours and at 4 weeks • Works across the syndrome of symptoms

Percent Reduction from Baseline in Individual IBS Symptom

Reductions across the Syndrome of Symptoms at 4 weeks2 0

Abdominal Pain or Discomfort

Abdominal Bloating or Distention

Pain at Evacuation

Urgency of BM

Constipation

Diarrhea

Gas or Mucus

Incomplete Evacuation

5 10 15 20 25 30 35

*

40 45

*

*

* Statistically significant vs. placebo (P =0.05)

50

Placebo 4 Weeks Active

* Percent Reduction from Baseline in Individual IBS Symptom (avg. of frequency and intensity)

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References: 1. Kellow JE, Philips SF. Altered bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology. 1987;92:1885-1893. 2. IBSRESTTM: A US-based, 4-week, randomized, placebo-controlled, multicenter trial studying 72 patients with IBS-D and IBS-M; Rome III criteria were employed; only patients suffering from high and persistent levels of abdominal pain *4.0 on a 0-10 scale and overall symptom scores of *2 on a 0-4 scale over the 2-week baseline period prior to randomization were enrolled. Data on file, CSR Tables 9 and 22, IM HealthScience®, LLC. © 2015 IM HealthScience®, LLC.

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A. IBgard® has been shown to start working in as early as 24 hours. It can help to: • Normalize the digestion of food and absorption of nutrients, which have been compromised by IBS. • Reduce the accompanying and often distressing symptoms of IBS including abdominal pain, bloating, diarrhea, diarrhea interrupted by constipation, urgency, gas, pain at evacuation and a sense of incomplete evacuation.

• Promote bacterial balance in the small intestine.

FDA. However, even food products can be unsafe if used improperly. IBgard® is a medical food and must contain ingredients that are Generally Recognized as Safe (GRAS) or are approved food additives. IBgard® is manufactured under Good Manufacturing Practices with no added fat, sugar, salt, starch, yeast, wheat, gluten, corn, lactose, egg, soy, peanuts, shellfish or preservatives.

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A. The usual adult dosage is 1-2 capsules, as needed, up to three times a day. IBgard® should be taken at least 30 minutes before or after food, with water. Dosage should not exx ® ceed eight capsules per day. IBgard® capsules Q. How does IBgard work? may be swallowed whole—not chewed. AlA. IBgard® harnesses the properties of ternatively, the contents of the capsule may L-menthol, the principal component of pepbe mixed with or sprinkled on applesauce permint oil, and delivers it quickly and reliand then ingested. ably to the small intestine where it is needed most, via a patented breakthrough technolo- Q. Are there clinical data showing that IBgard® is effective and well tolerated? gy called Site Specific Targeting (SST®).

It is designed to work fast. It is developed as A. There is new data from a randomized tiny, triple-coated microspheres that move placebo-controlled clinical trial conductthrough the pylorus quickly because the mi- ed in the U.S. called the Irritable Bowel crospheres are less than 2mm in diameter. Syndrome Reduction Evaluation and SafeTherefore, these tiny microspheres do not rely ty Trial (IBSREST™). On May 18, 2015, on gastric emptying. Also, the microspheres IBSREST™ findings were presented at the have been formulated with a non-muco- world’s premier gastroenterology meeting, adhesive coating to limit their sticking to the Digestive Disease Week. wall of the stomach or to food particles.

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L-menthol can help to enhance nutrient ab- A. The IBSREST™ data showed that adminsorption through the intestinal walls, mak- istration of IBgard® resulted in: Reduction ing it well suited for the management of IBS. in Total IBS Symptom Score (TISS) at 24 Peppermint oil has also been shown to help hours and 4 weeks: normalize intestinal transit times—thus • 18.8% reduction of symptoms vs. baseline helping normalize nutrient absorption. at 24 hrs. Significant compared to placebo Q. Is IBgard® approved by the FDA and (P=0.0092).

P is it safe?

• 39.6% reduction of symptoms from A. Like all medical food products, IBgard® baseline at 4 weeks. Significant compared to does not require prior approval from the placebo (P=0.0246).

P © 2015 IM HealthScience®, LLC.

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Reduction in Number of Unbearable or Severe Symptoms (high average of frequency and intensity) at 24 hours and 4 weeks: • 30% reduction in unbearable or severe symptoms from baseline at 24 hours compared to placebo (P=0.0910).

P % • 66 reduction in unbearable or severe symptoms from baseline at 4 weeks. Signiff icant compared to placebo (P=0.0282).

P Reduction in Patient Reported Unbearable or Severe Abdominal Pain Intensity: • 45.7% patients reported reduction in unbearable or severe abdominal pain or discomfort from baseline at 24 hours. Not significant compared to placebo (P=0.3658).

P % • 79.4 of patients reported reduction in unbearable or severe abdominal pain from baseline at 4 weeks. Significant compared to placebo (P=0.0009).

P In the study, IBgard® was well tolerated with side effects comparable to placebo.

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13

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Society Takes Aim at Bile Duct Injuries Trying to make a safe operation even safer

6.

NASHVILLE, TENN.—The — Society of American Gas- using “the doublet view,” meaning both anterior and posGet help from another surgeon, if possible, when trointestinal and Endoscopic Surgeons (SAGES) has terior laparoscopic views demonstrate the three compothe dissection or conditions are difficult. launched a nationwide initiative to prevent bile duct nents of the CVS. Organizers noted that the strategies are based on injuries during cholecystectomy.

Surgeons should understand the potential for the best available evidence and do not supplant surAt the 2015 annual meeting, SAGES kicked off the aberrant anatomy in all cases. Examples include a gical judgment in the individual patient. The final Safe Cholecystectomy Program, a major education cam- short cystic duct, aberrant hepatic ducts or a right hepatic decision on how to proceed should be made by the paign that aims to lower bile duct injury rates below the artery that crosses anteriorly to the common bile duct. operating surgeon, according to his or her experience current levels of 3,000 per year in the United States. and judgment.

Estimates suggest that bile duct injuries The program is not considered a new occur during three of every 1,000 cholestandard of care, Dr. Fanelli said.

‘This devastating complication can be cystectomies performed ((J Am Coll Surg “Instead, what we really want to do is 2011;213:267-274). change the culture around cholecystectomy compounded by lack of prompt recognition.’

In the 25 years since laparoscopic choto create a culture of safety in cholecysteclecystectomy was introduced into surgical tomy. The bottom line is that this is a safe —Jonah Stulberg, MD practice, bile duct injuries have continued operation; we want to try to make it safer.” to be a problem, said SAGES president L. Joshua Alley, MD, a bariatric and genMichael Brunt, MD, professor of surgery eral surgeon at the Guthrie Clinic, said and chief of minimally invasive surgery at he expects the program will be useful for Washington University School of Medicine, trainees and practicing surgeons. in St. Louis, during his presidential address.

“Many of us had widely varying experi“While the incidence of these injuries is ences learning lap chole in our residency low, a bile duct injury can be life-altering training, ranging from a ‘spread, spread, for a patient who otherwise would have clip, clip’ approach to a careful dissection of undergone an outpatient procedure with the hepatocystic triangle to achieve a critiprompt return to normal activities.” cal view. SAGES is particularly strong in In 2014, SAGES established a task force surgeon education and they shine here. led by surgeons Robert Fanelli, MD, and “I can’t speak for most surgeons but I Horacio Asbun, MD, to develop a multiwould say that this initiative, and some of modal educational program to address bile the sessions centered on it at the SAGES duct injuries. The final program, which will meeting, helps me put some structure into consist of a series of Web-based educamy thinking about cholecystectomy. It tional modules with videos, guidelines and helps me avoid complacency when doing photos, will detail best practices related to these cases that can seem routine, and the pre-, peri- and postoperative care for safe initiative lends a nice framework for OR performance of cholecystectomy. team training to the goal of a safe chole“We will look at each phase of the cystectomy culture.” patient–surgeon interaction. In other words, Jonah Stulberg, MD, PhD, MPH, chief what to do with someone who comes in resident in general surgery at Case Westwith acute inflammation compared with ern Reserve University, in Cleveland, said traditional elective circumstance? What’s the program could have a profound effect the best time for surgery in the patient’s on patient safety, particularly if the next illness? What’s the best timing to be doing stage of the program also deals with injury it in the [operating room] schedule?” said recognition.

Dr. Fanelli, chief of minimally invasive sur“This devastating complication can be compounded by lack of prompt recognigery and surgical endoscopy at the Guthrie Clinic, in Sayre, Pa., in an interview. tion. The majority of cases I have done Organizers plan to have the full program available Surgical teams should consider “liberal use” of to repair bile duct injuries are in patients in whom the online within the next 12 to 18 months. cholangiography or other methods to image the injury went undiagnosed for several days and sometimes For now, SAGES has asked surgeons to consider biliary tree intraoperatively, which may become especially weeks after surgery. This is a much bigger problem when adopting six strategies for every laparoscopic and open important in difficult cases or cases of unclear anatomy. it is not promptly diagnosed.” cholecystectomy.

Recognize when the dissection is approaching a Raymond Price, MD, associate director of the Center The strategies, which are available online at “zone of great danger” in cases of severe inflam- for Global Surgery at the University of Utah, in Salt www.sages.org, are: mation and halt the dissection before entering the Lake City, and co-chair of the SAGES guideline comUse the critical view of safety (CVS) method of zone. Surgeons should complete the operation by a safe mittee, said the surgical community never adequately identification of the cystic duct and cystic artery method other than cholecystectomy if the conditions addressed the issue of increased common bile duct injuduring laparoscopic cholecystectomy. The method, first around the gallbladder are too dangerous. (The SAGES ries after adoption of laparoscopic surgery. The Fundadescribed in 1995, involves three components: The hepa- task force noted that the CVS can be difficult to achieve mentals of Laparoscopic Surgery program was created tocystic triangle must be cleared of fat and fibrous tissue; in patients with severe inflammation in the porta hepatis by SAGES to improve the quality of all laparoscopic the lower one-third of the gallbladder must be separated and neck of the gallbladder. “This is a key benefit of the surgery in the United States but did not deal specifically from the liver to expose the cystic plate; and only two method since it alerts the surgeon to possible danger,” with bile duct injuries. structures should be seen entering the gallbladder. said Dr. Blunt. In these cases, laparoscopic subtotal cho“It’s not right to say ‘we accept this rate of common Perform an intraoperative time-out during lapa- lecystectomy, partial cholecystectomy or cholecystostomy bile duct injuries,’” Dr. Price said. “We need to find a roscopic cholecystectomy before clipping, cutting tube placement and/or conversion to an open procedure solution and make a change. So I think this program is or transecting any ductal structures. The time-out should should be considered, based on the judgment of the very useful.” include a pause to verify that the CVS has been achieved attending surgeon.)

—Christina Frangou

3.

4.

5.

1.

2.

er n

14

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

On the Spot: The State of Bariatrics in 2015

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lthough technology is offering new options to bariatric surgeons and their patients by way of new procedures and devices, it is a good time to take the pulse of these contributors on some general aspects of bariatrics that are still up for debate. Also, as we see more and more advances in genomics and genetic testing, the question arises: What do these advances potentially mean for the obese population? Although genetic testing is now being integrated into

oncologic and other areas of patient care, it has not developed to the point where

can—and that time is coming—the possibilities are endless. Read on for some

Read on, take a side, access On the Spot online and share your

Don’t miss the new section on page 16 in which I take the contributors’ temperatures on some existing and forthcoming new techniques and procedures.

There is quite a bit of variation among the responses.

view with a comment. Thanks for reading!

—Colleen Hutchinson we can use it for personalized intervention for the obese patient. But when we

insights from this group of experts about genomics in bariatrics.

S TAT E M E N T:

Single-anastomosis duodenal switch (DS) is a better surgical option for the bariatric surgery patient than classic DS.

Dr. Gagner: On the fence.

ASGE Recognized Industry Associate Program Gastrointestinal endoscopy is a rapidly advancing field of medicine in which the latest devices and drugs are important for patient care. Representatives of drug and device companies have both a role and a responsibility in facilitating the best care for patients, which includes effective interaction with physicians and staff, as well as ongoing technical proficiency.

To assist in this effort, ASGE has created the ASGE Recognized Industry Associate (ARIA) Program dedicated to industry professionals. The ARIA program is designed to create a shared understanding for improved communication between clinicians and industry representatives.

The ARIA Program fills a need to provide specialized education about gastroenterology and endoscopy, including hands-on training, to industry representatives who work with devices, pharmaceuticals and treatments relevant to this patient group. Industry representatives who successfully complete a pre-test, a full day of intensive training, as well as a post-test, are awarded the ASGE ARIA Certificate of Completion, are granted rights to use the ASGE ARIA program logo and receive a number of other prestigious recognition benefits.

The ARIA program is offered twice a year as a stand-alone course for individuals, as well as being offered to companies as a customizable training program for their employees.

Topics that are covered as part of the overall curriculum include:

Dr. Blackstone: Disagree.

Participating Companies ASGE is proud to recognize the organizations which have participated in the ARIA program, and we salute their dedication to the GI profession.

Boston Scientific Corporation

• Gastrointestinal Tract in Health: Basic Anatomy and Physiology y – Foregut, Midgut and Hepatopancreaticobiliary

Bracco Diagnostics, Inc.

• Tools of the Gastroenterologistt – Introduction to GI Endoscopy, and Other Tests Used by Gastroenterologists

ConMed

• Gastrointestinal Tract in Disease: Overview of Major GI Disorders – Foregut (Esophagus and Stomach), Midgut (Small Bowel), Hepatopancreaticobiliary Disease, Colon/Rectum and Communication Tips

Covidien

• Hands-on Stations – Basic Scope Handling/Foreign Body Removal, APC/Bicap/Thermal Therapies, Injections/Clip, and Bands/Polyps

EndoGastric Solutions, Inc.

Customized Training Opportunities

ERBE USA, Inc.

ASGE offers customized training for organizations seeking dedicated GI training for their representatives. Additional topics that can be added to the curriculum include Inflammatory Bowel Disease, Gastroesophageal Reflux Disease, Pancreaticobiliary Endoscopy 101, among others.

For more information on the document “The Role of Industry Representatives in the Endoscopy Unit”” or the ASGE ARIA program, contact Linda kay Tyler, Director for Sales and Business Development for ASGE at 630-5705601 or ltyler@asge.org or visit www.asge.org.

The American Society for Gastrointestinal Endoscopy (ASGE) has issued a new document (The Role of Industry Representatives in the Endoscopy Unit) t offering needed guidance on the role that device, accessory and pharmaceutical industry representatives play in endoscopy units. Industry representatives serve critical roles in communication and information delivery. Relationship building, mutual respect, and ethical conduct will lead to a strong and enduring partnership between the endoscopy unit staff and those acting on behalf of industry.

We need a randomized study comparing SADI [single-anastomosis duodenoileal bypass] and the classic DS, with a five-year follow-up. However, even if there is less weight loss, if there are fewer nutritional deficiencies and side effects, I think most surgeons and patients would go for it.

Cardinal Health Cook Medical CPC Pathology EndoChoice, Inc. Epix Anesthesia

Our specialty has always been at the forefront of investigational techniques.

The single-anastomosis DS may prove to be safe and effective, but there is very little data. Performing this procedure with institutional review board oversight and close and careful data collection (for instance, within the MBSAQIP [Metabolic and Bariatric Surgical Accreditation and Quality Improvement Program] registry) is essential to establish the safety record and begin to judge the effectiveness of the procedure. In addition, animal models need to be developed and studied so that the physiologic basis of the procedure can be ascertained.

FUJIFILM Medical Systems USA, Inc. GI Supply Ironwood Pharmaceuticals Medigus Ltd. MEDIVATORS Merit Medical Endotek MicroMed, LLC Olympus Corporation of the Americas PENTAX Medical Sedasys, a Division of Ethicon Endo-Surgery, Inc. Torax Medical, Inc. US Endoscopy

Dr. English: On the fence.

I need more data to be convinced further, but I’m impressed with what little data are available to us at this time. As the data matures, single-anastomosis DS may very well emerge as a better option as patients experience similar weight loss with fewer side effects (decreased risk for malnutrition and electrolyte abnormalities, fewer bowel movements and fewer complaints of foul-smelling flatulence) compared with classic DS

15

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Like or Dislike?

Participants

Air-Filled Balloon

FluidFilled Balloon

Endoscopic Suturing Gastric Plication

Endoscopic Stapling

DuodenalJejunal Barrier Sleeve

Gastric Sleeve Bypass

Dr. Rosenthal

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Dr. Gagner

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Dr. Zundel

On the fence

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On the fence

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Dr. Soto

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Dr. Ponce

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Dr. Blackstone Like

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Dr. Kurian

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Dr. English

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What is it? I’m intrigued.

Dr. Kothari

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patients. Decreased incidence of bowel obstructions and internal hernia may be seen in single-anastomosis DS as well.

that compares both approaches to determine that this statement is valid.

Robin Blackstone, MD, is medical director of Scottsdale Healthcare Bariatric Center, in Scottsdale, Ariz.

Wayne English, MD, is associate professor at Vanderbilt University Medical Center, in Nashville, Tenn.

Disclosure: Research support from Obalon and Reshape Medical.

Michel Gagner, MD, is president of the Clinique de Michel Gagner, and professor of surgery at Hôpital du Sacre Coeur, in Montreal, Canada.

Disclosure: Speaking honoraria from Boehringer Ingelheim, Covidien, Ethicon, Gore and Olympus; equity ownership in TransEnterix.

Shanu N. Kothari, MD, is director of minimally invasive bariatric surgery at Gundersen Health System, in La Crosse, Wisc.

Disclosure: Serves as a preceptor for Torax Medical.

Dr. Kurian: Agree.

Dr. Soto: Disagree.

A combination of gastric reduction, sleeve simile, with a malabsorptive component, loop of ileum anastomosed to the sleeve, and transection of the duodenum preserving the pylorus attached to the sleeve—sounds charming based on the fact that there is only “one anastomosis” involved. But there are not enough data yet to sustain how successful this procedure can be in terms of morbidity and mortality and long-term weight loss. Time will tell!

Dr. Ponce: Agree.

At least [based] on the few studies available, maybe fewer complications with similar weight loss. We need more studies.

Dr. Kothari: Disagree—partly depends on the definition of “better.”

If “better” means less technically complex, then yes. But efficacy in a head-to-head comparison based on a high-level study, to my knowledge, has yet to be performed. With all bariatric operations, we must weigh the risks versus benefits. In general, the higher the perioperative risk of the bariatric procedure, the better the weight loss and percentage chance of comorbidity reduction. Currently, DS provides the most weight loss and reduction of diabetes, but at the added risk for severe protein malnutrition in a small percentage of patients, requiring limb lengthening.

Where single-anastomosis DS falls in this spectrum of risk–benefit remains to be seen. I look forward to prospective studies currently being performed on this topic.

Dr. Rosenthal: Disagree.

Although the concept of a single-anastomosis malabsorptive procedure is attractive, there is no literature

So far, the data presented shows fewer perioperative complications and fewer long-term malnutrition complications compared with the DS. The improvements in comorbidities and excess weight loss also make it an attractive surgical option for selected patients.

Dr. Zundel: Disagree.

It seems that stomach intestinal pylorus-sparing surgery is a safe option. Overall results are not as good as the results of the classic DS, but has it been shown to be simpler? Fewer complications? It’s only been around for five years. We need more numbers and longer-term data to understand it better. Even some of the proponents of it still call it investigational.

S TAT E M E N T:

Reflux is a contraindication for sleeve gastrectomy.

Dr. Gagner: Disagree—not at all, and in fact, it is the reverse.

This has been well demonstrated by the study of Morino et al published in Annals of Surgery (2014;260:909-914), where the GERD [gastroesophageal reflux disease] is greatly improved, de novo GERD is only 5% and the LES [lower esophageal sphincter] is unchanged. The study looked at a group of LSG [laparoscopic sleeve gastrectomy] with preoperative nanometry, 24-hour pH studies, endoscopy and questionnaire, all repeated two years later. see Bariatrics, page 16

Marina Kurian, MD, is medical director of New York Minimally Invasive Surgery, and associate clinical professor of Surgery at NYU Langone Medical Center, in New York City.

Disclosure: Receives honoraria as a speaker and proctor for Apollo Endo urgery.

Jaime Ponce, MD, is bariatric surgery medical director at Hamilton Medical Center, in Dalton, Ga., and Memorial Hospital, in Chattanooga, Tenn.

Disclosure: Consultant for Apollo Endosurgery; receives research support from and is a consultant for Gore and Reshape Medical; receives research support from Obalon and USGI Medical; and serves as a speaker and consultant for ConMed and Olympus.

Raul Rosenthal, MD, is chief of staff and chairman of the Department of General Surgery; director of the Bariatric and Metabolic Institute at Cleveland Clinic Florida, in Weston; and professor of surgery at the Herbert Wertheim College of Medicine at Florida International University, in Miami.

Flavia C. Soto, MD, is a bariatric surgeon at the Weight Loss Center at Banner Health Gateway and Banner Estrella Medical Center, in Phoenix.

Natan Zundel, MD, is clinical professor of surgery and vice chairman, Department of Surgery at Herbert Wertheim College of Medicine, Florida International University, and medical director, Bariatric and Metabolic Institute at Jackson North Medical Center, in Miami. He is president of the International Federation for Obesity Surgery, Latin American chapter, for 2013-2015.

16

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Bariatrics

But most have GERD related to the mechanical and physiologic changes related to obesity, so those patients will Dr. English: Agree! do well if they lose weight. My cond Reflux should be considered a relative cern is the patients that have significontraindication for LSG. Although data cant GERD. In my practice, if a patient demonstrate low reflux rates after LSG, wants LSG, but has a history of using there are data showing reflux rates are proton pump inhibitors (PPIs) for long indeed significant. periods of time, I’m in favor of minand the need for ’I consider reflux a relative imizing the risk of upper endoscopy in contraindication to sleeve.’ subjecting a patient the past, we order to a potentially pH studies and —Shanu Kothari, MD unnecessary second manometry. Iff the operation to correct reflux is really sigsevere intractable acid reflux after sleeve. nificant, we offer him or her LRYGB You should consider a different surgical [laparoscopic Roux-en-Y gastric bypass] option in the symptomatic patient with instead. reflux and documented reflux esophagitis, as I feel these patients have the highest Dr. Kothari: On the fence. risk for developing worsening symptoms after surgery. I recommend using pH Currently, I consider reflux a relatesting liberally in patients who report tive contraindication to sleeve. We still reflux. have much to learn about the impact of LSG on GERD. There is a percentage of patients who develop clinically signifiDr. Zundel: Disagree. cant GERD post-LSG who did not have A fair amount of morbidly obese it preoperatively. There is a percentage of patients have GERD (up to 35%-40%). patients with preoperative GERD who

continued from page 15

have symptomatic resolution post-LSG, and, perhaps most worrisome, there is a percentage who develop asymptomatic esophagitis post-LSG. The patient variables and technical factors that go into sleeve construction that result in varying percentage rates of these three categories warrant further study.

score and/or Barrett’s are certainly contraindications. In the elderly or critically ill, the aforementioned contraindications become relative. We should study patients before making decisions. The great majority of these patients complain of GERD and take PPIs, but [this] was never studied properly.

Dr. Kurian: On the fence.

S TAT E M E N T:

There is a standard sleeve gastrectomy technique.

Dr. Rosenthal: Disagree.

Obesity is a reason for GERD and increased prevalence of hiatal hernias.

Weight loss and repair of hiatal hernias should resolve GERD. Depending on the DeMeester score of the patient, and the age and the degree of esophagitis, sleeve becomes a contraindication.

Young patients with high DeMeester

I think patients with severe GERD should have a gastric bypass, whereas patients with mild GERD and small hiatal hernias can do well with sleeve. I always counsel my patients that the Achilles heel of the sleeve is GERD, and I find this helps stratify the patients who are symptomatically at greater risk. I obtain routine endoscopy and selective pH and manometry tests in prospective sleeve patients.

Dr. Ponce: Disagree.

Reflux can improve, especially if crural repair is done. Severe reflux with complications might be a contraindication for sleeve. see Bariatrics, page 17

Gut Reaction: Clinical Bariatric Role of Gastric Banding: Obsolete

Mini Gastric Bypass as a First-Line Treatment Option

Staple-Line Reinforcement Necessary in LSG?

STAMPEDE Trial

IBD and the Bariatric Patient

Dr. Rosenthal

Not true

Interesting option

Agree

Best proven study that shows that Sleeve is best option. surgery is better than medical treatment and that sleeve and bypass are good options for diabetics.

Dr. Zundel

Today it’s the only approved procedure for low BMI.

Not yet; only for some revisions

It should be standard.

I learned a lot from it.

No contraindication. LSG looking good

Dr. Gagner

Yes

Not first-line

Yes

Too many women in one group

Sleeve

Dr. Soto

No, still an option for the right candidates

No, we have better options: sleeve and gastric bypass.

Yes, buttressing!

Great study! Hope we can see more future data

Sleeve!

Dr. Ponce

Still an option for some patients

I don’t think so.

I think it helps to reduce complications.

Very well done and valuable information

Can happen

Dr. Blackstone

I have not done this as a primary procedure since 2011.

Please; now seems to be making a new inroad as the mini-DS

Helps me sleep at Bariatric surgery treats uncontrolled night; I imbricate the diabetes effectively. staple line with a $2.80 suture.

IBD is used very loosely. Do we really have an identified etiology or even a standard way to identify it?

Dr. Kurian

Suitable for certain patients

Not in my hands

No, but I do some.

Validating and pivotal study

IBD can improve with weight loss surgery.

Dr. English

Perhaps soon, but should remain a treatment option

Bile reflux! However, data supports consideration.

Yes; decreased bleeding rate has been demonstrated.

Authoritative data supporting surgery as superior to medical treatment

Proceed with caution! Requires thorough preoperative evaluation

Dr. Kothari

The defense rests.

A sham gastric bypass

Depends on your personal outcomes

Should be read in its entirety

Beware, but not an absolute contraindication

BMI, body mass index; DS, duodenal switch; IBD, inflammatory bowel disease; LSG, laparoscopic sleeve gastrectomy; STAMPEDE, Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently

17

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Bariatrics continued from page 16

Dr. Soto: Agree!

A good assessment and diagnosis not only of GERD, but also of other hypomotility and dysmotility conditions prior to surgery, is key for a successful outcome after LSG. The sleeve gastrectomy is a high-pressure system that can exacerbate reflux. If there is a questionable diagnosis, a pH/manometry would obtain the answer (DeMeester score). For morbidly obese patients with reflux disease, the best option is the gastric bypass.

being considered. When it comes to bariatric surgery, LAGB [laparoscopic adjustable gastric banding] and LSG are the most reproducible or standardized.

Dr. Gagner: Agree.

We have done five consensus conferences defining how sleeve should be performed, and we have more standards than in gastric bypass, which has been around for more than 40 years.

fire and use of the appropriate staple height.

within the tube of the sleeve on distention due to patient variation.

Dr. English: Disagree!

Dr. Zundel: Totally disagree.

While surgeons follow the same basic tenets for performing LSG, there are too many variables of the procedure to say there is a standard technique. Variation in any one of these may result in different outcomes. These variables include bougie size, exploration for hiatal hernia

For the past two decades, I have been waiting for the standardization of gastric bypass. The question is do we know what a standard LSG looks like? Is it the one I do? (It is for me.) There is variation in technique among even the most experienced LSG surgeons today. Which is the variation that shows superior results and fewer complications, and is cost-effective and reproducible? That one we can call standard.

‘We have done five consensus conferences defining how sleeve Dr. Blackstone: Disagree.

should be performed, and we have more standards than in

GERD spans a continuum of severity seemingly unrelated to the incidence of hiatal hernia. There is little data on how weight loss by itself affects GERD, but we all believe that it improves just from the decrease in intraabdominal pressure. Certainly GERD is a risk, but with the current technique, [it is] less than 25%. By the time GERD surfaces a patient has lost a substantial amount of weight and it can be controlled with a PPI [proton pump inhibitor]. This is a critical point of education for the patient and the primary care physicians to understand. If GERD develops, the patient will need endoscopic surveillance to detect development of Barrett’s.

The incidence of Barrett’s after sleeve is not known.

gastric bypass, which has been around for more than 40 years.’

Dr. Rosenthal: Agree.

In reality, no surgery can be reproduced identically regardless of the surgical field

—Michel Gagner, MD

Everyone does it slightly different.

There are new devices coming to market that may help standardize the sleeve, such as the Covidien GastriSail, ViSiGi 3D [Boehringer Ingelheim] or the Standard Clamp from Standard Bariatrics. These may help achieve standardization.

or not, fat pad dissection or not, distance from pylorus, hugging the bougie or not, staple height used, staple-line reinforcement (buttressing, oversewing, imbrication) or not, degree of lateral traction during transection, distance from gastroesophageal junction, leak test or not; if so, endoscopy or not, omentoplasty or not, specimen bag or not.

Dr. Soto: Agree.

Dr. Blackstone: Disagree.

There are several steps we need to respect and follow to achieve best outcomes, some of which are a bougie size not smaller than 32 Fr, first fire 2 to 6 cm from the pylorus, complete mobilization of the fundus, staple-line reinforcement to decrease bleeding, avoidance of the [gastroesophageal] junction in the last

There is little or no standardization of any bariatric procedure. This is in part due to the surgeon’s individual technique (we practice an experiential “art”), but also because every patient has variations in the “material” of the tissue. So even using a standard scope or bougie may result in significant volume differences

Dr. Kurian: Disagree.

Dr. Ponce: Agree.

In my hands, there is now.

Dr. Kothari: Disagree.

Gastric bypass has been around decades longer than sleeve and we certainly don’t have a standard gastric bypass technique with regard to limb lengths, limb route or optimal choice of anastomotic construction to reduce complications and maximize results.

That being said, there is pooled data showing a lower leak rate with sleeve ggastrectomy when a bougie size of 40 or greater is used compared with less than 40 (Surg Endoscc 2012;26:1509-1515).

Use of buttress material has shown mixed results with regard to decreased bleeding from staple lines and stapleline leaks. Some have shown a reduction in these complications, and others have shown no effect.

WA 1

By the Numbers Persons infected with the outbreak strain of Salmonella paratyphi B variant L(+) tartrate(+), by state of residence, as of May 21, 2015.

SD 1

WI 1

IL 1

CA 31 AZ 10

NM 6 MS 1

Source: Centers for Disease Control and Prevention

Total ill persons 53

VA 1

18

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Magnetic Device Achieves Persistent Control Of GERD at Five Years WASHINGTON—Five years after surgical placement, a magnetic device to augment the lower esophageal sphincter continues to provide relatively tight control of gastroesophageal reflux, new data show.

The device (LINX Reflux Management System, Torax Medical) consists of a ring of magnetic beads that is placed laparoscopically and encircles the lower esophageal sphincter to restore function. The relatively sustained response was observed across many parameters of gastroesophageal reflux disease (GERD), including remaining off proton pump inhibitors (PPIs), according to the investigators.

“Magnetic sphincter augmentation should be considered first-line surgical therapy for those with gastroesophageal reflux disease based on results of this study,” said Robert A. Ganz, MD, of Minnesota Gastroenterology, in Minneapolis. Dr. Ganz presented the findings at Digestive Disease Week 2015 (abstract 688).

In contrast to many endoscopic procedures for control of GERD that have been associated with diminishing efficacy over time, the new results showed that the effectiveness of the magnetic system did not appear to wane significantly over time. These outcomes included subjective measures of quality of life (QoL) as well as pH scores, esophagitis grading and use of PPIs. For example, the proportion of patients completely off PPIs one year after surgery was 86%, according to data published previously (N Engl J Medd 2013;368:719727). At five years, the proportion was 75%. The proportion of patients who had at least a 50% improvement in a validated QoL measure was 89% at five years, compared with 92% at one year after surgery.

The five-year data come from followup of a study involving 14 centers mainly in the United States. One hundred patients were treated, and 85 provided data from the five-year mark. Of the remaining 15, eight were lost to followup or declined to participate; one died of cancer unrelated to treatment; and six had their device removed electively.

In four cases, removal was performed due to complaints of dysphagia, which resolved. In one, the removal was based on recurrent vomiting of unknown etiology, which persisted after device removal.

All patients included in the trial had persistent symptoms of GERD with at least partial response to PPIs. The average duration of PPI treatment before placement of the device was five years,

The LINX system Images courtesy of Torax Medical.

Patients reported moderate to severe heartburn

Patients reported moderate to severe regurgitation

Patients with esophagitis present

Year prior to placement of the device

89%

87%

40%

11.9%

1.2%

16%

Year 5 after placement of the device ‘I am certainly revisiting this concept on the basis of these results.’

—Gary W. Falk, MD with a range of one to 20 years. Slightly more than half of the patients were male, and the average age was 53 years.

The average procedure time to place the device was 36 minutes.

Many efficacy end points were monitored during follow-up, including acid exposure over 24 hours; GERD Health Related Quality of Life scale; PPI use; grading of esophagitis; DeMeester score; and scoring of specific symptoms, such as heartburn, dysphagia and regurgitation. Compared with baseline, all improved by a highly statistically and clinically significant degree at one year

and remained controlled with only slight decay at five years.

Notably, 11.9% of the patients reported moderate to severe heartburn at five years, down from 89% before placement of the device. The proportion with moderate to severe regurgitation fell from 87% to 1.2%. Esophagitis was present in 40% of the patients before the procedure but in 16% at year 5, of which 90% was grade A and none was grade C or higher.

The device has been well tolerated with no serious adverse events, according to the researchers. The most common side effect was dysphagia, reported by

the majority of patients in the immediate postoperative period but by only 11% by year 1 and 7% by year 5. No migrations, erosions or malfunctions were reported during the study period. No significant complications occurred in device placement or elective removal. Patients fitted with the device have reported no impairment in their ability to belch or vomit when neccessary.

The d durability of benefit correlates with tthe underlying magnetic force thatt augments the sphincter, but the device will separate to permit sphincter function. Dr. Ganz said th he magnetic attraction of the beads is “precise, will never decay an nd will last into perpetuity.”

The LINX system does not i volve the gastric fundus or any inv alteeration of the gastrointestinal anatoomy, and removal does not prevvent add ditional therapy with other techniques. T The device costs roughly $5,000, and surgeery to implant it adds another $10,000 or o more.

The ab bility of the magnet therapy to provide sustained control of acid and heartburn symptoms out to five years changed the minds of some of those accustomed to seeing diminishing efficacy of GERD treatments over time.

Gary W. Falk, MD, co-director of the GI motility/physiology program at the Hospital of the University of Pennsylvania, in Philadelphia, called the data “intriguing” and encouraging.

“I am certainly revisiting this concept on the basis of these results,” Dr. Falk said. For those selected on the basis of acid-driven symptoms, such as improvement with PPIs, “this may be something to add to the armamentarium,” he said.

However, Dr. Falk cautioned that the study population was relatively small and carefully selected, raising questions about whether there might be “nuances” in isolating those patients most likely to benefit. In particular, Dr. Falk pointed out that the patients studied had classic heartburn and acid regurgitation.

Selection for this study was not based on atypical GERD manifestations, poor response to PPIs or a large hiatal hernia.

As a result, Dr. Falk said, “I am very concerned about extrapolating these results to these more challenging patient groups, which were not the focus of this study.”

—Ted Bosworth Dr. Ganz has financial relationships with American Bioptics, Barrx Inc, Boston Scientific and Takeda. Dr. Falk has served as an advisor to Torax Medical.

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20

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Delays in Diagnosis of Celiac Disease Worry Experts

C

linicians are more likely to miss an early diagnosis in women with celiac disease and there is a long delay in the diagnosis of celiac disease in patients who do not present with the classic symptoms, two new studies have found.

In the first study, on average, patients with celiac disease without gastrointestinal (GI) symptoms went without a diagnosis for almost four years. In the second study, the average diagnostic delay was 30% longer for women than men. Results from both studies were presented at Digestive Disease Week 2015.

Celiac disease affects approximately 1% of the population worldwide and has variable clinical manifestations. Some patients present with GI symptoms, such as bloating, diarrhea and nausea, whereas others experience weight loss, fatigue and low bone mineral density.

“Having the disease undiagnosed for a long time often leads to other long-standing medical problems, so that is why we wanted to put a spotlight on this,” said Mukund Venu, MD, assistant professor of gastroenterology at Loyola University Medical Center, in Maywood, Ill. “These medical problems include

osteoporosis with potential bone fracture, an increased risk for small-bowel cancer such as lymphoma, and chronic anemia.”

Dr. Venu and his colleagues retrospectively reviewed the charts of 687 adults with a diagnostic code for celiac disease (abstract sa1302). The researchers were surprised to find that only 101 patients had undergone a biopsy, the gold standard for diagnosing celiac disease.

Among patients with biopsy-proven celiac disease, half (n=52) presented with GI symptoms and half (n=49) had unrelated complaints. The average delay in diagnosis was 2.3 months for patients with symptoms and 42 months for patients without symptoms (P<0.001). Delay was calculated as the time from first symptoms to the time of biopsy.

Patients who presented with symptoms unrelated to the GI tract were more likely to have abnormal thyroidstimulating hormone (TSH; 43.2% vs. 15.5%; P=0.004), P anemia (69.4% vs. 11.5%; P<0.001) and low bone density (68% vs. 41%; P=NS).

P “It is important for providers, primary care doctors as well as GI doctors to be aware of the global picture

Table. Diagnostic Delay in Celiac Disease Females

Males

P Value

Average diagnostic delay, mo

93.1

60.2

0.001

Average doctor diagnostic delay, mo

41.8

23.9

<0.001

■ <24 mo

P<0.001

■ ≥24 mo

80 70 P<0.001

Prevalence, %

60

P<0.001

50 40

P<0.001

30

P<0.001

20

P<0.001

10 0 Any Deficiency

Iron

Vitamin B12

Vitamin D

Vitamin E

Calcium

Figure 1. Nutritional deficiencies after celiac disease diagnosis according to diagnostic delay.

70

6

P<0.001

P<0.005

60 P<0.01

Prevalence, %

Rate, %

50

5

40 30 20

3 2 1

10 0

4

6 mo

12 mo

Figure 2a. Freedom from symptoms after diagnosis according to diagnostic delay.

0

6 mo

12 mo

Figure 2b. Need for steroids or immunosuppressive therapy after diagnosis according to diagnostic delay.

of celiac disease,” Dr. Venu said. “Just because someone doesn’t have GI symptoms doesn’t mean they don’t have celiac disease. It is an important diagnosis to keep in your differential when you are evaluating patients.”

In a second study, researchers reviewed the records of 1,689 patients diagnosed with celiac disease in Switzerland since 1970 (abstract sa1275). Roughly three-fourths were female; the average age was 41.3 years; and the average age at diagnosis was 31 years.

The researchers focused on evaluating diagnostic delay, which can be subdivided into patient delay, defined as the gap between the beginning of symptoms and first medical consultation, and doctor delay, defined as the gap between first medical consultation and a definitive diagnosis. The average total diagnostic delay was 87 months, with the delay split equally between patients (40.8 months) and physicians (37.9 months). The median delay was 24 months.

Longer diagnostic delay was associated with a more frequent need for immunosuppressants to treat celiac disease, more frequent nutritional deficiencies and a lower chance of clinical remission after diagnosis (Figure 1). An increased diagnostic delay of more than two years was associated with a lower chance of clinical remission six and 12 months after diagnosis (Figures 2a and 2b).

Women had longer diagnostic delays than men, and this difference was attributable solely to the physician (Table). The researchers also found that patients who were older than 30 years were more likely to have longer diagnostic delays than patients younger than 30.

A total of 15.3% of patients reported that irritable bowel syndrome (IBS) was diagnosed or suspected by their treating physicians before establishing the diagnosis of celiac disease, with more women than men reporting this experience (16.7% vs. 10.5%; P=0.004).

P Stephan Vavricka, MD, of the Division of Gastroenterology and Hepatology at Triemli Hospital, in Zurich, who led the study, said physicians “need to think earlier about celiac disease, especially in women, where you expect IBS.” Christina Tennyson, MD, a celiac specialist and physician in the Department of Gastroenterology at Icahn School of Medicine at Mount Sinai, in New York City, said the studies add to the growing evidence that many patients who present with celiac disease do not have classic GI symptoms ((Am J Medd 2006;119:355.e9-e14).

The recent availability of screening blood tests for the condition, such as tissue transglutaminase antibody IgA, has helped in diagnosis, but there is a need for more education of doctors and patients about the prevalence and symptoms of celiac disease, she said.

“The majority of patients who have celiac disease aren’t diagnosed,” said Dr. Tennyson, who was not involved in the latest research. “We need to increase physician education and awareness that celiac disease can present many different ways.”

According to Dr. Tennyson, the Swiss study was particularly interesting because it found that “although greater numbers of women are diagnosed with celiac, they are more likely to have a delay in their diagnosis.”

The study also has an important clinical message, she added: “If you diagnose the patient quicker, this suggests that there is an improved clinical course.”

—Kate O’Rourke Drs. Venu, Vavricka and Tennyson reported no relevant financial conflicts of interest.

21

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Navarro said. DILIN has created a cohort for populaDILI tion-based surveillance in Delaware, which demographcontinued from page 1 ically can serve as a model for the United States, he said. to researchers who spoke about the problem at a workLiver injuries have also been associated with green shop sponsored by the National Institute of Diabetes tea extract, black cohosh, anabolic steroids and epheand Digestive and Kidney Diseases (NIDDK) and the dra, the last of which was banned by the FDA in 2004, American Association for the Study of Liver Diseases. speakers at the workshop said. In 2013, 92 people “It’s a growing challenge,” said Jay Hoofnagle, MD, developed acute nonviral hepatitis, many in Hawaii. Of director of the liver disease research branch at NIDDK. those patients, 70 reported taking the weight loss supSupplements often contain multiple ingredients and plement OxyElite Pro; at least 45 of them were hospican vary from batch to batch. Product labels do not talized, at least three needed liver transplants and always accurately reflect the contents. Many one died, said Ethel Taylor, DVM, MPH, an patients take multiple supplements and epidemiologist with the Centers for DisSupplements don’t always report this to physicians. ease Control and Prevention, who invesrepresent Furthermore, unlike prescription or tigated the case. over-the-counter drugs, dietary suppleAlthough the FDA recalled OxyElite ments do not require premarket review Pro in 2012, the manufacturer substiof DILI or approval by the FDA. tuted an ingredient and reissued it without notifying the agency. This case highlights the A $35 Billion Black Box need to ask patients about supplement use in acute Dietary supplements are a big business in the United hepatitis cases, Dr. Taylor said. Several journal publicaStates, where about half of the population consumes tions about the incident are pending. them on a regular basis—often daily, said Paul Coates, PhD, director of the National Institute of Health’s Registry Efforts Gaining Momentum Office of Dietary Supplements. Even one-third of chilRegulation of supplements around the world varies dren take them, he said. Sales in the United States were widely, but similar registry efforts have been underway roughly $35 billion in 2013, including multivitamins, in the European Union, Latin America, Iceland, India juices, botanicals and herbs. and China, international researchers said. Supplements The NIH doesn’t know exactly how many products have been implicated in liver injury in these countries, are available, but the agency is compiling a database of too, representing 16% of 96 cases in Iceland, 10% of 198 dietary supplement labels that contains information on cases in the Spanish-Latin American DILI Network of about 40,000 products and is growing by about 1,000 a 10 countries, and 6% of 906 cases in Spain. month, Dr. Coates said. Fact sheets are available online, Assessing DILI is more complicated in India and in English and Spanish, at ods.od.nih.gov.

China, where traditional healers and herbs have been Over the past 10 years, sales of gingko biloba, gin- part of the culture for centuries. In India, more than 2 seng and Echinacea have fallen, while sales of fish oil, million health care providers (63%) practice an alternaomega-3 fatty acids, probiotics and melatonin have tive medicine called AYUSH (Ayurveda, Yoga, Unani, increased, said D. Craig Hopp, PhD, program director Siddha and Homeopathy); 95% of medicines used by for NIH’s National Center for Complementary these providers are plants or herbs, said Harand Integrative Health. This trend reflects shad Devarbhavi, MD, head of gastroenterFDA inspected just what science is showing in research and ology and hepatology at St. John’s Medical “tells us that the public is paying attenCollege Hospital, in Bangalore, India. tion to some degree of what is being Between 70% and 80% of residents, espeof manufacturing shown through clinical trials,” he said. cially in rural areas, use AYUSH mediTo monitor cases of drug-induced liver cines, said Dr. Devarbhavi, who spoke at facilities in 2012 injury (DILI), the NIH in 2003 established the NIH conference. the Drug-Induced Liver Injury Network, or A DILI network established in India in DILIN, which has six contributing hospitals. Research March 2013 found that reports of hepatotoxicity from conducted by the network has shown that supple- supplements are not rare, accounting for 7% of cases. ments are the second most common class of agents In China, researchers are finding that traditional Chicausing liver injury, after antimicrobials, representing nese medicinal herbs account for about 20% of cases of some 16% of DILI in a study of 845 patients (Hepatol- DILI, “but the current clinical evidence is poor,” said ogyy 2014;60:1399-1408). Problems seen among these Chenghai Liu, MD, PhD, director of the Institute of patients were largely from supplements that contained Liver Diseases at Shunguang Hospital, in Shanghai. A a mix of ingredients, “sometimes baffling mixtures,” Dr. network and website launched in 2014, www.hepatox.

Hoofnagle said. org, aims to enroll and characterize DILI cases attributProducts marketed for bodybuilding can cause liver able to prescription and traditional Chinese medicines, injury, although more severe injuries have been associ- Dr. Liu said. ated with products that tout weight loss and improved Supplements are regulated as foods, not drugs, and sexual performance, said Victor Navarro, MD, chair several factors limit the FDA’s ability to detect conof hepatology at the Einstein Healthcare Network in cerns about supplements and remove products from the Philadelphia, and a contributor to the network. market, said Lisa Van Arsdale, a senior analyst with the But DILIN is not population-based, and it’s tough U.S. Government Accountability Office. The agency to determine how big a problem DILI is nationally, Dr. has limited information on the number and types of Navarro said. There are three big barriers, he said: rare products available; consumers may underreport adverse events, lack of recognition and possible underreporting events; and the agency has difficulty establishing causalof events. ity between products and their alleged health outcomes.

“Clinicians simply don’t recognize sometimes when Requiring supplement manufacturers to provide their patient has an injury due to a supplement,” Dr. information on the products they sell has been part of

16%

18%

Resources for more information about herbal and dietary supplements The NIH Office of Dietary Supplements Label Database contains information for about 40,000 products www.dsld.nlm.nih.gov/dsld The Office of Dietary Supplements also has fact sheets that give a current overview of individual vitamins, minerals, and other supplements, in English and Spanish ods.od.nih.gov The Drug-Induced Liver Injury Network, established by NIDDK, analyzes cases of severe liver injury caused by prescription medicines, over-the-counter drugs, or herbal and dietary supplements. dilin.dcri.duke.edu The U.S. National Library of Medicine maintains a database of medications and supplements known to cause liver injury www.livertox.nih.gov The FDA runs MedWatch, a safety information and adverse event reporting program, through which individuals and practitioners can report events linked to medications or supplements www.fda.gov/Safety/MedWatch many proposed legislative efforts but has not become law, Ms. Van Arsdale said. The FDA inspected justt 18% of manufacturing facilities in 2012, and sampled orr examined on average 3% to 5% of imported supplementt shipments between fiscal year 2002 and March 2008, according to GAO studies.

For now, no specific test can identify a DILI, and assigning causality is challenging, said Leonard Seeff, MD, a hepatology consultant for the Einstein Healthcare Network. Early signs include abnormal serum enzymes and the occurrence of nonspecific symptoms such as jaundice, fatigue or itching. All other causes of liver injury first must be excluded through an extensive medical history and physical examination; defining the category of liver injury as hepatocellular, cholestatic or mixed; and searching for past evidence of liver injury induced by the drug, Dr. Seef said. The U.S. Library of Medicine maintains a database of medications and supplements known to cause liver injury (www.livertox.nih.gov).

Clinicians who suspect that a patient has been harmed by a supplement should obtain and keep the bottle the product came in, along with any unused portion, advised Pieter Cohen, MD, an internist with Harvard Medical School’s Cambridge Health Alliance, in Boston. Report adverse events to the FDA through MedWatch, the agency’s safety information and adverse event reporting program, he said, and if appropriate, also contact the local department of public health.

—Karen Blum The sources reported no relevant financial conflicts of interest.

22

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

The Best of Digestive Disease Week 2015: Par COMPILED AND WRITTEN BY CYNTHIA J. GORDON

In the first of a three-part series, our roster of experts highlights what they thought were some of the most important studies presented at Digestive Disease Week 2015.

Patients with hepatitis C virus (HCV) infection and cirrhosis represent a population that is most in need of treatment options, but one that is among the most Staff Clinician difficult to treat. These patients also tend to be underLiver Diseases Branch represented in clinical trials. In this study, researchers National Institute of Diabetes and analyzed data from Phase II and III clinical trials of Digestive and Kidney Diseases patients with HCV genotype 1 infection and compenNational Institutes of Health sated cirrhosis who were treated with a combination of Bethesda, Md. ledipasvir and sofosbuvir, with or without ribavirin, for 12 or 24 weeks.

More than 500 patients who met the inclusion criteria were included in the pooled analysis. Overall, MicroRNA 223 Ameliorates 96% achieved a sustained virologic response (SVR) at Alcoholic Liver Injury in Mice week 12. Notably, treatment-experienced patients who

by Suppressing Neutrophil received 12 weeks of treatment with ledipasvir and Infiltration and Functions (Li M et al) sofosbuvir achieved an SVR of 90%, whereas those who received ribavirin in addition to the combinaIn this study, investigators examined the regulation of tion for 12 weeks achieved an even higher SVR—96%. infiltration of neutrophils into the liver, a process that is SVR was also higher in treatment-experienced patients thought to contribute to the development of alcoholic when treatment was extended to 24 weeks. The invesliver disease (ALD). Because tigators concluded that treatmicroRNA 223 is one of the most ment with a combination abundant microRNAs expressed ‘If this microRNA 223 mechanism of ledipasvir and sofosbuvir in neutrophils, the researchers is “effective, safe and wellhypothesized that it could play a holds up in larger animal studies tolerated” in patients with role in regulating infiltration of and humans, it may open new HCV genotype 1 infection the cells and thereby contribute and compensated cirrhosis. avenues for therapy of alcoholic to the pathogenesis of ALD. Investigators subjected hepatitis, something that we Dr. Ghany: microRNA wild-type and haven’t had much improvement in knockout (–/–) mice to chronicA new generation of hepaplus-binge ethanol feeding. They for many years.’ titis C therapies has really observed elevated serum liver —Marc Ghany, MD revolutionized the manageenzyme concentrations and a ment of patients with the stronger oxidative reaction in the virus, with successful elimiknockout mice—the ones lacking microRNA. They nation of HCV now achievable in upward of 90% of concluded that “microRNA 223 protects against ALD individuals. Reddy and colleagues found that this hardby suppressing neutrophil infiltration and reactive oxy- to-treat group achieved more than 90% SVR. This gen species production,” thus making it an attractive would have been unheard-of not too long ago. The current FDA recommendations to use sofosbuvir and ledinovel therapeutic target for the treatment of ALD. pasvir in patients with cirrhosis is for a duration of 24 weeks. I think what this analysis shows is that we can get Dr. Ghany: the same, or even greater, efficacy by adding ribavirin to There are a number of laboratory studies that, if they sofosbuvir and ledipasvir, and shortening the duration translate into the clinic, hold great promise for how we to just 12 weeks. approach the therapy of certain liver diseases. This one Historically, patients with cirrhosis have been the deals with a murine model of alcoholic liver injury. The most difficult to treat. Even using these direct-acting findings demonstrated that this knock-out model wors- antiviral agents, their response rates are lower than those ened ALD. If this microRNA 223 mechanism holds up of patients without cirrhosis. I think what this study tells in larger animal studies and humans, it may open new us that is important, is really two things: 1) that patients avenues for therapy of alcoholic hepatitis, something that with cirrhosis can be safely and effectively treated, and in we haven’t had much improvement in for many years. this study, with the 12-week duration, we could achieve SVR rates of 96%—that’s pretty incredible; and 2) you An Integrated Safety, Efficacy, reduce the duration of therapy from the recommended and Virology Analysis of >500 24 weeks that’s in the label, to 12 weeks, and that’s going Patients With Compensated to be a huge cost savings for individuals with advanced Cirrhosis Treated With Ledipasvir/Sofosbuvir With liver disease. or Without Ribavirin (Reddy R et al) Dr. Ghany reported no relevant financial conflicts of interest.

Marc Ghany, MD, MHSc

282.

364.

KMarie Reid Lombardo, MD, MS Associate Professor of Surgery Mayo Clinic College of Medicine Rochester, Minn.

Sp319.

Prospects for Therapy of Hepatic Fibrosis

Dr. Reid Lombardo: “Hepatic fibrosis, and the prospects for therapy, have never been brighter,” said DDW session chair Scott Friedman, MD, introducing a session on hepatic fibrosis that he moderated.

Contributing to this promising outlook is the convergence of several factors, Dr. Friedman said: the recognition that fibrosis is reversible; the availability of new therapies for infections with the hepatitis B virus (HBV) and HCV; an understanding of the underlying biology of fibrogenesis, which has led to research in specific targets for antifibrotic therapy; and the emergence of an epidemic of nonalcoholic steatohepatitis (NASH), which has raised awareness among clinicians of liver fibrosis. “All of these [factors] create a climate that is very ripe for major progress,” Dr. Friedman said.

Natalie Torok, MD, of the UC Davis Medical Center, in Sacramento, elaborated on recent progress in the understanding of fibrosis pathogenesis and the identification of new therapeutic targets. see DDW, page 24

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DDW continued from page 22

“A lot of things happened in the recent past in terms of discovering novel pathways in fibrogenesis,” Dr. Torok said. A thorough analysis of all of these new discoveries could fill several days, she noted.

When the liver is exposed to chronic injury—such as through infection with HBV or HCV, NASH or chronic use of alcohol—liver cells die. Hepatic cell death triggers a cascade of events, from progressive inflammation to fibrosis and eventually

cirrhosis. During progression from fibrosis to cirrhosis, hepatocytes lose their capacity for regeneration and function.

“The link between fibrosis and how this decreased regeneration occurs is still not well known,” Dr. Torok said, and this is a primary area of focus in current research in liver fibrosis.

The progression of fibrosis to cirrhosis is variable: The process is slow, and it is influenced by many factors, including underlying liver disease, as well as epigenetic factors and genetic polymorphisms.

However, what is more interesting than

the progression of fibrosis is the regression of fibrosis, Dr. Torok said.

Researchers have known for several decades that fibrosis can regress, she said, and the literature includes cases of the phenomenon in patients with hepatitis. “We’ve made major headway in the recent past discovering the key pathways that cover fibrosis regression,” she said, and this is becoming a promising area for therapeutic targets.

Fibrosis, from stages 1 to 3, can regress a few stages, she said. For example, total resolution of fibrosis has been observed

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in patients with HCV infection who have achieved an SVR. “This process seems to be very slow,” she noted. “So, in planning future trials, none of the trials should be less than a year.”

Macrophages play an important role in the regression of fibrosis by releasing antifibrogenic factors that influence hepatocytes and other cells in the liver.

Macrophages also are involved in fibrogenesis by releasing pro-inflammatory factors in response to hepatocyte injury.

But this dual role of macrophages in fibrogenesis and fibrosis regression represents only one of the many therapeutic targets that researchers are studying in the treatment of fibrosis.

“Most likely, treatment will be combined approaches in the future. There won’t be one single, magic bullet therapy for fibrosis,” Dr. Torok said.

Antifibrogenic approaches, enhancing fibrosis reversal and a combination of these strategies will likely comprise future treatments for fibrosis.

“Of course, treating the underlying liver disease is an important strategy,” Dr. Torok added. “We’ve already made major advances,” for example, in treating HCV and HBV infection.

NASH and the link between obesity and liver disease is another area of active research. Several treatments for the condition are being investigated, including farnesoid X receptor and peroxisome proliferator-activated receptor agonists, vitamin E and inhibitors of lipogenesis.

Cellular crosstalk between adipocytes and other cells is involved in liver fibrogenesis, and factors regulating these mechanisms also are being investigated.

“Adipose tissue is actually a very crucial part of liver fibrogenesis,” Dr. Torok noted. For example, inflammation in adipose tissue can lead to the release of cytokines, also known as adipokines, that are important mediators in liver disease progression. Many of these adipokines— including interleukin-6 and tumor necrosis factor–α— are pro-fibrogenic and play an important role in fibrosis.

“Most of these circuits are back and forth, because liver-generated mediators also can influence adipose tissue inflammation,” Dr. Torok said.

Notably, bariatric surgery can reverse liver fibrosis, Dr. Torok added. Therefore, obesity and its underlying pathogenesis are an area of active investigation in the treatment of liver fibrosis.

In summary, Dr. Torok reiterated, future treatments for liver fibrosis will not be a “magic bullet” nor a single pill.

Treatment “will be targeted and tailored, individualized,” she said, including disease-specific, fibrosis stage– or reversalspecific and combined strategies.

Dr. Reid Lombardo reported no relevant financial conflicts of interest.

25

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

John Vargo, MD, MPH Chair, Department of Gastroenterology and Hepatology Cleveland Clinic Cleveland, Ohio

270.

EUS Guided Drainage of Peripancreatic Fluid Collections and Necroses Using a Novel Lumen-Apposing Stent: A Large Multicenter U.S. Experience (Siddiqui A et al) This study aimed to provide data on the success rate, clinical outcomes and safety of endoscopic ultrasound (EUS)guided drainage of pancreatic pseudocysts and walled-off pancreatic necroses using a novel lumen-apposing, self-expanding metal stent (AXIOS, Xlumena). As the study authors noted, preliminary data had shown promise, but few data from U.S. centers were available. The authors conducted a retrospective multicenter study, including four U.S. tertiary care centers, that looked at patients with symptomatic pancreatic pseudocysts and walledoff pancreatic necroses. Patients were observed until resolution of pancreatic fluid collection or death.

looked at a new lumen-apposing, selfexpanding metal stent to drain pancreatic pseudocysts as well as walled-off pancreatic necroses. They were able to successfully place the metal stent in 75 of their 80 cases, and 95% of those patients achieved resolution of those pancreatic fluid collections over the three-month period. Much of the success has to do with the fact that the metal stent has a much larger opening than those stenting devices that we currently use. While comparison studies need to take place, I think these results

show that clinicians have another tool available for them in treating these challenging disorders.

444.

A Randomized, Multi-Center Study to Evaluate the Safety and Effectiveness of an Intragastric Balloon As an Adjunct to a Behavioral Modification Program, in Comparison With a Behavioral Modification Program Alone in the Weight Management of Obese Subjects (Abu Dayyeh BK et al)

In this randomized, multicenter U.S. trial, investigators evaluated the safety and efficacy of the Orbera intragastric balloon (Allergan) in the management of mild to moderate obesity. Patients were randomly assigned to receive implantation with the intragastric balloon in combination with behavioral management, or behavioral management alone. Most of the patients in both groups were women, with a mean age of approximately 40 years. Patients were followed for 52 weeks (26 weeks after see DDW, page 26

Intercept Pharmaceuticals is focused on innovative research in chronic liver diseases.

‘I think these results show that clinicians have another tool available for them in treating these challenging disorders.’

—John Vargo, MD, MPH

Among 80 patients who were evaluated, technical success with stent placement was achieved in nearly 95%. Procedurerelated complications occurred in approximately 10% of patients and included stent maldeployment, self-limited bleeding and access-site infection. Patients were followed for a mean of 3.4 months; overall, most patients (>90%) achieved resolution of pancreatic fluid collection.

The investigators concluded that the new stent was associated with high technical and clinical success rates, and that because of the ease of use, the stent “may simplify and streamline EUS-guided management of pancreatic fluid collection, particularly for the endoscopic debridement of walled-off pancreatic necroses, and help in its widespread adoption as an alternative to surgery.”

Dr. Vargo: A study conducted by Siddiqui et al

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26

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

compared to the psychological intervention program alone.

This was found after six months after the balloon continued from page 25 was in place; and then after the balloon was removed, removal of the balloon), with approximately 75% of it was durable for another six months. I think these are patients in each group completing the study. very exciting data, and I look forward to longer-term At 26 weeks, 72% of data to answer the question of durapatients who received bility of response. balloon implantation I really believe that the study ‘I really believe that the study achieved 25% excess with the intragastric balloon has with the intragastric balloon weight loss, compared some incredible upsides: an endowith 32% of patients scopic therapy that was very well has some incredible upsides ...’ who received behavioral tolerated, with minimal or no side —John Vargo, MD, MPH management alone. At effects, that was placed temporarily; 52 weeks, 46% of balloon and it started to show durability of recipients achieved 25% excess weight loss, compared excess body weight loss, as well as reversal of some of with 33% of patients who did not have the balloon, the other comorbidities of obesity, such as dyslipidemia, with both groups showing a reduction in comorbid hypertension and diabetes mellitus. I think this has treconditions. mendous potential.

The investigators concluded that the Orbera intragastric balloon, in combination with behavioral management, resulted in “significant weight loss that is preserved even after device removal … representing a minimally-invasive and effective approach to manage Pancreatic Adenocarcinoma Is Associated With a Unique Spectrum of Serum Volatile obesity and associated comorbidities.”

Organic Compounds That Distinguishes It From Chronic Pancreatitis and Healthy Controls Dr. Vargo: (Confer B et al) This multicenter study found that the combined Pancreatic ductal adenocarcinoma often is diagintervention of the intragastric balloon placement, in nosed at an advanced stage. This new study aimed to addition to psychological intervention, led to a sig- determine if breath testing to detect volatile organic nificantly increased loss of excess body weight when compounds (VOCs) could discriminate patients with

DDW

Sa2040.

pancreatic ductal adenocarcinoma from patients with chronic pancreatitis and healthy patients.

Researchers assessed blood samples from 73 patients for VOCs and determined that seven of the compounds were associated with pancreatic ductal adenocarcinoma, with ethanol, isoprene and hydrogen sulfide best discriminating patients with pancreatic ductal adenocarcinoma from the other groups. Adjustments for alcohol and tobacco use enhanced these results. The investigators suggested that additional studies may determine whether VOCs could be detected in breath tests as a noninvasive aid in the diagnosis of pancreatic ductal adenocarcinoma.

Dr. Vargo: One area that’s really exciting is the use of serum and breath test technology to screen for various chronic digestive disorders, many of which are precursors to malignancy. This is an important area of exploration, because the ideal screening tool—in a perfect world— would be noninvasive, reproducible and inexpensive.

However, most of the current screening tools do not meet any of these three criteria.

The researchers discovered seven VOCs that discriminated pancreatic ductal adenocarcinoma patients from other groups studied. If these results can be validated with additional studies, we should be able to use this knowledge to develop a more powerful and ideal screening tool.

Dr. Vargo is a co-author of abstract Sa2040, and is a consultant for Paieon Medical, Inc.

Benefits of Frequent Colonoscopy Seen in IBD Patients PHILADELPHIA—New research supports early and frequent colonoscopy for patients with inflammatory bowel disease (IBD), who are at an elevated risk for colon cancer.

Patients with ulcerative colitis (UC) should begin receiving colonoscopy every one to three years, starting about eight years after diagnosis, according to guidelines from the American Society for Gastrointestinal Endoscopy and the American Gastroenterological Association.

“We know that screening colonoscopy in the general population is associated with a reduced incidence in mortality from CRC [colorectal cancer], and that a negative colonoscopy can be associated with a reduced risk for lesions,” said Ashwin Ananthakrishnan, MD, MBBS, MPH, assistant professor of medicine at Massachusetts General Hospital, in Boston, who presented the research at the 2014 meeting of the American College of Gastroenterology (abstract 9).

“The aim of our study was to identify whether colonoscopy alters the risk for CRC in patients with IBD. We postulated that colonoscopy may reduce CRC in patients with IBD by either allowing removal of dysplastic lesions or by facilitating referral to surgery at the stage of dysplasia.”

To examine their hypothesis,

Dr. Ananthakrishnan and his colleagues statistically significant. Of those with CRC. “Looking at that population, it’s evaluated data on 6,823 patients from a recent colonoscopy, 1.6% developed pretty striking that the 42 patients who a validated multi-institutional IBD CRC compared with 2.7% of those who had a recent colonoscopy had a much cohort, including only those who had had not undergone recent colonoscopy lower mortality rate than [the 112] who at least three years of follow-up for the (P=0.001).

P Those who developed CRC did not,” Dr. Ananthakrishnan said. condition at their institutions. Within tended to be older, male and to have UC Tauseef Ali, MD, a gastroenterologist 36 months, only 2,764 of the patients or primary sclerosing cholangitis (PSC). and an assistant professor of research had undergone colonoscopy.

In both the unadjusted and the fully at the University of Oklahoma College “From within these groups we were able adjusted models, having a colonoscopy of Medicine, in Oklahoma City, who to see who developed CRC and whether within three years was associated with a was not involved in the study, said that their outcomes differed from those who reduced incidence of CRC (odds ratio, it highlighted the benefits of screening. did not,” Dr. Ananthakrishnan said.

0.65; 95% confidence interval, 0.45-0.93). “This well-designed IBD cohort study The two groups differed in terms of These findings remained robust on various reaffirms the importance of screening disease type, patient age and medical sensitivity analyses adjusting for health colonoscopy among IBD patients, therapy. Those who did not have a recent care utilization, use of immunosuppressant and has once again shown the survival colonoscopy tended to be older and to or anti-tumor necrosis factor therapy, benefit of colonoscopic surveillance of be older at age of IBD diagnosis than inflammatory burden and coexisting PSC. CRC in clinical practice,” Dr. Ali told those who had, and colonoscopy was less Use of screening colonoscopy also Gastroenterology & Endoscopy News. common in patients with UC than in appeared to benefit those who developed “Now that the benefit of such a those with Crohn’s disease. se. screening test is well established, “Also, the group that did have this is aactually the time to work on colonoscopy tended to be sicker, developin ng optimal techniques, such as as we might expect, and so using chromoendoscopy for better Of those with a had more frequent use of detection of precancerous lesions, recent colonoscopy, immunomodulators and d an nd identifying optimal intervals compared with biologic therapy,” Dr.. for surveillance,” Dr. Ali Ananthakrishnan said. added. “Perhaps in the future, developed Of the entire study noninvasive tests, such as of those who had not CRC population, 154 patients fecal biomarkers, can replace undergone recent developed CRC during a endoscopic surveillance and lead colonoscopy mean follow-up of eigh ht tto more widespread adoption and years, and the difference adh herence by patients.” between the two group ps was —Monica J. Smith

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Antiviral Drug Prevents HBV Transmission During Pregnancy

T

he antiviral drug telbivudine appears to block the transmission of the hepatitis B virus (HBV) from an infected mother to her unborn baby, new research suggests.

Blood levels of HBV in pregnant women are strongly associated with the risk that their unborn babies will contract the infection. In the new study, pregnant women with HBV who received telbivudine were much less likely to pass the virus along to their babies than women who were not given the drug.

“Telbivudine significantly reduces vertical transmission of HBV from pregnant women to their infants; it is safe and well tolerated” by both mothers and babies, according to the researchers, who published their findings in Clinical Gastroenterology and Hepatology (2015;13:1170-1176).

The study, led by scientists at the Third Military Medical University, in Chongqing, China, included 450 women with HBV infection, of whom 269 took telbivudine—sold as Tyzeka by Novartis in the United States—during weeks 24 to 32 of their pregnancy. (The remaining women declined to take the drug

and were used as controls.) Newborns received standard HBV prophylaxis of a recombinant HBV vaccine and hepatitis B immunoglobulin.

Six months after birth, none of the babies of mothers who received telbivudine tested positive for HBV, compared with 14.7% of babies in the control group, according to the researchers.

Women who received the drug also were much less likely to have undetectable viral loads before giving birth than those who declined treatment. They also were significantly more likely to have undetectable levels of HBV in cord blood than untreated mothers (99.1% vs. 61.5%), the researchers reported.

Women who received telbivudine were more likely to have cesarean delivery than untreated women. Elective cesarean delivery has been linked to a lower risk for HBV transmission between mother and child than either urgent cesarean or vaginal birth. “Because no significant difference in vertical transmission between cesarean section and vaginal delivery was found in our study, we have been following up the 2 groups,” the authors wrote.

—GEN Staff

Narrow Band Imaging Can Inform ‘Resect and Discard’ in Everyday Practice WASHINGTON—Can academic gastroenterologists without previous training in narrow band imaging (NBI) achieve the thresholds recently set for predicting the histology of diminutive polyps?

Investigators at two U.S. academic medical centers teamed up to find out and concluded that they can, which would eliminate the need for pathologic examination. The researchers reported their findings at Digestive Disease Week 2015 (abstract 448).

“Endoscopists with no prior training in NBI can achieve a 95% negative predictive value [NPV] in the rectosigmoid colon and 89% agreement on surveillance interval, with the vast majority of patients screened on time or early,” said Swati G. Patel, MD, of the University of Michigan, in Ann Arbor, who helped conduct the study.

“Experts have shown a high-level performance of NBI in determining histology of polyps 5 mm and smaller, but it’s been unclear if endoscopists without training in NBI can achieve a similar level of performance.”

The American Society for Gastrointestinal Endoscopy (ASGE) has proposed that, before NBI is used in practice, endoscopists achieve two goals: at least 90% NPV for adenomas in the rectosigmoid colon and at least 90% agreement in the predicted and actual recommended surveillance intervals for “high-confidence” predictions.

The new study evaluated whether academic gastroenterologists without previous training in NBI can achieve the ASGE thresholds. It included 26 gastroenterologists at the University of Michigan and the University

of Colorado. Most had less than 10 years of experience and performed 200 to 500 colonoscopies per year. Physicians received standardized audiovisual training on NBI interpretation—reviewing patterns associated with hyperplastic and adenoma histology—and then made real-time predictions of diminutive polyp histology during routine colonoscopy.

Confidence Is Key The clinicians characterized each prediction with high or low confidence and determined surveillance interval based on NBI, when confidence in the prediction was at least 90%, and histologic diagnosis, when confidence was lower. This “mimicked real practice and application” of the ASGE’s statement, Dr. Patel explained.

The group of gastroenterologists performed a total of 1,458 colonoscopies (mean, 56 per participant) and made a prediction for surveillance in 905 (62%); the primary reason for lack of a prediction was identification of a polyp greater than 5 mm, which calls for screening within three years.

The clinicians found 3,012 diminutive polyps, with a mean of 115 per participant. The polyps were adenomas (53%), not adenomas (41%), sessile serrated (1.5%) and other types (1.8%), with none being high-grade dysplasia or cancer. Three percent were not retrieved or were missing histology.

Of the 3,012 diminutive polyps, 2,239 (74.3%) were diagnosed with high confidence and 731 (24.3%) were diagnosed with low confidence (with 1.4% missing data). Confidence levels were similar for the 1,135 rectosigmoid polyps.

The primary end point was the rectosigmoid highconfidence NPV. Of 1,058 rectosigmoid diminutive polyps, 818 were diagnosed with high confidence and 238 with low confidence. Endoscopists achieved a 94.7% NPV for rectosigmoid polyps characterized with high confidence, “far exceeding the threshold set by the ASGE,” Dr. Patel reported.

Endoscopists achieved an 88.8% agreement on the surveillance interval, “just shy” of the 90% threshold proposed, she said.

Most disagreements occurred because the endoscopist brought the patient back sooner than dictated by

29

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Surgery Bests Conservative Management For Recurrent Diverticulitis Results of randomized trial may offer evidence base for patient care WASHINGTON—In patients with recurrences and ongoing symptoms of diverticulitis, elective surgery is more likely to improve quality of life than conservative treatment, Dutch researchers have found.

At six months, a highly statistically significant advantage was found for surgery over conservative management on the primary end point of change in the Gastrointestinal Quality of Life Index (GIQLI). The multicenter, randomized trial is the first prospective controlled trial to investigate whether surgery outperforms conventional care for refractory diverticulitis, providing an evidence base for advising patients with the condition.

Although some patients experienced complications from surgery, “our findings suggest that the risks of surgery do not outweigh the benefits,” said Marguerite A. W. Stam, MD, of the Department of Surgery at Meander Medical Center, in Amersfoort, who helped conduct the study.

Enrollment in this study, presented at Digestive Disease Week 2015 (abstract 901C), was limited to two groups: patients with abdominal complaints persisting for more than three months after an episode of diverticulitis, and those who had at least three recurring episodes of diverticulitis. Resection was performed laparoscopically.

Conservative management could be any treatment that did not include surgery. These patients typically received stool softeners and analgesics.

At six months, the mean GIQLI scores

were 114.4 in the 53 patients who underwent surgery and 100.4 in the 56 patients who received conservative treatment (P<0.0001)—a clinically relevant differer ence, Dr. Stam said.

Two other quality-of-life tools th hat were included among secondary end d points also showed differences of a magnitude that are considered clinically relevant. Dr. Stam said these differences involved measures of physical rather than mental health.

Adverse events related to surgery included anastomotic leakage in seven patients (13.2%), wound infections (two patients) and wound dehiscence (one patient). Three patients sttill had a stoma at six months, but Dr. Staam said these were being managed effeectively. All patients with leakage underwent reoperation, two required treatment in the ICU, but all complications eventually resolved.

Seven patients (12.5%) in the group receiving conservative treatment experienced a recurrence of diverticulitis, the researchers reported, compared with none after surgery. A higher proportion of patients in the conservative treatment group also complained of intractable pain.

Dr. Stam said the study provides guidance for managing a difficult population.

Approximately 30% of patients with diverticulitis have persistent symptoms or recurrent episodes, she said, and expert opinion has been divided about the best course of management. Indeed, the disagreement delayed recruitment for this

histology. “Thus, 96.9% of patients would receive a surveillance exam on time or early if NBI were applied to diminutive polyps,” Dr. Patel pointed out.

For the variety of secondary end points, “overall perpolyp performance across the board was significantly better for diagnoses made with high confidence versus low confidence,” she said.

For decisions made with high and low confidence,

trial. The investigators found that many candidates were unwilling to be randomized due to bias for or against surgery.

“We found that both patients and physicians have preferences,” said Dr. Stam, who added that the study was terminated early because of the slow accrual.

Although fewer patients were enrolled than planned, the level of significance was adjusted to yield results with sufficient power to draw meaningful conclusions. Even after randomization, 13 patients getting conservative treatment subsequently demanded surgery, and six patients in the surgery group were managed conservatively.

Potential surgical risks and the subjective end point make resection unsuitable for every patient. Rather, Dr. Stam

sensitivity was 97.6% and 74.6%, respectively (P<0.001).

NPV was 98.3% versus 80.8% (P<0.001), and accuracy was 84.8% versus 60.2% (P<0.001).

Whether a polyp was characterized with high or low confidence clearly affected the accuracy of the initial assessment relative to histology. After adjusting for endoscopist characteristics, the study showed that clinicians who judged polyps with high confidence were almost 3.5 times more accurate than those who had low confidence in their initial judgment.

Dr. Patel noted that distinguishing between high- and low-confidence diagnoses is critically important, as a high-confidence diagnosis is a strong predictor of performance. If the practice of resect and discard becomes widespread, “we need to develop streamlined auditing strategies to assure adequate individual performance,” she said.

said the data provide a basis on whom to counsel for surgery.

Ronald Koretz, MD, emeritus professor of clinical medicine at the University of California, Los Angeles, cautioned about the limitations of an unblinded study with quality of life as an end point.

Such trials are inherently subjective, leaving significant room for bias.

“It is very difficult to blind a surgical trial, so this is not a criticism of the design,” Dr. Koretz said. Although he did not dismiss the value of these data as a tool for counseling diverticulitis patients about their options, he stressed that they are not definitive.

“I just think it is important to consider the role for bias when the end point is subjective and the treatment is known both to the patient and to the investigator,” Dr. Koretz said.

—Ted Bosworth Drs. Stam and Koretz reported no relevant financial conflicts of interest.

Samir Gupta, MD, associate professor of medicine at the University of California, San Diego, and a gastroenterologist at the San Diego Veterans Affairs Health System, said the study demonstrates “that colonoscopists can be taught to look at a small polyp and accurately rule out the presence of adenoma. In practice, this could allow us to make accurate decisions about whether to remove a polyp, and in polyps suspected to be adenomas, to remove the polyp and avoid having to send it to a pathologist to guide recommendations for timing of follow-up colonoscopy.

“This could add value by reducing the rate of unnecessary polypectomies, which reduces costs and complications, and the need to send all polyps to pathology for diagnosis, which also lowers costs,” Dr. Gupta said. “I think improving our ability to visually classify polyps is of value; whether we should leverage this for the ‘resect and discard’ approach, I think is still controversial.”

Drs. Patel and Gupta reported no relevant financial conflicts of interest.

—Caroline Helwick

30

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Surgical Residents Gain Competency in Colonoscopy With Structured Curriculum

J

unior surgery residents can be taught to perform screening colonoscopy safely and effectively, at least within a structured learning environment, new research has shown.

To address concerns of U.S. gastroenterology (GI) societies over the ability of surgical trainees to perform endoscopy competently, the American Board of Surgery (ABS) instituted a requirement that residents complete a curriculum in flexible endoscopy. The ABS had mandated that surgical residents complete 50 colonoscopies and 35 upper endoscopies before graduation. The GI societies, in turn, stated in February 2011 that the mandate

did not address cognitive competency and that the required numbers were insufficient to assess or achieve competency.

“The ABS maintains that endoscopy is a technical competency, part of the skills set residents must develop prior to graduation,” said John Ortolani, MD, a fourthyear general surgery resident at Virginia Tech Carilion School of Medicine, in Roanoke. “This is achieved primarily through simulated experience and supervised procedures. The motivation for our research project really stems from a fundamental disagreement between several prominent GI societies and the ABS,” said Dr. Ortolani, who reported his group’s findings at

Report Card continued from page 1

adjustment for patient age, sex and endoscopist (odds ratio, 1.45; Gastrointest Endoscc 2013;77:925-931).

“Setting expectations of quality seems to be critically important in ensuring physicians achieve high-quality exams,” said Rajesh Keswani, MD, associate professor of medicine, gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine, in Chicago, who led the study. Dr. Keswani’s group presented the findings at Digestive Disease Week 2015 (DDW; abstract 1043) and published them online ((Am J Gastroenteroll 2015 April 14. [Epub ahead of print]).

Screening colonoscopy with removal of adenomas reduces the incidence of colorectal cancer and deaths from the disease. About three years ago, gastroenterologists at Northwestern University implemented a two-pronged approach to improve the quality of colonoscopies at their institution. They started distributing colonoscopy quality report cards, which detailed clinician and institutional ADRs. Several months later, they implemented a minimum standard of practice.

Physicians were required to have a minimum five-minute withdrawal time in normal colonoscopies and a minimum ADR of 20%. The latter benchmark came from a Polish study that showed patients seen by endoscopists with an ADR of more than 20% had lower rates of interval colorectal cancer (N Engl J Medd 2010;362:1795-1803).

Gastroenterologists at Northwestern who did not meet these benchmarks were told they would have to undergo additional focused training or have their endoscopy block time changed.

“Most of our doctors schedule their colonoscopies in 35- to 40-minute blocks. If you don’t achieve a 20%

the 2015 Southeastern Surgical Congress, in Chattanooga, Tenn.

‘Safe and Competent’ To evaluate their own endoscopy curriculum, assess the ABS guidelines and track resident performance of screening colonoscopy, Dr. Ortolani and his colleagues conducted a prospective analysis of screening colonoscopies performed at their institution by surgical residents during the 2012-2013 academic year.

“Our hypothesis was that within a structured curriculum, surgical residents could perform safe and competent screening colonoscopy,” he said.

detection rate, either you are not spending enough time looking for polyps or your inspection technique is inadequate,” Dr. Keswani said.

The researchers collected data, such as ADR and withdrawal time, before initial report card distribution and the launch of the minimum standard of practice, after initial report card distribution, and after the second report card and implementation of the minimum standard of practice.

Only endoscopists averaging at least 15 colonoscopies per month were included in the analysis of data presented at the DDW meeting. The 20 endoscopists who met inclusion criteria performed 12,894 screening colonoscopies over the study period.

Outcomes improved across the board (Table). The average ADR, which was 28% at baseline, increased 3% after initial distribution of the report card (P<0.001); it rose 8% more after the minimum standard of practice was implemented (P<0.0001). The number of physicians attaining the minimum 20% ADR rose from 80% at baseline to 100% by the end of the study, according to the researchers.

‘I think report cards should be standard of care for all gastroenterologists. We all should know how we are performing in our high-volume procedures.’

—Rajesh Keswani, MD

The curriculum consisted of a dedicated postgraduate year 2 rotation featuring both simulation and clinical components. In the simulation component, residents were told to complete several specific modules using GI Mentor training software. They also completed a benchmarked practical examination before supervised clinical experience, Dr. Ortolani said.

A power analysis revealed that 108 procedures were necessary to generate sufficient data. Diagnostic and surveillance colonoscopies, and patients with known inflammatory bowel disease, polyposis syndromes or a history of colorectal cancer see Residents, page 33

Using estimates of the clinical impact of each 1% increase in ADR (N Engl J Medd 2014;370:1298-1306), the investigators determined that the 11% improvement in ADR would mean an overall 28% reduction in the relative risk for interval colorectal cancer and a 43% reduction in fatal colorectal cancer.

“I think report cards should be standard of care for all gastroenterologists. We all should know how we are performing in our high-volume procedures,” Dr. Keswani said. “The very unique part of our study is seeing what happens when you tell physicians ‘you must achieve this minimum benchmark or there will be some consequences on your practice.’” This alone, he said, made a dramatic difference in performance, and no physicians required retraining or alteration in endoscopy block time.

Charles Kahi, MD, a gastroenterologist at Indiana University and chief of the Gastroenterology Section at Roudebush VA Hospital, in Indianapolis, said the Northwestern study has “important implications.”

“It shows that implementation of a colonoscopy quality standard of practice and distribution of report cards to physicians can significantly increase endoscopists’ ADR, which is the most important surrogate marker for colonoscopy quality,” said Dr. Kahi, who led the group that published the Indianapolis study on report cards.

That paper concluded by calling for testing the report card concept in other health care settings.

The new study, he said, confirms the value of report cards. “The advantage of this strategy is that it is relatively straightforward to implement, intuitive, acceptable to providers.” Dr. Kahi added, “Now we see that it is reproducible and leads to measurable improvements in colonoscopy quality in different health care settings.”

—Kate O’Rourke Drs. Keswani and Kahi reported no relevant financial conflicts of interest.

Table. Impact of Report Card Distribution and Minimum Standard of Practice Period Before Report Card Distribution: November 2012-March 2013

Period After Report Card Distribution: April 2013-March 2014

Period After Report Card Distribution And Minimum Standard of Practice: April 2014-October 2014

Endoscopists with average ADR >20%

80%

90%

100%

Overall ADR, mean

28%

31%

39%

Endoscopists with mean withdrawal time >5 min

90%

95%

100%

ADR, adenoma detection rate

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Residents continued from page 30

were excluded from the study.

Under direct supervision of a surgical endoscopist, the residents performed 166 screening colonoscopies, of which 149 met the inclusion criteria. The researchers used quality metrics defined by the GI societies: colonoscope withdrawal time, total procedure time and cecal intubation rate and adenoma detection rate (ADR). On average, each resident performed 30 procedures.

“We found the bowel prep was adequate in over 90% of the cases, and our polyp detection rate was 30%. The average size of polyps was 7.7 mm, and we had no peri- or postprocedure complications,” Dr. Ortolani said. “When we analyzed our ADR, it was 23% overall; 18% in females and 29% in males.”

He noted that the ADR was higher than the benchmark values described by the GI societies (20% overall; 15% in females and 25% in males), although the difference between the resident cohort’s achievement and the established GI benchmarks was not statistically significant.

The cecal intubation rate of 96% also was high. “This may have been due to the high quality of colon preparations, as well as the extensive simulation training,” Dr. Ortolani said. “Our residents feel very comfortable going into their clinical experience having completed the earlier simulation tasks.”

A much larger study comparing faculty gastroenterologists and general surgery residents at a single institution in Texas also found the residents to be capable of performing colonoscopy under supervision of surgical staff, achieving metrics very close to those of the gastroenterologists ((J Surg Educc 2015;S1931-S7204 [Epub ahead of print]).

In this study, 818 colonoscopies were performed, 598 by the faculty GI service and 220 by surgical residents who had completed a self-paced endoscopy simulation curriculum. The gastroenterologists and residents attained cecal intubation rates of 98.4% and 93.5%, respectively, and their ADRs were similar as well, with the gastroenterologists achieving 29.8% in men and 15.3% in women, and the residents achieving 26.8% in men and 18.7% in women.

William Hope, MD, FACS, a surgeon specializing in minimally invasive surgery at the New Hanover Regional Medical Center, in Wilmington, N.C., said, “Assessing competency and teaching methods in endoscopy is a very important endeavor, and an area that is ripe for research. I believe that surgeons should be leaders in this area, and if we are not, we will surely be left behind.”

The ABS has mandated that residents

undergo a Fundamentals of Endoscopic Surgery component of training by the 2017-2018 academic year. However, some surgical residency programs do not yet offer a structured endoscopy curriculum.

Dr. Ortolani said Virginia Tech uses a Global Assessment of Gastrointestinal Endoscopic Skills (GAGES) worksheet to assess its surgical residents. “That worksheet numerically grades the level of intervention the surgical attending provides, and stratifies the extent to which the resident is able to complete the procedure,” he said.

As for the endoscopy simulation

curriculum, all residents at Virginia Tech who went through the program used GI Mentor simulation software, which features a mannequin and an endoscope “that allows us to measure resident performance both at handling the scope and detecting polyps,” Dr. Ortolani said. “All residents had to complete the simulation course and demonstrate proficiency on the benchmarked exam.”

But Dr. Hope wondered what institutions could do if they do not have access to simulation software, which can cost $40,000.

A future direction for the project is a longitudinal resident assessment, allowing resident data to be tracked over time.

The group plans to repeat the study in the senior years of residency. “This would allow us to assess the effect on ADR as residents continue their training,” Dr. Ortolani said. Ultimately, these metrics have the potential to be standardized by the ABS or the Accreditation Council for Graduate Medical Education for broader use in assessing resident competency in endoscopy.

—Monica J. Smith

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

HRT

‘We cannot make a causal link

continued from page 1

The risk for bleeding appears to be concentrated in the lower GI tract and correlates with increasing duration of hormone replacement therapy (HRT), according to the study of more than 70,000 women.

Experts said the findings are not surprising, given previous evidence of the association and the speculation that HRT increases the risk for thromboemboli.

“Increasing exposure to HRT was associated with an increased risk of both GI bleeds overall and lower GI bleeds specifically, and this association persists after controlling for a large number of confounding variables,” reported Prashant Singh, MD, of the Department of Internal Medicine at Massachusetts General Hospital, in Boston, who helped conduct the study.

“We cannot make a causal link on the basis of this study, but there is good evidence that HRT is associated with clotting and this is plausible in that HRT was also found to increase the risk of ischemic colitis,” Dr. Singh said. When the blood supply to the intestines is blocked by ischemic colitis, the mucosa is affected and sloughs off, leading to GI bleeding, said Dr. Singh, who presented his group’s findings at Digestive Disease Week 2015 (abstract 783).

The researchers used data from participants in the Nurses’ Health Study, which has been following a large population of women for more than 25 years. Participants were enrolled between ages 24 and 44 years, and were followed prospectively with surveys every two years.

The incidence of bleeds was adjusted through multivariate analysis for several other risk factors with the potential to promote such bleeding, including aspirin use, use of nonsteroidal anti-inflammatory drugs (NSAIDs), previous use of oral contraceptives, smoking status and body mass index.

The modestly greater hazard ratio (HR) for GI bleeds among women who had ever used HRT compared with those who never had taken the medication did not reach statistical significance (HR, 1.19; P P=0.27), but the risk was nearly 50% greater and reached significance for current users compared with never users (HR, 1.46; P P=0.02), the researchers reported.

The risk for intestinal bleeding increased further when the investigators focused on bleeding in the lower intestinal tract, particularly when comparing current users and never users. For current HRT users, the risk was more than twice as great (HR, 2.12; P<0.01). Importantly as a potential signal of causation, use of HRT was associated with a doubling of the risk for ischemic colitis (HR, 2.30; P=0.04).

P Although HRT did not appear to increase the risk for bleeding in the upper

on the basis of this study, GI tract for current users over never users (HR, 097; P P=0.91), the risk for bleeds overall, and for lower bleeds in particular, was significantly associated with duration of exposure (P<0.01 for both).

“This study confirms our speculation that hormonal therapy increases the risk of GI bleeding, particularly in the lower GI tract,” Dr. Singh said.

However, the significance of these data in clinical decision making is less clear.

but there is good evidence that HRT is associated with clotting, and this is plausible in that HRT was also found to increase the risk of ischemic colitis.’

—Prashant Singh, MD

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Patients take HRT for a broad range of indications, many of which may outweigh the significant relative risk for GI bleeding.

Still, the findings suggest that use of HRT deserves consideration in otherwise unexplained lower GI bleeding among postmenopausal women. For women without a compelling indication for HRT, the risk may warrant avoiding such therapy, particularly for those with a history of lower GI bleeding, Dr. Singh said.

An expert who has written about risk factors for GI bleeding, Angel Lanas, MD, clinical chief of gastroenterology at University Hospital, in Zaragoza, Spain, called the new data “interesting” and said they should be the “basis for further studies” to both confirm the association and understand the clinical implications.

“Lower GI bleeding hospitalizations are rising everywhere, especially in the elderly, and we should understand the risk factors

for this complication, which will allow us to implement prevention strategies,” said Dr. Lanas, referring to an article he published several years ago (Am ( J Gastroenterol 2009;104:1633-1641). “Whether HRT is one of those risk factors needs confirmation in new and more specific studies.”

—Ted Bosworth Dr. Singh reported no relevant financial conflicts of interest. Dr. Lanas has a financial relationship with Bayer.

36

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

More Evidence Shows Aspirin May Lower Risk for GI Cancers PHILADELPHIA— —Use of two or more 325mg doses of aspirin weekly for 16 years or longer is associated with a modest overall reduction in cancer risk, mainly from fewer gastrointestinal (GI) malignancies, according to two studies that prospectively followed more than 130,000 health care professionals. No protective relationship was observed between aspirin use and breast, lung and advanced prostate cancers.

“The association of aspirin use with reduced cancer risk was similar for women

and men and did not vary by race, history of diabetes, family history of cancer, body mass index, smoking history, or regular use of [nonsteroidal anti-inflammatory drugs] or multivitamins,” reported Yin Cao, ScD, MPH, a research fellow in the Department of Nutrition at the Harvard School of Public Health, in Boston.

Presenting these data at the 2015 annual meeting of the American Association for Cancer Research (AACR; abstract 876), Dr. Cao noted that multiple

case–control studies have previously associated aspirin with a reduction in cancer risk, particularly GI cancers, but the findings of this study are strengthened by the prospective collection of data and the large population sample.

“Previous studies of aspirin and cancer have been limited in terms of their size, length of follow-up or ability to examine aspirin use in the context of other lifestyle factors,” Dr. Cao said.

The current study used data from

82,600 women in the Nurses’ Health Study, established in 1980, and 47,651 men in the Health Professionals Followup Study, initiated in 1986. For both studies, participants have been providing detailed information about a broad range of lifestyle factors and health. Over 32 years of follow-up to date, 27,985 cancer cases were documented.

The overall cancer risk was 5% lower (relative risk [RR], 0.95; 95% confidence interval [CI], 0.93-0.98) in regular users

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37

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

of aspirin, defined as those taking at leaast 325 mg of aspirin twice weekly, compared with less regular users. How-ever, the risk reduction appeared to bee limited to GI cancers, including a 25% % decrease in colorectal cancer (CRC)), a 14% decrease in gastroesophageal cancer and a 20% reduction in GI cancers overall. The risk reduction n became nonsignificant when GI can-cers were excluded (hazard ratio, 0.98; 98; 95% CI, 0.99-1.01). The protection from cancer was no longer evident four years after aspirin use was discontinued.

25% decrease in colorectal l t l cancer

14% decrease in gastroesophageal t h l cancer

20% decrease in GI cancers overall

Although the reduction in cancer risk w aspirin use joins strong evidence of with protection against cardiovascular dispro eaase, aspirin use is also associated with GII bleeding. As a result, a calculation off the benefit-to-risk ratio is likely to vvary for each individual, said Andrew T. Chan, MD, MPH, director of the T Gastroenterology Training Program at Massachusetts General Hospital, in Boston. However, Dr. Chan, who delivered a plenary talk on aspirin chemoprevention at the AACR annual see Aspirin, page 38

Free Colonoscopies Save System Money NYC hospital finds no-cost screening avoids costly cancers New York—Cost is recognized as one of the barriers to screening colonoscopy, the uptake of which hovers at around 65% of the eligible population in the United States. Although it may seem counterintuitive in today’s cost-conscious medical landscape, offering screening colonoscopy free of charge may be a feasible way around this obstacle.

38

Aspirin continued from page 37

meeting and co-authored the latest study, said that the greatest benefit from aspirin for some individuals is likely to be cancer prevention.

These data “strengthen the case for further research into defining subsets of the populations that may obtain preferential benefit from regular aspirin use,” Dr. Chan said. He observed that calculations that take into account genetic susceptibilities to the diseases prevented and complications

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

caused by aspirin are likely to offer the best opportunity to provide clinical benefit.

To that end, a recent study by the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) evaluated use of aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and single-nucleotide polymorphisms (SNPs) related to the risk for CRC to identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention ((JAMA 2015;313:1133-1142). Hongmei Nan,

‘The association of aspirin use with reduced cancer risk was similar for women and men and did not vary by race, history of diabetes, family history of cancer, body mass index, smoking history, or regular use of [nonsteroidal anti-inflammatory drugs] or multivitamins,’ —Yin Cao, ScD, MPH MD, PhD, from the Indiana University Melvin and Bren Simon Cancer Center, in Indianapolis, and her colleagues in the

CCFR and GE ECCO evaluated 8,634 CRC cases and 8,553 matched controls using data from m five case–control and

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39

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

five cohort studies conduccted across the United States, Canada, Australia and Germany in patients of European descent.

The investigators found that compared d with nonregular use, reegular use of aspirin and/or NSAIDs was associated with reduced risk for CRC (38% vs. 28%; P =6.2x10 -28 ).

However, they H ffound some differences in d

risk based on genetic variants. Looking at the SNP rs2965667 located near the MGST1 gene on chromosome 12, they found that individuals with the TT genotype who regularly took aspirin and/or NSAIDs had a lower risk for CRC (28% -33 vs. 38%; P=7.7x10 P ), but those with rare (4%) TA or AA genotypes had a higher risk (35% vs. 29%; P P=0.002). Looking at the SNP rs16973225 located near the IL16 gene on chromosome 15, they found that individuals with AA genotype who took aspirin or NSAIDs regularly had a lower risk for CRC (28% vs. 38%;

P=1.9x10-30), but patients with the less P common (9%) AC or CC genotypes had no reduced CRC risk when taking the drugs (36% vs. 39%; P=0.76).

P A study presented at ASCO 2015 (abstract e12594) found that in patients with a PIK3CA A mutant gene on chromosome 3 seemed to gain enhanced protection against CRC by taking aspirin after diagnosis compared with those with the wild-type gene (HR, 0.71; P P=0.04). An earlier study also had similar findings. (N Engl J Medd 2012;367:1596-1606). In that study, among patients who regularly took

aspirin after their diagnosis, those with mutated-PIK3CA A CRC had improved CRC-specific survival (P<0.001), whereas patients with wild-type PIK3CA did not (P=0.76).

P The precise mechanisms that might associate these variants with CRC risk and aspirin or NSAID use remain unclear. But the CCFR and GECCO investigators suggested that validation of their recent “findings in additional populations may facilitate targeted colorectal cancer prevention strategies.”

—Ted Bosworth and Sarah Tilyou

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

WHO Issues Guidelines for Treating Hepatitis B First-ever document by international body addresses care of roughly 240 million worldwide

T

he World Health Organization (WHO) has issued its first-ever clinical guidelines on the prevention and treatment of chronic hepatitis B. Effective medicines exist for preventing cirrhosis and liver cancer in individuals with chronic hepatitis B infection.

But until the new recommendations, evidence-based guidance for low- and middle-income countries regarding who

should be treated, and how, have been lacking. An estimated 240 million people worldwide are chronically infected with hepatitis B, and there is a need for lowand middle-income countries to scale up prevention, care and treatment of the virus, according to the new guidelines.

“The guidelines are significant for parts of the world where there are no existing national guidelines and where

the regional liver association guidelines, such as AASLD [American Association for the Study of Liver Diseases], APASL [Asian Pacific Association for the Study of the Liver] and EASL [European Association for the Study of the Liver] cannot be applied [because of ] limited resources” in some countries, said Anna Lok, MD, director of clinical hepatology and professor in the Department of

Internal Medicine at the University of Michigan Health Center, in Ann Arbor.

Dr. Lok, who helped develop both the WHO and AASLD guidelines, said that unlike professional society guidelines, which are aimed only at health care providers, the WHO document is written for a broad audience.

In addition to educating clinicians about hepatitis B prevention, screening

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

and treatment, the publication is aimed at helping health departments and governments to set standards and allocate national resources (Table). The guidelines also provide information to nongovernmental organizations that provide financial assistance and infrastructure to support and implement the recommendations.

Dr. Lok said the WHO guidelines do not pertain to the United States. Although the fundamental principles are the same as those in the AASLD guidelines, the two documents contain many differences.

“The WHO guidelines are written

41

Table. Selected WHO Hepatitis B Recommendations Tenofovir and entecavir are the preferred drugs for chronic hepatitis B given their high barrier to drug resistance, limited side effects, generic availability and convenience as oncedaily pills.

The APRI is recommended as the preferred noninvasive test to assess for the presence of cirrhosis in resource-limited settings. Transient elastography (e.g., FibroScan [Sandhill Scientific]) or FibroTest/FibroSure (Biopredictive; LabCorp) may be the preferred noninvasive test in settings where they are available and cost is not a major constraint.

As a priority, all adults, adolescents and children with chronic hepatitis B and clinical evidence of compensated or decompensated cirrhosis (or cirrhosis based on APRI score >2 in adults) should be treated, regardless of alanine aminotransferase levels, hepatitis B e antigen status or HBV DNA levels.

APRI, aspartate aminotransferase-to-platelet ratio index; HBV, hepatitis B virus; WHO, World Health Organization

mainly for low- and low-middle income countries. Thus, there are provisions with how to monitor and treat patients when it is not possible to get HBV [hepatitis B virus] DNA testing, when FibroScan [Sandhill Scientific] is not available to measure liver stiffness, and when there is no pathologist to interpret liver biopsies or no hepatologist to perform the procedure,” Dr. Lok said. “WHO guidelines also cater to persons who live in remote areas, with no physicians and no easy transportation to cities where most physicians are.”

Dr. Lok added that the AASLD is updating its recommendations for hepatitis B and will release the revisions in late 2015.

David E. Kaplan, MD, director of hepatology at the Philadelphia Veterans Affairs Medical Center, called the document “clearly significant.”

The recommendations “have taken into account resource access in both the developing and developed world and have a broader constituency than the AASLD, APASL and EASL guidelines individually have,” Dr. Kaplan noted.

The WHO’s “Guidelines for the Prevention, Care, and Treatment of Persons With Chronic Hepatitis B Infection” can be found at www.who.int/hiv/pub/ hepatitis/hepatitis-b-guidelines/en.

—Kate O’Rourke Dr. Lok has received research grants from Bristol-Myers Squibb and Gilead Sciences and has served on the advisory boards of Gilead and GlaxoSmithKline. Dr. Kaplan reported no relevant financial conflicts of interest.

42

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Military Deployment Linked to Lower Rates of Crohn’s Disease

T

he stress of an overseas military deployment does not appear to raise a soldier’s risk for Crohn’s disease, researchers have found.

Indeed, a retrospective database study of nearly 2,000 U.S. military personnel has found lower rates of Crohn’s disease among those deployed abroad. The researchers, who presented their results at the 2014 Advances in Inflammatory Bowel Diseases, Crohn’s and Colitis Foundation conference (poster 046), said they were surprised to find that military personnel who stayed stateside were almost 50% more likely to develop Crohn’s than were soldiers sent overseas.

“We were expecting to find higher rates of Crohn’s disease because deployed individuals are exposed to potential infectious diseases of the gut and other systems as well as physical and emotional stressors, which prior studies have linked to inflammatory bowel disease,” said Capt. Noah Hall, MD, a gastroenterology fellow at Walter Reed National Military Medical Center, in Washington, D.C. (Gastroenterology 2008;135:781-786).

Dr. Hall and his team used U.S. military electronic health records to identify roughly 1,000 active duty personnel who had served between 1996 and 2012 and were

disease were 49% less likely than matched controls to have been deployed before the index date (P<0.0001).

The greatest disparity in deployment rates was found among individuals sent to Afghanistan, Dr. Hall’s team found, where Crohn’s patients were 66% less Military personnel likely than controls to have been deployed who stayed stateside before the index date of their diagnosis (P<0.0001). were almost Although the findings demonstrate a possible correlation, Dr. Hall said there is more likely to at least one bias that the study’s methodology could not account for. develop Crohn’s “It’s possible that service members disease who went on to develop Crohn’s disease may have displayed early subclinical diagnosed with Crohn’s at least one year after beginning symptoms that prevented them from meeting predeactive duty. The researchers compared their deployment ployment physical and health standards,” Dr. Hall said. history before an index date when they were diagnosed Ashwin Ananthakrishnan, MBBS, MPH, an instrucwith the bowel disorder to the same number of active duty tor at Harvard Medical School and faculty in the gastropersonnel matched according to age, sex and military ser- intestinal unit at Massachusetts General Hospital, both in vice who had not been diagnosed with the illness at that Boston, and an expert in the epidemiology of inflammatime. Individuals were a mean 29 years of age on the index tory bowel disease (IBD), said the findings were “interestdate; 82% were men and most were white. ing and novel and the [researchers] are to be congratulated The researchers found that, after controlling for on the development of a powerful data set.” the matching variables, those diagnosed with Crohn’s see Deploy, page 48

50%

Study Sheds Light on ‘Ominous s’ Effect Of C. difficile in IBD Patients s Table. Predictors of Recurrent CDI Among IBD Patients

P

atients with inflammatory bowel disease who become infected with Clostridium difficilee appear to be at increased risk for recurrent infections, researchers have found.

Patients with IBD were more than 30% more likely than those without the condition to suffer recurrent C. difficile infections (CDIs), according to new data presented at Canadian Digestive Diseases Week 2015 (abstract 144). The study, which included more than 100 patients with both IBD and C. difficile, as well as nearly 400 patients without bowel disease, also found that many IBD treatments are associated with an increased risk for recurrent infections.

“This is a very important study that provides data on the very ominous clinical trajectory in IBD patients with C. difficilee infection,” said David Binion MD, co-director of the University of Pittsburgh Medical Center’s Inflammatory Bowel Disease Center, who was not involved in the research.

Patients with IBD are known to be more likely to develop CDIs than those without IBD (Curr Gastroenterol Rep 2014;16:393). “Although several studies have identified risk factors for recurrent C. difficilee in the general population, no one has really looked at recurrent infections in the IBD population,” said

Roshan Razik, MD, chief residen nt in gastroenterology at Mount Sinai Hospital and the University of Toronto, booth in Toronto, Ontario, Canada, who led the latest work.

To fill this gap in the medical literature, Dr. Razik and his colleagues retroospectively analyzed medical records from 54 patients with Crohn’s disease, 56 pattients with ulcerative colitis and 393 pattients with no bowel disease. All patientss had been treated for C. difficilee at Mount Sinai Hospital between 2010 and 2013.

According to Dr. Razik, recurrence was greater among patients with IBD, 32% of whom (35 of 110) experienced at least two. In contrast, 24% (94 of 393) of patients without IBD experienced recurrent infections (P<0.01).

The analysis also found that 6.4% of patients with IBD and CDI required colectomy during the course of their infection compared with 0.3% of patients with IBD who did not have the pathogen (P<0.001).

Dr. Razik’s team identified several risk factors significantly associated with recurrent C. difficile, including use of antibiotics, 5-aminosalicylic acid, corticosteroids and immunosuppressive medications.

Patients without prior bowel resections, and patients with Crohn’s disease and non-ileal disease, also had an increased risk (P<0.01 for all; Table).

Odds Ratio (95% Confidence Interval) Non-ileal Crohn’s disease

2.59 (1.66-4.05)

Recent antibiotic therapy

2.60 (1.55-4.35)

5-ASA use

3.06 (1.78-5.29)

Steroid use

2.94 (1.70-5.10)

Immunosuppression

2.50 (1.45-4.31)

Recent hospitalization

2.62 (1.64-4.20)

No previous bowel resections

1.72 (1.09-2.72)

ASA, aminosalicylic acid, CDI, Clostridium difficile infection; IBD, inflammatory bowel disease P≤0.001 for all except P=0.020 for history of bowel resection

As in the non-IBD population, recent hospitalization among patients with IBD was associated with an increased risk for recurrent C. difficile, Dr. Razik’s team found. However, the rate of recent hospitalization was lower among patients with IBD. “Roughly 40% of the non-IBD patients with C. difficilee infections in our study were recently hospitalized, compared with only 20% of IBD patients, which indicates the IBD population tends to acquire their infection in the outpatient setting,” he noted.

As for the clinical implications of their findings, Dr. Razik said, “the question of what clinicians can do to reduce the risk

of C. difficilee is a big one.

“The next step in this line of research would be to look at other potential risk factors, such as comorbid illnesses and lab values, and build a model or scoring system that would allow clinicians to reliably predict which patients may have worse outcomes,” he said.

Dr. Binion said future studies also should explore the effectiveness of targeted antibiotic use and restoration of the dysbiotic gastrointestinal microbiome in preventing recurrent infections in the IBD patient population.

—David Wild Drs. Razik and Binion reported no relevant financial conflicts of interest.

Albert Einstein used with permission of the HUJ/GreenLight.

INDICATION HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.

Please see Brief Summary of full Prescribing Information adjacent to this ad.

HARVONI is the only HCV treatment offering an 8-week course of therapy1 % SVR12 among treatment-naïve HCV GT 1 subjects without cirrhosis who had baseline HCV RNA <6 million IU/mL1

100 90 Percent (%) Subjects

80

97%

70 60 50 40 30 20 10 0

n=119/123

HARVONI 8 weeks ION-3

• Overall SVR12 was 94% (n=202/215) in subjects receiving HARVONI for 8 weeks1,a • In treatment-naïve subjects taking HARVONI for 12 weeks, 96% (n=208/216) achieved SVR12 in the ION-3 trial and 99% (n=210/213) achieved SVR12 in the ION-1 trial1,a • The recommended treatment duration for treatment-naïve patients is 12 weeks1 • HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL1 Study Designs ION-11: a randomized, open-label trial evaluating HARVONI with or without ribavirin (RBV) in GT 1 treatment-naïve subjects (N=865) with or without cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + RBV for 12 weeks, HARVONI for 24 weeks, or HARVONI + RBV for 24 weeks, and stratifi fied by presence or absence of cirrhosis and HCV genotype (1a vs 1b).

ION-31: a randomized, open-label trial in GT 1 treatment-naïve subjects (N=647) without cirrhosis. Subjects were randomized in a 1:1:1 ratio to receive HARVONI for 8 weeks, HARVONI + RBV for 8 weeks, or HARVONI for 12 weeks, and stratified fi by HCV genotype (1a vs 1b). a SVR12 was the primary endpoint and was defined fi as HCV RNA <25 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR is considered a virologic cure.2 RBV was not shown to increase the response rates observed with HARVONI in ION-1 or ION-3. Therefore, the HARVONI + RBV arms are not presented.1

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS • Risk of Serious Symptomatic Bradycardia when Coadministered with Amiodarone: Amiodarone is not recommended for use with HARVONI due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

• Risk of Reduced Therapeutic Eff ffect of HARVONI Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with HARVONI as they may signifi ficantly decrease ledipasvir and sofosbuvir plasma concentrations.

• Related Products Not Recommended: HARVONI is not recommended for use with other products containing sofosbuvir (SOVALDI®).

HARVONI is the only once-daily single-tablet regimen for HCV GT 1 patients1

Recommended treatment duration1

1

HARVONI TABLET ONCE DAILY WITH OR WITHOUT FOOD

Can be considered in treatmentnaïve patients without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL

8

weeks

Treatment-naïve patients with or without cirrhosis

Treatment-experienced patientsb without cirrhosis

12

weeks

12

weeks

Treatment-experienced patientsb with cirrhosis

24

weeks

Treatment-experienced patients who failed treatment with either peginterferon (Peg-IFN) alfa + ribavirin (RBV) or an HCV protease inhibitor + Peg-IFN + RBV.1

b

• HARVONI is interferon- and RBV-free for GT 1 treatment-naïve and treatment-experienced patients with or without cirrhosis, regardless of GT 1a or 1b subtype1 • Each HARVONI tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir1 • Relapse rates are aff ffected by baseline host and viral factors and diff ffer between treatment 1 durations for certain subgroups • No dose adjustments are required based on advanced age, mild or moderate renal impairment, or mild, moderate, or severe hepatic impairment. The safety and effi fficacy of HARVONI have 1 not been established in patients with decompensated cirrhosis • No dose recommendations can be given for patients with severe renal impairment (estimated glomerular fi filtration rate [eGFR] <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite1

IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS Most common (≥10%, all grades) adverse reactions were fatigue and headache.

DRUG INTERACTIONS • In addition to rifampin and St. John’s wort, coadministration of HARVONI is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect ff of HARVONI. • Coadministration of HARVONI is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for HARVONI for more information on potentially significant fi drug interactions, including clinical comments.

Please see Brief Summary of full Prescribing Information on the following pages.

Visit harvoni.com/hcp

HARVONI® (ledipasvir 90 mg and sofosbuvir 400 mg) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only.

INDICATIONS AND USAGE: HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.

CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with HARVONI. Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with HARVONI is not recommended. For patients taking amiodarone who will be coadministered HARVONI and patients taking HARVONI who need to start amiodarone, who have no other alternative, viable treatment options; and due to amiodarone’s long half-life for patients discontinuing amiodarone just prior to starting HARVONI: Counsel patients about the risk of serious symptomatic bradycardia; and cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately.

Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems.

Risk of Reduced Therapeutic Effect Due to P-gp Inducers: Concomitant use may significantly decrease ledipasvir and sofosbuvir concentrations and may lead to a reduced HARVONI effect. Use of HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended.

Related Products Not Recommended: Use of HARVONI with products containing sofosbuvir (SOVALDI®) is not recommended.

ADVERSE REACTIONS: The safety assessment of HARVONI was based on pooled data from three Phase 3 clinical trials in subjects with genotype 1 CHC with compensated liver disease (with and without cirrhosis) who received HARVONI for 8 (N=215), 12 (N=539) and 24 (N=326) weeks. Adverse events led to permanent treatment discontinuation in 0%, <1% and 1% of subjects receiving HARVONI for 8, 12 and 24 weeks, respectively.

Adverse Reactions (adverse events assessed as causally related by the investigator): The most common adverse reactions (≥10%; all grades) were fatigue and headache. Adverse reactions (all grades; majority Grade 1) observed in ≥5% of subjects by treatment duration were:

• HARVONI for 8 weeks: fatigue (16%); headache (11%); nausea (6%); diarrhea (4%); and insomnia (3%) • HARVONI for 12 weeks: fatigue (13%); headache (14%); nausea (7%); diarrhea (3%); and insomnia (5%) • HARVONI for 24 weeks: fatigue (18%); headache (17%); nausea (9%); diarrhea (7%); and insomnia (6%) Direct comparison across trials should not be made due to differing trial designs.

Laboratory Abnormalities: Bilirubin Elevations: Bilirubin elevations of greater than 1.5x ULN were observed in 3%, <1% and 2% of subjects treated with HARVONI for 8, 12 and 24 weeks, respectively. Lipase p Elevations: Transient, asymptomatic lipase elevations of greater than 3x ULN were observed in <1%, 2% and 3% of subjects treated with HARVONI for 8, 12 and 24 weeks, respectively. Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials of HARVONI. Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials.

Postmarketing Experience Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with HARVONI during post approval use of HARVONI. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

DRUG INTERACTIONS: Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters.

Ledipasvir and sofosbuvir are substrates of P-gp and BCRP while the inactive sofosbuvir metabolite GS-331007 is not. P-gp inducers (e.g. rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect; use of HARVONI with P-gp inducers is not recommended.

Established and Potentially Significant Drug Interactions: The drug interactions described are based on studies conducted in healthy adults with either HARVONI, the components of HARVONI as individual agents, or are predicted drug interactions that may occur with HARVONI. This list includes potentially significant interactions but is not all inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with HARVONI: • Acid Reducing Agents: Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease ledipasvir concentration.

• Antacids: Separate HARVONI and antacid administration by 4 hours.

• H2-receptor antagonists: Doses comparable to famotidine 40 mg twice daily or lower may be administered simultaneously with or 12 hours apart from HARVONI. • Proton-pump inhibitors: Doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions.

Brief Summary (cont.)

USE IN SPECIFIC POPULATIONS:

• Antiarrhythmics (amiodarone; digoxin) Amiodarone: Coadministration of amiodarone with HARVONI may result in serious symptomatic bradycardia and is not recommended.

Mechanism of effect is unknown. If coadministration is required, cardiac monitoring is recommended. Digoxin: Increased digoxin concentration. Monitor digoxin therapeutic concentration during coadministration with HARVONI.

Pregnancy: HARVONI is Pregnancy Category B; there are no adequate and well-controlled studies in pregnant women.

HARVONI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Anticonvulsants (carbamazepine; phenytoin; phenobarbital; oxcarbazepine): Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect.

Coadministration is not recommended.

• Antimycobacterials (rifabutin; rifampin; rifapentine): Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended.

• HIV Antiretrovirals • Regimens containing tenofovir disoproxil fumarate (DF) and an HIV protease inhibitor/ritonavir (emtricitabine/tenofovir DF plus atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ ritonavir): The safety of increased tenofovir concentrations has not been established. Consider alternative HCV or antiretroviral therapy. If coadministration is necessary, monitor for tenofovirassociated adverse reactions. Refer to VIREAD or TRUVADA prescribing information for renal monitoring recommendations.

• Efavirenz/emtricitabine/tenofovir DF: Monitor for tenofovirassociated adverse reactions. Refer to VIREAD, TRUVADA or ATRIPLA prescribing information for renal monitoring recommendations.

• Elvitegravir/cobicistat/emtricitabine/tenofovir DF: The safety of increased tenofovir concentrations has not been established.

Coadministration is not recommended.

• Tipranavir/ritonavir: Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended.

Nursing Mothers: Studies in rats have demonstrated that ledipasvir and GS-331007 are secreted in milk but had no effect on nursing pups. It is not known if HARVONI and its metabolites are secreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HARVONI and any potential adverse effects on the nursing child from the drug or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of HARVONI have not been established in pediatric patients.

Geriatric Use: Clinical trials of HARVONI included 117 subjects aged 65 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. No dosage adjustment of HARVONI is warranted in geriatric patients.

Renal Impairment: No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD. Hepatic Impairment: No dosage adjustment of HARVONI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis.

• HCV Products (simeprevir): Increased ledipasvir and simeprevir concentrations. Coadministration is not recommended.

• Herbal Supplements (St. John’s wort): Decreased ledipasvir and sofosbuvir concentrations. Coadministration is not recommended.

• HMG-CoA Reductase Inhibitors (rosuvastatin): Significant increase in rosuvastatin concentrations and risk of rosuvastatin associated myopathy, including rhabdomyolysis. Coadministration is not recommended.

Drugs without Clinically Significant Interactions with HARVONI: Based on drug interaction studies conducted with HARVONI or its components, no clinically significant drug interactions have been observed or are expected when used with the following drugs individually: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir DF or verapamil.

Consult the full Prescribing Information prior to and during treatment with HARVONI for potential drug interactions; this list is not all inclusive.

References: 1. HARVONI US full Prescribing Information.

Gilead Sciences, Inc. Foster City, CA. March 2015.

2. US Department of Health and Human Services, Center for Drug Evaluation and Research. Draft Guidance for Industry.

Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. October 2013.

HARVONI, the HARVONI logo, SOVALDI, TRUVADA, VIREAD, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. ©2015 Gilead Sciences, Inc. All rights reserved. HVNP0241 04/15

48

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Inhibition of COX/EGFR Keeps FAP in Check WASHINGTON—A two-pronged strategy that blocks both a key inflammatory compound and a receptor associated with growth of tumor cells appears to markedly reduce the risk for duodenal cancers in patients with a form of inherited colorectal cancer.

Six months of treatment that inhibits cyclooxygenase (COX) and epidermal growth factor receptor (EGFR) can significantly reduce duodenal neoplasia in patients with familial

{ AAAHC

adenomatous polyposis (FAP), Utah researchers have found. The drugs used in the study already are approved for other conditions.

“Ours is the first study to show a significant chemopreventive effect in FAP patients, for a major cause of morbidity and mortality,” said N. Jewel Samadder, MD, of the Huntsman Cancer Institute, in Salt Lake City, who led the study. “We showed a reduction in duodenal polyp burden and number in patients with FAP,

and the effect was evident after only six months of therapy.” Dr. Samadder’s group reported the findings at Digestive Disease Week 2015 (abstract 447).

The standard of care for FAP is colectomy. However, even after surgery, FAP patients are left with a major cause of morbidity and mortality from the development of duodenal carcinomas. Duodenal adenomas form in more than 50% of FAP patients, creating a lifetime risk for duodenal carcinoma of approximately

Total duodenal polyp count fell

20% with the combination treatment

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12%. Management options are suboptimal, including endoscopic surveillance and duodenectomy as well as the morbidity associated with Whipple procedures, Dr. Samadder said.

Preclinical data have suggested there is a synergistic chemopreventive effect when the COX inhibitor sulindac (Clinoril, Merck) is combined with an EGFR inhibitor. This combination was shown to diminish the development of small intestinal adenomas in mice with germline APC C mutations, the anomalies associated with FAP. “These results led us to test the hypothesis that a combination of COX and EGFR inhibition—sulindac and erlotinib [Tarceva, Genentech/Astellas]—would inhibit duodenal adenoma formation in patients with FAP,” Dr. Samadder said.

Study Details Patients in the randomized, doubleblind trial received combination therapy with 150 mg of sulindac twice daily and

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However, he said there are several limitations that weaken the conclusions.

“There is no information on a number of important risk factors, such as family history of inflammatory bowel disease, smoking history and other potential confounding variables,” said Dr. Ananthakrishnan, who was not involved in the research.

“Several factors, including enteric infections and the stress and anxiety of combat, may increase the risk for IBD, but others, like helminthic infections, for example, may reduce the risk,”

49

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

erlotinib—an EGFR inhibitor approved for non-small cell lung cancer—75 mg daily or placebo for six months. The total number and size of polyps in a segment of duodenum between 0 and 10 cm from the bulb were mapped at baseline and six months. The primary outcome was change in total polyp burden, calculated as the sum of the diameters of the polyps.

The investigators had randomized 92 patients when the study was stopped after the second interim analysis, when the results met the statistical guidelines for an early halt.

The study was completed by 73 patients (mean age, 42 years), of whom 37 received sulindac and erlotinib. Demographic characteristics of the treatment and placebo groups were comparable; in the combined treatment group, baseline sum diameter was 19 for the sulindac and erlotinib group and 22 for the placebo arm, a difference that was not significant.

Total duodenal polyp burden six months after starting treatment was significantly less in the sulindac and erlotinib arm than in the placebo arm. In fact, total polyp burden diminished by 9 mm with the combination treatment, but increased by 6 mm with placebo, a highly significant difference (P<0.000000002).

The total duodenal polyp count fell 20% from baseline for patients who received active therapy and rose 10% for patients who received placebo (P<0.0001), the researchers reported.

“Nearly all treated patients have a decrease in polyp burden at six months, but almost all placebo patients have an increase,” Dr. Samadder said. “The treatment was efficacious in both FAP and attenuated FAP patients, including those with a wide range in polyp numbers,” he added.

Dr. Ananthakrishnan said (Inflamm Bowel Dis 2013;19:614-620).

Dr. Hall said a joint study by the U.S. Department of Defense and Johns Hopkins University, in Baltimore, that is currently underway might shed light on the precise effect of exposure to a variety of infections.

“The study is using serum samples from service members to look at exposure to specific viral or bacterial pathogens and to identify possible infectious triggers of Crohn’s disease,” he said.

—David Wild Drs. Hall and Ananthakrishnan reported no relevant financial conflicts of interest.

Side effects were all more common with the combination treatment, including acneiform rash (95% vs. 22%), oral mucositis (40% vs. 11%), diarrhea (30% vs. 11%) and nausea (30% vs. 8%), but none exceeded grade 2 on a 5-point toxicity scale.

Cancer patients who take erlotinib frequently develop acneiform rash, but this adverse event usually is more severe than what the Utah researchers observed, Dr. Samadder said. For FAP prevention, he used less than half the dose of erlotinib given to cancer patients. “So the rash is

milder than we see in cancer patients, and it’s almost always treatable with topical clindamycin,” he said.

Andrew Chan, MD, associate professor of medicine at Harvard Medical School, and director of the Gastroenterology Training Program at Massachusetts General Hospital, both in Boston, called the latest study proof of the concept “that you can use a combination approach to ameliorate this difficult problem in patients with FAP.” However, the problem going forward will be the “translation of the research,”

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added Dr. Chan, who has led seminal research in the role of aspirin in preventing colorectal adenomas and colon cancer (see story, page 42). “Are these the kind of agents that people will want to take longterm? In treatment, we use such drugs for a more limited time. For prevention, whether people can take them over the long term remains to be seen.”

—Caroline Helwick Dr. Samadder has received fees for consulting, speaking and teaching for Cook Medical and Covidien Medical. Dr. Chan has consulted for Bayer Healthcare, Pfizer Inc., and Pozen Inc.

50

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Better Bowel Prep Is a Click Away BANFF, ALBERTA, CANADA—Walking — patients through the preparation for a colonoscopy may be a tedious process, but it could become much easier if programs like one that Canadian gastroenterologists have developed gain traction.

The Web-based instructional program resulted in a significant increase in excellent preparations compared with traditional paper-based instructions, a new study has found.

“In our experience, giving patients directions for bowel preparation in advance of colonoscopy is a very repetitious process,” said Robert Enns, MD, clinical professor of medicine at the University of British Columbia, in Vancouver. “In particular, we had one coordinator who found that giving the same talk over and over again required a great deal of time and labor.”

To help address this issue, Dr. Enns and his colleagues created a Webbased instructional tool to educate their patients, then enrolled 160 patients into the prospective, observational trial. The patients, aged 19 years and older, and undergoing planned outpatient colonoscopy, were randomized to receive traditional paper-based instructions or were directed to the Web tool.

“The patient agrees to have an email with a domain link sent to them,” Dr. Enns told Gastroenterology & Endoscopy News. “Although the site contains generalized instructions that emphasize how to do the preparation and why it’s important, the last two pages have specific, printable instructions customized for each patient.”

After two endoscopists rated the quality of each preparation using the

Boston Bowel Preparation Scale, it was found that significantly more patients in the Web group achieved an excellent score (≥7) than did those in the paper group (50 vs. 30; P=0.04). What’s more, patients in the Web group had 50% fewer inadequate bowel preparations than did their counterparts in the paper group (five vs. 11; P=0.17).

Nearly all patients (95%) who received their instructions through the website found them very helpful, according to the researchers.

Yet the most important benefit, Dr. Enns explained, is clinical. “You can’t find polyps if you can’t see them. So the better the instructions, the better they’re understood, the better the preparation, the cleaner the colon, the more polyps you find, and the more cancer you prevent,” he said. “So, it may sound silly, but in improving the understanding, we believe that in the end it benefits the patient more than anyone else.”

Implementing programs such as this one is feasible at other institutions,

‘It may sound silly, but in improving the understanding, we believe that in the end it benefits the patient more than anyone else.’

—Robert Enns, MD The Web-based approach has several advantages over printed information, according to Dr. Enns. It decreases labor, freeing up staff time for other responsibilities. There’s no risk that the patients will lose the instructions, which themselves contain more information than their printed form. The Web instructions are also interactive: A feedback loop encourages understanding by the patient, further ensuring they will be read and understood.

although Dr. Enns pointed out the importance of maintaining patient confidentiality. “As you can imagine, hackers and viruses are a significant concern,” he said. “So the programming has been developed at an extremely high level.”

Equally important is the fact that the website is not associated with industry, which gives providers the autonomy to make unfettered decisions regarding their patients’ care.

Study Seeks Answers to Growth Mystery In Kids With Crohn’s esearchers have long known that many children with Crohn’s disease experience delayed growth.

Paradoxically, although girls with the condition generally suffer a more severe course of illness, boys experience more growth impairment.

“Findings from our earlier studies, including an observed increased risk for surgery in females with pediatric Crohn’s disease, suggest a more severe disease course in females. In sharp contrast to this finding, males had more growth failure. It doesn’t make sense— we would expect more severe disease to lead to more growth failure,” said Neera Gupta, MD, MAS, a pediatric gastroenterologist at Weill Cornell Medical College and the NewYork-Presbyterian Phyllis and David Komansky Center for Children’s Health, both in New York City.

To help answer this question, Dr. Gupta has received more than $3 million from the National Institutes of Health’s National Institute of Child Health and Human Development to fund the study, “Sex Differences in

R

Statural Growth Impairment in Pediatric Crohn’s Disease” (also called the “Growth Study”).

“The male-female dichotomy in risk for growth impairment in Crohn’s disease is a window for understanding the effects of inflammation on growth in both sexes,” Dr. Gupta said.

Two other centers, Goryeb Children’s Hospital, in Morristown, N.J., and the University of North Carolina at Chapel Hill, will be enrolling patients. Columbia University, in New York City, and the University of California, San Francisco, also are participating in the research.

Dr. Gupta and her colleagues hope to gather data on 125 boys and girls with Crohn’s disease, following them for two years starting from the time they join the study.

Boys aged 9 to 15 years and girls aged 8 to 13 are

“The program does not favor one preparation over another,” Dr. Enns noted.

“That puts its strength in the physicians’ hands to use the prep they think is best without going to a company.”

To help validate these results, the researchers are currently conducting a randomized controlled trial comparing the standard of care—printed sheets of paper—with online instruction.

Robert J. Hilsden, MD, PhD, associate professor of medicine at the University of Calgary, in Alberta, agreed that Web-based programs have distinct advantages over conventional prep instruction. “The other problem we run into is if you have different people involved, they may be giving different information to different patients,” Dr. Hilsden said. “Having a standardized process that provides the right information is important, especially in the best format for people to learn.”

Offering the right format for each patient is the key to optimizing preparation. “A potential drawback to the website approach would be if you have a person who that’s not the right thing for,” Dr. Hilsden added. “If you don’t have any other options, that could be a problem.”

Other approaches for colonoscopy preparation have included smartphone apps and large-group presentations, both of which address the issues of repetition and standardization.

The investigators reported no relevant financial relationships with regard to the study, which they reported at Canadian Digestive Diseases Week 2015 (abstract A39).

—Michael Vlessides

eligible for a screening visit to determine their bone age through an x-ray of the left hand.

The researchers will obtain sequential boneage studies, measurements of biomarkers in blood and nutritional assessments to better understand how children with Crohn’s grow over time.

“We will develop a predictive model, separately for boys and girls, to identify children and adolescents at highest risk for growth impairment refractory to standard approaches to therapy,” Dr. Gupta said. “Our next step will be an interventional clinical trial in children at greatest risk for remaining growth-impaired. The findings of this current study will significantly improve our understanding of growth impairment in Crohn’s disease.

Our goal is to improve the care we provide to our patients.”

Clinicians seeking to enroll patients in the Growth Study should contact Rafael Aguilar, research coordinator, at (646) 962-4968 or raa2030@med.cornell. edu, or Dr. Gupta at (646) 962-3869.

—GEN Staff

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To be sure of your diagnosis AND confirm treatment success, choose BreathTek UBT • Antibiotic resistance is approaching 25%, increasing the need for eradication confirmation1-3 • ACG* calls the UBT method “the most reliable nonendoscopic test…“ to confirm H. pylori eradication4 • BreathTek UBT offers excellent sensitivity (96%) and specificity (96%) to confirm eradication in adult patients5 • False negative test results may be caused by: − Ingestion of proton pump inhibitors (PPIs) within 2 weeks prior to performing the BreathTek UBT. If a negative result is obtained from a patient ingesting a PPI within 2 weeks prior to the BreathTek UBT, it may be a false-negative result and the test should be repeated 2 weeks after discontinuing the PPI treatment. A positive result for a patient on a PPI could be considered positive and be acted upon − Ingestion of antimicrobials or bismuth preparations within 2 weeks prior to performing the BreathTek UBT − Premature POST-DOSE breath collection time for a patient with a marginally positive BreathTek UBT result − Post-treatment assessment with the BreathTek UBT less than 4 weeks after completion of treatment for the eradication of H. pylori • False positive test results may be caused by urease associated with other gastric spiral organisms observed in humans, such as Helicobacter heilmannii or achlorhydria.

H. pylori can’t hide from BreathTek UBT… Approved as an aid for the detection and post-treatment monitoring of H. pylori infection in adults and children ages 3 to 17 years Please see BRIEF SUMMARY on adjacent page or visit BreathTek.com.

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May 2015

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Are PPIs Enough? Controlling Acid After Ablation of Barrett’s Esophagus

P

ersistent gastroesophageal reflux after eradication of Barrett’s esophagus (BE) is thought to be among the most important risk factors for recurrence of the abnormal cells.

But with data effectively mute on an optimal method to suppress gastric acid after procedures such as radiofrequency ablation (RFA) or endoscopic mucosal

resection (EMR), experts tend to rely on an empirical approach at the time of follow-up surveillance.

Most experts advocate tight acid control with proton pump inhibitors (PPIs) after ablation, but there is no guidelinedetermined standard in regard to dose or regimen.

“If the endoscopy shows erosive disease

or the biopsies show lots of inflammation, we intensify therapy,” explained Nicholas Shaheen, MD, chief of the Division of Gastroenterology & Hepatology at the University of North Carolina School of Medicine, in Chapel Hill. Although intensifying therapy means improving acid control, Dr. Shaheen reported, “I do not routinely monitor pH.”

Brief Summary about BreathTek UBT Intended Use The BreathTek® UBT for H. pylorii Kit (BreathTek UBT Kit) is intended for use in the qualitative detection of urease associated with H. pylorii in the human stomach and is indicated as an aid in the initial diagnosis and post-treatment monitoring of H. pylori infection in adult patients and pediatric patients 3 to 17 years old. The test may be used for monitoring treatment if used at least 4 weeks following completion of therapy. For these purposes, the system utilizes an Infrared Spectrophotometer for the measurement of the ratio of 13CO2 to 12CO2 in breath samples, in clinical laboratories or point-of-care settings. The Pediatric Urea Hydrolysis Rate Calculation Application (pUHR-CA), provided as a web-based calculation program, is required to obtain pediatric test results.

The BreathTek UBT Kit is for administration by a health care professional, as ordered by a licensed health care practitioner.

Warnings and Precautions • For in vitro diagnostic use only. The Pranactin®-Citric solution is taken orally as part of the diagnostic procedure and contains Phenylalanine (one of the protein components of Aspartame), 84 mg per dosage unit, and should be used with caution in diabetic patients. (For reference, 12 ounces of typical diet cola soft drinks contain approximately 80 mg of Phenylalanine.)

• A negative result does not rule out the possibility of H. pylorii infection. False negative results do occur with this procedure.

If clinical signs are suggestive of H. pylorii infection, retest with a new sample or an alternate method.

• False negative test results may be caused by: — Ingestion of proton pump inhibitors (PPIs) within 2 weeks prior to performing the BreathTek UBT. If a negative result is obtained from a patient ingesting a PPI within 2 weeks prior to the BreathTek UBT, it may be a false-negative result and the test should be repeated 2 weeks after discontinuing the PPI treatment. A positive result for a patient on a PPI could be considered positive and be acted upon.

— Ingestion of antimicrobials, or bismuth preparations within 2 weeks prior to performing the BreathTek UBT — Premature POST-DOSE breath collection time for a patient with a marginally positive BreathTek UBT result — Post-treatment assessment with the BreathTek UBT less than 4 weeks after completion of treatment for the eradication of H. pylori.

• False positive test results may be caused by urease associated with other gastric spiral organisms observed in humans such as Helicobacter heilmanniii or achlorhydria.

• If particulate matter is visible in the reconstituted Pranactin-Citric solution after thorough mixing, the solution should not be used.

• Patients who are hypersensitive to mannitol, citric acid or Aspartame should avoid taking the drug solution as this drug solution contains these ingredients. Use with caution in patients with difficulty swallowing or who may be at high risk of aspiration due to medical or physical conditions.

• No information is available on use of the Pranactin-Citric solution during pregnancy.

• For pediatric test results, the Urea Hydrolysis Rate (UHR) results must be calculated. The Delta over Baseline (DOB) results are only used to calculate the UHR metrics to determine H. pylorii infection in pediatric patients. DOB results cannot be used to determine the infection status of pediatric patients. Use the web-based pUHR-CA (https://BreathTekKids.com) to calculate the UHR. • Safety and effectiveness has not been established in children below the age of 3 years.

Adverse Events During post-approval use of the BreathTek UBT in adults, the following adverse events have been identified: anaphylactic reaction, hypersensitivity, rash, burning sensation in the stomach, tingling in the skin, vomiting and diarrhea. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.

In two clinical studies conducted in 176 (analyzed) pediatric patients ages 3 to 17 years to determine the initial diagnosis and post treatment monitoring of H. pylori, the following adverse events experienced by ≥1% of these patients were: vomiting (5.1%), oropharyngeal pain (4.5% to include throat irritation, sore throat, throat burning), nausea (2.3%), restlessness (2.3%), stomach ache/belly pain (1.1%), and diarrhea (1.1%). Most of the adverse events were experienced by patients within minutes to hours of ingestion of the Pranactin-Citric solution.

In another clinical study comparing the UBiT®-IR300 and POCone® in pediatric patients ages 3 to 17 years, the following adverse events were observed among the 99 subjects enrolled: 2 incidences of headache, and 1 incidence each of cough, dry mouth and acute upper respiratory infection.

References: 1. Vakil N, Megraud F. Eradication therapy for Helicobacter pylori. Gastroenterology. 2007;133(3):985-1001. 2. Vakil N, Fendrick AM. How to test for Helicobacter pylori in 2005. Cleve Clin J Med. 2005;72(suppl 2):S8-S13. 3. Chu Y-T, Wang Y-H, Wu J-J, Lei H-Y. Invasion and multiplication of Helicobacter pylori in gastric epithelial cells and implications for antibiotic resistance. Infect Immun. 2010;78(10):4157-4165. 4. Chey WD, Wong BCY; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102(8):1808-1825. 5. Package Insert for BreathTek UBT. Otsuka America Pharmaceutical, Inc; 2014.

©2015 Otsuka America Pharmaceutical, Inc.

Mayy 2014

May 2015

05US14EBP1200

05US15EBP0026

‘Most of my post-RFA patients are on PPIs twice daily, and serious troubles with inadequate acid control have been rare. I have had a halfdozen or so cases in which we employed antireflux surgery to either allow completion of ablation or to maintain the ablated area free of inflammation, but this has been rare in my practice.’

—Nicholas Shaheen, MD

After RFA, “I usually offer double-dose PPIs to reduce acid exposure in the esophagus,” said Prateek Sharma, MD, professor of gastroenterology at the University of Kansas Medical Center, in Kansas City.

Although he is aggressive with medical management, Dr. Sharma does not routinely conduct pH monitoring or otherwise objectively confirm acid control.

“If there is evidence of continued patient symptoms or presence of erosions in the esophagus on repeated endoscopy, I will increase the dose of PPI further,” Dr. Sharma said. However, he added, continued exposure to acid may be one of the major risk factors making it difficult to eradicate or stop recurrence of disease after successful therapy.

Strong Rationale, Weak Support Acid control is considered essential after eradication of BE because gastroesophageal reflux disease (GERD) is implicated in the primary injury that drives BE. The ability of PPI therapy to reduce the risk for dysplasia and neoplastic progression has been suggested by a large cohort study (Clin Gastroenterol Hepatoll 2013;11:382-388). Still, no level 1 evidence from a randomized prospective trial supports this benefit either in BE patients managed initially with PPIs or to protect against recurrent BE following eradication.

Small studies, such as one that followed 39 patients (Endoscopyy 2002;34:950-955), have associated normalization of pH with

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Barrett’s epithelium (Gastroenterologyy 2013;145:79-86). Nearly 20% of these recurrences included dysplasia.

The authors were unable to identify any endoscopic or demographic predictors of recurrent intestinal metaplasia but did not have data on relative acid control over the course of follow-up.

Due to the risk for recurrence, organizations such as the American Society for Gastrointestinal Endoscopy recommend surveillance after ablation or resection, but that group and others have acknowledged that the optimal surveillance

interval has not been identified. More frequent surveillance intervals are common in the first two to three years after eradication, particularly for those with high-grade dysplasia, followed by longer intervals in patients who remain recurrence-free in this initial period.

Based on the premise that injury to the mucosa from acid or another noxious agent initiates BE (Ther Clin Risk Managg 2007;3:1035-1045), eradication of BE could be curative if the mucosa was protected from further insult. Tight acid control after RFA with EMR is

attractive for its potential to reduce risk for recurrence and newer agents that suppress acid more effectively may be helpful, but trials are needed to determine whether relative acid control is important as an independent factor in sustained disease control.

—Ted Bosworth Dr. Shaheen reported financial relationships with Covidien, CSA Medical, Diagnovus, Gi Dynamics, Oncoscope, Shire and Takeda.

Dr. Sharma has a financial relationship with Takeda, and is a member of the editorial board of Gastroenterology & Endoscopy News.

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a reduced risk for recurrence of BE after ablation, but protection may not be absolute. Injury to lower esophageal mucosa by other factors, such as biliary reflux, has been implicated in the process that leads to BE ((Aliment Pharmacol Ther 2005;15:969-975).

In reducing the risk for recurrence, antireflux surgery has the theoretical advantage over PPIs in preventing acid and bile from reaching the lower esophageal mucosa to cause injury. Again, however, no evidence confirms this advantage.

Indeed, a 2014 review concluded that the limited clinical studies evaluating this question do not support greater protection from relapse after surgery (N Engl J Medd 2014;371:836-845).

Dr. Shaheen suggested that, in his experience, PPIs have been adequate in most patients.

“Most of my post-RFA patients are on PPIs twice daily, and serious troubles with inadequate acid control have been rare,” he said. “I have had a half-dozen or so cases in which we employed antireflux surgery to either allow completion of ablation or to maintain the ablated area free of inflammation, but this has been rare in my practice.”

Yet, better strategies to prevent recurrences after eradication are needed based on current evidence. In a study that looked specifically at rates of recurrence two years after complete remission of intestinal metaplasia with RFA or EMR, 33% had new areas of

GESAP VIIII is an online product that delivers the most robust learning experience in GI endoscopy. Take advantage of a fully-interactive format with images and videos, 370+ peer-reviewed questions offered as 10 study modules by topic area, real-life scenarios, a rationale for each correct answer, as well as references.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Diabetes Ups Risk for Pancreatitis and Vice Versa PHILADELPHIA— —The relationship between acute pancreatitis and diabetes mellitus has been thought to go both ways, with each condition appearing to drive up a person’s risk for the other.

New research supports these findings, while pointing to a strong association between the severity of pancreatitis and the risk for developing diabetes. That contradicts a recent meta-analysis that found the risk for diabetes after a bout of acute pancreatitis to be 23% (Gut 2014;63:818-831).

“Interestingly, none of the studies in that review were conducted in the United States,” said Kishore Vipperla, MD, FACP, a clinical assistant professor of medicine at the University of Pittsburgh Medical Center. “We therefore wanted to explore this relationship in acute pancreatitis patients treated in the United States, and to understand factors influencing this risk.”

Dr. Vipperla and his colleagues examined data from 127 patients who were prospectively enrolled at their center during an initial attack of pancreatitis, survived and had sufficient follow-up data available, a median of 53 months.

Their study outcomes were endocrine and exocrine insufficiency. Endocrine insufficiency was defined by a diagnosis of diabetes using fasting blood sugar, a test for hemoglobin A1c or glucose tolerance testing. Exocrine insufficiency was defined by the use of oral pancreatic enzyme supplements.

The patient cohort was comprised equally of men and women with a mean age of 54 years. The main cause of acute pancreatitis was biliary, seen in 46% of cases. Alcohol, pancreatitis after endoscopic retrograde cholangiopancreatography and idiopathic onset were the other common causes. “Given the tertiary setting, our cohort had a higher rate of severe acute pancreatitis,” Dr. Vipperla said.

Of the 127 patients, 73 (57%) never developed diabetes; 36 (20%) had coexisting diabetes at admission; and 28 (22%) developed diabetes during the study, 19 during index admission and nine during follow-up. Most of these patients eventually required treatment with insulin with or without oral diabetes medications. Body mass index was similar among patients who did and did not develop diabetes, about 30 and 29 kg/m2, respectively, according to the researchers.

“We wanted to see if and how patients who develop diabetes after an acute pancreatitis attack differed from those who did not,” Dr. Vipperla said. They found that patients more likely to develop diabetes during index admission tended to

have more severe disease compared with patients who did not develop diabetes. “Importantly, all of them had either organ failure or pancreatic necrosis, and they had a mean [hospital] length of stay of 31 days. The nine patients who developed diabetes during follow-up also tended to have more severe acute pancreatitis,” he added.

In terms of exocrine insufficiency, 11 patients (9%) received pancreatic enzymes, six after developing symptoms

and five after pancreatic surgery or debridement.

“In conclusion, one out of five patients with acute pancreatitis have coexisting diabetes, new-onset diabetes develops in an additional 20% to 25% of these patients during follow-up,” Dr. Vipperla said. “Also, the risk for new-onset diabetes appears to be influenced by the severity of the attack. The risk after mild acute pancreatitis was lower than that recorded in the systematic review,

although nearly 10% of these patients also developed diabetes.”

William Silverman, MD, a clinical professor in the Department of Internal Medicine at the University of Iowa Hospitals and Clinics, in Iowa City, noted that the majority of the patients in this study experienced biliary pancreatitis.

“That’s critical, because gallstone pancreatitis is the most common cause of pancreatitis in all comers,” he told Gastroenterology & Endoscopy News.

Up to 40% of patients taking oral iron n suffer difficult-to-tolerate side effects1

IMPORTANT SAFETY INFORMATION ABOUT INJECTAFER® INDICATIONS/CONTRAINDICATIONS Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.

WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable

following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.

In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.

In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes.

Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

‘The risk for developing diabetes is significant after an episode of acute pancreatitis; and in view of the significant morbidity and mortality associated with diabetes, acute pancreatitis patients, especially those with severe disease and/or pancreatic necrosis, should be regularly screened for diabetes and treated appropriately.’

—William Silverman, MD

Inflammation in IBD and malabsorrption in post-gastric bypass and celiac disease may impair intestinal iron absorption Intravenous iron therapy with Injectafer® (ferric carboxym maltose injection) • The onlyy non-dextran IV iron approved in adult patien nts for the treatment of iron deficiency anemia (IDA) of various etiologies including: • IBD • celiac disease • bariatric surgery who are intolerant to or do not respond to oral iron • Avoids inflammation and malabsorption issues that may be exxperienced with IBD patients on oral iron2 • Avoids intestinal malabsorption with oral iron in celiac disease and post-op gastric bypass patients3, 4 Safe ety and Efficacy • No black box warning, no test dose or premedication required • Safety comparable to Venofer® (iron sucrose injection, USP)5 • Greater increases in Hb levels compared to oral iron or other IV V irons5

Inje ectafer® is indicated for the treaatment of iron deficiency ane emia in adult patients who have intolerance to oral iron or u unsatisfactory response to orall iron

www.injectafer.com In the 24 hours following administration of Injectafer®, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer®.

Please see Brief Summary of Full Prescribing Information on the following page.

ADVERSE REACTIONS In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).

REFERENCES 1. Crichton RR, Danielson BG, Geisser P. Iron Therapy With Special Emphasis on Intravenous Administration. 2nd ed. Bremen, Germany; UNI-MED Verlag AG.; 2005. 2. Zhu A, Kaneshiro M, Kaunitz. Evaluation and Treatment of Iron Deficiency Anemia: A Gastroenterological Perspective. Dig Dis Sci 2010;55(3):548–559. doi: 10.1007/ s10620-009-1108-6. Epub 2010 2010 Jan 27. 3. Hershko C, Patz J. Ironing out the mechanism of anemia in celiac disease. Haematologica. 2008;93(12):1761-1765. doi:10.3324/haematol.2008.000828. 4. Gesquiere I, Lannoo M, Augustijns P, Matthys C, Van der Schueren B, Foulon V. Iron deficiency after Roux-en-Y gastric bypass: insufficent iron absorption from oral iron supplements. Obes Surg. 2014;24:56-61. doi: 10.1007/s11695-013-1042-8.

5. Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia. Transfusion.

2014;54(2):306-15. doi: 10.1111/trf.12289. Epub 2013 Jun 17. ®

The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

Injectafer® is manufactured under license from Vifor (International), Inc. Switzerland. © 2015 American Regent, Inc. FCM167 Rev. 4/2015

“The two take-home messages here would be: The risk for developing diabetes is significant after an episode of acute pancreatitis; and in view of the significant morbidity and mortality associated with diabetes, acute pancreatitis patients, especially those with severe disease and/ or pancreatic necrosis, should be regularly screened for diabetes and treated appropriately.”

Dr. Vipperla presented the study at the 2014 meeting of the American College of Gastroenterology (abstract 51).

—Monica J. Smith

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GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JULY 2015

Rifaximin Eases IBS-D in Adults WASHINGTONâ&#x20AC;&#x201D;Patients with diarrheapredominant irritable bowel syndrome (IBS-D) who relapse after successful treatment with rifaximin can obtain relief from their symptoms with a subsequent course or two of the same regimen, new data show.

Rifaximin (Xifaxan, Salix Pharmaceuticals) is indicated for treatment of abdominal pain and diarrhea in adults with IBS-D. Those experiencing a recurrence can be retreated for 14 days, up to

two times. The drug, an antibiotic derived from rifampin, was previously approved as treatment for travelerâ&#x20AC;&#x2122;s diarrhea caused by Escherichia colii and for reducing a personâ&#x20AC;&#x2122;s risk for overt hepatic encephalopathy. â&#x20AC;&#x153;Repeat treatment with rifaximin 550 mg [three times daily] for 14 days in patients with recurrent IBS-D symptoms confers significant improvement during treatment-free follow-up periods,â&#x20AC;? said William D. Chey, MD, the Timothy T. Nostrant Professor of Medicine and

)YPLM :\TTHY` VM -\SS 7YLZJYPIPUN 0UMVYTH[PVU 051,*;(-,9ÂŽ MLYYPJ JHYIV_`THS[VZL PUQLJ[PVU

9_ 6US`

05+0*(;065: (5+ <:(.,! InjectaferÂŽ (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deďŹ ciency anemia in adult patients: s WHO HAVE INTOLERANCE TO ORAL IRON OR WHO HAVE HAD UNSATISFACTORY RESPONSE TO ORAL IRON

s WHO HAVE NON DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE +6:(., (5+ (+4050:;9(;065! &OR PATIENTS WEIGHING KG LB OR MORE 'IVE InjectaferÂŽ IN TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE &OR PATIENTS WEIGHING LESS THAN KG LB 'IVE )NJECTAFERÂŽ IN TWO DOSES SEPARATED BY AT LEAST DAYS 'IVE EACH DOSE AS MG KG BODY WEIGHT FOR A TOTAL CUMULATIVE DOSE NOT TO EXCEED MG OF IRON PER COURSE InjectaferÂŽ TREATMENT MAY BE REPEATED IF IRON DElCIENCY ANEMIA REOCCURS Administer InjectaferÂŽ INTRAVENOUSLY EITHER AS AN UNDILUTED SLOW INTRAVENOUS PUSH OR BY INFUSION 7HEN ADMINISTERING AS A SLOW INTRAVENOUS PUSH GIVE AT THE RATE OF APPROXIMATELY MG M, PER MINUTE 7HEN ADMINISTERED VIA INFUSION DILUTE UP TO MG OF IRON IN NO MORE THAN M, OF STERILE SODIUM CHLORIDE INJECTION 530 SUCH THAT THE CONCENTRATION 0 OF THE INFUSION IS NOT LESS THAN MG OF IRON PER M, AND ADMINISTER OVER AT LEAST MINUTES )NSPECT PARENTERAL DRUG PRODUCTS VISUALLY FOR THE ABSENCE OF PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION 4HE PRODUCT CONTAINS NO PRESERVATIVES )NJECTAFERÂŽ is a SINGLE USE VIAL $ISCARD UNUSED PORTION !VOID EXTRAVASATION OF )NJECTAFERÂŽ SINCE BROWN DISCOLORATION OF THE EXTRAVASATION SITE MAY BE LONG LASTING -ONITOR FOR EXTRAVASATION )F EXTRAVASATION OCCURS DISCONTINUE THE )NJECTAFERÂŽ ADMINISTRATION AT THAT SITE +6:(., -694: (5+ :;9,5.;/:! 3INGLE USE VIALS CONTAINING MG ELEMENTAL IRON PER M, IN THE FOLLOWING PRESENTATION MG IRON M, *65;9(05+0*(;065:! (YPERSENSITIVITY TO )NJECTAFERÂŽ OR ANY OF ITS INACTIVE COMPONENTS >(9505.: (5+ 79,*(<;065: /`WLYZLUZP[P]P[` 9LHJ[PVUZ! Serious hypersensitivity reactions, including anaphylactictype reactions, some of which have been life-threatening and fatal, have been reported in patients receiving InjectaferÂŽ. Patients may present with shock, clinically signiďŹ cant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after InjectaferrÂŽ administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer InjectaferÂŽ when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. )N CLINICAL TRIALS SERIOUS ANAPHYLACTIC ANAPHYLACTOID REACTIONS WERE REPORTED IN OF SUBJECTS RECEIVING )NJECTAFERRÂŽ /THER SERIOUS OR SEVERE ADVERSE REACTIONS POTENTIALLY ASSOCIATED WITH HYPERSENSITIVITY WHICH INCLUDED BUT NOT LIMITED TO PRURITUS

RASH URTICARIA WHEEZING OR HYPOTENSION WERE REPORTED IN OF THESE SUBJECTS /`WLY[LUZPVU! )N CLINICAL STUDIES HYPERTENSION WAS REPORTED IN OF SUBJECTS IN CLINICAL TRIALS AND 4RANSIENT ELEVATIONS IN SYSTOLIC BLOOD PRESSURE SOMETIMES OCCURRING WITH FACIAL mUSHING DIZZINESS OR NAUSEA WERE OBSERVED IN OF SUBJECTS IN THESE TWO CLINICAL TRIALS 4HESE ELEVATIONS GENERALLY OCCURRED IMMEDIATELY AFTER DOSING AND RESOLVED WITHIN MINUTES -ONITOR PATIENTS FOR SIGNS AND SYMPTOMS OF HYPERTENSION FOLLOWING EACH InjectaferÂŽ ADMINISTRATION 3HIVYH[VY` ;LZ[ (S[LYH[PVUZ! )N THE HOURS FOLLOWING ADMINISTRATION OF )NJECTAFERÂŽ

LABORATORY ASSAYS MAY OVERESTIMATE SERUM IRON AND TRANSFERRIN BOUND IRON BY ALSO MEASURING the iron in InjectaferÂŽ (+=,9:, 9,(*;065: (K]LYZL 9LHJ[PVUZ PU *SPUPJHS ;YPHSZ! "ECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS THE ADVERSE REACTION RATES OBSERVED CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REmECT THE RATES OBSERVED IN CLINICAL PRACTICE )N TWO RANDOMIZED CLINICAL STUDIES A TOTAL OF PATIENTS WERE EXPOSED TO )NJECTAFERÂŽ MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON !DVERSE REACTIONS REPORTED BY * OF TREATED PATIENTS ARE SHOWN IN THE FOLLOWING TABLE 4ABLE !DVERSE REACTIONS REPORTED IN * OF 3TUDY 0ATIENTS IN #LINICAL 4RIALS AND InjectaferÂŽ 0OOLED #OMPARATORSa . .

.AUSEA

Hypertension

&LUSHING (OT &LUSH

"LOOD 0HOSPHORUS $ECREASE

$IZZINESS

6OMITING

)NJECTION 3ITE $ISCOLORATION

Headache

Alanine Aminotransferase Increase

$YSGEUSIA

Hypotension

#ONSTIPATION

a Includes oral iron and all formulations of IV iron other than InjectaferÂŽ 4ERM

/RAL IRON .

4RANSIENT DECREASES IN LABORATORY BLOOD PHOSPHORUS LEVELS MG D, HAVE BEEN OBSERVED IN OF PATIENTS IN CLINICAL TRIALS

director of the GI physiology laboratory and the GI Nutrition and Behavioral Wellness Program at the University of Michigan, in Ann Arbor, in a presentation at Digestive Disease Week 2015 (abstract 313).

The safety and effectiveness of rifaximin for treatment of IBS-D were established in three double-blind, placebo-controlled trials. More patients who received the drug reported improvements in abdominal pain and stool consistency than those

(K]LYZL 9LHJ[PVUZ MYVT 7VZ[ THYRL[PUN ,_WLYPLUJL! 4HE FOLLOWING SERIOUS ADVERSE REACTIONS HAVE BEEN MOST COMMONLY REPORTED FROM THE POST MARKETING SPONTANEOUS REPORTS WITH )NJECTAFERÂŽ URTICARIA DYSPNEA PRURITUS TACHYCARDIA ERYTHEMA PYREXIA CHEST DISCOMFORT

CHILLS ANGIOEDEMA BACK PAIN ARTHRALGIA AND SYNCOPE /NE CASE OF HYPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A SUBJECT WHO RECEIVED MG OF )NJECTAFERÂŽ EVERY WEEKS FOR A TOTAL OF WEEKS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ +9<. 05;,9(*;065:! &ORMAL DRUG INTERACTION STUDIES HAVE NOT BEEN PERFORMED WITH )NJECTAFERÂŽ <:, 05 :7,*0-0* 767<3(;065: 7YLNUHUJ` 0REGNANCY #ATEGORY # !DEQUATE AND WELL CONTROLLED STUDIES IN PREGNANT WOMEN HAVE NOT BEEN CONDUCTED )NJECTAFERÂŽ SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENElT JUSTIlES THE POTENTIAL RISK TO THE FETUS 5\YZPUN 4V[OLYZ! ! STUDY TO DETERMINE IRON CONCENTRATIONS IN BREAST MILK AFTER ADMINISTRATION of InjectaferÂŽ N OR ORAL FERROUS SULFATE N WAS CONDUCTED IN LACTATING WOMEN WITH POSTPARTUM IRON DElCIENCY ANEMIA -EAN BREAST MILK IRON LEVELS WERE HIGHER IN LACTATING WOMEN RECEIVING )NJECTAFERÂŽ THAN IN LACTATING WOMEN RECEIVING ORAL FERROUS SULFATE 7LKPH[YPJ <ZL! 3AFETY AND EFFECTIVENESS HAS NOT BEEN ESTABLISHED IN PEDIATRIC PATIENTS .LYPH[YPJ <ZL! /F THE SUBJECTS IN CLINICAL STUDIES OF )NJECTAFERÂŽ WERE YEARS AND OVER WHILE WERE YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE SUBJECTS AND YOUNGER SUBJECTS AND OTHER REPORTED CLINICAL EXPERIENCE HAS NOT IDENTIlED DIFFERENCES IN RESPONSES BETWEEN THE ELDERLY AND YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT 6=,9+6:(.,! %XCESSIVE DOSAGES OF )NJECTAFERÂŽ MAY LEAD TO ACCUMULATION OF IRON IN STORAGE SITES POTENTIALLY LEADING TO HEMOSIDEROSIS ! PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS DEVELOPED HEMOSIDEROSIS WITH MULTIPLE JOINT DISORDER WALKING DISABILITY AND ASTHENIA (YPOPHOSPHATEMIC OSTEOMALACIA WAS REPORTED IN A PATIENT WHO RECEIVED )NJECTAFERÂŽ MG OVER MONTHS 0ARTIAL RECOVERY FOLLOWED DISCONTINUATION OF )NJECTAFERÂŽ +,:*907;065! Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide O ÄŽ-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate.

4(R)-(poly-(1Äş4)-OIt has a relative molecular weight of approximately 150,000 Da. ÂŽ Injectafer FERRIC CARBOXYMALTOSE INJECTION IS A DARK BROWN STERILE AQUEOUS ISOTONIC COLLOIDAL SOLUTION FOR INTRAVENOUS INJECTION %ACH M, CONTAINS MG IRON AS FERRIC CARBOXYMALTOSE IN WATER FOR INJECTION 3ODIUM HYDROXIDE AND OR HYDROCHLORIC ACID MAY HAVE BEEN ADDED TO ADJUST THE P( TO 4HE VIAL CLOSURE IS NOT MADE WITH NATURAL RUBBER LATEX *3050*(3 7/(94(*636.@ 4LJOHUPZT VM (J[PVU! Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex WITH CARBOXYMALTOSE A CARBOHYDRATE POLYMER THAT RELEASES IRON 7OHYTHJVK`UHTPJZ! 5SING POSITRON EMISSION TOMOGRAPHY 0%4 IT WAS DEMONSTRATED THAT RED CELL UPTAKE OF Fe and Fe from InjectaferÂŽ RANGED FROM TO )N PATIENTS WITH IRON DElCIENCY RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS InjectaferÂŽ DOSE )N PATIENTS WITH RENAL ANEMIA RED CELL UPTAKE OF RADIO LABELED IRON RANGED FROM TO AFTER DAYS )NJECTAFERÂŽ DOSE 7OHYTHJVRPUL[PJZ! !FTER ADMINISTRATION OF A SINGLE DOSE OF )NJECTAFERÂŽ OF TO MG OF IRON IN IRON DElCIENT PATIENTS MAXIMUM IRON LEVELS OF ÂŤG M, TO ÂŤG M, WERE OBTAINED RESPECTIVELY AFTER MINUTES TO HOURS POST DOSE 4HE VOLUME OF DISTRIBUTION WAS ESTIMATED TO BE , 4HE IRON INJECTED OR INFUSED WAS RAPIDLY CLEARED FROM THE PLASMA THE TERMINAL HALF LIFE RANGED FROM TO HOURS 2ENAL ELIMINATION OF IRON WAS NEGLIGIBLE 565*3050*(3 ;6?0*636.@ *HYJPUVNLULZPZ 4\[HNLULZPZ HUK 0TWHPYTLU[ VM -LY[PSP[`! #ARCINOGENICITY STUDIES HAVE NOT BEEN PERFORMED WITH FERRIC CARBOXYMALTOSE &ERRIC CARBOXYMALTOSE WAS NOT GENOTOXIC IN THE FOLLOWING GENETIC TOXICOLOGY STUDIES in vitroo MICROBIAL MUTAGENESIS !MES ASSAY in vitroo chromosome aberration test in human LYMPHOCYTES in vitro MAMMALIAN CELL MUTATION ASSAY IN MOUSE LYMPHOMA , 9 4+ C o ELLS

in vivo MOUSE MICRONUCLEUS TEST AT SINGLE INTRAVENOUS DOSES UP TO o MG KG )N A COMBINED MALE AND FEMALE FERTILITY STUDY FERRIC CARBOXYMALTOSE WAS ADMINISTERED INTRAVENOUSLY OVER ONE HOUR TO MALE AND FEMALE RATS AT IRON DOSES OF UP TO MG KG !NIMALS WERE DOSED TIMES PER WEEK ON $AYS

AND 4HERE WAS NO EFFECT ON MATING FUNCTION

FERTILITY OR EARLY EMBRYONIC DEVELOPMENT 4HE DOSE OF MG KG IN ANIMALS IS APPROXIMATELY OF THE HUMAN DOSE OF MG BASED ON BODY SURFACE AREA *3050*(3 :;<+0,:! 4HE SAFETY AND EFlCACY OF )NJECTAFERÂŽ for treatment of iron deďŹ ciency ANEMIA WERE EVALUATED IN TWO RANDOMIZED OPEN LABEL CONTROLLED CLINICAL TRIALS 4RIAL AND 4RIAL )N THESE TWO TRIALS )NJECTAFERÂŽ WAS ADMINISTERED AT DOSE OF MG KG BODY WEIGHT UP TO A MAXIMUM SINGLE DOSE OF MG OF IRON ON TWO OCCASIONS SEPARATED BY AT LEAST DAYS UP TO A CUMULATIVE DOSE OF MG OF IRON 7(;0,5; *6<5:,305. 05-694(;065 s 1UESTION PATIENTS REGARDING ANY PRIOR HISTORY OF REACTIONS TO PARENTERAL IRON PRODUCTS s !DVISE PATIENTS OF THE RISKS ASSOCIATED WITH )NJECTAFERÂŽ s !DVISE PATIENTS TO REPORT ANY SIGNS AND SYMPTOMS OF HYPERSENSITIVITY THAT MAY DEVELOP DURING AND FOLLOWING )NJECTAFERÂŽ ADMINISTRATION SUCH AS RASH ITCHING DIZZINESS

LIGHTHEADEDNESS SWELLING AND BREATHING PROBLEMS InjectaferÂŽ IS MANUFACTURED UNDER LICENSE FROM 6IFOR )NTERNATIONAL )NC 3WITZERLAND

)SS

given placebo. Rifaximin also was associated with significantly greater improvement in bloating, a symptom commonly associated with constipation, thus suggesting that antibiotic therapy may ease IBS with and without constipation.

The TARGET 1 and TARGET 2 studies established the efficacy of a single two-week course of rifaximin in relieving the common IBS-D symptoms of abdominal pain, bloating and urgency (N Engl J Medd 2011;364:22-32). The randomized, placebo-controlled TARGET 3 trial was designed to evaluate the safety and efficacy of a subsequent course of rifaximin in patients with IBS-D who responded to an initial course of the drug.

The study enrolled 2,579 subjects with IBS-D who met the following criteria: average daily symptom scores of 3 or greater for abdominal pain (on an 11-point Likert scale), 3 or greater for bloating (on a seven-point Likert scale), and at least two days per week with a stool consistency score of 6 (loose) or 7 (watery) on the Bristol Stool Scale (BSS).

Of these, 1,074 responded to an openlabel, two-week course of rifaximin three times daily. Among responders, 692 (64%) experienced a recurrence of symptoms within an 18-week observation period. Patients who relapsed were randomized to receive two two-week, double-blind, repeat treatments separated by 10 weeks. The first four weeks comprised the primary evaluation period.

The primary end point, assessed after the first repeat treatment during a fourweek follow-up period, was at least a 30% decrease from baseline in mean weekly

57

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

analysis, responses were seen in 35.4% and 25.6%, respectively (P=0.0051).

P “For the primary outcome measure, you can see that both types of analyses yielded a statistically significant benefit for retreatment, compared to placebo.

Roughly one-third responded, and the therapeutic gain was 8% to 10%,” Dr. Chey said. “The differences were statistically significant for all the individual components. The breadth of critical IBS symptoms seemed to improve with [rifaximin] retreatment,” he added.

The results were similar for the second

retreatment phase, in which there was a 7.6% absolute improvement in the composite end point with rifaximin retreatment over placebo (P=0.0375).

P Adverse events were rare and were not significantly greater in the rifaximin arm, according to the investigators.

Marc Pimentel, MD, director of the GI Motility Program at Cedars-Sinai Medical Center, in Los Angeles, noted that 36% of patients treated with openlabel rifaximin responded and “never needed it again. The drug worked.”

The others were “repeat offenders,” and

perhaps had more “dramatic” IBS. “Those are not your star quarterbacks,” Dr. Pimentel said. “But interestingly, when they relapsed, they had less severe symptoms. Now, it gets harder to detect a [therapeutic] difference. Yet despite those obstacles, rifaximin worked, again and again. That’s really robust.”

—Caroline Helwick Drs. Chey and Pimentel received consulting fees from Salix Pharmaceuticals and other pharmaceutical companies. Dr. Pimentel is the author of “A New IBS Solution” (Health Point Press, 2006), which focuses on the role of bacterial overgrowth in IBS.

Crohn’s & Colitis Foundation of America’s Clinical & Research Conference

pain score and at least a 50% improvement in stool consistency from baseline.

Secondary end points included the proportion of responders for the individual symptoms of pain, stool consistency, urgency and bloating.

A “responder” was defined as a subject who had a positive response to treatment in a given month for at least two of four weeks, as determined by a list of questions they answered daily. “Recurrence” was defined as a loss of response for at least three of four weeks.

“Interestingly, individuals who recurred and entered into the retreatment phase did not have the same level of IBS symptoms as they did when entering the open-label study at baseline,” Dr. Chey said. On all the outcomes, scores were significantly lower as they entered the retreatment phase.

Significant IBS Improvements Seen Repeat treatment with rifaximin led to a significantly greater likelihood of improvement in IBS-related symptoms compared with placebo, Dr. Chey reported.

TARGET 3 met its primary end point, improving IBS-related abdominal pain and stool consistency in both the worstcase analysis, in which subjects with fewer than four days of diary entries in a given week were considered nonresponders, and in the last observation carried forward (LOCF) analysis, in which the last observed data were entered where there were missing values, the researchers said.

In the worst-case analysis, 32.6% of patients who received rifaximin responded to treatment, compared with 25% of those given placebo (P=0.0232).

P In the LOCF

AIBD 2015

ADVANCES in INFLAMMATORY

BOWEL DISEASES DECEMBER 10-12 , 2015 ORLANDO, FLORIDA | HILTON, ORLANDO CHAIRS

ENDORSED BY:

RICHARD P. MACDERMOTT, MD, MACG, AGAF, FACP Emeritus Proffessor, Albany Medical Center STEPHEN B. HANAUER, MD, FACG, AGAF Feinberg School of Medicine

CALL FOR ABSTRACTS DEADLINE: SEPTEMBER 14, 2015

W W W. A D VA N C E S I N I B D . C O M

58

Surge continued from page 1

Gastroenterology at MetroHealth Medical Center, in Cleveland, and a study co-author.

Ronnie Fass, MD, director of the Division of Gastroenterology and Hepatology at MetroHealth, who helped conduct the study, said more research is needed to identify the underlying basis for the trend.

“The impetus behind the study was the growing number of younger patients with GERD [gastroesophageal reflux disease]-related symptoms who were diagnosed with Barrett’s Barrett s esophaesopha gus in our clinic,” Dr. Fass said. “It was important for us to further assess this trend because of the important

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

impact it will likely have on our current guidelines for BE screening.”

Dr. Sakiani’s group presented the findings at Digestive Disease Week 2015 (abstract SA1881). The researchers analyzed the Explorys database, which includes data from 317,000 providers admitting patients to 360 hospitals in the United States. The database was initially surveyed by the International Classification of Diseases, 9th edition code for GERD, symptoms of heartburn and other risk factors for BE. The researchers conducted additional analyses to find patients who underwent endoscopy and received a diagnosis of BE between 2008 and 2013, to establish an annual

incidence by patient age, sex and race.

“There was a steady increase in both the number of endoscopic procedures performed each year and the incidence of BE,” Dr. Sakiani said. By 2013, the number of endoscopies had risen to 201,140 from 79,040 in 2008, while the incidence of BE increased from 1,970 to 4,269 over that period.

When the data were stratified by age, rates of BE rose from 1.5% in 2008 to 2.4% in 2013 for ages 25 to 34 years (P=0.01); P from 5.2% to 6.4% for ages 35 to 44 (P=0.001) P and from 14% to 16.3% for ages 45 to 54 (P=0.004).

P The rate for ages 65 years or older fell from 53% in 2008 to 46% in 2013 ((P P<0.0001). <0 The increasing rate of o endoscopies may be driven in part by in ncreasing concern over the rising incideence of adenocarcinoma in n the United States an nd worldwide (World J Gastroenterol 2013;19: 5598-5606).

Although most of the BE cases in the health care dattabase were detected amongg patients over age 55, the rising raates in younger patients was notablle. No statistically significant trendss were observed for sex or race over the sstudy period.

BE progresses to esophaageal adenocarcinoma at a rate estimated d to be 0.15% per year. While the risk ffor malignancy increases with duratioon of BE, “BE has been considered d to be a disease of middle-agged, Caucasian males w with a long history oof heartburn,” Dr. Sakiani said.

Currrently, the med dian age for devvelopment of adeenocarcinoma is 667. An earlier

onset of BE may suggest a younger age at cancer onset and an absolute increase in the rate of esophageal adenocarcinoma.

The reason for the increasing incidence of BE in younger people is unknown, but the growing prevalence of obesity is one potential explanation. Obesity is a wellestablished risk factor for both GERD and BE. Further validation of these trends is needed. If they are confirmed, Dr. Sakiani suggested that “future guidelines for BE screening should be taking into account this important demographic trend.”

Joel H. Rubenstein, MD, MSc, assistant professor of gastroenterology at the University of Michigan Medical School, in Ann Arbor, called the data “intriguing,” but he cautioned that there is an inherent selection bias in analyzing data limited to those patients undergoing endoscopy, rather than a representative population sample. The findings can also have several possible explanations.

“The observed trend could be real or could instead be a result of a relative increase in patients undergoing endoscopy at a younger age,” Dr. Rubenstein said. He suggested that a relative increase in BE rates among younger patients would be seen if the study group was well represented by older patients whose BE has already been diagnosed. In addition, he noted that the implications are unknown even if rates of BE at a young age are increased.

Despite the theoretical risk, Dr. Rubenstein added, “the data available from other sources are not clear about whether age at onset of Barrett’s esophagus is an important risk factor for progression to cancer.”

—Ted Bosworth Drs. Rubenstein and Sakiani reported no relevant financial conflicts of interest. Dr. Fass has financial relationships with Altana, AstraZeneca, Eisai and TAP Pharmaceuticals.

Norovirus Spread Can Be Airborne

N

oroviruses, a group of viruses responsible for more than 50% of global gastroenteritis cases, can be spread by air up to several meters from an infected individual, Quebec researchers have found.

Because routes of exposure of this highly contagious virus in hospitals were thought to be direct contact with contaminated surfaces, the discovery suggests that measures used in hospitals during gastroenteritis outbreaks may be insufficient to effectively contain this infection (Clin Infect Diss 2015 Apr 21. [Epub ahead of print]). Previously known routes of exposure included contact with an infected individual, fecal

matter or vomitus and contaminated surfaces. However, an individual can also be exposed to this intestinal parasite by consuming contaminated food or beverages.

The researchers explained that aerosolized virus could settle in the pharynx and be swallowed by the patient.

Norovirus is the most common cause of acute gastroenteritis in the United States, causing 19 million to 21 million illnesses, and contributes to 56,000 to 71,000 hospitalizations and 570 to 800 deaths each year.

The team led by Caroline Duchaine, PhD, a professor at Université Laval’s Faculty of Science and Engineering and a researcher at the Quebec Heart

and Lung Institute (IUCPQ) Research Centre, in Canada, conducted the study at eight hospitals and long-term care facilities affected by gastroenteritis outbreaks. The researchers gathered air samples at a distance of 1 m from patients, at the doors to their rooms and at nursing stations.

Noroviruses, nonenveloped, singlestranded RNA viruses, were found in the air at six of the eight facilities studied. The viruses were detected in 54% of the rooms housing patients with gastroenteritis, 38% of the hallways leading to their rooms and 50% of nursing stations.

Viral concentrations ranged from 13 to 2,350 particles/m3 of air. A dose of 20

particles of norovirus is usually enough to cause gastroenteritis.

According to Dr. Duchaine, this previously unknown mode of norovirus propagation could explain why gastroenteritis outbreaks are so hard to contain.

“The measures applied in hospital settings are only designed to limit direct contact with infected patients. In light of our results, these rules need to be reviewed to take into account the possibility of airborne transmission of noroviruses. Use of mobile air filtration units or the wearing of respiratory protection around patients with gastroenteritis are measures worth testing.”

—GEN Staff

THEY TALK BLOATING, GAS, RUMBLING, DISCOMFORT

WE TALK SCIENCE ACTIVIA® is a probiotic yogurt that may help reduce the frequency of minor digestive issues like bloating, gas, rumbling, and discomfort when consumed twice per day for four weeks as part of a balanced diet and healthy lifestyle.

Figure 1 Forest Plot of Composite Score of the Frequency of Minor Digestive Issues LSmeans = least squares means; CI = confidence interval; N = number of subjects that completed study LSmeans and 95% CI

N

LSmeans

95% CI

Study 1

199

– 0.64

[–1.19; –0.08]

Study 2

336

– 0.41

[–0.79; –0.02]

Pooled analysis

535

– 0.48

[–0.80; – 0.16]

–1.5

–1.0

– 0.5

Favors ACTIVIA®

0.0

0.5

Favors control product

Two double-blind, randomized, placebo-controlled studies, and a pooled analysis of these studies, show that ACTIVIA® may help reduce the frequency of minor digestive issues like bloating, gas, rumbling, and discomfort.1,2 Both studies were designed to investigate the effect of ACTIVIA® on different gastrointestinal (GI) outcomes, including GI well-being and frequency of minor digestive issues, in healthy women lacking any diagnosed GI disorders.

In both studies, the composite score of minor digestive issues over the four-week test period in the ACTIVIA® group was significantly lower (P<0.05) than that in the control group [Study 1: LSmean –0.64; 95% CI (–1.19; –0.08), Study 2: LSmean –0.41; 95% CI (–0.79; –0.02)] (Figure 1). Results from the pooled analysis confirmed these findings [LSmean –0.48; 95% CI (–0.80; –0.16)]2 and strengthen the conclusion that ACTIVIA® may help reduce the frequency of minor digestive issues such as bloating, gas, rumbling, and discomfort when consumed twice per day for four weeks as part of a balanced diet and healthy lifestyle.

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1. Guyonnet et al. Br J Nutrr 2009;102(11):1654-62. 2. Marteauu et al. Neurogastrooenterol Motill 2013;25(4):331-e252.

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60

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Intestinal Transplants Fare Well in Crohn’s Patients

P

atients with Crohn’s disease (CD) who undergo an intestinal transplant have similar risks for acute rejection and death as patients who undergo the surgery for reasons other than this disease, researchers have found.

However, patients with CD did appear to have a higher rate of graft failure, according to the study.

“Crohn’s disease should not be a deterrent for performing this procedure, with the caveat that we need to further explore the reasons for graft failure,” said Berkeley Limketkai, MD, clinical assistant professor of gastroenterology and hepatology at Stanford School of Medicine, in Stanford, Calif., who led the study. Dr. Limketkai and his colleagues presented their findings at Digestive Disease Week 2015 (abstract Sa1151).

Candidates for intestinal transplants include individuals who have short bowel syndrome after extensive resections following mesenteric ischemia—after thrombosis, embolism, volvulus or trauma, for example—inflammatory bowel disease or tumors in the small bowel. Donor intestines come from cadavers.

Half of patients with CD will require an intestinal resection 10 years after diagnosis, and one-third will require repeat resection in the next 10 years. Progressive shortening of the colon may lead to shortgut syndrome and the need for long-term total parenteral nutrition (TPN). Patients who cannot tolerate this therapy—because they develop TPN-associated liver failure, loss of vascular access or recurrent catheter-associated sepsis—often are referred for intestinal transplant.

Only 31 centers in the United States perform intestinal transplants. According to the U.S. Department of Health and Human Services, 139 intestinal transplants were performed in 2014, and roughly 245 candidates were on the waitlist for an intestine at the time this article went to press.

Table 1. Characteristics of Crohn’s Disease Patients Undergoing Surgery

population could have more difficulty with transplant rejection because Crohn’s is a chronic inflammatory disease that carries a high risk for recurrence.

In the new study, investigators at Stanford, Johns Hopkins in Baltimore and Mount Sinai in New York City set out to characterize the long-term risk for

Table 2. Outcomes in Patients With Crohn’s Disease Receiving an Intestinal Transplant

Average age, 44.7 y

Year 1

Year 3

Year 5

74% had a normal or overweight body mass index

Risk for rejection, %

23.1

37.7

41.7

77% were on the waitlist <6 mo

Graft failure, %

4.8

14.6

18.2

20% were hospitalized prior to transplantation

Death rate, %

22.6

38.6

49.1

‘Compared with other solid organ transplants, immunosuppression in small-bowel transplant is the most challenging to control short- and long-term, because unlike other organs that are placed in a sterile environment, the small bowel is continually exposed to foreign antigens in the food and stool passing through it.’

—Berkeley Limketkai, MD

“Compared with other solid organ transplants, immunosuppression in smallbowel transplant is the most challenging to control short- and long-term, because unlike other organs that are placed in a sterile environment, the small bowel is continually exposed to foreign antigens in the food and stool passing through it,” Dr. Limketkai said.

Few data exist on the efficacy of intestinal transplants in CD patients.

Theoretically, Dr. Limketkai said, this

rejection, graft failure and death in a large cohort of CD patients who received an intestinal transplant. They analyzed data from all adults who underwent intestinal transplantation between May 1990 and November 2013 in the U.S. Scientific Registry of Transplant Recipients. Of the 1,155 transplants, 12.7% were performed for CD (Table 1). Patients were followed for a median of three and a maximum of five years.

In patients with CD, the risk for

rejection was 23.1% by year 1 and 42% by year 5; graft failure was 4.8% by year 1 and 18.2% by year 5 (Table 2). The rate of death was nearly 50% by year 5.

Patients with CD had a similar risk for acute rejection and death as patients who received a transplant for other indications, but the risk for graft failure was nearly twice as high for patients with CD as other patients in the registry (hazard ratio, 1.87; 95% confidence interval, 1.08-3.25; P P=0.03; Table 2).

“Although we found a statistically significant difference in graft failure, I do not yet know whether that equates to a clinically meaningful difference,” Dr. Limketkai said. “We need to investigate the reasons, or identify predictors, for this increased risk in graft failures.”

David Binion, MD, co-director of the IBD Center at the University of Pittsburgh, said the study is significant because it provides a multiyear perspective on the outcomes in small-bowel transplantation, as well as specific information regarding transplant recipients with CD. The high mortality rate shows that more should be done to prevent the need for intestinal transplants.

“The paper emphasizes the need to try to prevent small-bowel transplantation in Crohn’s disease patients by achieving a durable, sustained remission,” Dr. Binion said. “Small-bowel transplantation is lifesaving, but mortality post procedure unfortunately remains high, 50% at five years.”

—Kate O’Rourke Dr. Limketkai and Dr. Binion reported no relevant financial conflicts of interest.

Administering Death, Terminating Suffering (Part 2)

O

regon passed its Death with Dignity Act (DWDA) in 1997, allowing doctors to write a lethal prescription for terminally ill patients.

The state tracks DWDA’s use in an annual report. While the reporting isn’t flawless, it’s clear that year after year more people obtain a DWDA prescription than use it.

In 2014, 155 patients obtained a DWDA prescription and 105 people died by using it. Since the law passed, 1,327 people have had DWDA prescriptions written and 859 patients have died from the medication. The same is true in Washington, whose law became active in 2008. In 2013, 173 prescriptions were written and 119

individuals were confirmed to have died by taking the medication.

Some patients die from their illness before taking the medication. But for others, like the patient in New Jersey of Lawrence Egbert, MD, knowing there is an alternative to a painful end or a messy, possibly botched suicide attempt may be enough. Brittany Maynard ultimately used her DWDA prescription, but in the short video she recorded for Compassion & Choices that propelled her into the national limelight, she explained that it was “a relief ” to know that she was in possession of an alternative to the death she was told to expect if she chose to let her brain cancer take its course.

“You get some peace of mind knowing that the end of your life is within your control and not dependent on someone else,” Frank Kavanaugh, PhD, of Final Exit Network, said, “or that you won’t end up in a critical care unit with things plugged into every orifice.”

Mildred Z. Solomon, EdD, president and CEO of The Hastings Center, a nonprofit bioethics research institute in New York, said the physician aid-in-dying movement touches the fundamental cultural fabric of our nation.

“Support for physician aid-in-dying, or what opponents call assisted suicide, aligns with the American emphasis on choice and autonomy and our desire to enable self-determination,” she said.

Critics of physician-assisted suicide fear that the practice will become widespread and disproportionately affect the poor and the disabled. Dr. Solomon had similar concerns, but now says the data show otherwise. In Oregon and Washington, the number of people using DWDA has risen over time (in 1998, only 24 people got a DWDA prescription and 16 died), but the overall number of people who use the act is relatively small. The vast majority are white, well educated and suffering from cancer (although 2014 did show an uptick in those with amyotrophic lateral sclerosis). The median age in Oregon was 72 years, and 93% of those who sought a DWDA prescription were enrolled in hospice care.

Dr. Solomon said many of the potential abuses that people originally worried about have not come to pass, and she wouldn’t be surprised if twice as many states have laws on the books in the next 18 months. However, she worries see Suffering, page 64

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Oil of Allay: Peppermint Microcapsules Tame IBS Symptoms

A

slow-release formulation of concentrated peppermint oil provides significant relief of the symptoms of irritable bowel syndrome (IBS), researchers have found.

The formulation (IBgard, IM HealthScience) contains purified, coated microbeads of peppermint oil that can pass through the stomach to dissolve slowly in the small intestine. The randomized controlled trial found that patients with IBS who took the peppermint oil reported a 40% decline in bowel symptoms and nearly a 50% decrease in symptom intensity from baseline, according to the researchers.

Peppermint oil, which contains L-menthol, is approved for the treatment of IBS in Europe, where it is used as a

Table. Improvement With Peppermint Oil Versus Placebo Symptom

P Value

Frequency/intensity of abdominal pain/discomfort

0.0183

Abdominal bloating/ distention

0.0474

Pain at evacuation

0.0328

Urgency of bowel movement

0.0336

first-line therapy for the condition. However, clinicians in the United States have not embraced the substance, nor does it have FDA approval for IBS. The formulation used in the latest study is available over the counter as a “medical food.”

Manufacturers of medical foods can make disease claims about their products but do not have to conduct randomized controlled trials to prove those claims.

The new study, the IBSREST (Irritable Bowel Syndrome Reduction

Evaluation and Safety Trial), included 72 men and women with moderate IBS who received either peppermint oil or placebo for four weeks.

After one week, patients taking the peppermint oil reported a statistically significant improvement in total IBS symptoms, which declined by 40% compared with baseline (P<0.0001). Symptom severity also fell, by 49% (P<0.0001), as did mean frequency of symptoms (P<0.0001; Table).

The difference between active therapy and placebo also was statistically significant for reduction in total symptoms (P=0.025) P and symptom intensity (P=0.028).

P The oil was well tolerated, and no patient discontinued the study because of problems with the therapy, according to the researchers.

The researchers reported their findings at Digestive Disease Week 2015 (abstract Mo1290).

—Adam Marcus

Advances in Probiotic Therapy For Diarrhea-Associated Illness To participate in this FREE CME activity, log on to

www.CMEZone.com

Release Date: February 10, 2014

Expiration Date: August 11, 2015

Chair

Statement of Need

Intended Audience

William D. Chey, MD

Probiotics can be powerful tools in managing a number of medical conditions. However, efficacy may be suboptimal if these agents are not used appropriately. As public interest in the benefits of probiotics increases, so does the need for clinical education.

Many physicians and patients are unfamiliar with the nuances of probiotic pharmacology, or—with many probiotics available for over-the-counter purchase— may not be aware that their patients are selecting ineffective therapies. Thus, it is important for health care professionals to familiarize themselves with the latest research data on probiotic use.

Gastroenterologists, primary care physicians, nurse practitioners, nurses, physician assistants, pharmacists, and other health care professionals involved in the care of patients who may benefit from the use of probiotic therapy.

Professor of Internal Medicine Director, Gastrointestinal Physiology Laboratory Co-Director, Michigan Bowel Control Program H. Marvin Pollard Institute Scholar Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Faculty Brooks Cash, MD Professor of Medicine Division of Gastroenterology University of South Alabama Mobile, Alabama

Shanti Eswaran, MD Clinical Assistant Professor Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Goal The goal of this educational activity is to provide clinicians with current evidence and strategies for effective probiotic therapy in a variety of disease states.

Learning Objectives Upon completion of this activity, the participant will be better prepared to do the following: 1 Review key differentiating characteristics of various probiotic therapies, including mechanism of action.

2 Describe the importance of strain specificity in the clinical applicability of probiotic therapies.

Estimated Time for Completion 1 hour

Course Format Monograph

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc., Advancing Knowledge in Healthcare, and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation AKH Inc. designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

3 Discuss the role of probiotic therapy in clinical digestive ailments.

4 Review strategies for appropriate patient selection and education in the use of probiotic therapies.

Jointly sponsored by AKH Inc. and Applied Clinical Education

Supported via an educational grant from Procter & Gamble

Distributed via CMEZone and Gastroenterology and Endoscopy News

62

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62

JULY 2015

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JULY 2015

Gastroenterologist Opportunity Geisinger Health System (GHS), a national leader in quality and integrated healthcare is seeking a BC/BE Gastroenterologist with an interest in ERCP, motility or IBD to join its innovative practice at Geisinger Medical Center in Danville, PA. Ability to perform ERCP will be supported in a new state-of-the-art endoscopy suite with 3 dedicated advanced procedure rooms. Become part of a closely integrated department comprised of more than 23 gastroenterologists, 3 hepatologists and 10 fellows with some of the best resources available for academic and clinical practice. Call is equally shared and is no more than 5 to 6 weeks per year. Transplant Hepatology, and our Gastroenterology and Advanced Endoscopy fellowship programs are located at Geisinger Medical Center.

As a part of Geisingerâ&#x20AC;&#x2122;s team, you will work in an academic environment, backed by the resources of one of the nationâ&#x20AC;&#x2122;s most progressive integrated health systems. Enjoy the balance of a favorable call

schedule with the collegiality of a unique practice and surrounding community that offers a low cost of living, superb public schools, numerous outdoor and cultural activities, and easy access to major metropolitan areas including New York City, Baltimore, Philadelphia and Washington, D.C. Geisinger Health System serves nearly 3 million people in Northeastern and Central Pennsylvania and has been nationally recognized for innovative practices. A mature electronic health record connects a comprehensive network of 9 hospital campuses, 43 community practice sites and more than 1,200 Geisinger primary and specialty care physicians.

Discover for yourself the Geisinger difference.

For more information visit geisinger.org/careers or contact: Mathew McKinney, &GRCTVOGPV QH 2TQHGUUKQPCN 5VCHĆ&#x201A;PI CV QT OYOEMKPPG["IGKUKPIGT GFW

PRESBYTERIAN PRESBYTERIAN HEALTHCARE SERVICES Albuquerque, NM Presbyterian Healthcare Services is seeking Board CertiďŹ ed Gastroenterology trained physicians to join our established practice of 11 physicians, 2 Gastroenterology Hospitalists and 7 advanced practitioners. Our medical group employs more than 600 primary care and specialty providers and is the fastest growing employed physician group in New Mexico. Presbyterian Healthcare Services is a locally owned, not-for-proďŹ t organization based in Albuquerque. Our integrated healthcare system includes eight hospitals in seven New Mexico cities, a medical group, multispecialty clinics and a health plan (over 400,000 members).

We have been proudly providing care to New Mexicans for 105 years.

GASTROENTEROLOGIST Join our team in bettering the health of our region â&#x20AC;&#x201C; exciting opportunity located in beautiful Big Sky Country â&#x20AC;&#x201C; Billings, s Montana â&#x20AC;˘

If you love spending time in the outdoors and are looking for a wonderful community to live and to raise a family, this is the job for you

â&#x20AC;˘

In Montana, you can hike, golf, ski, fish, bike, camp and enjoy the extensive beauty and opportunities our region has to offer year round

â&#x20AC;˘

You will connect to patients in a broad geography

â&#x20AC;˘

Billings, Montana was rated by Kiplinger as one of the top 10 places to live

â&#x20AC;˘

For more information, please contact Carrie Ballard, Physician Recruiter at (406) 237-4002 carrie.ballard@sclhs.net

In addition to a guaranteed base salary we also offer a sign on bonus, incentive bonus, malpractice, relocation, house hunting trip, health, dental, vision, 403(b) w/ contribution from PHS 457(b), short & long term disability, CME allowance, etc.

Albuquerque thrives as New Mexicoâ&#x20AC;&#x2122;s largest metropolitan center with a population of 700,000. Albuquerque has been listed as one of the best places to live in the United States by Newsweek, U.S. News & World Report, Money and Entrepreneur Magazines! Albuquerque is considered a destination city for most types of outdoor activities with 310 days of sunshine. A truly diverse and multicultural city, Albuquerque offers you and your family a great variety of activities and entertainment including national theater productions, sporting events, golf courses ranked among the best in the country, the largest hot air balloon festival in the US, American Indian Cultural activities and much more.

For more information, e-mail Kelly Herrera at kherrera@phs.org or call 505-923-5662.

Visit our website at www.phs.org EOE

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JULY 2015

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

63

Colorado Gastroenterologist Outstanding Opportunity!

Digestive Health Associates, P.C., and Southwest Endoscopy Center, r in the nationally acclaimed community of Durango Colorado, offers an excellent employment opportunity for a board certified/ board eligible, gastroenterologist. This is a first tier opportunity!

Our physician-owned medical group offers an outstanding, technologically advanced, and patient-centered private practice that includes an AAAHC accredited and ASGE quality recognized ambulatory endoscopy center. We have experienced strong and steady growth, deliver excellent physician income levels, and enjoy a stellar reputation and lifestyle in Southwest Colorado.

The community of Durango sits in the spectacular Animas River Valley at the base of the San Juan Mountains and has earned the title from Outside Magazine as one of the “Top Ten Best Communities in Which to live”. Smithsonian Magazine has named it as one of the top “20 Best Small Towns in America”. Durango is the mountain and road biking capital of the United States and also boasts the very best in downhill, cross country, and back country skiing. Our area of outdoor paradise is well known for whitewater kayaking, river running, hiking, backpacking, hunting, and gold medal fly-fishing. It is a picturesque and friendly community that is home to the steam trains of the Durango and Silverton Narrow Gauge Railroad. Durango has a wonderful state college, regional symphony, many significant cultural events, and is very child and family friendly. Durango is a wholesome, dynamic, healthy, safe, smart, well balanced, and growing community.

As a gastroenterologist, you have options.

As a healthcare leader, we have opportunities.

For a wide range of options, talk with a team that can offe ff r a wide range of opportunities. We W are one of the nation’s leading operators of general, acute-care hospitals. Our affiliates operate more than 200 hospitals in 29 stat a es and these locat a ions could provide ideal env n ironments fo f r your profe f ssional success.

Comp m ensation packag ages may a include: • Flexible and generous start-up incentives • Medical education debt assistance • Va V rious practice typ y es

For more r info f rmat a ion vi v sit i : www. w ch c smedcare r ers r .com Email: docj c obs@chs.net or Call: 800-367-6813

Do you want to practice great medicine in a very high quality setting, have experienced physician partners you enjoy and trust, be paid well and control your daily practice and resulting revenue? Is the possibility of being employed or becoming a full partner in a clinically superb, patient friendly medical practice and endoscopy center of your own enticing to you? Would you and your family thrive living in one of the very finest communities in the United States and experiencing the very best in lifestyle?

Don’t miss this employment opportunity. You

can have it all!

Please contact:

Stephen Veals, s recruitment specialist at (970) 946-9416 or sav@hcsas.org

GASTROENTEROLOGY IN SOUTHERN CALIFORNIA Loma Linda University Faculty Medical Group, Division of Gastroenterology, is seeking a full-time Gastroenterologist. The ideal candidate will be a consummate clinician, preferably with at least 5 years’ experience after fellowship at an academic center or large group practice. Clinical time will be allocated between see patients in the outpatient clinic and performing endoscopies with time spent at Loma Linda University and Riverside University Medical Center. Mentorship and protected time will be provided for career development.

The Division of Gastroenterology includes 18 faculty practicing at the University Hospital and the VA. The mission of the Loma Linda University Medical Center and the LLU School of Medicine is to deliver whole-person care at a world class level of clinical excellence. The Medical Center serves as the largest tertiary referral source in both Riverside and San Bernardino counties with a surrounding population approaching 4 million.

Loma Linda is located between Los Angeles and Palm Springs. Nestled at the foot of the San Bernardino mountains, we have convenient access to beaches, cities, skiing, hiking and a variety of other outdoor activities. This region also has excellent private and public school systems.

Interested individuals should contact: Michael Volk, MD, MSc Director of Transplant Hepatology and Division Head, Gastroenterology mvolk@llu.edu www.socaldocs.com

GASTROENTEROLOGIST Gundersen Health System in La Crosse, Wisconsin is seeking a BC/BE Gastroenterologist to join its established medical team.

Practice in our state-off the-art Endoscopy Center and modern outpatient clinic.

Outreach services are provided at our satellite clinics located within an easy drive from La Crosse. In addition, you will have opportunities fo f r clinical research and will be actively involved in teaching our Surgical, Transitional, and Internal Medicine residents. Yo Y u’ll join a physician-led, not-fo f r-profit health system with a top-ranked teaching hospital and one of the largest multi-specialty group practices with about 700 physicians and associate medical staff. ff Visit gundersenhealth.org/MedCareers Send CV to Kalah Haug, Medical Staff Recruitment, Gundersen Health System, 1900 South Ave., CO3-OO8, La Crosse, WI 54601 or call (608)775-1005.

Career Opportunities

Got Job Openings?

Promote your positions to the largest audience Contact Craig Wilson, Sales Associate, Classifieds 212-957-5300 xĂăĆƫƫđƫƫcwilson@mcmahonmed.com

63

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

Suffering continued from page 60

that over the long term, as health care costs rise and more financial burdens are placed on families, people may seek to use legalized death with dignity laws to save their families from the cost of a prolonged illness. “That’s not a reason not to legalize it, but there should be vigilant monitoring to make sure states with legal assisted death adhere to protocols,” she said.

Dr. Solomon noted that the conversation will become more complex as the

number of people living longer with Alzheimer’s and other dementias increases.

Current death with dignity laws do not apply to people with dementia because they lack the mental capacity to make such decisions. But people in the early stages of Alzheimer’s, or who are worried that they will develop the disease, may want to assert a right to choose assistance with death.

A Global Movement Outside the United States, both assisted suicide and euthanasia appear to be gaining some ground. The practices

are legal in Switzerland, Germany, Albania, Colombia and Japan. There are more than 50 right-to-die societies in approximately 23 countries.

A Swiss organization, Exit, announced in mid-March that its membership has been surging in recent years. In the German- and Italian-speaking parts of Switzerland, the group’s membership rose to 81,015 people, up from 67,602 in 2013.

In 2014, Exit helped 583 people to die.

Belgium and the Netherlands have some of the most liberal policies, including ones allowing euthanasia. The Dutch,

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere. gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Real-World Data Mimic Trial Findings For HCV Treatment BOSTON—Drugs often fall short of the expectations set in clinical trials, because the trials often exclude patients with various comorbidities and the sickest of the sick.

This does not seem to be the case with the latest generation of medications to treat hepatitis C virus (HCV) infection, which so far are meeting the high bar they set in pre-approval trials. see Real World, page 28

‘Normal’ Stomach On Endoscopy May Be Anything But Precautionary biopsies make sense PHILADELPHIA A—Nearly 30% of stomachs that appear to be normal during endoscopy in fact may have significant gastric pathology, according to a new study, which suggests that endoscopists may want to consider taking more biopsies as a precaution. see Biopsy, page 38

Falling Through the Cracks: Mothers With Hepatitis B Receive Inadequate Treatment, Follow-up

M

ore than on ne-third of women with the hepatitis B virus (HBV) are initially diagnoosed with the infection at their first prenatal care visit, but they do not receive follow-up care for the infection after their pregnaancy, researchers have found.

The retrospective stud dy examined the medical records of 243 women with HBV who receiveed prenatal care at facilities under th he umbrella of Massachusetts Gen neral Hospital (MGH).

“It’s clear from the data that these women are getting lostt to followup or not getting ap ppropriate care to begin with,” saaid Ruma Rajbhandari, MD, MPH, a gastroenterology and hepatology fellow at MGH H, in Boston, who led the sttudy.

“It’s a real shame. It is siimilar to getting diagnosed with HIV and not receiving any follow-up care for it.”

The researchers presented theeir findings at the 2014 Liver Meetin ng of the American Association for th he Study of Liver Diseases (AAS SLD), in Boston (abstract 1552).

In 1990, the Centers for Disease Control and Prevention created the U.S. Perinatal Hep patitis B Prevention Program (P PHBPP) in an effort too reduce perinatal trransmission of the disease.

Under the P PHBPP, pregnantt women are rroutinely screened for H HBV and their inffants are treated an nd monitored approopriately.

The prograam has resulted in a sharp reduction of p perinatal infections with HBV. see Hep B, page 36

I N S I D E

Are We There Yet? Women still feel gender disparities in pediatric gastroenterology

W

hen it comes to compensation, mentoring and promotions, women in pediatric gastroenterology believe they continue to lag behind their male peers, a new survey has found. see Disparities, page 24

-/Ê" Ê ÊÓä£{\Ê* ,/ÊÓ 8* ,/-½Ê* -Ê More of the Best of the American College of Gastroenterology annual meeting.................... «>}iÊ£{

Gary Lichtenstein, MD

*iÌiÀÊ }} Ã] MD

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EDUCATIONAL REVIEW

Hemorrhoids: Evaluation and Management for the Office-based Clinician ERIC FONTENOT, MD

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STEPHEN W. LANDRENEAU, MD

Louisiana State University School of Medicine Department of Medicine Section of Gastroenterology New Orleans, Louisiana

Louisiana State University School of Medicine Department of Medicine Section of Gastroenterology New Orleans, Louisiana

The authors report no relevant financial conflicts of interest.

T

he medical literature on hemorrhoidal disease dates back at least as far

Hemorrhoids: Evaluation and Management for the Office-based Clinician

as Hippocrates, who described techniques that will be familiar to practitioners even today. This article will cover the epidemiology,

Internal hemorrhoidal plexus

normal anatomy and physiology, pathophysiology, and classification of

Dentate line

hemorrhoids, with a particular focus

External hemorrhoidal plexus

on the office-based physician.

Epidemiology Hemorrhoids are a common problem, estimated in a large epidemiologic study to have an overall prevalence of as much as 4.4% in the United States.1 Both sexes demonstrate a peak prevalence in the age range of 45 to 65 years, with increased rates associated with higher socioeconomic status.1 However, the true prevalence of hemorrhoidal disease may be underestimated because many patients do not seek medical attention, or overestimated because some patients erroneously attribute any anorectal problem to “hemorrhoids.”2

Anatomy The anal canal (Figure 1) consists of the approximately 4 cm between the distal rectum and the anal verge. In the approximate midpoint of the canal is the dentate line, an important anatomic landmark in the

Figure 1. Normal anorectal anatomy.

Courtesy of Iain Cleator MD, Vancouver, BC, Canada

evaluation and treatment of hemorrhoidal disease.

The dentate line represents the junction between the embryologic endoderm and ectoderm and is the point that the mucosa of the anal canal changes from the insensitive columnar epithelium of the rectum to the highly sensitive squamous epithelium of the anoderm.

Found proximally to the dentate line, the internal hemorrhoids are a specialized collection of 3 fibrovascular “cushions” arranged in a left lateral, right anterior, and right posterior configuration.3 They are composed of an arteriovenous plexus where branches of the superior, middle, and, to a lesser extent, inferior hemorrhoidal

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1

who decriminalized both euthanasia and physician-assisted suicide in 2001, had more than 4,000 people die by choice in 2013. Most were older people and about 80% to 90% had cancer, but the Dutch law allows anyone in “hopeless and unbearable suffering” to seek euthanasia, without the requirement of a terminal diagnosis.

While the number of people opting for euthanasia is growing, Rob Jonquiere, MD, a retired physician and now communications director of the World Federation of Right to Die Societies, attributed this to greater awareness of the law and more open conversation in Dutch society about death than to the proverbial slippery slope.

“If it was a slippery slope, you would see maybe only 60% of cases were terminal cancer, for example,” he said. “We can only explain the growth by saying the medical society and the patients are more or less used to the fact that euthanasia is a possibility and it’s now integrated with palliative care.”

Dr. Jonquiere, a general practice doctor who has performed euthanasia, was the CEO of the Dutch Right to Die Society until 2008, and has been extensively involved in the development and implementation of the Dutch euthanasia law.

He sees the global tide swaying in favor of the right to die movement, something he attributes to the baby boomer generation.

“The people who grew up after World War II is the group who has formed their own lives and made choices all their lives for contraception and marriage—that group is now getting to the age when they’re going to die and they want to make the choice there as well,” he said. “By legalizing and protocolizing an act that’s being practiced by doctors, you make it possible to not do things in secret where it can be abused.”

‘Do No Harm’ It is an argument used by advocates for everything from the legalization of abortion to marijuana—that it’s better to put controversial practices into the mainstream where they can be regulated.

Some believe that doctors in the United States are already offering physicianassisted suicide, writing out prescriptions for sleeping pills with a wink and a nod.

As is often the case with certain hotbutton social issues, religious groups object on moral grounds. But what of the ethics issues for doctors? The American Medical Association stated in its opinion 2.211, “Physician-assisted suicide is fundamentally incompatible with the physician’s role as healer, would be difficult or impossible to control, and would pose serious societal risks.”

Dr. Egbert stated he doesn’t like what he did as an exit guide, but that he is very proud that he had the courage to step out of the mainstream and help those in need.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2015

‘Our whole system [was] designed for an era when we died of acute illness or died of infection, not for the baby boomers who will have long-term chronic illnesses. There’s so much we need to do for the vast majority of people, why not get just as passionate about redesigning a system that will help everyone?’

—Mildred Z. Solomon, EdD, president and CEO of The Hastings Center

Dr. Jonquiere, who was practicing euthanasia in the Netherlands before it was legal, said, “No doctor in the Netherlands kills his or her patient—the law is about terminating sufferingg not terminating life. This is not wordplay, but the basis of our law. In the Hippocratic Oath, you have the obligation to take away suffering and sometimes that can only be done by taking away life.”

Dr. Solomon agreed with this point.

“Ending suffering is part of the physician’s role and relief of suffering is just as important, if not more, than cure,” she stated. “But, physician aid-in-dying isn’t the only way to alleviate suffering.”

She noted that when the issue is looked at on a case-by-case basis, it’s easy to be swayed by compassion. Ms. Maynard used her video to describe the death she planned: “I will die upstairs in my bedroom that I share with my husband, with my mother and my husband by my side, and pass peacefully with some music that I like in the background.” Dr. Solomon pointed out that individual stories are very moving, but focusing on one person’s tragic circumstances gives physician aidin-dying more prominence in the media than it warrants. When she looks at the data coming out of Washington and Oregon, she sees a practice that is very important to a small number of people.

“Unfortunately, though, there is far less attention paid to the larger, systemic need to reform and improve palliative care that could benefit so many more people.”

“Our whole system is designed for an era when we died of acute illness or died of infection, not for the baby boomers who will have long-term chronic illnesses,” she said. “There’s so much we need to do for the vast majority of people, why not get just as passionate about redesigning a system that will help everyone?”

The AMA opinion continued: “Instead of participating in assisted suicide, physicians must aggressively respond to the needs of patients at the end of life.

Patients should not be abandoned once it is determined that cure is impossible.

Multidisciplinary interventions should be sought, including specialty consultation, hospice care, pastoral support, family counseling, and other modalities.”

Yet it is just this, the feeling of abandonment, that assisted suicide advocates say is often the problem. Dr. Kavanaugh said his years as a professor of medical and public affairs at George Washington

University Health Center, in Washington, D.C., were eye-opening. “I came away with the feeling that we did a really great job of intervening in people’s lives

1978

—

and making them better, but when we couldn’t do that, too often we walked away from them at the most critical point in their life.”

Dr. Egbert believes that many patients in need of palliative resources get lost in a quagmire of specialists and consults. “[Guides] are there to educate a person about how to do this themselves, but the other key word would be ‘comfort,’” he said. “A lot of people who are suffering and getting ready to die are very lonely and find out that a lot of physicians abandon them.”

According to Dr. Egbert, most patients and families thank him for his help in guiding a loved one to a peaceful, dignified death. But what about the woman with terminal cancer in Texas who started him on this path?

“Her daughter talked her out of it,” he said. “According to the minister, she lived two months in horrible pain. But she died with the respect of her daughter.

So which one is better or worse? I don’t know the answer to that, but I know that she chose.”

—Christianna McCausland

37th Anniversary — 2015

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Update on Endoscopic Eradication Therapy for Barrett’s Esophagus SHREYAS SALIGRAM, MD, MRCPa,b PRASHANTH VENNALAGANTI, MDa PRATEEK SHARMA, MDa,b a

Departm Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Un K Kansas City, Kansas Dr. Sharma has received grant support from Barrx Medical, CDX Labs, D Coo Cook Medical, Ninepoint Medical, and Olympus Inc. Drs. Saligram and Venna Vennalaganti reported no relevant financial conflicts of interest.

B

arrett’s esophagus (BE) is the precursor lesion to esophageal adenocarcinoma, which in an

inva invasive stage causes significant m morbidity and mortality. Surgery w the mainstay of treatment for was pa patients with high-grade dysplasia (HGD) and adenocarcinoma associated with BE. However, surgery in itself carries substan ntial morbidity. m substantial There has been tremen ndou progress in the minimally invasive tremendous tre treatment of BE in the past decade.

The premise to be aggressive in treating dysplasttic BE and early-stage adenocarcinoma is to prevent pro progression to an advanced-stage cancer. Most interventional endoscopists are comfortable treating dysplasia and intramuc intramucosal esophageal cancer, although recently there have been emer emerging data on the treatment of early submucosal cancer in BE. This article reviews the different modes of and strategies for endoscopic treatment of BE with emphasis on newer techniques.

Barrett’s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (IM; goblet cells) proximal to the gastroesophageal junction. The overall population prevalence is estimated at 1.6%1 with an annual incidence of 62 per 100,000.2 In patients with BE, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12% and 0.5%.3-6 Intestinal metaplasia can have a histologic

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transformation from no dysplasia to low-grade dysplasia (LGD), HGD, and eventually to esophageal adenocarcinoma.7 Patients with HGD have the highest tendency to progress to esophageal adenocarcinoma. Therefore, endoscopic eradication therapy increasingly is used to treat HGD and early esophageal adenocarcinoma to decrease the progression to invasive disease. Data from the US National Cancer Institute show a 6-fold increase in the incidence of esophageal adenocarcinoma in 2001; the disease now is considered the fastest rising cancer in the United States.8

Rationale for Endoscopic Eradication Barrettâ&#x20AC;&#x2122;s esophagus has the potential to transform into esophageal adenocarcinoma by genetic alteration of IM, where there is unregulated cell growth due to inactivation of tumor suppressor genes and activation of oncogenes. This genetic activity causes a morphologic change in the lining of the epithelium of the esophagus called dysplasia (cytologic atypia, architectural complexity due to nuclear pleomorphism and hyperchromatism confined to basement membrane).9,10 The aim of ablation/eradication therapy is to destroy this abnormal lining of the esophagus and reinstate the neosquamous epithelium.

Natural History of Dysplasia in BE Before embarking on endoscopic therapy for BE, it is important to understand the risks for dysplasia and cancer in these patients. Contemporary literature suggests that the reported rate of progression to cancer or dysplasia from IM, or nondysplastic BE, is low.6 Nondysplastic BE, which is the early stage of the condition, has the lowest incidence of transforming to dysplasia or esophageal adenocarcinoma. A retrospective study of 1,204 patients diagnosed with nondysplastic BE during index endoscopy and followed for a mean period of 5.52 years found that 98.6% and 97.1% were cancer-free after 5 and 10 years, respectively. Per-year incidence of esophageal adenocarcinoma was reported to be 0.27%, 0.48% for HGD, and 3.6% for LGD.11 A recent meta-analysis, which included 11,434 patients diagnosed with nondysplastic BE and followed for 58,547 patient-years, reported a low annual incidence of cancer, at 0.3%.12 Similar findings were reported from a large populationbased study from Denmark, which found that the risk for cancer in patients with nondysplastic BE was less than 0.2% per year.

Low-grade dysplasia has a lower degree of dysplastic cells and is the initial stage of dysplasia. Several studies have shown varying results for LGD developing into HGD or cancer. A multicenter study including 210 patients with LGD followed for an average of 6.2 years reported a low incidence of esophageal adenocarcinoma (0.44% per year) and HGD (1.6% per year). Combined esophageal adenocarcinoma and HGD was 1.83% per year with a mean time of progression to esophageal

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adenocarcinoma of 4.41 years. Based on survival analysis, 97.4% of patients were cancer-free after 5 years of follow-up.13 Based on this study, only 2.6% of patients developed cancer at the end of 5 years; overall, patients with LGD had a low risk for developing malignancies.

However, other studies found a higher incidence (up to 13.6% per year) of combined HGD and esophageal adenocarcinoma developing from LGD.14-16 This inconsistent incidence in the rate of LGD that becomes HGD and cancer was long suspected to reflect a sampling error and significant interobserver variability among pathologists.13,17 The natural course of LGD thus appears to be highly variable. A recent multicenter randomized controlled trial from Europe suggested higher rates of progression of LGD to cancer. The study included 136 patients with LGD; 68 were randomized to undergo radiofrequency ablation (RFA) and 68 were monitored by surveillance endoscopy every 6 to 12 months. After 3 years of follow-up, 1.4% of patients undergoing RFA and 8.8% being followed without RFA developed esophageal adenocarcinoma.18 By comparison, a recent meta-analysis of cancer risk in patients with LGD (24 studies; 2,694 patients) showed a 0.5% risk for cancer.19 Clearly, LGD remains a difficult disease to diagnose.

High-grade dysplasia has a greater prevalence of dysplastic cells and is the advanced stage of dysplasia. Timely treatment at this stage can prevent dysplasia from progressing to cancer. A 2008 meta-analysis found a high incidence of esophageal adenocarcinoma (6% per year) in patients with HGD who had not undergone ablation or surgery. Of the 236 patients who met the inclusion criteria for the study, 69 developed esophageal adenocarcinoma within 1.5 to 7 years of followup.20 A multicenter sham control trial in 2009 randomly assigned 63 patients with HGD to receive either RFA or sham procedure and followed them for 12 months.

Although 19% of the patients in the control group experienced spontaneous regression of dysplasia, a significant proportion progressed to esophageal adenocarcinoma.21 These data and the meta-analysis show beyond doubt that untreated HGD has a significant risk for developing into cancer.

Endoscopic Eradication Esophagectomy is effective in treating early-stage esophageal adenocarcinoma but is a radical therapy and carries significant morbidity (30%-40%) and mortality (1%-4%).22-27 Therefore, it is used for patients at a high risk for or with the presence of lymph node metastasis.

A systematic review of 1,350 patients who underwent esophagectomy for intramucosal (T1a) esophageal adenocarcinoma showed that only 26 (1.39%) had lymph node metastasis in the final pathology.28 A retrospective review of 70 patients with T1a esophageal adenocarcinoma and 56 patients with submucosal (T1b) esophageal adenocarcinoma revealed lymph node metastasis

Table. Endoscopic Eradication Therapy for Barrettâ&#x20AC;&#x2122;s Esophagus Thermal ablation therapy

Argon plasma coagulation Laser therapy Multipolar electrocoagulation

Nonthermal ablation therapy

Cryotherapy Photodynamic therapy Radiofrequency ablation

Endoscopic resection

Endoscopic mucosal resection Endoscopic submucosal dissection

in 1.3% and 22%, respectively. Lymphovascular invasion, tumor size of at least 2 cm in diameter, and poor differentiation were associated with an increased risk for lymph node metastasis.29 All T1b lesions, regardless of the depth of T1b (SM1 indicates invasion into the superficial third of the submucosa, SM2 invasion into the middle third, and SM3 invasion into the deepest third of the submucosa), were associated with significant lymph node metastasis (12.9%-20.4%).30 The risk for lymph node metastasis in early esophageal adenocarcinoma therefore is low and endoscopic eradication therapy can be attempted in the vast majority of patients with T1a lesions. However, endoscopic eradication therapy typically is precluded in patients with T1b esophageal adenocarcinoma because of the higher risk for metastasis to the lymph node.

To obtain accurate tumor staging of visible lesions and patients with esophageal cancer, endoscopic mucosal resection (EMR) is performed to assess depth of the lesion. In patients with known cancer on biopsies, the accuracy of TNM staging is enhanced when endoscopic ultrasound is combined with EMR.31 After accurate staging and resection of early esophageal adenocarcinoma, it is important to ensure that the rest of the BE is eradicated completely to prevent recurrence of cancer. A retrospective study of 349 patients treated with ablation therapy for BE found occurrence of metachronous lesions in 21.5% of patients at a median of 15 months. The metachronous lesions were not found in the group that had undergone complete eradication of IM (CE-IM).32 The current practice for endoscopic eradication therapy of BE is resection of any visible lesions by EMR, ablation of residual BE to prevent metachronous lesions or recurrent neoplasm, and follow-up surveillance.

Multimodal endoscopic eradication therapy with EMR and RFA commonly is used. Visible or flat lesions are described by Paris classification33 and endoscopic inspection for visible or flat lesions is performed under white light endoscopy. Advanced imaging techniques including chromoendoscopy and virtual chromoendoscopy; optical frequency domain imaging; or confocal laser endomicroscopy are available but underused. A recent meta-analysis showed that detection of HGD or cancer increased by 34% when clinicians used advanced imaging techniques.34 Based on the available evidence, the American Gastroenterological Association issued guidelines for endoscopic surveillance and eradication therapy of BE. Endoscopic surveillance should be performed every 3 to 5 years for nondysplastic BE, every 6 to 12 months for LGD, and every 3 months for HGD if endoscopic eradication therapy is not performed. All patients with dysplasia should have the diagnosis confirmed by at least 2 experienced gastrointestinal pathologists.

The treatment of early-stage dysplastic lesions is controversial given the variability in the diagnosis and natural history. In a recently concluded multicenter study, which classified LGD as inflammatory and dysplastic, interobserver agreement among expert pathologists was poor, with kappa values for inflammatory and dysplastic lesions of 0.03 and 0.04, respectively.

The overall kappa value for LGD was 0.2.35 The aim of endoscopic eradication therapy should be to eradicate BE completely once dysplasia has been eradicated to prevent the progression of residual IM to recurrent or metachronous neoplasia.36

MODALITIES

OF

ENDOSCOPIC ERADICATION

The different modalities of endoscopic eradication therapy are listed in the Table. The advent of RFA as the primary therapy has displaced some of the older therapies such as thermal (multipolar electrocoagulation, argon plasma coagulation, Yag laser) and nonthermal (photodynamic therapy) methods.37 Argon plasma coagulation for eradication of residual BE tissue after use of EMR and/or RFA is still used for the treatment of focal areas.

Endoscopic resection consists of 2 approaches, EMR and endoscopic submucosal dissection (ESD), depending on the depth of the tissue removed.

Endoscopic Mucosal Resection The 2 types of EMR that can be performed are focal and radical, or wide area.38 Focal EMR is a technique used to excise visible polypoid, flat, or nodular lesions of esophageal mucosa suspected to be harboring cancer. It serves both as a diagnostic tool for tumor staging and as a therapeutic tool for excising the neoplastic lesion. Two commonly used techniques are the multiband ligator and the cap-assisted device.39 The multiband ligator40 uses suction to draw lesions into a cap and a rubber band is applied to create a pseudopolypoid

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Figure 1. Barrett’s esophagus with visible lesion before and after endoscopic mucosal resection. lesion, which is then snared using electrocoagulation, and the specimen is subsequently retrieved. The capassisted technique41 uses saline or diluted epinephrine (1:100,000) to lift the suspected lesion. A prelooping of the snare to the rim of the transparent cap attached to the endoscope tip is performed after raising the suspected lesion. The raised lesion is then sucked into a cap, creating a pseudopolyp, which is then snared by electrocoagulation before the specimen is retrieved (Figure 1).

Radical EMR is used to remove larger areas of BE. Side-by-side resections can achieve complete eradication of the neoplastic and metaplastic tissue, and the procedure is repeated every 2 to 3 months until all visible BE has been removed. This technique frequently is used in patients with noncircumferential BE, and those with maximal extents of lesions up to 4 to 5 cm in diameter.

Short-Term Results: Few studies have used EMR as the sole treatment for eradication of all BE tissue. The majority of studies have used a multimodal approach, such as initial focal EMR followed by ablation to evaluate the efficacy of EMR in treating HGD and early esophageal adenocarcinoma. A retrospective study of 49 patients (67% HGD and 33% T1a adenocarcinoma) who underwent radical EMR with a mean follow-up of 22.9 months reported CE-IM in 97% of cases. No recurrence of dysplasia or cancer was observed in the 32 patients who completed the eradication protocol. However, nearly one-third of patients developed symptomatic stenosis that was successfully dilated.42 A multicenter randomized clinical trial enrolled 25 patients in a radical EMR group and 22 patients in a combined modality group (focal EMR with ablation therapy). During a mean follow-up of 24 months, 92% of patients in the radical EMR group achieved

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CE-IM compared with 96% in the combined modality group; similar high rates of CE-dysplasia or cancer were observed (all patients in the radical EMR group vs 96% in the group receiving the combined modality).43 Based on these studies and several others, radical EMR appears to have good short-term efficacy in treating HGD and early esophageal adenocarcinoma.44,45 Long-Term Results: Robust data now exist for longterm efficacy of EMR in patients with HGD and early esophageal adenocarcinoma. A prospective study of 100 T1a patients who underwent EMR with a mean follow-up of 36.7 months revealed CE-dysplasia or cancer in 99%—with metachronous lesions noted in 11%—that was successfully retreated with EMR.46 A retrospective study of 132 T1a patients with a mean follow-up of 43 months found that of the 75 patients who underwent EMR alone, 96% had CE-dysplasia or cancer, with 11% recurrences. All were successfully treated with a repeat EMR. 47 Another recent retrospective study of 76 patients with HGD or T1a cancer who underwent radical EMR and were followed for a mean of 40.6 months reported a CE-IM rate of 71% and CE-dysplasia or cancer in 100%.48 A recent meta-analysis of 10 studies of patients (n=620) who underwent radical EMR showed that CE-neoplasia was achieved in 95.7% of the patients, with CE-IM in 78%. During an average follow-up of 25.6 months, the estimated recurrences were esophageal adenocarcinoma: 1.7%; dysplasia: 3.9%; and IM: 14.3%.49 Based on the above studies, eradication of BE by widespread EMR has an excellent short-term efficacy with rates of 92% to 100%. However, during long-term follow-up to 5 years, metachronous lesions recurred in up to 10% to 15% of patients.

Complications: Adverse events associated with EMR generally are uncommon. Dysphagia, strictures

Figure 2. Barrett’s esophagus before and after radiofrequency ablation. requiring dilation,43,50-54 bleeding—both immediate and delayed for more than 48 hours after the procedure42,54-57—chest pain, and perforation are among the reported complications.58 Resection of more than 50% of the esophageal circumference is associated with higher rates of strictures.51 Radical EMR has been linked to more complications than focal EMR, including a high rate of strictures.42,43,58-63 In a recent metaanalysis on the use of complete EMR, major adverse events reported included perforation (1.8%), symptomatic strictures (36.5%), and significant bleeding (8.2%), with no deaths related to the procedure.49 Endoscopic Submucosal Dissection This technique is used for en bloc resection of larger lesions. Pioneered in Japan mainly for early gastric lesions, the practitioner uses a coagulation tip to mark around the lesion. Diluted epinephrine with 10% glycerol (multiple other agents such as hyaluronidate, mannitol, epinephrine, and indigo carmine can be used as well) is injected into submucosa to separate the lesion from the muscle layer. The mucosa initially is resected by needle knife and subsequently submucosal fibers and vessels by hook knife. The resected lesions are obtained for histopathology. The advantage of ESD over EMR is that larger lesions (7 cm) can be resected en bloc and more accurate information about depth of the lesion can be obtained.64,65 Short-Term Results: A single published study evaluated the outcome of ESD. The trial included 29 patients known to have large T1a cancers, with a median diameter of 2 cm, in the setting of BE. The patients underwent ESD. They were followed for a mean period of 17 months. An R0 resection was achieved in only 38.5% of the patients. CE-IM and CE-neoplasia were achieved in 53.6% and 96.4% of patients, respectively. The CE-IM

rate increased to 80% when additional treatment with RFA was performed.66 Another retrospective study evaluated the efficacy and safety of ESD in 75 patients for the treatment of visible lesions (median size, 2 cm) in BE (98.6% neoplasia and 76.4% esophageal adenocarcinoma [both T1a and T1b]). They were followed for a mean period of 20 months. The en bloc resection rate was 90%. CE-neoplasia was achieved in 92% and CE-IM was achieved in 73%.67 Long-Term Results: As ESD is relatively new, few studies have reported the long-term efficacy of the technique. One such study, of 25 patients (both T1a and T1b) who underwent the procedure with a mean follow-up of 30.6 months, showed that en bloc resection was achieved in 100% of patients but R0 resection was attained in only 72%. The mean size of resected lesions was 1.6 cm. There were no reports of neoplasia recurrence in patients who achieved R0 resection.65 Complications: Although the data are limited, published reports suggest that complications in expert hands are minimal. Some of the known complications are delayed bleeding, sudden cardiac death, incomplete R0 resection, and strictures.65,66 Radiofrequency Ablation Radiofrequency ablation is the most commonly used and best studied ablative therapy currently available for the treatment of BE (Figure 2). RFA can be performed with either a circumferential or focal device. The circumferential ablation device has a 3-cm cylindrical balloon with circular electrodes delivering the preset energy to ablate in a circumferential fashion. The focal ablation device is placed over the tip of the endoscope to ablate smaller areas with preset energy.

Short-Term Results: Several published studies have evaluated the short-term efficacy of RFA, which

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Figure 3. Barrettâ&#x20AC;&#x2122;s esophagus before and after cryotherapy. appears to be excellent. A retrospective registry study from 19 centers in the United Kingdom included 335 patients (HGD, 72%; T1a esophageal adenocarcinoma, 24%; and LGD, 4%) treated with either focal EMR and RFA (49%) or RFA alone (51%). After a mean of 2.5 treatments and 12 months of follow-up, CE-IM and CE-dysplasia were achieved in 62% and 81% of patients, respectively. Invasive cancer developed in 3% of patients and the cumulative risk for cancer progression at more than 5 years was 8%.68 Another retrospective study of a U.S. cohort of 54 patients with T1a cancer who underwent focal EMR combined with ablation therapy (81%) with a mean follow-up of 23 months, reported CE-dysplasia/cancer in 96% and CE-IM in 59%.54 A recent meta-analysis that included 3,802 patients from 18 studies evaluated the efficacy of RFA in treatment of BE during a 20.5-month followup period. The overall rates of CE-IM and CE-dysplasia were 78% and 91%, respectively.69 A recent Cochrane review of 1,074 patients from 16 studies evaluated the efficacy of RFA in treatment of BE during a 12-month follow-up period. The overall rates of CE-IM and CEdysplasia were 82% and 94%, respectively.37 Thus, based on the available evidence, short-term efficacy of RFA for CE-IM has been reported to be 62% to 82%, and CE-dysplasia as 81% to 94%. Cancer recurrence was seen in 3% of patients at the end of 12 months.

Long-Term Results: Several recent studies have focused on the long-term efficacy of RFA therapy after achieving initial successful eradication of BE.70 A multicenter analysis of 448 patients (HGD, 60%; T1a esophageal adenocarcinoma, 11%; LGD, 15%; and nondysplastic BE, 14%) who underwent EMR (55%) and RFA revealed that CE-IM was achieved in 26%, 56%, and 71% at 1, 2, and 3 years, respectively. Kaplan-Meier analysis showed that the incidence of recurrent IM at 1 and 2 years was 20% and 33%, respectively. Younger

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patients and those with short-segment BE responded much better to RFA.68 A single-center, long-term retrospective study of BE was conducted of 72 patients (HGD, 49%; T1a esophageal adenocarcinoma, 22%; and LGD, 17%). All patients underwent RFA alone. After a mean of 2.3 treatments and 9.5 months of follow-up, CE-IM and CE-dysplasia were achieved in 79% and 89% of patients, respectively. Superficial adenocarcinoma persisted in 5% of patients requiring esophagectomy. Thirty-four patients who achieved CE-IM were followed for 3 years with no further recurrences noted.

The overall rate of CE-IM was 73%.71 A recent retrospective multicenter study evaluated multimodal endoscopic eradication therapy in patients with HGD (n=135) and esophageal adenocarcinoma (n=111) who were followed for a median of at least 30 months. Despite initial high rates of CE, neoplasia reccurred in 8% and 9.5% of the 2 groups, respectively.72 A recent meta-analysis of multimodal endoscopic eradication therapy of focal EMR and RFA (7 studies; 348 patients; average follow-up: 20.5 months) showed pooled estimates of efficacy rates of CE-neoplasia of 95.4% and CE-IM 75.1%. The recurrence rates were as follows: esophageal adenocarcinoma: 1.8%; dysplasia: 2.7%; and IM: 15.7%. Progression to cancer was observed in 1.4% of patients.73 RFA therefore appears to have excellent short-term efficacy in achieving CE-IM (71%-93%) and CE-dysplasia (98%-100%). However, during long-term follow-up, 15% to 30% of the patients can experience recurrence of IM, and 8% can experience dysplasia, within 2 to 3 years of achieving CE-IM, thereby requiring ongoing surveillance.

Complications: RFA is generally well tolerated.

Bleeding, mucosal tears, dysrhythmias, chest pain, buried metaplasia (IM buried under neosquamous epithelium),70 recurrent esophageal adenocarcinoma, and

HGD68,75-80 are among the reported complications. A systematic review in 2011 showed that of 1,004 patients who underwent RFA, only 0.9% had buried metaplasia.74 Cryotherapy Cryotherapy is a relatively new technique to ablate BE, using an extremely low temperature to target tissue for destruction and ablation (Figure 3). This technique uses the concept of cellular apoptosis occurring between the temperatures of –76°C and –158°C.81 A repetitive cycle of rapid freezing and slow thawing results in the formation of extracellular and intracellular ice, which disrupts cell membranes and causes tissue ischemia through vascular thrombosis due to vascular stasis.51-83 Two types of cryotherapy devices are available: CSA Medical, Inc., with a modified cryo-decompression tube, delivers liquid nitrogen at –196°C, and GI Supply, with a suction catheter attached to the tip of the endoscope, uses high-pressure gas carbon dioxide at –78°C. The depth of the tissue injury depends on the duration of the freeze time.

The technical advantage of cryotherapy over other ablative therapies is that it is easy to spray over large areas of mucosa, causing destruction without precise close contact. Hence, it is particularly helpful in tortuous esophageal anatomy and at the area of the gastroesophageal junction. However, both robust short- and long-term results are lacking for this technique.

Short-Term Results: Two small observational studies reported the short-term efficacy of cryotherapy.

A retrospective study of 60 patients followed for a mean of 10.5 months found that after a mean of 3.4 treatments of liquid nitrogen cryotherapy, CE-dysplasia was achieved in 87% and CE-IM in 57% of treated patients.84 In another small study, 30 patients with BE (HGD, 25 and T1a, 5) underwent liquid nitrogen cryotherapy and were followed for a mean of 12 months.

There was downgrading of pathology in 90% of the patients with a mean of 5 sessions. The reported rates of CE-IM and CE-dysplasia/cancer were 3.3% and 60%, respectively.85 Finally, a trial of 23 patients treated with 6 courses of carbon dioxide cryotherapy and followed for a mean of 11.5 months found CE-IM and CE-dysplasia in 95.6% of patients. Twenty-five of these patients had failed earlier treatment with RFA, photodynamic therapy, and EMR.86 Long-Term Results: A single retrospective study including 32 patients with HGD evaluated the longterm efficacy of cyrotherapy. Patients underwent a mean of 4 treatments and were followed for a mean of 37 months. In this study, CE-HGD was achieved in 96% and CE-IM in 81% of patients.87 Long-term results were also recently reported for carbon dioxide cryotherapy. Sixty-four patients (20 treatment-naive, 44 rescue treatment) with HGD or esophageal adenocarcinoma were treated with carbon dioxide cryotherapy and followed for a median of 4.2 years. CE-neoplasia was achieved in 94% of the patients, with failure of

treatment noted in 6% of patients who were all essentially rescue treatment patients.88 Complications: Adverse effects reported with cryotherapy usually are self-limiting. Chest pain and dysphagia are the predominant complications with minimal stricture and rare perforation. Odynophagia and sore throat are among the other known complications.84,85,89 Buried BE was detected in 7% patients post-cryotherapy.88

Summary Current evidence suggests that multimodal endoscopic eradication therapy with focal EMR and RFA is the best treatment for BE with HGD and T1a esophageal adenocarcinoma and should be the preferred management option over surgery. Defining LGD remains a challenge, with poor interobserver agreement and wide variability rates in cancer progression reported in the literature (0.5% in a recent meta-analysis to 8.8% in a randomized controlled trial in Europe). Radical EMR is associated with more complications than focal EMR. Endoscopic submucosal dissection is technically challenging, with low R0 resection rates, making it less attractive. Therefore, the procedure is still in an incipient stage. Cryotherapy appears promising due to its low cost and the ease of the procedure, but more evidence regarding its long-term efficacy is required. Continued surveillance after achieving CE-IM is recommended due to risk for recurrence of IM, buried metaplasia, and subsequent development of neoplasia.77,90

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