June 2015 by McMahon Group

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The Independent Monthly Newspaper for Gastroenterologists

Volume 66, Number 6 • June 2015

ENDOSCOPY SUITE

Missed Manners? Scope group offers conduct guide for industry reps

he American Society for Gastrointestinal Endoscopy (ASGE) calls representatives of drug and device makers an “important” element in the provision of endoscopy care. But a lack see ASGE, page 14

Complications After Colonoscopy May Escape GI Tract PHILADELPHIA—Clinicians who perform colonoscopy tend to focus on the prevention of perforation, bleeding and other adverse events in the gastrointestinal tract that are commonly associated with the procedure. However, they should also be concerned about the see non-GI, page 14

Psychosocia al Issues Critical in Transition From Pediatrric to Adult IBD Care

arly Lindsay recalled her second-to-last visit with her pediatric gastroenterologist, at the age of 17. It was the first time her mother had sent her in alone. “S She was my ride to appointments. She was always there with me,“ said Ms. Lindsay, now 22 and a fourth-year student at Queen’s University in Kingston, Ontario, Canada. In the following months, Ms. Lindsay would meet her adult provider, see her pediatrician one final time, and d begin preparations to leave home for college and take on full responsibility for care of her ulcerative colitis. “The transition went really smoothly,” added Ms. Lindsay, who plans to become a nurse and help other young people with inflammatory bowel disease (IBD). Unfortunately, that wasn’t thee case for many of Ms. Lindsay’s peers with IBD, who encountered issues ranging from social isollation to financial constraints. Roughly 25% of people with IBD are diagnosed before the age of 20 years. The unique needs faced by patiients when they shift from adolescen nce to adulthood are often left unm met, a point underscored by research presented at the 2014 annual meetting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, in Atlaanta see Transition, page 22 (NASPGHAN; abstract 190).

I N S I D E

Celiac Sends Early Warning Signals

EXPERT ROUNDTABLE

Antibodies present years, even decades, before diagnosis

James J. Weber, MD Scott R. Ketover, MD Klaus Mergener, MD

WASHINGTON— —The immune signals of celiac disease appear long before diagnosis in some patients, researchers have found, suggesting an opportunity for much earlier identification—and treatment—of the condition. Using samples from military personnel, the investigators found that at least one antibody specific to celiac disease was present in serum in more

Daniel G. Walker, MD Bergein F. Overholt, MD

Managing a GI practic ce in an environment of change ........................................................... page 4

see Celiac, page 46 PRINTER-FRIENDLY L VERSION AVA V ILABLE A AT GASTROENDONEWS.COM

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First-Line Treatment Strategies for Helicobacter pylori Infection

Informatics promises clinical advances .............. page 20

RICHARD SAAD, MD, MS

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Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

see insert after page 46

WILLIAM D. CHEY, MD, AGAF, FAC F G, F FACP, RFF Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan Dr. Saad reports no relevant financial conflicts of interest. Dr. Chey has served as a consultant for AstraZeneca and Takeda.

First-Line Treatment Strategies Forr Helicobacter pylori Infection

elicobacter pylori remains a major cause

Appendicitis rates linked to industrialization...... page 30

of chronic gastritis and peptic ulcer disease; is strongly associated with

gastric mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma; and has been causally associated with unexplained iron-deficiency anemia, primary immune thrombocytopenia (formally termed idiopathic thrombocytopenic purpura), and vitamin B12 deficiency (Table 1). Given these known and purported potential complications of chronic H. pylorii infection, its identification mandates effective eradication. To date, no eradication therapy has been identified that guarantees a 100% cure rate. Moreover, a reduced efficacy of eradication regimens is observed over time, largely due to the development of antibiotic resistance by H. pylori. In clinical practice, the initial course of eradication therapy generally offers the greatest likelihood of treatment success. Therefore, careful selection of a firstline eradication regimen is essential. The most important factors to consider when choosing an initial course of eradication therapy should include the antibiotics previously taken by the patient and, when available, the regional antibiotic-resistance profile of H. pylori.

H. pylorii Eradication Therapy A variety of treatment regimens have been developed for the eradication of H. pylorii typically employing an antisecretory agent combined with 2 or 3 drugs possessing

antimicrobial activity taken concomitantly or sequentially for periods ranging from 3 to 14 days (Table 2). The overwhelming majority of recent clinical trials evaluating the efficacy of eradication therapy have been performed in southern Europe and the Far East. This is an important consideration given the regional variability in strains and antibiotic-resistance patterns of H. pylori.

Legacy First-Line Eradication Therapies The American College of Gastroenterology (ACG) last provided recommendations for the treatment of H. pylorii in the United States in 2007.1 The guideline recommended 14 days of a proton pump inhibitor (PPI), clarithromycin and amoxicillin (clarithromycin-based triple therapy); or 10 to 14 days of a PPI or histamine receptor antagonist, bismuth, metronidazole, and tetracycline (bismuth quadruple therapy) as the initial course

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • J U N E 2 0 1 5

Race, ethnicity, income tied to GI outcomes ...... page 34

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Novel Colon Cancer Model Implicates Four Genes nvestigators in the Netherlands have developed a novel cell culture model of colon cancer progression that they say mimics the disease more closely than any other model to date. The study, published in Nature (2015 Apr 29. [Epub ahead of print]), details how investigators from Hubrecht Institute and the University Medical Center Utrecht used a genome editing system to make genetic alterations to an organoid model of the small intestine and colon. An organoid is a three-dimensional cell culture model that functionally recreates an organ. Unlike two-dimensional models derived from cancerous lesions, an organoid can be derived from healthy tissue. Those features allow researchers to isolate the effects of individual mutations on cancer development, which often involves hundreds

Heard Here First See page 48

to thousands of mutations, said Jarno Drost, PhD, a postdoctoral student at Hubrecht Institute and first author of the study. Dr. Drost and his colleagues introduced specific mutations in four of the most commonly altered genes in colon cancer—KRAS, APC, TP53 and SMAD4—and performed an in-depth analysis of their contribution to the development of cancer. The findings indicate that mutating all four of these genes at one time is sufficient to convert a normal intestinal cell into an invasive tumor cell, Dr. Drost said. The new model will enable researchers to closely study the processes involved in colon cancer development, Dr. Drost said, and identify mutations that could be targets for novel treatments. —Ajai Raj

People have long focused their attention on other complex and expensive therapies but often ignore the importance of providing basic nutrition [in the ICU].

Vol. 66, No. 6

MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, PHD

Farmington Hills, Michigan

Sacramento, California

FREDRIC DAUM, MD

PETER R. MCNALLY, DO

Mineola, New York

Fort Carson, Colorado

STEVEN M. FABER, MD Elizabeth City, North Carolina

TARUN MULLICK, MD St. Charles, Illinois

RONNIE FASS, MD

JOEL E. RICHTER, MD

Cleveland, Ohio

Tampa, Florida

BARBARA B. FRANK, MD

DAVID ROBBINS, MD

Philadelphia, Pennsylvania

New York, New York

FRANK G. GRESS, MD

ELLEN J. SCHERL, MD

New York, New York

CHRISTOPHER JOLLEY, MD

PRATEEK SHARMA, MD

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

June 2015

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EXPERT ROUNDTABLE

GASTROENTEROLOGY & END DOSCOPY NEWS • JUNE 2015

Managing a Practice in an Environment of Change COMPILED BY MONICA J. SMITH

Bergein F. Overholt, MD

Scott R. Ketover, MD

James J. Weber, MD

Gastrointestinal Associates, Knoxville, Tennessee

President and CEO, Minnesota Gastroenterology, Plymouth

President and a CEO, Texas Dig Digestive Disease Consultants, Dallas s

Daniel G. Walker

Klaus Mergener, MD, PhD

Chief Operating Officer, Ohio Gastroenterology and Liver Institute, Cincinnati

GI Hospitalist st Se Services, Digestive tive H Health Specialists, Tacoma, Washington Taco

BOSTON—Before the 2015 GI Roundtable, a meeting dedicated to exploring issues and challenges relevant to the current climate of gastroenterology practice, the organizers invited attendees to send in their most pressing questions to be addressed on the floor during a lightly moderated discussion. Gastroenterology & Endoscopy News asked several participants to revisit those questions and expand on their answers. Should we develop an in-house pharmacy? Dr. Overholt: Like many of you, we have been thinking about this very seriously, and here are some of the observations that have emerged in the process. First, you’ll need to be a large enough group to support an inhouse pharmacy, which likely means five or six gastroenterologists. You will need to provide infusion services with biologics as well as standard generic drugs. You must be knowledgeable in your state rules and regulations, particularly staffing requirements. Forming a joint venture with a local compounding pharmacy to provide in-house pharmacy services may be a solution for a GI practice, or you can form a joint venture with one or another national pharmacy/infusion company. Finally, be sure to check with your medical liability company to be certain you are covered.

We do most of our procedures in a hospital that uses EPIC for their electronic medical records, and it will not incorporate a separate endowriter. How can we achieve the data input into the GI Quality Improvement Consortium (GIQuIC) through EPIC? Dr. Overholt: I previously discussed this issue with GIQuIC to ask how they deal with EPIC and the other EMR systems [that are incompatible]. They said

there are two things you can do. First is to download a form on the GIQuIC website. You or an endoscopic assistant can fill it out, and then your input clerk can upload it into GIQuIC. The second thing you can do is create your own GIQuICapproved template for your practice management system that allows you to input data from the hospital’s system into the template and then into GIQuIC. This option requires a bit of an investment and may be more feasible for a large GI practice. I know a large Illinois group used this approach.

We’re interested in creating a Center of Excellence (CoE) and would like to learn from other large GI practices that have created CoEs around GI disease states. What sort of components should we consider? Should we try to form a joint venture with a local hospital or other local partner? Dr. Overholt: Our group is in the process of developing a CoE in inflammatory bowel disease (IBD). We have obtained a great deal of help and advice from William Holderman, MD (Digestive Health Specialists, Tacoma, Wash.) and Larry Kosinski, MD (Illinois Gastroenterology Group). The CoE is a patient-centric group of professionals dedicated to providing excellence in care for, in our case, IBD patients. The CoE includes a gastroenterologist

director, an IBD-trained nurse practitioner or physician assistant, a registered nurse or licensed practical nurse for providing infusions, a dietician, a GI pathologist, a radiologist and importantly, surgical excellence with a colorectal surgeon interested in IBD. Access to a mental health professional is desirable. Also needed is experienced billing and precertification staff. The support of the GI group, including financial start-up costs and support of the group’s CEO, is vital. The team needs to have periodic educational updates. The focus of the entire team is on the patient. Education, communication, close and frequent monitoring, and early intervention for worsening patient symptoms are essential. Quality benchmarking and data tracking systems are also critically important components of the CoE. Such a team approach can be shown to insurance companies, and with the presentation of data and improved outcomes, reimbursement rate increases for the CoE are a clear possibility.

‘Forming a joint venture with a local compounding pharmacy to provide inhouse pharmacy services may be a solution for a GI practice, or you can form a joint venture with one or another national pharmacy/infusion company.’ —Bergein F. Overholt, MD

Whether to form a joint venture with a local hospital or medical group or do it alone is a local decision, and has to be determined locally. But if you do decide to form a joint venture, be certain you control the aspects of care mentioned above. Ultimately, excellence in team management of the patient and the CoE’s ability to provide superior care for the IBD patient will determine its success.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

How should we deal with integrated delivery systems and accountable care organizations (ACOs)? Dr. Ketover: I’m the chairman of a private A ACO in Minneapolis, with 1,200 independents and 1,600 to 1,700 employed physicians. The reason I think we should be involved in these networks is that, as GI w physicians, we’re pretty good at measuring our performance data. Very few other specialty physician groups do that, and this allows us to help lead the formation of quality metrics for the network. If these systems are going to be developed in your neighborhood, you might as well be at the table to have input into how the network can achieve improved delivery of care. w

What is your ratio of MDs to nonphysician providers? What do you use them for, how do you train them and what sources do you use to hire them? Dr. Ketover: Currently, Minnesota Gastroenterology (MNGI) has 67 GI physicians and 20 nurse practitioner/physician assistants (NPPAs). Our human resources professionals work closely with our site managers to recruit and hire the NPPAs. We will hire qualified candidates who are already in practice, or new graduates, and most do not have any GI-specific background. MNGI has a well-developed, three-phase training program for the newly hired NPPAs: a full week of classroom training at our central site, printed and electronic educational materials about GI diagnoses and treatments produced in-house for self-study, and two to three months of mentoring and shadowing our seasoned NPPAs. Our NPPAs work closely with our physicians. They see patients in both the hospital and clinic for consultations and follow-ups.

Statewide GI organizations: What are the pros and cons? Dr. Ketover: Our state does not have a GIspecific medical organization. We are very active in the national GI societies and DHPA [Digestive Health Physicians Association]. Health care reform and changes in performance and payment mechanisms will continue for the foreseeable future, and it is essential that independent GI practices become engaged at the front lines of health care reform to ensure that the independent private practice model of care delivery can thrive in the new world. Active participation in state and national medical organizations, particularly those with a GI focus, allows us the opportunity to help create our future.

How do we determine compensation for a GI hospitalist? Dr. Weber: GI hospitalists often feel like secondrate citizens. We have to treat our GI hospitalists like partners. Treat them fairly and compensate them well. As you all know, the compensation at the hospital for the physician’s inpatient care is not great, so we base our pay on the physicians’ billings rather than their collections. We pay them for the time they are in the hospital and especially for the night and weekend call they do,

EXPERT ROUNDTABLE

which frees up my doctors and me, and helps us be more productive during the week. When possible, I include them in the ancillaries—pathology, anesthesia and some of the other models.

How do you handle the slowing-down senior physician? Dr. Weber: One of the things we’ve done is establish a time frame. This gives the senior physician an idea of what life will be like after making the transition from full practice, and it also gives the practice a chance to hire a new physician. But we have found that the most contentious piece of all this is call. To let one physician out of call is very difficult for the younger doctor.

‘Ultimately, we need to change the physician reimbursement model from a production, or ‘eat what you kill’ model, to one that rewards physicians financially for their work effort—from which one can calculate a work relative value unit—and for the quality of that work.’ —James J. Weber, MD

Some centers set up a pay-for-call scheme. For example, if you have five doctors and you split up the call so that each doctor is responsible for 20%, the doctor who wants to get out of call can pay another physician a flat sum to take the responsibility away from him. We do this on market value, raising the price until someone is willing to pay to take that call. If you pay enough, someone is usually willing to do that.

How do you deal with an increasing number of lower-paying patients or plans? Dr. Weber: This is a very challenging problem, and one where I think having a relationship with the payor and being able to work with them is how we’ll get to the bottom line. We want to take care of the patients, and we want to take care of our referring doctors, but we have to change the mentality of how we do things internally. Ultimately, we need to change the physician reimbursement model from a production, or ‘eat what you kill’ model, to one that rewards physicians financially for their work effort—from which one can calculate a work relative value unit—and for the quality of that work. This quality may be defined by such metrics as patient outcomes, following proper screening intervals for endoscopy, adenoma detection rates, proper utilization of medicine, lower hospitalization rates and so forth.

Do you use any third-party services to optimize your website, portray your providers and to monitor and respond to Web activities and online ratings of your providers by patients?

Mr. Walker: We do not use a third-party website; we do those things minimally within the practice. As far as the marketing and promotion, that is one aspect of our practice that we should give more attention to. We have someone internally who reviews the various websites and we respond ourselves when necessary. At this point, we have no plans to employ a third-party service, and I’m not aware that many GI practices do.

Do you have any bundled payment arrangements with any of your local payors? If so, do these arrangements include “risk,” such as warranties for managing complications? Mr. Walker: We have had a couple of bundled payment arrangements with self-insured employers over the years, but not at this time. We have discussed the idea of bundling with insurers for 10 years or more, but they have historically indicated that they would have technological problems processing payments. The bundled payment arrangements we’ve had with the self-insured employers were not risk contracts. I’m aware of several gastroenterology practices that have or have had bundled payment arrangements, and we’re all wondering when the risk aspect of that is going to come into play. I know we’re all willing to discuss and evaluate this, but we haven’t been able to get many people interested in bundled fee-for-service arrangements, let alone including risk. I think many selfinsured employers don’t necessarily want to deal with each specialty one-by-one. Perhaps initiating bundled payment arrangements, including those with risk, may gain more traction in areas where there is a collaborative group of specialists, particularly independent specialists with independent ancillaries.

Ancillaries: Discussions in our past meetings have been all about acquiring them. Should we continue to add, just keep the ones we have or sell them? Dr. Mergener: Over the past 10 years, GI practices have added various ancillary services, namely pathology and anesthesia, because they provide important medical services to the patients and generate revenue. If practices use those additional monies wisely and reinvest them, it puts them in a good position to deal with this era of health care reform, where we have had to start using EMRs, measuring quality and restructuring our practices. My recommendation is if you’re already providing these services, consider continuing to provide them for their service to patients and revenue, but also, importantly, because bundled payments are likely to become more important for us, and we want to control all components of that bundle. If you have to send a biopsy to a third-party lab, you cannot provide your payor easily with a bundled price. If you don’t have ancillaries at this time, I think you should look into adding them.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Study Supports Living-Donor Liver Transplants BOSTON—Patients who receive a liver transplant from a living donor experience outcomes as good as—if not better than—those of individuals who receive an organ from a deceased donor, researchers have found. The findings mark a shift from studies in the 1990s and early 2000s, when three-year survival rates for live-donor liver grafts were not much above 60%. Now they are over 80% and appear to be climbing, according to the researchers,

19 7 8

—

who presented their findings at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases (AASLD; abstract 3). Experts said the results indicate that live-donor livers can help ease shortage of the organs available for transplant. “As a community, we should consider increased use of living-donor liver transplantation to help bridge the organ-supply demand gap, as long as it can be done without compromising donor safety,” said

David Goldberg, MD, medical director for living-donor liver transplantation at the Hospital of the University of Pennsylvania, in Philadelphia, who led the study. “Recent AASLD guidelines for transplantation suggest that living-donor transplantation is controversial. These data suggest that the issue, at least from the recipient side, is less controversial.” In the new study, researchers examined national transplant data from the Organ Procurement and Transplant Network/

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United Network for Organ Sharing between 1999 and 2012, to compare outcomes of liver transplant recipients when living versus deceased donors were used. Patients receiving a second liver and recipients of multiple organs were excluded from the analysis. The three-year unadjusted graft survival from living-donor liver transplants steadily rose over time, from 63.4% in 1999 to 82.2% in 2008. By 2008, outcomes were similar in terms of patient survival and graft survival whether a deceased or living donor was used. Center experience was clearly associated with transplant outcomes. Patients with autoimmune hepatitis or cholestatic liver disease were more likely to survive a live-donor transplant if they received care at an experienced center, defined as one that had performed at least 15 adult living-donor procedures.

‘I think decisions about whether to proceed to livingdonor liver transplant have to be made with the individual patient in mind, considering the patient’s disease, organ availability and center expertise. This study supports that approach.’ —Julie Heimbach, MD

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The researchers calculated a livingdonor risk index score to identify donor– recipient combinations to achieve the best outcomes. The formula included factors such as recipient age, weight, diagnosis and serum albumin, as well as donor age, weight and graft type. The researchers said they were surprised that the Model for End-Stage Liver Disease (MELD) score was not significantly associated with outcomes

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

among living-donor recipients, but that may reflect the fact that there was a narrow range of MELD scores and few living-donor recipients with a score greater than 25 at transplantation. At one, three and five years, the risk index score was moderately accurate at predicting graft survival. “This score, when validated in a separate cohort, which we are currently doing, may help to identify donor–recipient combinations to achieve best livingdonor transplant outcomes. This could potentially work under several different

scenarios,” Dr. Goldberg said. First, he said, when a recipient has several potential donors, the score might help to objectively measure the best donor for that given recipient. Currently, there is no quantitative way to do that. Second, the score could be used in the future if paired liver exchanges become a reality. Finally, by having data on predicted graft outcomes, clinicians may be able to counsel patients on predicted outcomes. Dr. Goldberg cautioned that the score was not yet ready to use for clinical purposes and requires further validation.

Julie Heimbach, MD, surgical director of Liver Transplantation at Mayo Clinic, in Rochester, Minn., said the study highlights patient populations that may do quite well following living-donor liver transplant. But Dr. Heimbach said she was not convinced it would translate into a change in clinical practice. “We would all much prefer not to operate on healthy people who are undergoing a major procedure for the benefit of someone else, thus having two people at risk for complications related to the surgery instead of one. If the

deceased-donor volume could meet the extreme shortage, that would be much better,” said Dr. Heimbach, who was not involved in the study. “I think decisions about whether to proceed to living-donor liver transplant have to be made with the individual patient in mind, considering the patient’s disease, organ availability and center expertise. This study supports that approach.” —Kate O’Rourke Drs. Goldberg and Heimbach reported no relevant financial conflicts of interest.

McMahon Group Acknowledges Exemplary Staff Every year the entire McMahon Group staff takes a moment to review the past year and celebrate the achievements of its various departments and the company overall. McMahon Group’s print and digital properties enjoyed signiﬁcant successes during 2014, often advancing in both readership and revenues. The following employees were singled out as exemplary at this year’s annual celebration. We thank them, and we thank our readers for their continued enthusiasm for our medical journalism, which has made many of our publications the best read in their specialty.

2014

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is senior lead developer in the IT Department, having input in all things digital, including our various websites, internal content management systems, and apps, to name a few.

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This award is for the outstanding editor among the publication, copy and projects editorial staffs. KEVIN HORTY Y won for his editorial direction of General Surgery News, the best-read publication in general surgery. His contributions have included an important effort to enhance our Web-based video offerings.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Industry, Patient Advocates at Odds on Gen Drug Labels

n late March, stakeholders gathered at an FDA meeting to debate a proposed rule that would allow generic drug companies to quickly update safety labeling without FDA approval. Currently, only brand-name companies have this authority. Representatives from Public Citizen, the National Center for Health Research, Consumers Union and other entities argued for passage of the FDA rule as written. A parade of individuals harmed by inadequately labeled generic

drugs also testified in support, including a woman who lost her hand to gangrene after Phenergan was delivered by IV push and a woman disabled from ciprofloxacin. Supporters argue that once generics enter the market, brand-name market shares drop and manufacturers are less vigilant about labeling updates. Brandname manufacturers also often cease production of their product and then there is no one responsible for updating safety concerns.

In the pivotal 2011 Pliva v. Mensing decision, the U.S. Supreme Court concluded that a generic company cannot be found liable when its labeling fails to include warnings about an adverse event, as long as the label matches brand-name labeling, even if a company is aware of potential problems. The Hatch-Waxman Act of 1984, which governs generic drugs, dictates that, with a few exceptions, generic drugs must carry the same label as their brand-name counterparts.

“Americans assume that they have the same legal protections and most upto-date safety information regardless of whether their drug is a brand name or not,” said Anna Mazzucco, PhD, scientific advisor at the National Center for Health Research. “The current situation creates a terrible double standard, making patients with generic drugs second-class citizens.” Testifying against the proposed rule were officials from companies including

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Apotex, Mylan, Perrigo and Sandoz, wh ho ho argued that the rule went against the sameness principle of the Hatch-Waxman Acct ct, generic companies did not have adequaatte information to update labels and consum mers would be confused by differing labelss.. “Patients are smart enough to undeerrstand why different labels may differr,” Dr. Mazzucco testified. “Temporary diiffferences in labeling between generic an nd brand-name drugs are far outweighed by the benefit to public health that comes from updating labels with drug safeetty information as quickly as possible.”

‘Americans assume that they have the same legal protections and most upto-date safety information regardless of whether their drug is a brand name or not. The current situation creates a terrible double standard, making patients with generic drugs second-class citizens.’

Almost all generic drug companies are backing an alternative solution proposed by the Generic Pharmaceutical Association (GPhA) and Pharmaceutical Research and Manufacturers of America. They argue that after a generic manufacturer enters the market, neither the generic nor the brand-name manufacturer should be able to update the safety warnings without first obtaining FDA approval. They ask that the FDA establish an expedited process for reviewing new safety information from see Generic, page 10

—Anna Mazzucco, PhD

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 Chair William D. Chey, MD 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

Statement of Need

Intended Audience

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 Medicine Division of Gastroenterology University of South Alabama Mobile, Alabama

Goal

Shanti Eswaran, MD

Learning Objectives

Clinical Assistant Professor Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Expiration Date: August 11, 2015

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. 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

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Generic continued from page 9

a brand-name or generic drug manufacturer. The FDA would notify all drug manufacturers if it deemed a change was necessary and a labeling change would then be made within 30 days through e-labeling, available via the Internet. “In order to achieve parity, [the] FDA should take responsibility rather than making ANDA [abbreviated new drug application] holders responsible,” testified Candis Edwards, senior vice president of

regulatory and clinical affairs at Amneal Pharmaceuticals. She argued that generic companies do not have complete information to make an informed label change. “If I have 10% of the market share, I don’t have access to the safety data generated by the other 90% of the consumers using a drug,” she said.

Increased Costs a Concern Industry representatives also argued that the proposed rule would greatly increase costs through increased liability

exposure and that these costs would be passed on to consumers. A study sponsored by GPhA estimated the proposed rule would increase generic drug spending by 5.4% and cost the government and private payors $4 billion annually. This figure is vastly different from the FDA’s estimate of $26,000 annually, which analysts say is low because the agency didn’t consider liability costs. Still, several individuals who testified at the meeting discounted the GPhA study estimate. “If patients knew they could not rely on the accuracy

of generic drug labels or seek legal remedies if harmed ... patients would demand brand-name drugs, and that would result in higher medical costs,” said Paul Brown, a representative of the Patient, Consumer, and Public Health Coalition. Michael Carome, MD, director of Public Citizen’s Health Research Group, said the alternative solution would slow down communication of safety information and make companies less liable. A final rule is expected Sept. 30, 2015. —Kate O’Rourke

Cases in Hyponatremia Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014 Faculty Michael L. Moritz, MD Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Expiration Date: November 11, 2015

Goal The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their significance in treatment. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Keeping Bariatric Patients From Coming Back

ith the risk for death from bariatric surgery now lower than that for hip replacement surgery, the bariatric surgery community is enlisting pharmacists to help achieve a new goal: reducing readmissions after the procedure. “I see pharmacists taking on a bigger role in care of bariatric surgical patients going forward,” said Bishoy Luka, PharmD, director of Clinical Pharmacy Services and Education at North Shore University

Hospital, in Manhasset, N.Y. Dr. Luka is one of a group of clinical pharmacists working with the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP), an initiative that establishes national standards for facilities and surgeons performing bariatric surgery. Earlier this year, MBSAQIP launched a national quality improvement project, Decreasing Readmissions through Opportunities Provided (DROP), which

aims to reduce by 20% the annual rate of readmissions within 30 days of bariatric surgery. One in every 20 patients who undergoes bariatric surgery in the United States is readmitted to the hospital within 30 days, according to an analysis of 18,296 bariatric procedures carried out in 2012 and presented at the 2014 Clinical Congress of the American College of Surgeons (abstract SP01), in San Francisco. When investigators looked more

closely at those readmissions, they found many could have been avoided by dietary counseling and filling prescriptions before hospital discharge. Based on that analysis, Dr. Luka and his colleagues put together a guideline for health care providers’ discussions with patients about medications. They also made a patient information video that highlights the need for diligent medication reconciliation.

In collaboration with

Innovations in HCV Screening and Treatment The Role of Direct-Acting Antiviral Agents To participate in this FREE CME activity, log on to

www.CMEZone.com Release Date: April 1, 2015

Expiration Date: April 1, 2016

Goal

Faculty Nizar N. Zein, MD Chief of Hepatology Medical Director of Liver Transplantation Cleveland Clinic Cleveland, Ohio Tarek T. Elsawy, MD, FACP Chief Medical Officer Cleveland Clinic Community Physician Partnership and Quality Alliance Cleveland, Ohio

Hepatitis C virus (HCV) infection is the most common chronic blood-transmitted infection in the United States; the goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of HCV.

Learning Objectives 1 2 3 4 5

Review the epidemiology, burden, and pathophysiology of HCV. Screen for and diagnose HCV infection in accordance with current recommendations. Discuss current and emerging treatments for HCV, including DAAs. Practice evidence-based management of AEs related to treatment of HCV infection. Formulate evidence-based treatment plans that optimize outcomes for patients with HCV.

Intended audience Supported by an educational grant from AbbVie.

The intended audience for this educational activity is primary care physicians and other clinicians who treat patients at risk for HCV or requiring treatment for HCV.

Accreditation Statement This activity has been approved for AMA PRA Category 1 Credit TM.

Acknowledgement Distributed via CMEZone

The Cleveland Clinic Foundation Center for Continuing Education acknowledges educational grants for support of this activity from AbbVie.

Now Available!

see Return, page 12

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

‘Pharmacists may be able to

Return continued from page 11

Polypharmacy a Problem Before undergoing surgery, patients typically are taking a significant number of medications to manage their comorbidities. After surgery, those medication requirements often change and drop dramatically, with one recent study presented at the bariatric meeting (abstract 103) showing use of diabetes and cardiac drugs fell by 73.7% and 47%, respectively, after surgery.

Pharmacists need to be involved in medication management and counseling, Dr. Luka said. “When we look at nationwide data, 3% to 5% of all emergency department visits are adverse drug– related,” he said. “Those are the kind of things that we are trying to prevent with better education.” Closing that education gap is “a role that pharmacists can fill,” Dr. Luka said. “I see that there needs to be much more involvement by pharmacists communicating with patients and with outpatient services. We need a communication plan

enhance patient throughput by providing the added benefit of tailoring medication therapy [on an individual patient basis.]’ —Bishoy Luka, PharmD

that includes hospital pharmacists, community pharmacists, primary care providers, surgeons and patients.” He stressed that pharmacists have a

unique role in relaying complex medication information to those who lack the depth of knowledge. “When we give a portion of that role to the pharmacist,

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

we allow for a focused and individualized educational session to tailor medication therapy across different patient populations. Pharmacists may be able to enhance patient throughput by providing the added benefit of tailoring medication therapy” to the patient. DROP requires pharmacists, or nurse practitioners working with hospital pharmacists, to meet with patients pre- and postoperatively to review their medications, he pointed out. Pharmacists or nurse practitioners counsel patients about use of β-blockers at the time of surgery,

management of antihypertensives, and discuss any medications for pain, posttransplant, anticoagulation, diabetes and mood disorders. DROP organizers identified patients considered at high risk for readmission. The list includes those with a body mass index greater than 50 kg/m2 (30.2% vs. 24.6% for patients who were not readmitted; P<0.001); longer operating times (115 vs. 132 minutes; P<0.001), index length of stay longer than four days (9.57% vs. 3.36%; P<0.001) and a preoperative diagnosis of diabetes (31.1% vs. 27.7; P<0.02).

“What’s helpful about that is for patients at a higher risk for readmission, we escalate coordination of care early on,” said John Morton, MD, president of the American Society for Metabolic and Bariatric Surgery and director of bariatric surgery at Stanford University School of Medicine, in Stanford, Calif. “We can decrease readmissions with a lot of commonsense things that can be done at the right time for the right patient.” In February, the DROP program was rolled out at about 100 randomly selected bariatric surgery centers in the

United States. It will be evaluated over a 12-month period before a final version is extended to all MBSAQIP centers. DROP was piloted in 2008 by Stanford’s Bariatric Surgery Department, where it reduced bariatric surgery readmissions by 75% by implementing changes in patient education, discharge planning and preand postoperative checklists. —Christina Frangou

Bill Proposes Changing CMS Readmissions Penalties

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.

esearchers who looked at readmission rates for acute myocardial infarction, congestive heart failure and pneumonia in 4,000 hospitals found that nearly 60% of the variation in hospital readmission rates was due to factors beyond the control of hospital staff, such as community attributes including unemployment rates, never-married residents and fewer general practitioners per capita ((BMC Health Serv Res 2015 Feb. [Epub ahead of print]). Yet, the Centers for Medicare & Medicaid Services (CMS) penalizes hospitals for an excessive number of readmissions for certain conditions. Hospitals in low-income neighborhoods have higher readmissions scores, and therefore receive lower reimbursements than hospitals in middle-class or wealthy neighborhoods, according to the American Hospital Association (AHA). The AHA urged Congress to support the Establishing Beneficiary Equity in the Hospital Readmission Program bill (Act, S. 688/H.R. 134), which would require CMS to account for patient sociodemographic status when making risk adjustments to the readmissions penalties. At a briefing on Capitol Hill, the AHA also released a new TrendWatch Report showing that overall the national readmission rate fell to 17.5% in 2013, after holding steady at around 19.5% for many years. However, certain populations are more likely to be readmitted. Medicare beneficiaries with multiple chronic conditions have higher readmission rates (9% if they have one condition and 25% if they have six or more). —GEN Staff

ASGE continued from page 1

of professionalism and other problems, including rare instances of reps performing procedures on patients, has prompted the group to release new guidelines for incorporating these visitors into clinical settings. The recommendations touch on issues ranging from the appropriate roles and credentialing of reps to the limits of their involvement in procedures. The industry groups AdvaMed and Pharma already have codes of conduct for company representatives who deal with clinicians in a patient care setting. However, the statement “was prepared because there is no formal guidance to define the roles and responsibilities of industry representatives in the endoscopy unit,” according to the ASGE (Tables 1 and 2). Douglas Faigel, MD, FASGE, a coauthor of the guidance and presidentelect of the ASGE, said the society has been working “on the issue of representatives and their education for a long time. The more we thought about it, the more we decided we really needed a document to cover all of the types of industry rep that we interact with, and the level of professionalism clinicians should expect.” Dr. Faigel, of Mayo Clinic, in Scottsdale, Ariz., said some of the ASGE’s

roughly 10,000 members had relayed concerns that industry reps at times seemed uncertain “about what it is we do. Sometimes we’d hear of interactions that were less than optimal.” More concerning, the ASGE has received reports from members concerned that reps had been too involved in clinical procedures—something that should never happen, Dr. Faigel said. A representative “should not under any circumstance participate in the procedure or any patient care activity,” according to the guidance. “The role of the representative is strictly observational or limited to providing technical advice or information related to the product being used.”

Some Openings for Interpretation But vague language leaves some room in the document for interpretation, most notably on the issue of patient consent to the presence of representatives during a procedure. In one instance, the guidelines state that patient consent “is recommended and should comply with institutional policy.” However, in a subsequent passage, the document states that representatives should be allowed “only upon the consent of the patient.” The ASGE guidelines are not intended to supplant an institution or practice’s own procedures, Dr. Faigel

non-GI continued from page 1

potential for non-GI complications in patients with certain risk factors, according to research presented at the 2014 annual meeting of the American College of Gastroenterology (abstract P1636). “We found a considerable risk for delayed vascular, cardiac and pulmonary adverse events within 30 days post-colonoscopy in patients with identifiable comorbid conditions,” David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, in Norfolk, told Gastroenterology & Endoscopy News. To identify factors that put patients at risk for postcolonoscopy adverse events, Dr. Johnson and his colleagues analyzed data from 495,902 commercially insured patients who underwent diagnostic or interventional endoscopy in the United States between March 2011 and the end of February 2012. The data were obtained from the IMS LifeLink Health Claims Database. Using billing and diagnostic codes, the researchers tracked the occurrence of gastroenterological and nonGI adverse events 15 and 30 days after colonoscopy in patients taking (high risk) and not taking (average risk) prescription antithrombotic drugs, and those who had (high risk) or did not have (average risk) obstructive sleep apnea (OSA) or chronic obstructive pulmonary disease (COPD). In their primary analysis comparing average-risk patients with high-risk patients who underwent colonoscopy, Dr. Johnson’s group found that the risk for non-GI adverse events was significantly higher among patients on antithrombotics and those with OSA or COPD than

Key Recommendations from rom The American Society forr Gastrointestinal Endoscopy opy • Appropriate training and education for representatives is essential. • Representatives must comply withh AdvaMed and Pharma codes and local policies on interactions with health care professionals. • Patient consent is recommended for intraprocedural observation. • Representatives should not take vvideos or photographs during procedures. • Negative commentary regarding a competing device or device manufacturerr should be avoided by all professionals. • Representatives may not participate in a “hands-on” fashion during endoscope procedures. • Representatives should not advise on clinical decisions or equipment selection for specific procedures or patients.

added, but rather are meant as a list of best practices. “These are not rules. Every institution and endoscopy unit has to set up their own procedures,” he said. The guidance concludes with a 14-point list of “key recommendations”

among average-risk patients. In the latter, the most common complication was GI bleeding. The risk for overall complications was 4.67% in average-risk patients, 15.41% in patients on antithrombotic drugs and 6.63% in patients with OSA or COPD. The vast majority of adverse events (94%) occurred within two weeks of colonoscopy, according to the investigators. The secondary analysis, comparing matched cohorts of 355,132 patients who had colonoscopy with the same number of those who did not, found that the risk for non-GI adverse events was higher in highrisk patients who had undergone a colonoscopy. The researchers also found that the risk for non-GI adverse events increased with age. “I think we’re naive to recognizing the perhaps more serious implications when we talk about vascular, cardiac and pulmonary events that occur in these patients with comorbid diseases,” Dr. Johnson said. “The global risk is way beyond the periprocedural risk that we consider with a GI focus. We need to be aware of this as we develop risk mitigation strategies for these patients, and to use a better risk-to-benefit assessment for selecting endoscopy in patients with comorbid conditions that put them at risk for adverse events that may be more formidable over time after the colonoscopy,” he added.

Real-World Picture? Linda S. Lee, MD, director of endoscopic education and Women’s GI Health at Brigham and Women’s Hospital, and assistant professor at Harvard Medical School, both in Boston, noted that the study found a higher rate of complications after colonoscopy than what is typically reported. “This could be because the data draw from all centers

(b ) T (box). Topping i th the li list: t “A “Appropriate i t training and education for representatives is essential.” That item dovetails with the ASGE’s own effort to train representatives, the Recognized Industry Associate program (ARIA). According to the ASGE website, the ARIA course, which costs $1,000 per registrant, “is intended to provide an overview of basic GI [gastrointestinal] anatomy and physiology as well as commonly encountered gastrointestinal diseases and their endoscopic findings see ASGE, page 17

across the United States and not just expert centers,” Dr. Lee said. “So this may be more reflective of what happens in the real world across various communities and not only at academic centers.” Dr. Lee said the increased rate of non-GI cardiac events in patients on antithrombotic medications was concerning. “It is unclear whether this resulted from not resuming the antiplatelet and/or anticoagulant agents soon enough after the colonoscopy,” she said. “Despite the matched cohort portion of the study showing increased rate of non-GI adverse events in patients who had undergone colonoscopy, it is still possible that some of those non-GI adverse events were not a direct result of the colonoscopy itself, as other comorbidities including diabetes and history of cardiac disease were not examined.” Dr. Lee added that it would also be helpful to know what type of sedation patients received and if that affected the rate of complications, as well as any differences in complications between patients who underwent pure diagnostic colonoscopy and those whose procedure included polypectomy, biopsy or other intervention. “Overall, having any comorbidity examined in this study starting at the age of 50 seems to increase the rate of complications with the highest risk for those prescribed antithrombotic medications at any age, and especially worse in those over 70,” Dr. Lee said. “The higher risk of adverse events in those 70 and older supports the need for a discussion with these patients about the risks and benefits of undergoing colon cancer screening with colonoscopy. Also, this data supports that being on multiple antithrombotic agents leads to increased adverse events.” —Monica J. Smith Given Imaging/Covidien provided support for the data extraction from IMS Database.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

ENDOSCOPY SUITE

The Quality Colonoscopy: Do You Know It When You See It? PHILADELPHIA—High-quality colonoscopy is critical for the detection and prevention of colorectal cancer, the reduction of missed tumors and, in this era of increasing transparency, the financial health of a practice. In January, the Task Force on Quality of Endoscopy published an update on quality indicators for colonoscopy including three previous and 15 proposed quality indicators ((Am J Gastroenteroll 2015;110:72-90). Aasma Shaukat, MD, described three of these indicators—adenoma detection rate (ADR), withdrawal time and bowel preparation—and how to improve quality in practice at the 2014 annual meeting of the American College of Gastroenterology. “Quality indicators should be evidence-based, interpretable and, if necessary, modifiable by intervention,” said

Dr. Shaukat, chief of gastroenterology at the Veterans Affairs Medical Center and associate professor of medicine at the University of Minnesota, in Minneapolis. ADR is well accepted as a quality indicator and has been shown to have an inverse relationship with interval cancers (N Engl J Medd 2010;362:1795-1803; N Engl J Medd 2014;370:2539-2541). “Factors associated with higher ADRs are complex and there are a lot of them,” Dr. Shaukat said. Bowel preparation is endorsed as a quality measure by the Multi-Society Task Force on Colorectal Cancer Screening and is gauged by both documentation of the quality of the bowel preparation and the number of colonoscopies that need to be repeated as a result of poor bowel preparation.

‘We have to be dedicated to quality and our best practices. Attention to detail, clear understanding of the technology and dedication to patients’ needs are necessary.’ —Felice Schnoll-Sussman, MD

The recommended withdrawal time for exams without biopsies or polypectomies is six minutes, but timing is meaningless without good technique, Dr. Shaukat said. “Adequate distension, washing and cleanup, looking behind folds and segmental inspection are four essential components of technique. Simply mandating longer withdrawal time is not sufficient.”

Improving Quality Measures In Practice Although it’s impossible to guess how many gastroenterologists engage in quality improvement efforts, the concept of quality seems to be increasingly on physicians’ radar. “It would be hard to find a GI meeting where quality was not on the curriculum,” said Irving Pike, MD, senior vice president and chief medical officer of John Muir Health, in Walnut Creek, Calif. Felice Schnoll-Sussman, MD, associate professor of clinical medicine at Weill Cornell Medical College, in New York City, said all physicians should strive for consistent quality when delivering GI care. “We have to be dedicated to quality and our best practices. Attention to detail, clear understanding of the technology and dedication to patients’ needs are necessary,” Dr. Schnoll-Sussman said. “We need to look carefully at who performs these procedures. Our patients deserve the best, always.”

Raising awareness is the first step in any trend or movement, but how do physicians go about actually improving the quality of their exams? Dr. Shaukat described a few approaches. “There is a host of emerging technologies with some promising data; it’s an exciting area and we’ll probably see more of these [technologies] as studies come out on their role in improving ADR,” she said. Meanwhile, one rather prosaic approach, the use of a split-dose bowel preparation, addresses two quality indicators by increasing the likelihood of patients achieving an excellent prep and possibly doubling physicians’ ADR (Ali( ment Pharmacol Therr 2010;32:637-644). “This is a very effective intervention, and if you’re not doing it already, you should consider doing so,” Dr. Shaukat said. The simple act of being observed, known as the Hawthorne effect, also improves the quality of exams ((Am J Gastroenteroll 2010;105:2312-2317). “Scores taken before and after physicians knew they were being recorded improved in every quality aspect,” Dr. Shaukat said. She does not recommend that physicians be observed or monitored in general, but that “proctoring could be considered for low performers.” Multipronged interventions have had mixed results. The EQUIP trial see Quality, page 18

Scans Detect Complete Normalization in Crohn’s Patients

nflammatory changes in Crohn’s disease, as seen on computed tomography, can be reversed with biologic agents, new research shows. The study suggests that sequential computed tomography enterography (CTE) may prove particularly valuable in assessing the activity of Crohn’s disease and patients’ response to therapy. The researchers presented their findings at the 2014 annual Advances in Inflammatory Bowel Diseases conference (abstract P-44). “An emerging paradigm for the management of Crohn’s is the concept of ‘treat to target,’” said Parakkal Deepak, MD, a gastroenterologist at Mayo Clinic, in Rochester, Minn., who led the new study. “But the target is in question.” The complete healing of the mucosa, as ascertained by colonoscopy, has been a proposed target, Dr. Deepak said. Yet Crohn’s disease mainly affects the small bowel—many parts of which cannot be visualized with colonoscopy. Could CTE help complete the picture? In an attempt to answer that question, Dr. Deepak and his team performed a retrospective study of patients with Crohn’s disease who underwent serial CTE while being treated at Mayo Clinic between 2002 and 2008. Of the 63 patients identified, 28 (44%) responded to therapy, with all lesions improved on the second CTE. Six (10%) patients had complete normalization, defined as a score of 0 or 1 on a 5-point scale (0 = none, 1 =

equivocal, 2 = mild, 3 = moderate, 4 = severe) for all recorded parameters of intestinal inflammation—mural enhancement, comb sign, stratification and fatty proliferation—as well as a reduction in lesion length to zero. All six patients who achieved complete normalization of abnormalities detected on CTE underwent two scans, with a median time between scans of about 810 days. The six patients were also taking combination therapy with a thiopurine (azathioprine or 6-mercaptopurine). The researchers observed no significant differences between healers and nonhealers in terms of median age at first CTE, sex or median duration of disease. Sample sizes, however, were small, limiting the power of the comparisons, Dr. Deepak said. The new research follows previous work published in 2011 from a team led by David Bruining, MD, a gastroenterologist at Mayo Clinic, in Rochester. In that study, the researchers concluded that radiologic response in patients who underwent serial CTE imaging while receiving infliximab (Remicade, Janssen) did not always align with clinical symptoms, serum biomarkers or endoscopic appearance. They noted that CTE might be used as a “complementary approach to identify mural healing or inflammation not detected by other methods” (Clin Gastroenterol Hepatoll 2011;9:679-683). “It is good to know that CTE does change with medical therapy,” said Maria Abreu, MD, a gastroenterologist

at the University of Miami’s Miller School of Medicine, who was not involved in the new study. She noted, however, that it is not clear from the study how long it might take after starting therapy before a patient experiences improvement. Therefore, it is also not clear when the imaging should be repeated. Dr. Deepak’s team is now looking into how patients fare further down the road. They’re tracking treatments, surgeries and hospitalizations among those who had a radiologic response at first follow-up CTE or magnetic resonance enterography. Meanwhile, the team also hopes to better identify which patients with Crohn’s disease might achieve complete healing of inflammation markers on follow-up scans. “We want to be able to predict down the line who these patients are,” he said. “This is a preliminary study toward that goal.” —Lynne Peeples Dr. Deepak reported no relevant conflicts of interest. Dr. Abreu reports that she and/or her spouse/life partner have at present and/or have had within the past 12 months a relevant financial relationship in the form of consultant fees with AbbVie Labs, Asana Medical, Ferring Pharmaceuticals, Focus Medical, GI Health Foundation, GSK Holding Americas, Hospira, Janssen, Mucosal Health Board, Pfizer, Prometheus Labs, Prova Education, Salix Pharmaceuticals, Sanofi Aventis, Shire Pharmaceuticals, Takeda, UCB, UEGW Israeli Physicians Group and WebMD Health.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

ASGE continued from page 14

through a lecture-based format. A handson experience will introduce both basic and advanced endoscopic techniques. To ensure industry representatives are being recognized for their efforts, participants who successfully complete the ARIA course are recognized with the ASGE ‘ARIA Seal,’ an ASGE certificate of completion, and also receive a number of other prestigious recognition benefits and marketing tools.” The first live course took place in 2013; a course last fall led to a marked increase in basic knowledge about GI issues, boosting the average score from 52.1% before the test to 96% after, according to the society. Manoop S. Bhutani, MD, professor of medicine and director of endoscopic research and development at the University of Texas MD Anderson Cancer Center, in Houston, said industry “make[s] an important contribution to the endoscopy unit by providing in-service and training to the endoscopy staff and the physicians. This is even more important when a new technology or device is introduced, and during those times it is extremely helpful to have the reps in the room during the endoscopy procedure.” Feedback provided by the endoscopist and the staff to representatives about the technical performance of a device—or lack thereof—helps industry to improve

ENDOSCOPY SUITE

technology and fix any technical failures, Dr. Bhutani added. “Overall, I believe this helps patient care, education and technological development in endoscopy. A code of conduct for industry reps should be extremely helpful going forward to various endoscopy units around the country to establish their own written policy regarding industry reps in the endoscopy unit and endoscopy procedure rooms.” Dr. Bhutani said that although he has never had a bad experience with a rep, “I am sure many colleagues around the country have had them. The guidelines

would have certainly helped them.” Dr. Bhutani added that in his view, “the endoscopist in the room is in charge of the case, and it is his or her duty to ensure that a rep in the room is acting in a professional manner, and if that is not the case, to rectify the situation one way or another.” That can include asking the rep to leave or correcting an action by the rep that deviates from proper conduct. “No rep is allowed in my procedure room without my permission,” he said. “Sometimes just educating the rep about what is acceptable and not acceptable

may be enough, as nobody may have called their attention to the issue in the past. I usually find reps to be very receptive about any feedback I give them, and most of the time they are really appreciative about the privilege of being in the procedure room. It is a mutually beneficial endeavor, as the fringe benefit of the education they receive by being in the procedure room is enormous, making them better at their job as well.” —Adam Marcus Dr. Bhutani is a member of the editorial board off Gastroenterology & Endoscopy News.

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Table 1. Types of Industry Representatives

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Device and accessory sales Endoscope and equipment sales Pharmaceutical Product support specialists Market development managers Scientific liaisons Senior leadership team members Other (project-specific) representatives

Table 2. Roles of Industry Representatives Provide sales and service for device and accessories Provide sales and service for endoscope and major equipment Introduce and incorporate new technology Provide equipment-related in-service for staff Deliver provider and staff education for use of pharmaceuticals

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

ENDOSCOPY SUITE

Life in the Era of CRE BOSTON—In recent months, after the deaths of two endoscopy patients from carbapenem-resistant Enterobacteriaceaee (CRE) infection at the Ronald Reagan UCLA Medical Center, in Los Angeles, the use of reprocessed duodenoscopes has received increased attention from the FDA and the media (see Gastroenterology & Endoscopy News, April 2015, page 1). Steven Edmundowicz, MD, professor of medicine and chief of endoscopy at Washington University Hospital, in St. Louis, fielded CRE-related questions and concerns from gastroenterologists at the 2015 meeting of the GI Roundtable.

history of infections associated Q: The Q with use of duodenoscopes goes back

more than 40 years. Why is this problem getting so much attention now? A: There has been no real change in our practice; the difference is that these bacteria can now be “fingerprinted” and tracked by molecular biological techniques. It is now possible to show that the bacterial infection in patient A is the same exact bacteria that were present in patient B the week before.

likely is it that a CRE outbreak Q: How will occur at my institution? A: We still believe the risk is quite low, with less than 200 known cases in the United States with a case volume of 500,000 endoscopic retrograde cholangiopancreatographies (ERCPs) per year. But the incidence of CRE infections is slowly increasing and all of us are going to have this problem at our institutions within the next 10 years.

Q: What should I tell worried patients?

A: Tell your patients what your hospital is doing about the issue. For instance, let them know that you are reviewing your high-level disinfection process with the manufacturer of your endoscope and that you are following all steps: maneuvering the elevator during the cleaning process and using the specific brushes and

Quality continued from page 16

showed that educational interventions improved ADR considerably ((Am J Gastroenterol 2013;108:219226), but other studies have shown no change in ADR after performance discussions and counseling of low performers (Endoscopy 2007;39:314-318; Gastrointest Endoscc 2010;71:1253-1259). In her own experience, however, when Dr. Shaukat and her colleagues tested the effectiveness of multiple interventions in their practice, they found that education and feedback did eventually prove useful. “With some persistence, we did see improvement, and over time ADR improved significantly,” she said.

soak times the manufacturer recommends. Even doing that, there is about a 2% failure rate of high-level disinfection eliminating bacteria from those endoscopes; most of our informed consent does relay the risk for infection with ERCP.

more or less likely Q: toArepassanyonendoscopes CRE infection? A: I would assume that every endoscope with an elevator has a risk for transmitting CRE infection. Endoscopic ultrasound (EUS) scopes with elevators are also at risk. We do know of one case of a transmission with an EUS endoscope reported to a local health agency, so it does occur.

Mason Medical Center, Q: inVirginia Q Seattle, has doubled the number

of duodenoscopes it uses so that it can put them through the sterilization process and wait for cultures to come back while avoiding bottlenecks in patient care. Is that approach likely to become the national standard? A: Current recommendations from the Centers for Disease Control and Prevention and the FDA do not include this process for all centers. There are some problems associated with this approach, which Virginia Mason adopted due to the lack of availability of ethylene oxide (ETO) sterilization in the Seattle region. We have now had two outbreaks where endoscopes cultured after the infection [was transmitted] were culture-negative, so there may be false-negative cultures. Also, it would cost each institution $1 million to $2 million to double or triple its endoscope supply and institute a culture-andhold process. Clearly, if you have an outbreak, something like this or ETO sterilization has to be done.

all facilities perform ATPase Q: Should testing? A: We have employed ATPase testing at our facility and have found that even endoscopes we thought very well cleaned had high levels of adenosine triphosphatase

Dr. Shaukat urged her colleagues in the specialty to make a commitment to quality if they have not already done so. “Have a plan to measure and report quality metrics; consider developing a quality improvement plan; and consider participating in a registry such as GIQuIC [GI Quality Improvement Consortium],” she said. Dr. Pike said many physicians are thinking about quality, but he is concerned that even those who are measuring quality in their practice internally may not be submitting those data to a registry, an oversight that could have significant financial consequences sooner than they think. “Physicians who are not reporting to PQRS [Physician Quality

Reporting System] or through a quality clinical data registry such as GIQuIC today, in 2015, will face a 2% to 6% reduction in reimbursements from CMS [Centers for Medicare & Medicaid Services] starting in 2017,” he said. According to the CMS’ 2012 Experience Report, 5,875 gastroenterologists are participating in PQRS, representing about 43% of those who are eligible to participate in the program. “Before, there was only a carrot for measuring and reporting quality,” Dr. Pike said “Now, there are very few carrots for doing this, but there’s a pretty big stick for nott doing it.” —Monica J. Smith

(ATP) remaining. After we ran them through the cleaning process several times, the levels were almost down to zero. There is no validation, however, that ATPase testing protects your endoscopes from having bacteSteven Edmundowicz, MD ria—endoscopes that have had very low ATP levels have been culture-positive, and endoscopes with high levels have been culture-negative. You could use ATPase testing as a guide to detect individuals who are not cleaning endoscopes satisfactorily.

Why not put the elevator into the Q: disposable piece? A: I think all manufacturers have looked into ways to solve this problem, and that has been considered. The problem is, we like the feel we get from the elevator system. Our ability to manipulate the tools carefully requires a quality instrument. Whatever manufacturers do, it will take several years for them to implement a design change, get it approved and roll it out. In the meantime, we need to deal with this problem.

If a new design will be a long time Q: coming, Q do we have any other novel solutions to look forward to?

A: The biggest hope now may be with some of the sterilizing agents that are coming out, such as the hydrogen peroxide–like substances and oxygen free radical substances that may be able to sterilize scopes with a soak time of an hour or so. What I would suggest for now is to review your endoscope cleaning processes; make sure you talk to your infection control officer and know what you’re going to do at your site; and be prepared to answer questions from your patients. —Compiled by Monica J. Smith

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Biomedical Informa Profound Clinical A PHOENIX— —The best days are ahead for biomedical informatics, with the fast-growing field being analogous to aviation before the advent of the jet age, an expert told attendees of the Society for Technology in Anesthesia 2015 annual meeting. Biomedical informatics and the overarching discipline of informatics are fast gaining traction across the nation’s health care system as more and more clinicians gain expertise in the field, said Edward H. Shortliffe, MD, PhD, a leading informatics expert. The changes have the potential to transform how data are gathered and used in a way that could revolutionize both medical research and patient care, said Dr. Shortliffe, professor and senior advisor to the executive vice provost in the College of Health Solutions at Arizona State University, in Scottsdale, and adjunct professor of biomedical informatics at Columbia University, in New York City. Yet challenges remain, with some of the technology still problematic and with lingering skepticism among some medical care providers about the utility of “big data” in the medical arena.

Electronic Health Records

Regional and National Public Health and Disease Registries

Providers Caring for Patients

New Standards for Prevention, Diagnosis and Treatment Information, Decision-Support and Order-Entry Systems

Decades of Growth “We are basically a couple of decades into a very long process, and getting it right will take decades more,” Dr. Shortliffe said. Biomedical informatics has its roots in the dawn of the computer age. The use of statistics and computers for diagnosis was first recognized in a seminal piece that appeared in Sciencee in 1959, “Reasoning Foundations of Medical Diagnosis” (1959;130:9-21). Computers were first used in biomedicine in the 1960s, a decade that also saw the first discussion of the possibility of electronic storage of medical records, Dr. Shortliffe noted. Then-president George W. Bush’s 2004 call for universal electronic medical records within 10 years set the stage for the latest surge in innovation. Stimulus legislation passed in 2009 under the Obama administration further fueled the health care technology boom, using carrots and sticks to push providers to adopt electronic record keeping and data collection. A spokeswoman for the Department of Health and Human Services has estimated that 90% of doctors will be using health care information technology (IT) by 2019, Dr. Shortliffe said. There also has been an explosion in “mid-career learning” that is starting to produce more and more clinicians with a deeper understanding of informatics, exemplified by the announcement by the American Board of Medical Specialties (ABMS), in 2011, of plans for a new subspecialty in clinical informatics. A thousand medical practitioners, from surgeons to anesthesiologists, took the board exams in 2013 and 2014, with another large group expected to sit for the boards this fall, Dr. Shortliffe said. Starting in 2018, only physicians who have taken a fellowship in clinical informatics will be able to become board-certified by the ABMS in the new subspecialty, he said. That, in turn, will provide a spur to medical schools to integrate informatics more closely into their teaching. Currently, there are already a growing number of educational programs in biomedical informatics at colleges and universities at the MS and PhD levels, as well as fellowships for working professionals in the field.

Pooled Clinical Data

Biomedical and Clinical Research

Creation of Protocols, Guidelines and Educational Materials

A “Learning Health Care System”

Figure. An Envisioned Cycle That Ties Patient Care with Knowledge Creation and Dissemination. The number of training programs in applied health IT is on the rise, while health care organizations are hiring chief medical information officers who increasingly have this kind of training and experience, Dr. Shortliffe said. “I am hoping this will have a salutary effect on how medical schools look at their curricula,” he added.

Informatics and Anesthesia As interest in informatics grows, one challenge has been to hammer out a nomenclature for the field that is universally accepted. A variety of terms are now in use, not only “biomedical informatics,” but also “health informatics” and “medical informatics.” Dr. Shortliffe said his solution has been to refer to biomedical informatics, or “BMI,” when speaking of the core science of the field as it relates to biomedicine and health, with the unmodified term “informatics” reserved for the larger domain-independent discipline of information management and data analysis. The characteristics of BMI include: • Developing theories, methods and processes for the generation, storage, retrieval, use and sharing of biomedical data • Building on computing, communication and information sciences and their application in biomedicine • Supporting reasoning, modeling, simulation, experimentation and translation across the spectrum from molecules to populations • Drawing on the social and behavioral sciences to inform the design and evaluation of technical sciences with the recognition that people are the ultimate users of biomedical information.

The use of cognitive informatics has provided valuable insights into both clinicians and patients as computer users. This knowledge, in turn, has helped reduce errors, boost patient safety and clinical teaching, and improve decision support systems, Dr. Shortliffe said. Big data—massive data sets culled from social media and other sources—are also starting to play an increasingly important role, with one example being the analysis of millions of Internet searches to detect negative but previously unknown drug interactions. As an example, researchers in 2011 confirmed a major health problem affecting patients through data mining of the FDA’s Adverse Event Reporting System. Patients who took both pravastatin (Pravachol, Bristol-Myers Squibb) and paroxetine wound up with elevated glucose levels, regardless of whether they had diabetes. Two years later, another group of researchers published a paper in the Journal of the American Medical Informatics Association (2013;20:404-408) that came to a startling conclusion. A review of Internet search logs revealed a spike in searches by consumers featuring the two drugs in question as well as symptoms associated with hyperglycemia, with 82 million queries in 2010, Dr. Shortliffe said. The report concluded that “logs of the search activities of populations of computer users can contribute to drug safety surveillance,” he said. Such a search, had it been conducted at the time rather than after the fact, could have provided an early warning of the problem.

The ‘Learning Health Care System’ Meanwhile, there are exciting possibilities. For instance, there is potential for more sophisticated see Advantages, page 23

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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.

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Transition continued from page 1

The Wish List “Right now, a lot of the transition programs focus on making sure a person knows about their disease, their medications, their current status,” said senior author Herbert Brill, MD, associate professor of gastroenterology in the Department of Pediatrics, McMaster University, in Hamilton, Ontario. “I think in transition, we need to take a more broad-stroke

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

approach to preparing people for life as an adult with their chronic disease.” Psychosocial support is at the top of the wish list, noted John Marshall, MD, professor of medicine and a gastroenterologist at McMaster, who helped conduct the new study. He also happens to be Ms. Lindsay’s adult doctor. “This is an area where there’s been relatively little rigorous research to inform what we should do,” Dr. Marshall said. To help fill that gap, Dr. Marshall and his team recruited and interviewed 21 patients aged 18 through 30, from

the McMaster University Medical Centre IBD Clinic between July 2012 and May 2013. Emerging from the questions posed to the 15 young adult volunteers diagnosed under age 18 were common troubles in finding support networks, overcoming social barriers and coping with anger, depression, sadness and anxiety. Participants discussed how their condition often led to intentional selfisolation from social settings. The remaining six patients, who had been diagnosed as adults, were more likely to seek peer support groups and

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.

Mayy 2014

May 2015

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more often faced difficulties with access to health care, cost of treatment and social isolation. Dr. Marshall and his team concluded that a greater focus on psychosocial and financial readiness during transitions is critical—not only for adolescents and young adults with IBD, but potentially for patients with a variety of life-long illnesses. “This highlights how the health care system underrecognizes this issue,” Dr. Marshall told Gastroenterology & Endoscopy News. “For the most part, the focus is clinical disease management. Some of these equally important concerns get overlooked and unaddressed. We could do a lot better.” Time pressures, as well as a lack of training or access to multidisciplinary services, may impede a clinician’s ability to go beyond managing a disease, he added. Michael Rosen, MD, assistant professor of pediatrics and a gastroenterologist at the Schubert-Martin Inflammatory Bowel Disease Center at Cincinnati Children’s Hospital Medical Center, said he is among the clinicians lucky enough to have the tools to address psychosocial issues in a “proactive fashion,” with patient screening surveys and the help of in-house psychologists and social workers. Dr. Rosen said he tries to educate young patients about their disease, medications and other things that “patients diagnosed as adults may take for granted.” “As a pediatrician, it is my responsibility to think about this transition, not just when a patient turns 18, but from an earlier age and incrementally begin to make sure we’re giving them the information and slowly building the skills,” added Dr. Rosen, also a co-chair of the Crohn’s and Colitis Foundation of America (CCFA). The CCFA is currently sponsoring research to develop an evidence-based transition program based on the needs of patients, parents and providers. Although his current approach falls within recommendations from NASPGHAN and the CCFA (Inflamm Bowel Diss 2011;17:2169–2173), he noted that the new abstract and pending CCFAsponsored research add important insights. “A lot of our guidelines [regarding the transition of care] come from recommendations from physicians,” Dr. Rosen said. “There’s real strength in learning from our patients what they need rather than just doctors sitting in a room trying to figure it out.” The stakes can be high. He pointed to research related to other diseases, such as type 1 diabetes, that found patients to be at greater risk for disease exacerbation during the child-to-adult transition (Pediatricss 2013;131:e1062-e1070).

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Many Questions “ This time when they may be transitioning is also a time of incredible change in their lives,” Dr. Rosen said. As many young adults are graduating high school, going to college or getting their first job, he pointed to some of the questions they might face: “Do I tell my boss about my IBD? Who do I tell at college? What do I do about my living arrangements and bathroom facilities in the dorm?” Dr. Marshall also highlighted the increased financial responsibility that comes with adulthood. “There’s a sudden need to take ownership over their care,” he said. “That’s a huge stress.” Eric Benchimol, MD, PhD, a pediatric gastroenterologist at the Children’s Hospital of Eastern Ontario, in Ottawa, Canada, said there is a clear need for more education on financial readiness and access to health care, such as dealing with insurance carriers and paying

‘As a pediatrician, it is my responsibility to think about this transition, not just when a patient turns 18, but from an earlier age and incrementally begin to make sure we’re giving them the information and slowly building the skills.’ —Michael Rosen, MD with a private wasshroom in the dorm. Although she has mostly sailed through college without maajor complications in caring for her IBD, she’s aware that her transition is not yett over. “I’m graduating now, so I’m getting kicked off my paren nt’s health insurance next month,” said Ms. Lindsay, who was not part of thee new study. “My ostomy supplies are covered under my dad d’s plan, so they willl become costs thatt I have to take on.”

‘A lot of our guidelines [regarding the transition of care] come from recommendations from physicians. There’s real strength in learning from our patients what they need rather than just doctors sitting in a room trying to figure it out.’ —Michael Rosen, MD

for medications. Research has shown that adolescents are “least knowledgeable” about these components of their health care, Dr. Benchimol said. He also added that developing psychosocial support services for individuals with IBD can be challenging, as adolescents are sometimes reluctant to attend support sessions. Ms. Lindsay knows these issues well. At Queen’s University, she has been allotted extra time on exams in case she needs to use the washroom. A doctor’s note also enabled her to secure a private room

Still, she considders herself lucky, both financially—she has budgeted for the added costs—and psychosocially. Ms. Lindsay underwent ileostomy surgery shortly after her diagnosis at age 9. “I don’t really remember what life was like before my ostomy,” she said. She knows patients diagnosed later in life who have struggled to accept the changes in their body image, often a result of medication side effects, disease symptoms or surgery. Paying for drugs is also a problem for

some of Ms. Lindsay’s friends. “Medications can be quite expensive if you don’t have insurance or don’t qualify for a grant,” she said. In addition to now asking his own young adult patients more questions to “actively elicit” any impacts of their illness on their lives, Dr. Marshall said his team is looking at models to bridge the gap between pediatric and adult care. For example, having the same nurse attend

the last few pediatric visits and the first few adult visits might enhance communication between teams and provide a familiar face for the patient and family. “Otherwise,” he added, “that transition can be abrupt and daunting,” —Lynne Peeples, with additional reporting by Chelsea Harvey Ms. Lindsay, and Drs. Benchimol, Marshall and Rosen reported no relevant financial conflicts of interest.

‘I am hoping this will have a salutary effect on how

Advantages

medical schools look at

continued from page 20

their curricula.’ —Edward H. Shortliffe, MD, PhD

decision support that is “aware of complex clinical contexts,” as well as “models of patients and the care process,” Dr. Shortliffe said. Other possibilities mentioned by Dr. Shortliffe: “Identification of contextspecific information or knowledge needs; better integration of systems and transferability of decision-support capabilities between systems; and user education and engagement.” There’s also the potential

to incorporate data from personal devices. Dr. Shortliffe said informatics may eventually make possible a “learning health care system,” an “envisioned cycle that ties patient care with knowledge creation and dissemination.”

In his presentation, Dr. Shortliffe displayed a chart showing a circular flow of data collected from patients as part of their medical care and treatment (Figure). The pooled data spurs research, leading to new treatments and standards that benefit

patients. “It’s closing the loop—we ought to be learning from what we do,” he said. A number of obstacles stand in the way of a learning health care system, including the tendency of institutions to guard their data jealously, even if they lack plans for using the information, Dr. Shortliffe warned. Even so, biomedical informatics and its application in clinical settings have exhibited dramatic progress and growth. “The changes in the last decade are really remarkable,” Dr. Shortliffe said. “Things are really taking off.” —Scott Van Voorhis

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Five Factors Seen To Help Guide Treatment Plan for C. Difficile Identifying patients who could benefit from surgery CHATTANOOGA, TENN.—Clostridium difficile infection (CDI) has become one of the most common nosocomial infections encountered by the clinician, but the development of treatment guidelines has been hindered by a lack of reliable and widely accepted severity prediction models. Researchers at the University of Tennessee College of Medicine in Chattanooga, however, have identified five variables that may help develop a clinical prediction tool for guiding treatment decisions in severe cases.

‘This will ultimately allow better classification of severity and help surgeons identify patients who would benefit from early surgical intervention.’ —Matthew Figh, MD

who will do well, not who will do poorly.” The primary objective of their study was to determine a combination of risk factors that would identify patients most likely to die with surgical intervention. The researchers examined data on 876 patients with CDI between 2003 and

2010, of whom 82 (9.3%) died. They conducted a complete chart review of 274 of those patients, including all deaths. “We looked at 32 variables taken at the time of admission, the time of diagnosis of CDI and 48 hours after CDI diagnosis,” Dr. Figh said. Of those 32 variables,

five emerged as being statistically significant and, in combination, predictive of mortality: age greater than 60 years, use of vasopressor agents at time of diagnosis, acute or chronic renal disease at time of diagnosis and albumin less than 3.0 g/dL. “Most of these are actually comorbidities, but our aim was to find risk factors associated with morbidity and mortality,” Dr. Figh said. The five variables “represent an overall deterioration of normal physiology, and they do not exist in a vacuum. We believe it is a combination of these factors [that determines] the overall severity.”

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“The surgical literature has shown early surgical intervention to lower mortality, but typically the operations in the most severe cases include a total abdominal colectomy, which is a very morbid procedure,” said Matthew Figh, MD, chief surgery resident at that institution, who presented the group’s results at the Southeastern Surgical Congress. “We would like to identify and isolate the patients who would benefit from this. The ultimate question now is when is a case likely futile? A clinical prediction tool would be very useful in helping to identify those patients,” he said. There are clinical prediction models currently available, but Dr. Figh and his colleagues believe they are of little help. “The main issue with them is that they use the ICU admission and surgical intervention as their end points. Since a clinical prediction tool is used to make treatment decisions based on an algorithm, it seems a circular argument to base your end points of that treatment,” he said. “These models are typically better at predicting

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Dr. Figh concluded that defining the five variables, easy to identify at bedside, is the first step in his institution’s goal of creating a clinical prediction tool. “This will ultimately allow better classification of severity and help surgeons identify patients who would benefit from early surgical intervention. It will also help us identify patients who would benefit better from medical treatment and avoid the morbidity associated with aggressive treatments like total abdominal colectomy,” he said. Denis W. Ashley, MD, Milford B.

Hatcher Professor and chair of the Department of Surgery at Mercer University School of Medicine, in Macon, Ga., reviewed the study ahead of time. He challenged several points of the statistical analysis, all of which Dr. Figh answered to his satisfaction (e.g., the variables were not taken into groups, each variable was considered independently for its predictive ability; the researchers used a multivariate, not a multivariable logistic regression). However, Dr. Ashley also had a practical, clinical question. “What do we take

home from this paper, and how can we use it to manage our patients?” he asked. “If we have a patient over 60, on vasopressors and steroids at the time of diagnosis, what do we do?” Most surgeons, he posited, would classify this type of patient as critically ill and consider surgical intervention expecting a high likelihood of death. “Does this tell us something we don’t already know? Should we continue to look for variables that so far have been elusive that would help us identify patients with a high risk for mortality before they get so sick?” he

asked. “Dr. Figh alluded in his presentation that this is a first step, and I would agree with that.” Dr. Figh pointed out that the availability of a prediction tool may help physicians explain treatment options to patients and their families. “In a situation where you have all five of these variables present, being able to give them statistical information as far as expected mortality can help the family come to a better understanding of your treatment suggestions,” he said. —Monica J. Smith

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Genetic Predictors of 5-FU Toxicity Identified SAN FRANCISCO—Investigators from Mayo Clinic have identified new genetic predictors of toxicity from 5-fluorouracil (5-FU) treatment in colon cancer patients, but the associations are complex. “Severe adverse events [AEs] related to 5-FU constitute a major dilemma in colon cancer treatment,” said investigator Adam Lee, PhD, from the Department of Molecular Pharmacology & Experimental Therapeutics at Mayo Clinic, in Rochester, Minn. “Our goal in this study was to

assess the relationship between the DPYD HapB3 haplotype (and its individual variants), the deep intronic variant, and severe AEs common to 5-FU–based therapy.” Presenting their findings at the 2015 Gastrointestinal Cancers Symposium, Dr. Lee said the novel haplotype HapB3 and the deep intronic variant c.1129-5923 C>G were shown to be moderately predictive of severe toxicity related to treatment with 5-FU in stage III colon cancer patients who do not harbor the DPYD*2A, D949V

and I560SS variants that already have been associated with treatment toxicity. Specific variables—patient sex, treatment regimen and KRASS status—significantly influenced their predictive value for AEs. “Significant interactions between DPYD D variants and patient characteristics [related to] 5-FU AEs, along with the subcohort analysis, suggest a much greater predictive effect in Caucasian females compared to males, patients treated with FOLFOX only compared

to FOLFOX plus cetuximab (Erbitux, Bristol-Myers Squibb), and patients with wild-type KRAS S status compared to mutant KRAS S patients,” Dr. Lee said. Dr. Lee’s study involved 2,134 white, stage III colon cancer patients who lack the DPYD*2A, D949V V and I560S variants already associated with toxicity (from the NCCTG N0147 trial). The patients received adjuvant FOLFOX (leucovorin, fluorouracil and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil and irinotecan)

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with or without cetuximab and were genotyped by multiplexed single-base extension assays on the Sequenom MassARRAY. A total of 1,339 patients (62.8%) reported at least one grade 3+ AE and and 705 patients (33%) reported a 5-FU– related AE.

Predictive in Subcohorts Related To Gender, Regimen and KRAS Status “Among the primary cohort,” Dr. Lee noted, “a moderate association was

identified between grade 3+ 5-FU– related AEs and the deep intronic c.1129-5923 C>G variant” (odds ratio [OR], 1.539; 95% confidence interval (CI), 1.001-2.367; P P=0.0493). “However,” he added, “after adjusting for multiple covariates, this association was no longer statistically significant” (OR, 1.558; 95% CI, 0.976-2.488; P=0.0630). P Only the more frequent DPYD HapB3 variant c.680+139 G>A showed a significant association with the overall grade 3+ AE rate (OR, 1.263; 95% CI, 1.0161.572; P=0.0356). P

Generally, in the absence of DPYD*2A, D949V V and I560S, the HapB3 haplotype and the deep intronic variant have limited predictive value for severe toxicity to adjuvant 5-FU–based combination chemotherapy, but they were predictive in subcohorts related to patient sex, treatment regimen and KRAS S status. “Significant interaction effects on grade 3+ 5-FU–related AEs were identified between DPYD D variants and sex and KRAS/BRAF F mutation status,” Dr. Lee said, “with a moderate interaction effect with treatment.”

Subcohort analysis found that the following groups were significantly more likely to experience grade 3+ AEs: • Females with variants c.959-51 T>C, c.1236 G>A, c.483+18 G>A or c.1129-5923 C>G, and HapB3 with or without c.1129-5923 C>G; • Patients treated with FOLFOX only (minus cetuximab) with variants c.959-51 T>C, c.1236 G>A, c.483+18 G>A, c.1129-5923 C>G and HapB3 with or without c.11295923 C>G; see Toxicity, page 28

Toxicity continued from page 27

• KRAS S wild-type (WT)/BRAF WT patients and KRAS WT/ BRAF mutant patients with variants c.1236 G>A or c.1129-5923 C>G, and HapB3 with or without c.11295923 C>G; • c.680+139 G>A was significantly associated with overall grade 3+ AEs in patients receiving irinotecan (OR, 4.684; P=0.0005) and showed moderate associations with grade 3+

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

overall AEs in males (OR, 1.310; P=0.0642) and KRAS/BRAF F WT patients (OR, 1.317; P =0.0653). The DPYD D gene has more than 16,500 reported variants, nearly 130 of which result in a change to the amino acid sequence. However, as Dr. Lee observed, the majority have yet to be functionally characterized. Dr. Lee said that “further analysis is needed to determine the effect of other common DPYD D variants on 5-FU– related toxicity,” but “ultimately, we

would like to have our patients tested. It may only detect a small proportion of patients who will develop toxicity, but if your patient is within that 5%, it’s important to know. It should someday be cheap and easy to test for this, and you can get that data within an hour.” Robert S. Warren, MD, director of surgical oncology at the University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center, said that Dr. Lee’s study added to a growing body of data regarding gender

differences in outcomes, in relation to genotype. Dr. Warren recently led a study (CALGB 89803) in which women harboring a TP53 mutation had better survival after adjuvant treatment for stage III colon cancer. “In Dr. Lee’s study,” Dr. Warren said, “the gender difference was correlated with toxicity; in ours, it was survival. But it’s not just gender—it’s gender interacting with genotype.” —Chase Doyle

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Appendicitis Rates Linked to Industrialization

ases of appendicitis appear to surge as countries become more industrialized, and then taper as economies mature, Canadian researchers have found. What accounts for the correlation is unclear, but experts have suggested everything from poor air quality to improved access to health care as possible explanations. Pedro Teixeira, MD, a surgeon at the

University of Southern California, in Los Angeles, who has researched appendicitis, applauded the study for providing important epidemiologic data. “It could be that the better sanitation and water treatment that accompanies industrialization decreases exposure to intestinal pathogens and consequently alters immune response to infections, increasing the risk for appendicitis,” said Dr. Teixeira, who was not involved in the latest work.

Gilaad Kaplan, MD, MPH, associate professor of medicine at the University of Calgary, Alberta, and his colleagues used Canadian and U.S. administrative databases to document the annual incidence of appendicitis between 2004 and 2008. They also analyzed data from 92 population-based studies from the two countries as well as several other countries. Dr. Kaplan, who presented the findings at Canadian Digestive Diseases

Week 2015 (abstract 70), said his team found that the incidence of appendicitis peaked in the middle of the 20th century, with 383 cases per 100,000 people in North America. In contrast, the average incidence of appendicitis between 2004 and 2008 was 85.8 and 98.1 cases per 100,000 people in Canada and the United States, respectively, he said. Rates of appendicitis in Europe mirrored North American trends, peaking in the

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

mid-20th century at 601 cases per 100,000 people, Dr. Kaplan’s group reported. Buttressing the link between industrialization and appendicitis was another of the researchers’ findings, which showed appendicitis rates have been more recently steadily increasing in the Middle East and Asia. Industrialization began later there and is now intensifying. Dr. Kaplan said air pollution may also have contributed to rising appendicitis rates—a link that has some support. “My own prior research has found that more air pollution can trigger or

exacerbate appendicitis and other autoimmune illnesses, including inflammatory bowel disease,” he said (Environ Health Perspect 2013;121:939-943). “Conversely, as we learned to better manage air pollution over time, in Canada, for example, we saw a coinciding decrease or stabilization of appendicitis rates.” Yet another explanation for the decreases in appendicitis rates that occurred in the later 20th century and early 21st century is a greater accuracy in the diagnosis of appendicitis, Dr. Teixeira added. “One plausible explanation is that with improved access to medical care there were possibly higher rates of negative appendectomies, which could have artificially inflated the incidence of appendicitis,” he said. Subsequent improvements in diagnosis would have reduced rates of appendicitis, he said. A separate but related study presented by Dr. Kaplan’s team at Canadian Digestive Diseases Week (abstract 73) provides an important caveat to the above findings. Namely, his group found that using administrative databases could overestimate incidence rates by up to 15%. “The problem with administrative databases is that there’s an inherent risk for misclassification, since a provider might code for appendicitis when a patient is admitted to hospital but if the patient is subsequently diagnosed with a different illness, that code may not be revised by the provider,” he explained. His team compared appendicitis rates between 2000 and 2008 as documented in two sources: a pathology-proven hospital registry including information from 8,822 Calgarians and a hospital discharge database that included data from 10,162 patients treated at all four of the city’s hospitals. The discharge database included diagnostic codes for appendicitis. The comparison showed that the pathology-proven registry pegged the average annual incidence of appendicitis between 2000 and 2008 at 84.2 per 100,000 people, whereas the hospital database showed an incidence of 97.3 cases per 100,000 people. Dr. Kaplan said his team did not account for this methodological limitation in their first study, which means the incidence they estimated could be high. —David Wild

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Few Approved Targeted Therapies for GE Cancers AUSTIN, TEXAS—In the United States alone, gastroesophageal (GE) cancers cause more than 15,000 deaths each year. Although much is known about the various pathways involved in the development and progression of GE cancer, finding effective targeted therapies for this disease remains somewhat elusive. Two targeted agents are approved for GE cancer, and many are being studied, said Shrina Duggal, PharmD, who reviewed some of this research at the

annual meeting of the Hematology/ Oncology Pharmacy Association held recently. “We still have a lot to learn about the molecular components of GE cancers,” said Dr. Duggal, who is a clinical pharmacy specialist at the University of Pittsburgh Medical Center Cancer Center. Surgery with or without radiation or chemotherapy is the standard of care for patients with GE cancers. However, there are patients with unresectable tumors,

and who develop metastatic or advanced disease regardless of therapy. Targeted therapies are being investigated in the adjuvant setting after resection, according to Khaldoun Almhanna, MD, MPH, a medical oncologist in the Department of Gastrointestinal Oncology at H. Lee Moffitt Cancer Center and assistant professor of oncology at the University of South Florida College of Medicine, both in Tampa. The primary signaling pathways to

target are the human epidermal growth factor receptors, HER2 and EGFR; vascular endothelial growth factor (VEGF); the ligand, hepatocyte growth factor (HGF); the receptor tyrosine kinase MET; the lipid kinase, phosphatidylinositol 3-kinase; the family of serine threonine kinases Akt; and the mammalian target of rapamycin (PI3K/Akt/mTOR). HER2 is overexpressed in about 35% of GE cancer patients (Lancett 2010; 376:687-697), but the prognostic implications of this are unclear, Dr. Duggal said. Some studies have associated HER2 with aggressive disease and poor prognosis.

‘We still have a lot to learn about the molecular components of GE cancers.’

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—Shrina Duggal, PharmD

Because of the experience with breast cancer, she said, “HER2 is a great target in terms of knowing how to manage these patients. If patients do have HER2-positive disease, it certainly gives us the option of trastuzumab [Herceptin, Genentech], and potentially pertuzumab [Perjeta, Genentech] and T-DM1 [adotrastuzumab emtansine].” Based on the ToGA (Trastuzumab for Gastric Cancer) trial of 584 HER2positive patients with advanced gastric or gastroesophageal junction (GEJ) cancer that compared trastuzumab plus chemotherapy with chemotherapy alone, trastuzumab was approved to treat patients with advanced GE and gastric cancers who express HER2. Additive antitumor effects have been seen when trastuzumab was combined with capecitabine or fluorouracil (FU) plus cisplatin, she said. ToGA researchers saw significant improvement in all of the end points. The median overall survival (OS) improved from 11.1 months with chemotherapy alone to 13.8 months with chemotherapy plus trastuzumab (P=0.0046). P The duration of response was also significantly improved from 4.8 to 6.9 months. The overall response rate (ORR) was 35% in the chemotherapy group and 47% in the trastuzumab group (P=0.00175). P The side-effect profile was similar in both groups (Lancett 2010;376:687-697). JACOB is a Phase III study using a combination of pertuzumab, trastuzumab and chemotherapy in patients with HER2-postitive metastatic gastric or GEJ cancer. In breast cancer, using

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

pertuzumab plus trastuzumab blocks the HER2 receptor. The aim of the ongoing JACOB trial is to determine whether the results will carry over to GE cancers. VEGF-A is a key mediator of physiologic and pathologic angiogenesis. Its activity is mediated by two tyrosine kinase receptors (VEGFR-1 and VEGFR-2). Several anti-VEGF drugs have been used in gastric cancer. Dr. Duggal discussed bevacizumab (Avastin, Genentech), ramucirumab (Cyramza, Lilly) and regorafenib (Stivarga, Bayer). Using any of these agents should block VEGFR and inhibit the formation of blood vessels. The AVAGAST (Avastin in Gastric Cancer) Phase III trial randomized 774 patients into two arms: standard twodrug treatment and standard treatment with bevacizumab. The study did not meet the end point of improving OS (P=0.1002), only improving survival by a little more than one month (6.7 vs. 5.3). However, there was improvement in progression-free survival (PFS) and ORR (P=0.0037 and P=0.0315, respectively) (J ( Clin Oncoll 2011;29:3968-3976). “But without having significant survival improvement, it is difficult to make a case to use this drug consistently in patients,” Dr. Duggal said. The Phase III REGARD trial examined another VEGF inhibitor, ramucirumab, with placebo and best supportive care in 355 patients with GEJ disease. There was an improvement in all primary end points, including median PFS (2.1 vs. 1.3 months; P<0.0001) and median OS (5.2 vs. 3.8 months; P P=0.047) (Lancet 2014;383:31-39). RAINBOW also investigated ramucirumab in combination with paclitaxel versus paclitaxel alone in patients with advanced or metastatic GE cancer who failed first-line treatment or progressed on a 5-FU– or cisplatin-based regimen. The median PFS was 4.4 months in the ramucirumab combination arm versus 2.9 months in the placebo arm (P<0.0001). Median OS was 9.6 versus P and ORR was 7.4 months (P=0.017) 28% over 16% (P=0.0001) P (Lancet Oncol 2014;15:1224-1235). “There is certainly an improved benefit with ramucirumab over paclitaxel, so this is now regarded as our standard of care for patients with advanced gastric cancer who progressed on cisplatin-based therapy,” Dr. Duggal said. Regorafenib is being looked at in the INTEGRATE trial, a Phase II trial for GE patients with unresectable disease unresponsive to chemotherapy. Early results showed that PFS had improved significantly over placebo (11.1 vs. 3.9 weeks in the placebo arm) (J ( Clin Oncol 2014;3:6 2013 suppl; abstr TPS4157). “This drug has major promise and we are hoping to see overall survival rates by

the end of the year,” she noted. Onartuzumab (MetMab, Roche), a humanized monovalent monoclonal antibody directed against the hepatocyte growth factor receptor (c-Met), has potential antineoplastic activity. Onartuzumab binds to the extracellular domain of c-Met, preventing the binding of its ligand, HGF. A receptor tyrosine kinase, c-Met is overexpressed on the cell surfaces of a variety of cancer cell types and may play a role in their proliferation, spread and survival. Onartuzumab is being studied in the

MetGastric trial of 800 patients with metastatic HER2-negative and METpositive adenocarcinoma of the stomach or GEJ. Results are expected later this year, according to Dr. Duggal. Overexpression of EGFR has been seen in up to 55% of tumors and like HER2, EGFR is associated with aggressive disease and poor prognosis. Several Phase III trials (EXPAND and REAL3) have evaluated targeted therapies against this pathway, but to date, the results have not been promising, Dr. Duggal said. Until more is known about targeted

therapies for GE cancers, only two targeted therapies have been approved: trastuzumab in first-line therapy, and ramucirumab for second-line or beyond. The National Comprehensive Cancer Network recommends a two-drug chemotherapy combination except for those patients who can tolerate more aggressive therapy. There are occasions where a three-drug regimen would be appropriate, Dr. Duggal said. —Marie Rosenthal Drs. Duggal and Almhanna reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Hospital Outcomes for Crohn’s Patients Differ by Race, Income

ace and income may account for some of the disparity in outcomes among patients hospitalized with Crohn’s disease, researchers have found. The findings, presented at the 2014 annual Advances in Inflammatory Bowel Diseases conference, suggest that black and low-income patients tend to fare worse than whites and those with higher incomes (abstract P-45). “Crohn’s disease complications have generally been on the rise,” said Cheng Zhang, MD, PhD, assistant professor of gastroenterology, hepatology and nutrition at The Ohio State University College of Medicine, in Columbus, who led the study. Dr. Zhang noted that he and his colleagues had observed an increase in hospitalizations for Crohn’s complications at their institution. They had also witnessed

outcome trends that appeared linked to certain patient demographics. In an effort to tease out those disparities and identify what could be done to address them, Dr. Zhang’s team conducted a cross-sectional study using data from the Nationwide Inpatient Sample. They analyzed 70,383 and 80,250 patients by race and income, respectively. The researchers found that the two

factors did not affect in-hospital mortality, total hospitalization cost or frequency of receiving parenteral nutrition. In contrast, other outcomes appeared to vary. Compared with white patients, for example, blacks were more likely to receive blood transfusions (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.10-1.64) and less likely to undergo surgery (OR, 0.80; 95% CI, 0.70-0.92).

“We’ve noticed from our experience, and from the literature, that minority patients—particularly African American patients—receive suboptimal care for inflammatory bowel disease for varied reasons,” said Dr. Zhang, who added that this gap could be driving the increased rate of blood transfusions among black patients. He pointed to a study from see Race, page 46

Toll of Pancreattic Illnesses Varies By Race, Ethnic city

ew research suggests there is sign nificant disparity among racial and ethnic grou ups when it comes to diseases of the pancreas. The study found wide ranges among diffe ferent populations in measures such as length of stay in the hospital and use of health care resources for pancreattic illnesses, perhaps because of language or cultural differences, according to the investigators. “Overall, gastroenterology doesn’t have much literature when it comes to racial inequities, and theree’s a paucity of literature on that topic in pancreatic disorrders,” Darwin L. Conwell, MD, MS, director of gastrooenterology, hepatology and nutrition at The Ohio Statee University, in Columbus, told Gastroenterology & Endosccopy News. “When it comes to triaging patients who present at the emergency department, it’s important nt to have a sense of who’s going to get sick and who’s not. If there is a racial disparity that impedes health care delivery, can we figure out why and establish programs to correct it?” The study, presented at the 2014 annual meeting of the American College of Gastroenterology (abstract P712), evaluated discharge data from the Nationwide Inpatient Sample on 340,231 patients aged 18 years and older with a primary diagnosis of acute pancreatitis (83%), chronic pancreatitis (5%) and pancreatic ductal adenocarcinoma (12%) from 2011. The patient population was 65.5% white, 16.9% black, 12.2% Hispanic, 1.7% Asian/Pacific Islander, 0.7% Native American and 2.9% other race. “The racial distribution was very similar to the nation in general,” said lead author Jean Park, MD, a clinical assistant hospitalist at Ohio State. Economic demographics varied significantly, with most black and Native American patients in the lowest income quartile, the majority of the Asian/Pacific

Islander patients in the top two income quartiles, and the Hispanic populations equally distributed across all quartiles, Dr. Park said. Native Americans had the lowest mortality rate (0.5%), shortest length of stay (2.8 days) and lowest total hospital charges ($15,646); Asian/Pacific Islanders, who had the highest mortality rate, at 2.4%, also had the highest total hospital charge ($32,836). Multivariate analysis showed similar differences, demonstrating that the difference in length of stay was significantly different for blacks, Hispanics and Native Americans compared with whites. Hospital charges were significantly lower for blacks ($19,612) but significantly higher for both Asian/ Pacific Islanders ($29,357) and Hispanic ($28,009) populations compared with whites ($22,099). “Essentially, for the Hispanic and Asian/Pacific Islander populations, hospital charges were significantly higher, 26.8% and 32%, than for the Caucasian population, which was our reference point,” Dr. Park said. Girish Mishra, MD, MSc, professor and vice chief of internal medicine-gastroenterology at Wake Forest School of Medicine in Winston-Salem, N.C., said,“It was interesting that they found Native Americans had the lowest mortality rate, length of stay and hospital charges, but you can’t tell why. Is it because Native Americans don’t like to be in the hospital? Is there a biological difference?” he asked. “You can’t get that information from a study like this, but it’s interesting.” One theory that may explain some disparities is that

language barriers create a significant delay to care, Dr. Park said. “We have a large immigrant population in Columbus, and a lot of patients who don’t speak English as their primary language,” Dr. Park said. “It’s much harder to obtain a history: how patients describe their pain and what we infer it to mean.” In an earlier study, Dr. Conwell and his colleagues found a disparity in emergency department waiting times for gastroenterological illnesses in general. “We concluded that this was related primarily to language and communication barriers. If the physician is seeing a patient who doesn’t speak English, that’s going to delay care,” Dr. Conwell said ((Am J Gastroenterol 2009;104:1668-1673). Dr. Mishra concurred. “I think that’s a plausible explanation,” he said. —Monica J. Smith

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

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

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

weeks

Treatment-naïve patients with or without cirrhosis

Treatment-experienced patientsb without cirrhosis

weeks

Treatment-experienced patientsb with cirrhosis

weeks

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

• 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

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Pediatric Feeding Gap in ICU Hurts Hospitals, Patients LONG BEACH, CALIF.—Malnutrition among critically ill children is a common and significant contributor to poor clinical outcomes and greater hospital costs, according to abstracts presented at the 2015 annual meeting of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). To reverse that concerning trend, researchers presented novel tools to calculate optimal feeding and diagnose malnutrition, among other relatively simple strategies that could help sick children and enhance bottom lines. “Feeding is [not enough of a priority] in the intensive care units,” said Nilesh Mehta, MD, associate professor of

anesthesia at Harvard Medical School, Boston, and director of critical care nutrition at Boston Children’s Hospital. “People have long focused their attention on other complex and expensive therapies but often ignore the importance of providing basic nutrition.” Although malnutrition concerns are increasingly recognized for adults, children may be the most vulnerable to the unintentional neglect. “Critically ill children bring another level of complexity,” said Carol Rollins, MS, RD, PharmD, a coordinator for the nutrition support team at the University of Arizona Medical Center, in Tucson. With lower energy reserves, she noted,

‘We are uniformly bad at delivering protein to critically ill children.’ —Nilesh Mehta, MD

350

■ No malnutrition ■ Malnutrition

300

Patients, n

250

200

150 n=110 100

50 n=7 0

Previous Method

MTool

Figure. Malnutrition identification by method.

children can fall into a starvation state quicker than adults. She also highlighted a child’s growth as a critical consideration. “We know that for a neonate or infant, a malnourished brain may not meet its full potential,” Dr. Rollins said. Several years ago, when Dr. Mehta and his colleagues noticed the stark heterogeneity in feeding practices for critically ill children at their hospital, they decided to take action. “Everyone was doing what they thought was best, but there was no uniform strategy employed,” Dr. Mehta said. “Also, there wasn’t much evidence to guide nutrition practices at the bedside.” He led an interdisciplinary group of dietitians, gastroenterologists, pharmacists, critical care physicians and nurses to develop a feeding algorithm. Today, that algorithm provides stepwise guidance for initiating and advancing the delivery of nutrients in critically ill children at hospitals worldwide. A paper his team published last year showed the algorithm improved delivery of energy and protein, resulted in fewer unintended feeding interruptions and decreased use of parenteral nutrition (Pediatr Crit Care Med 2014;15:583-589). In their latest study, presented at A.S.P.E.N. (abstract 14), Dr. Mehta and his team described nutrition delivery and clinical outcomes for 1,245 children requiring mechanical ventilation from 59 pediatric ICUs (PICUs) across 15 countries. Interruptions in feeding and shortages in both daily energy and protein were common throughout the international cohort. The majority of patients (985; 79%) received enteral nutrition. Among these children, 74% had their feeding interrupted for an average of eight hours a day. Overall, patients received far less energy and protein than prescribed: 36% and 47%, respectively. “We are uniformly bad at delivering protein to critically ill children,” Dr. Mehta said. The shortfall appeared to predict poor outcomes. After adjusting for the severity of a child’s illness, mortality was significantly associated with insufficient enteral protein intake, independent of energy intake (P<0.001). An increase in protein adequacy—from less than 20% to more than 60%—led to a significant drop in 60-day mortality (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.16-0.65). Once again, knowledge can be power. Based on their findings, the team highlighted “modifiable factors” that could improve protein delivery, including early initiation of enteral nutrition, use of post-pyloric enteral route, decreased interruptions and the presence of a dedicated dietitian.

Monitoring Malnutrition Of course, malnutrition must first be recognized before it can be addressed. The University of Michigan C.S. Mott Children’s Hospital’s MTool provides an innovative approach. In developing their standardized tool to diagnose pediatric malnutrition—its first iteration dating back to 2013—researchers examined the relevant scientific literature. In particular, said Kate Ludwig, MPH, RD, a pediatric clinical dietitian at the hospital, they referenced an article by Dr. Mehta ((J Parenter Enteral Nutr 2013;37:460-481) that describes a paradigm shift toward an etiology-based definition of pediatric malnutrition endorsed by A.S.P.E.N, the Academy of Nutrition and Dietetics and the American Academy of Pediatrics. Height, weight, weight for length and body mass index and z-scores are used in the first step of the process as indicators to alert practitioners of a potential problem, Ms. Ludwig explained. The team then performs a thorough nutritional assessment to determine the etiology of malnutrition: Is a medical condition, dietary intake, socioeconomic status or inflammation playing a role? In a study presented at A.S.P.E.N. (abstract 28), Ms. Ludwig used the MTool to look retrospectively at 327 children who were admitted to and stayed for at least four days in her institution’s PICUs between Jan. 1 and Dec. 31, 2012. Before applying the MTool, 2% of patients were diagnosed with malnutrition. Once the tool was applied, that number jumped to 34%. MTool characterized 26% of those patients as having severe malnutrition (Figure). The highest rates of malnutrition were among children with respiratory and neurologic diagnoses. Ms. Ludwig further determined that children identified by the tool as malnourished fared worse than those not flagged. The patients diagnosed with malnutrition had significantly higher incidence of death (10% vs. 4%; P P=0.046). Although not statistically significant, these children also spent 1.2 days longer on a ventilator (P=0.315) P and stayed an average of 2.3 days longer (P=0.302) P in the hospital compared with nonmalnourished children. “Unfortunately, because it was retrospective, we weren’t able to act on anything,” Ms. Ludwig said. However, today, she added, her hospital is able to apply MTool to identify at-risk patients earlier and therefore intervene sooner to improve outcomes. MTool is currently available for purchase through the University of Michigan Mott Children’s Hospital Patient Food and Nutrition Services website.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Ms. Ludwig noted that they’ve received requests from all over the United States, with distribution to more than 200 institutions shortly after it became available. Dr. Rollins underscored the shortcomings of retrospective data, which currently predominate malnutrition research. Given the limits of such data, “we’re still in a quandary,” she said. “But the more data we can put into the equations, hopefully the closer we are.” Clinical judgment will always be required, she added, as no one equation will ever spit out the perfect answer for every patient’s nutritional needs.

efforts to improve anthropometry performance after PICU admission.

More Help for Nurses Several other efforts are also underway at his hospital. To support fatigued and overburdened nurses, Dr. Srinivasan and his colleagues recently began exploring how nursing aides may help obtain measurements. His team just completed an international survey of the potential barriers to anthropometry and identified differences in perceptions of these barriers between ordering providers and nurses

((Am J Crit Care, in press). Based on these findings, they are now pursuing targeted education for various clinician groups. Even when anthropometry measures are attempted, other factors can get in the way. Dr. Srinivasan noted the difficulty, for example, in obtaining length measurements of sick kids, especially those with cerebral palsy. So, his team is also looking to identify potential surrogate measures, such as mid-arm span or knee-to-heel length. Given common fluid shifts in the ICU, Ms. Ludwig added the possibility of using triceps skinfold and mid-upper arm

circumferences in conjunction with weight. Meanwhile, Dr. Mehta’s institution is now raising awareness for this critical component of care with a program they call “Weights on Wednesdays”—an initiative by the critical care nurses to facilitate weight and height measurements at least once a week. “Something simple like that can go a long way,” he said. —Lynne Peeples Drs. Mehta, Srinivasan, Ludwig and Rollins reported no relevant financial conflicts of interest. Note: This is the second part of a two-part series.

Challenging Measures The failure to recognize malnutrition in critically ill children often results from not recording weights and lengths. Dr. Mehta noted that these measurements are not just relevant for detecting the nutritional status of patients, but are also “crucial for all aspects of care”—from ventilator and fluid management to medication dosage. In another study presented at the A.S.P.E.N. meeting (abstract 29), Vijay Srinivasan, MD, and his colleagues evaluated anthropometry measurements following admission to the Children’s Hospital of Philadelphia’s PICU. The hospital requires measurements be made within 24 hours of admission, said Dr. Srinivasan, assistant professor of anesthesiology for critical care and pediatrics at Perelman School of Medicine at the University of Pennsylvania, in Philadelphia. Yet staff compliance fell “dismally” short of that standard when they conducted a baseline audit in 2011 and 2012. To improve that performance outcome, Dr. Srinivasan worked with an interdisciplinary quality improvement team of ICU parenteral nutrition clinicians. In addition to educating staff about the importance of taking measurements, they offered computer-based and hands-on training on the use of equipment. That equipment now includes new length boards and PICU beds that can take weights. The team also modified the electronic health records (EHRs) with prechecked orders to obtain anthropometry following PICU admission. After allowing time for the staff to adjust to the protocol, they re-evaluated compliance—prospectively collecting anthropometry data from the EHRs of all patients for 12 weeks in 2013. Most anthropometry orders did improve compared with the baseline audit: weight (56% vs. 85%; P<0.001), stature (5% vs. 81%; P<0.001) and head circumference (8% vs. 37%; P<0.001). Compliance with orders for recurring weight measurements also increased (23% vs. 40%; P<0.001). Still, the PICU fell short of acceptable standards. Dr. Srinivasan said they are redoubling

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Administering Death, Terminating Suffering (Part I) Baby boomers fuel growing interest in the right to die; physicians’ role still hotly debated

n November 2014, Brittany Maynard ended her life in Oregon, availing herself of that state’s right to die law. Young, attractive and willing to speak with candor about her decision, Maynard captured the nation’s attention. A month later, in Baltimore, Lawrence Egbert, MD, an 87-year-old anesthesiologist, trained at Johns Hopkins University and the University of Maryland, lost his medical license for allegedly helping six Maryland residents end their lives. Maynard and Egbert are two faces from the same conversation, grabbing headlines and reinvigorating the debate over physician-assisted suicide—or what proponents call physician aid-in-dying—and what role, if any, doctors should have in helping sick individuals end their lives.

The New ‘Dr. Death’ Dr. Egbert has been hailed—and condemned—as the new Jack Kevorkian. The six deaths cited in the Maryland Board of Physicians’ decision for license revocation took place when he was the medical director of Final Exit Network (FEN), an organization that provides education and guidance for people seeking to end their lives. He was the medical director from FEN’s founding in 2004 until his arrest in 2009 on charges stemming from a death in Georgia. During his tenure, Dr. Egbert signed off on about 300 applications for guidance and was present at the deaths of 100 people. He is planning to appeal the State of Maryland’s decision on principle, although he no longer acts as a guide for those seeking death; and the last time he practiced anesthesia in a clinical setting was in Kosovo in 1999, with a team from Doctors Without Borders. Currently, only Oregon, Vermont, Washington, New Mexico and Montana have legal forms of assisted death. People elsewhere must move to a state where it is legal (as Maynard did), go to Switzerland (where citizenship is not needed) or seek alternatives such as FEN. It’s important to note that unlike any of the existing laws, which require that a patient be mentally competent with a terminal condition where death is imminent to qualify for a right-to-die prescription, FEN will consider cases where the patient has an irreversible chronic condition like Alzheimer’s and death may be farther in the future. Dr. Egbert’s interest in doctor-administered death stretches back to 1982, when he was living in Dallas and working at Parkland Memorial Hospital. He read in a newspaper that an anesthetic was used to execute a death row prisoner and that a professor of anesthesia at the University of Oklahoma advised the state on the practice. He was furious. Shortly after, he was asked by a minister from his Unitarian Universalist church if he would consider giving a deadly dose of anesthesia to a fellow parishioner who had terminal cancer. He met the woman, and “I realized I was getting into the mode of helping her,” he said.

‘We never encourage anyone to end his or her life; we never provide anyone the means to do so; and we never assist them. The First Amendment keeps us out of jail, but not out of court.’ —Frank Kavanaugh, PhD, member of the board of directors of Final Exit Network

In an interview with Anesthesiology News, Dr. Egbert stated without irony, “I oppose doctors killing people. If you study the death penalty, you realize it’s totally crazy. It’s racist and doesn’t prevent crime.” Unlike the prisoner, who was killed by the state, the patient was exercising her right to choose death. Dr. Egbert said what distinguished the two cases was simple: “The desire is the difference.”

The ‘Guiding’ Principle After the consultation in Texas, Dr. Egbert discovered The Hemlock Society, an early right to die

organization founded by Derek Humphry, who authored “Final Exit: The Practicalities of Self-Deliverance and Assisted Suicide for the Dying” in 1991. (The book is in its third edition.) That group eventually split into Compassion & Choices, a nonprofit that presses states to enact death with dignity laws, and FEN, which seeks to help people die while others debated whether they had the right to do so. “Our organization holds that mentally competent adults suffering from a fatal or irreversible physical illness have a basic human right to end their life when they judge the quality of their life to be unacceptable,” said Frank Kavanaugh, a member of the FEN board of directors since 2007, and a PhD in health care information systems. Dr. Kavanaugh said FEN doesn’t tell anyone anything they can’t find online or in the local library. What FEN does offer is a vetting process to make sure the patient is an appropriate candidate for end-of-life guidance and education to ensure the patient does the procedure properly. FEN will also have someone present at the death if the patient wishes it. “We never encourage anyone to end his or her life; we never provide anyone the means to do so; and we never assist them,” Dr. Kavanaugh pointed out adamantly. FEN practitioners use the term “guide” rather than assist, a distinction that is more than mere semantics. As long as the “guide” doesn’t assist the patient in any physical way, their actions pretty much fall under the protection of free speech. “The First Amendment keeps us out of jail, but not out of court,” Dr. Kavanaugh said. Dr. Egbert knows that well enough. In addition to the charges in Georgia for which he was arrested in 2009 (the case was dropped when the Supreme Court struck down the law under which he was being prosecuted), he was acquitted of charges in Arizona and is still facing charges in Minnesota. Dr. Egbert is no stranger to arrest for a cause, and his unassuming, elderly appearance can be deceptive. His home, which he shares with his third wife, has anti-war posters on the wall. The octogenarian still rides a bicycle from his row house in Baltimore’s Hampden neighborhood to the office of Physicians for Social Responsibility, a group that advocates against nuclear proliferation and for environmental causes. Now that he’s no longer working with FEN, he has stopped guiding and uses his time to review the medical reports of alleged victims of torture for a human rights lawyer based in Philadelphia. Dr. Egbert is a classic activist. “Larry stands on a soapbox and shouts for what he believes,” Dr. Kavanaugh said. “He’s very dedicated, very outspoken and not afraid of going to jail.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

‘We always ask the patient, “are you sure you The Dying Process Dr. Kavanaugh added that Dr. Egbert’s frankness has jumpstarted the death with dignity conversation. When it comes to talking about dying, Dr. Egbert is not shy. He explains that The Hemlock Society offered a weekend-long course on how to become a guide. Many guides have no medical background. “Medical school didn’t train me to do this at all—most of that training came from being a student with other guides,” he said. “What I did learn [from medical training] was the willingness and some ability to talk to people about very complicated subjects.” The moral issue of choosing to take one’s own life may be complex, but the process is fairly straightforward. To be considered for end-of-life guidance, Dr. Egbert said, “You have to have a horrible disease that I can verify from paper records that will show that you’ve done everything possible to ameliorate the symptoms of the disease and to make life tolerable.” Like most FEN guides, Dr. Egbert is an advocate of death by helium inhalation. He says they know it’s a peaceful way to go because volunteers inhaled the gas to the point of danger and experienced no choking or discomfort. Helium tanks are readily available at any party store, unlike barbiturates or other prescription medications that would need to be stored away over time or obtained by questionable means. In addition to the gas, a durable, 10-Liter plastic bag with a hose can be obtained online. “We always ask the patient, ‘are you sure you want to do this?’ right up to the end,” he said. “We can ask so many times, sometimes the person gets irritated.” Once they’ve agreed, it is supposed to be entirely in the patient’s hands to do what comes next. The patient places the bag on his or her head, turns on the helium and fills the bag to ensure it’s airtight. Then the patient must pull the bag over his or her face so it is snug around the neck. Dr. Egbert explained that the patient usually loses consciousness within 30 to 60 seconds. The guide or another person present checks the patient’s pulse after 10 minutes. “I tell the family to wait two hours to call anyone,” said Dr. Egbert, noting that if the paramedics were to arrive too soon, the patient might be resuscitated but brain dead. He has been criticized for facilitating the death of a woman who was clinically depressed, but he stated that he vetted every case on which he signed off and sometimes found alternate outcomes. He pointed to a woman in chronic pain

want to do this?” right up to the end. We can who was seeking end-of-life counseling. When he reviewed her records, it became clear that her pain medication management was incorrect. The woman worked with her doctor and pharmacist to get on the right medication regime and she no longer wanted to die. In another case, a woman with chronic obstructive pulmonary disease (COPD) had arranged her date of death with Dr. Egbert, but when the day arrived, the

ask so many times, sometimes the person gets irritated.’ —Lawrence Egbert, MD, former medical director of Final Exit Network

friend who was to sit with her at the end couldn’t make it. That woman is still alive. In 2012, she told The Washington

Post that she still keeps the helium tanks in case she wants to use them someday. —Christianna McCausland

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GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JUNE 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. 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

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 uâ&#x20AC;&#x2122;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.

EUS Gastroenterologist Opportunity We seek a BE/BC Gastroenterologist to join our collegial group. Provide a full spectrum of gastroenterology care to patients both in the hospital and through outpatient procedures. â&#x20AC;˘ 50% EUS and 50% General Gastroenterology â&#x20AC;˘ Call 1:5 â&#x20AC;˘ State-of-the-art cancer center nationally recognized for clinical excellence â&#x20AC;˘ Regionâ&#x20AC;&#x2122;s tertiary referral center â&#x20AC;˘ EMR â&#x20AC;˘ Research opportunities

Contact: Rochelle Woods 1-888-554-5922 physicianrecruiter@billingsclinic.org

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Physician P Physician-Led Physic Phys hy hysici hysician-Led ysician iciancian-Le an-Led -Led Led Med Medi Medicine Med edic dicin dicine cine ne e in n Montana Mont M Mon Mo t Billing Billin Bil Billings illings ngs gss Clinic Clin Clinic is an integrated, inte t d multi-specialty, multi-s mu multi multi-special lti-spe specialty, y, physician-led physici l d org ization and a proud organ organization pro d member me ber of o the h Mayo Clinic C i icc Care Netw Car Network. k Loc Located in th the he e magnificent magn ificent Rocky R Mo Mou M Mountains ountains ount nta t ins tain ins iin n Billings, Billing s, Mont Montana Montana, ana na, a, this th t is frie fr ffriendly i ndl iend dly dly college colleg e comm com community ommu munity munit unity nityy has ha h s great grea g eat gr att schoo sc schools, choo ools, ols, safe s ne neighborhoods neigh neighborh ghbo borh orho hoo ods ds and ds an and d abundant, abundan abu undant, ant, t, yearye year-round ear-rou r-round round und d fam ffamily amiilly activities. activities ttivities. s. Excitin Exciting Exc citing ng out outdo o outdoor tdoo oorr recreation recreatio eation minu m minutes nutes es from from h home. om ome. 300 days 3 dayys of sunshin sunshine! ssuns shine! ne!

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Pediatric Gastroenterologist The Children’s Hospital at Dartmouth-Hitchcock (CHaD) seeks a dynamic BC/ BE physician to join its Section of Pediatric Gastroenterology. Depending on candidate’s qualiﬁcations and goals, an opportunity for a leadership position within Pediatric Gastroenterology is available. This position includes an appointment to the faculty of the Geisel School of Medicine at Dartmouth at a rank commensurate with experience and academic portfolio. CHaD, Geisel, and their sister institution the Dartmouth Institute for Health Policy and Clinical Practice provide opportunities for clinical investigation, the science of health care delivery, and quality improvement. CHaD is a regional academic pediatric health system that includes a 65 - bed children’s hospital within a hospital located at Dartmouth-Hitchcock Medical Center (DHMC). The Section of Gastroenterology provides a full range of ambulatory and inpatient services at two locations, DHMC and the DartmouthHitchcock Clinic in Manchester, NH. The Section of Gastroenterology also has a clinical and academic relationship with the Gastroenterology Division at Boston Children’s Hospital.

GI PHYSICIAN – DAYTONA BEACH, FLORIDA GI with advanced endoscopy skills needed in the beautiful coastal area of Daytona Beach. All benefits/CME education paid during partnership track. Competitive salary, bonus structure during track, and ancillary revenue in addition to clinical upon partnership. Join large single specialty GI group and enjoy the advantages of what a large practice can offer. Daytona Beach is 30 minutes from Orlando, 1 hour from Jacksonville, and 4 hours to Miami. Area is without the skills of an advanced endoscopist, 2 large hospital systems, growing population that is directed to other large cities for these services. Join a 6 GI physician practice, and enjoy the amenities Daytona has to offer. Send resume to vking@bgclinic.com.

DHMC is a tertiary care academic medical center located in Lebanon, New Hampshire in the Upper Connecticut River Valley on the Vermont border. Home to Dartmouth College, the Upper Valley is a vibrant academic and professional community offering excellent schools, lively arts, and an unmatched quality of life in a beautiful, rural setting. Amenities associated with urban areas in Boston MA, Burlington VT, and Montreal, QC are all within a few hours drive. DartmouthHitchcock has been consistently ranked by U.S. News & World Report as One of America’s Best Hospitals.

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Study Strongly Links PPIs and Kidney ey Injury in Older Adults

lder adults prescribed proton pump inhibitors are more than twice as likely to develop acute kidney injury than patients who do not take the reflux drugs, Canadian researchers have found. The study included more than 290,000 men and women with gastroesophageal reflux who started using proton pump inhibitors between 2002 and 2011, and an equal number of people who did not use the medication (CMAJ Open 2015;3:E166-E171). The researchers found that the rate of hospital admission with acute kidney injury within 120 days of starting a proton pump inhibitor was 13.49 per 1,000 person-years, compared with a hospital admission rate of 5.46 per 1,000 person-years in controls (hazard ratio [HR], 2.52; 95% confidence interval [CI], 2.27-2.79). The rate of acute interstitial nephritis was also significantly elevated in the treatment group, at 0.32 versus 0.11 per 1,000 person-years (HR, 3; 95% CI, 1.47-6.14). “Gastroenterologists should continue doing what they have likely been doing: ensuring that patients prescribed proton pump inhibitors have a valid indication for these drugs, periodically re-examining the need for these drugs in

GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,500 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2013).

patients they see and supporting ongoing efforts to curtail the indiscriminate use of these drugs,” said Tony Antoniou, PhD, a pharmacist at St. Michael’s Hospital, in Toronto, Ontario, and a researcher at the Institute for Clinical Evaluation, also in Toronto, who led the study. “When viewed together with other studies reporting a similar association, our findings also suggest that regulatory action—such as advisories to clinicians advising them to be vigilant for this adverse effect—may be warranted.” —Rosemary Frei, MSc

Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2015 by McMahon Publishing.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JUNE 2015

Celiac continued from page 1

than 60% of patients before diagnosis. The median time from the positive test to diagnosis was nine years, but stretched to nearly 20 years in one patient, according to the study by gastroenterologists at Mayo Clinic, in Rochester, Minn. The researchers presented their findings at Digestive Disease Week 2015 (abstract Mo1217). “Celiac disease is there a long time before it gets diagnosed,” said Joseph A. Murray, MD, professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic, who led the work. “If you’re going to be screening people, we’ve got a wide window of opportunity. There is the opportunity for early detection.”

Military Samples Provide Research Arsenal Dr. Murray’s group analyzed blood samples from 250 soldiers with celiac disease that had been collected for the Department of Defense Serum Repository as part of routine medical testing for HIV and other conditions. The researchers looked at four samples from each individual, taken at diagnosis of celiac disease, two and four years before diagnosis, and when the soldier started active duty. For 100 of those subjects, the Mayo team tested the samples for any of three antibodies associated with celiac disease: deamidated gliadin peptide [DGP]-IgG, DGP-IgA and tissue transglutaminase-IgA. The majority of soldiers with celiac disease had signs of the condition long before diagnosis (Table 1). Samples from 62 of the 100 subjects in the preliminary study were positive for at least one antibody associated with the disease. In soldiers who initially were positive for one of the antibodies, titers rose by as much

Table 1. Antibodies to Celiac Disease

Table 2. Conditions Associated With Celiac Disease

At Earliest Sample, %

Anemia

Transglutaminase-IgA

Deamidated gliadin peptide-IgG

Deamidated gliadin peptide-IgA

At Diagnosis, %

Diarrhea Lymphocytic colitis Microscopic colitis Painful bloating/gas after eating

Transglutaminase-IgA

Deamidated gliadin peptide-IgG

Premature osteoporosis

Deamidated gliadin peptide-IgA

Type 1 diabetes

as 32% (in the case of transglutaminaseIgA) over the study period, the researchers reported. “We may feel great about making a diagnosis in May 2015, but that patient may have had that disease for 10 years,” Dr. Murray said. “This data tells us that

Race continued from page 34

2000, which highlighted a range of obstacles to care, from delaying appointments due to financial concerns to difficulty traveling to their provider’s office (Am ( J Gastroenteroll 2000;95:479-483). “But I truly don’t know the reason why African Americans would require less surgery,” he said. “It might be the genetic background of Caucasians that predisposes them to more severe complications of Crohn’s disease. But whatever the reason, it’s very important. More study is required.” The team further found that patients in the highest of three income brackets were less likely to develop postsurgical complications (OR, 0.86; 95% CI, 0.75-0.90), and stayed an average of 0.68 fewer days in the hospital (P=0.02), P than patients in the lowest third of income. An

celiac disease is present a long time before it’s diagnosed.” Gastroenterologists and other clinicians are being encouraged to think about celiac disease earlier, Dr. Murray said, but the condition often goes unidentified, even in people with known symptoms

explanation for that difference might be more obvious. “It’s likely that they are sicker,” Dr. Zhang said, and lack medication and care in the outpatient setting. The findings should be a reminder, he added, of the extra attention often required for these patients— a population that may struggle more than others with compliance. Better follow-up could reduce the burden of disease, as well as decrease costly complications in the hospital, Dr. Zhang noted. Sunanda Kane, MD, a gastroenterologist and professor of medicine at Mayo Clinic, in Rochester, Minn., cautioned against overinterpreting the findings. “I am in favor of continuing to find opportunities in predicting high-risk patients and improving care,” Dr. Kane said. Although the large national database provides an opportunity to identify “big signals,” she said, “the lack of granularity for the other important clinical

including diarrhea, anemia and painful gas after eating (Table 2). “If we’re not asking people if they have a family history of celiac disease, they might not volunteer it. Patients know it and nobody asks them,” Dr. Murray said. “It’s not part of the routine questionnaire.” “I would say that there is good evidence to test all people with signs or symptoms potentially consistent with celiac disease,” said Daniel Leffler, MD, MS, director of clinical research at the Celiac Center at Beth Israel Deaconess Medical Center, and director of quality improvement in the Division of Gastroenterology at Beth Israel, in Boston. “Right now, the evidence is insufficient to recommend screening of at-risk adults, including those with a family history or with related autoimmune conditions.” For children, Dr. Leffler said, although the data on testing are “more limited” than for adults “due to potential irreversible effects on growth and development, we are more aggressive with testing children in high-risk groups. Children with a family member with celiac disease or children with type 1 diabetes mellitus should be tested for celiac disease every few years or with onset of suspicious symptoms.” However, Dr. Leffler added, the benefits of early detection of celiac disease are uncertain. “We really do not know if earlier diagnosis in general improves long-term outcomes, but for people with signs and symptoms, they are not going to improve until they are treated. So, you can substantially reduce the burden of disease and improve quality of life by prompt diagnosis of symptomatic individuals.” —Adam Marcus

variables of each individual patient leaves a lot of questions and potential bias.” Alan Moss, MD, a gastroenterologist at Beth Israel Deaconess Medical Center, in Boston, said the results are “notable for health care planners and case managers for identifying ‘at-risk’ individuals.” Dr. Moss, who is also associate professor of medicine at Harvard Medical School, in Boston, said the findings might extend beyond patients dealing with inflammatory bowel disease. “Similar adverse outcomes are more frequent in patients who have difficult social or economic conditions with any chronic disease,” he said. “The race association with treatment decisions has also been noted in other diseases.” —Lynne Peeples Drs. Zhang, Kane and Moss reported no relevant financial conflicts of interest.

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First-Line Treatment Strategies for Helicobacter pylori Infection RICHARD SAAD, MD, MS Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

WILLIAM D. CHEY, MD, AGAF, FACG, FACP, RFF Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan Dr. Saad reports no relevant financial conflicts of interest. Dr. Chey has served as a consultant for AstraZeneca and Takeda.

elicobacter pylori remains a major cause of chronic gastritis and peptic ulcer disease; is strongly associated with

H. pylorii Eradication Therapy A variety of treatment regimens have been developed for the eradication of H. pylorii typically employing an antisecretory agent combined with 2 or 3 drugs possessing

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS â&#x20AC;˘ J U N E 2 0 1 5

Table 1. Indications for Helicobacter pylorii Testing as Recommended By Expert Panels American College of Gastroenterology (2007)1

Maastricht/Florence Consensus Conference (2012)9

Asia-Pacific Consensus (2009)11

Established indications

PUD

Active PUD

Gastric MALT lymphoma

MALT lymphoma

Confirmed history of PUD but not previously treated for H. pylori

Following endoscopic resection of early gastric cancer

Atrophic gastritis

Gastric MALT lymphoma

Uninvestigated dyspepsia (if H. pylori prevalence >20%)

Following endoscopic resection of early gastric cancer

Functional dyspepsia

First-degree relative with gastric cancer

Uninvestigated dyspepsia (if H. pylorii prevalence >20%)

Before use of NSAIDs with history of PUD

If desired by patient (after full consultation with physician)

Controversial indications

Chronic NSAID or low-dose ASA use

Functional dyspepsia

Chronic PPI use (>1 y)

Use of NSAIDs (especially those with a history of PUD or initiating NSAID therapy)

Unexplained iron deficiency, idiopathic thrombocytopenic purpura, B12 deficiency

Unexplained iron deficiency

First-degree relative with gastric cancer

Long-term low-dose ASA use with history of upper gastrointestinal bleeding or perforation

Severe pan-gastritis, corpuspredominant gastritis, severe mucosal atrophy

Screening strategy in communities with high incidence of gastric cancer

Chronic gastric inhibition for >1 y

Unexplained iron deficiency or idiopathic thrombocytopenic purpura

Populations at increased risk for gastric cancer

Environmental risk factors for gastric cancer (heavy smoking; high exposure to dust, coal, quartz, cement, or quarry work)

Following resection of gastric cancer

NSAID-naive users Before long-term ASA use if at high risk for PUD and PUD-related complications

ASA, aspirin; MALT, mucosa-associated lymphoid tissue; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor; PUD, peptic ulcer disease

of eradication therapy. In cases of penicillin allergy, metronidazole was recommended instead of amoxicillin or use of the bismuth quadruple therapy. Eradication rates were reported to be 70% to 85% for the clarithromycinbased triple therapy and 75% to 90% for the bismuth quadruple therapy.1 The negative impact of clarithromycin resistance on clarithromycin-based triple therapy is substantial. A recent meta-analysis demonstrated an eradication rate of only 22% in clarithromycin-resistant strains versus 90% in strains sensitive to clarithromycin.2 Evidence suggests that rates of clarithromycin resistance in H. pylori have been gradually increasing in the United States. The Helicobacter pylorii Antimicrobial Resistance Monitoring Program (HARP), a multicenter US network that tracks national incidence rates of H. pylorii antimicrobial resistance, initially reported a clarithromycin resistance rate of 10.1% in 3,624 H. pylori strains collected between 1993

G AST R O E N D O N E WS .CO M

and 1999.3 That rate increased to 12.9% in 347 strains collected from 11 hospitals in 4 regions of the country between 1998 and 2002.4 Although no organized, national surveillance of H. pylorii antimicrobial resistance has occurred in the United States since 2003, a large metropolitan hospital in Houston found a clarithromycin resistance rate of 16.4% in 128 strains collected between 2009 and 2013 (Table 3).5 Given the relative paucity of H. pylori resistance data from the United States, the ACG guidelines also recommended avoiding clarithromycin-based triple therapy in patients reporting a history of repeated use of macrolide antibiotics for any indication, as this has been shown to increase the likelihood of harboring a clarithromycin-resistant strain of H. pylori.6 This concern has been reaffirmed by a large study assessing the association between antibiotic-resistance profiles and outpatient antibiotic consumption in more than 2,200 patients

Table 2. First-Line Helicobacter pylori Eradication Therapies Treatment Duration, d

Practical Considerations

Legacy Therapies a

, clarithromycin 500 mg bid, amoxicillin 1,000 mg bid

7-14

7 d recommended in Asia; 10-14 d elsewhere (US) Use in penicillin-allergic patients

Standard-dose PPI bida, clarithromycin 500 mg bid, metronidazole 500 mg bid

7-14

10-14 d of therapy more effective than 7 d Use in penicillin-allergic patients

Bismuth subsalicylate 525 mg qid, metronidazole 250 mg qid, tetracycline 500 mg qid, ranitidine 150 mg bid or standard-dose PPI bida

10-14

May consider doxycycline 100 mg bid if tetracycline unavailable33,35,38

Standard-dose PPI bida + amoxicillin 1,000 mg bid for first 5 d followed by standard-dose PPI bida + clarithromycin 500 mg bid + tinidazole 500 mg bid for subsequent 5 d

Requires validation in North America

Standard-dose PPI bida, amoxicillin 1,000 mg bid, clarithromycin 500 mg bid, and tinidazole 500 mg bid or metronidazole 500 mg tid

10-14

Requires validation in North America

Emerging Therapies

Trend toward greater eradication efficacy with longer duration of therapy Variable-dose PPI bidb + amoxicillin 1,000 mg bid for the first 7 d followed by esomeprazole 40 mg bid, amoxicillin 1,000 mg bid, clarithromycin 500 mg bid, and metronidazole 500 mg bid for additional 7 d

Requires validation in North America

Levofloxacin 250 mg qd, omeprazole 40 mg qd, nitazoxanide 500 mg bid, and doxycycline 100 mg qd (PM dosing)

Superior to standard triple therapy in US clinical trial

PPI, proton pump inhibitor a

Standard-dose PPI: omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, rabeprazole 20 mg. Esomeprazole 40 mg once daily is equivalent to standard-dose PPI bid. b

Esomeprazole 40 mg, omeprazole 40 mg, pantoprazole 40 mg.

from 18 countries in Europe.7 Another recent study identified an increasing risk for antibiotic resistance based on number of previous antibiotic exposures (Table 4).8 International guidelines have presented similar recommendations for first-line eradication therapy with some notable differences. The fourth Maastricht/Florence Consensus Conference, with delegates from 24 countries, presented its most recent H. pylorii treatment recommendations primarily for the European community in 2012.9 In regions with low resistance to clarithromycin, clarithromycin-based triple therapy was recommended as initial treatment, with bismuth quadruple therapy as an alternative. However, in regions where the clarithromycin resistance rate exceeded 15% to 20%, bismuth quadruple therapy was recommended as the initial therapy.

A recent large-scale multicenter study involving 18 European countries found an overall clarithromycin resistance rate of 17.5%.7 Antibiotic resistance rates varied widely in different regions of Europe highlighting the difficulties of designing a one-size-fits-all approach to first-line treatment for any region or country. Clarithromycin resistance rates in Asia also vary widely, from 0% in Bhutan to as high as 58.8% in India.10 The Maastricht/Florence Consensus Conference also concluded that the use of a regimen containing twicedaily, high-dose PPI therapy increased the eradication rate of clarithromycin-based triple therapy. This conclusion was supported by results of a meta-analysis of randomized controlled trials (RCTs) that yielded a cure rate of 82% using twice-daily, high-dose PPI versus 74% with

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Table 3. Helicobacter pylori Resistance in a Male Veteran Population in Houston, Texas (2009-2013)5 Antibiotic Clarithromycin

n (% of cohort tested; N=128) 21 (16.4; 95% CI, 9.9%-22.9%)

Clarithromycin only Clarithromycin + metronidazole Clarithromycin + levofloxacin Clarithromycin + metronidazole + levofloxacin Metronidazole

3 (2.3) 9 (7) 3 (2.3)

26 (20.3; 95% CI, 13.2%-27.4%)

Metronidazole only Metronidazole + clarithromycin Metronidazole + levofloxacin Metronidazole + clarithromycin + levofloxacin Levofloxacin

6 (4.7)

13 (10.2) 3 (2.3) 7 (5.5) 3 (2.3)

40 (31.3; 95% CI, 23.1%-39.4%)

Levofloxacin only Levofloxacin + clarithromycin Levofloxacin + metronidazole Levofloxacin + clarithromycin + metronidazole

21 (16.4)

Tetracycline

1 (0.8)

9 (7) 7 (5.5) 3 (2.3)

twice-daily standard-dose therapy. The second AsiaPacific Consensus reported its expert panel recommendations in 2009 for Asian populations.11 A 7-day course of clarithromycin-based triple therapy was recommended as first-line therapy despite the panel’s acknowledgment of rising resistance to clarithromycin in Asia and the negative effect on eradication rates. The panel also recommended bismuth quadruple therapy as an alternative to clarithromycin-based triple therapy.

Emerging First-Line Eradication Therapies Sequential therapy was introduced in 2000 to address the diminishing efficacy of clarithromycinbased triple therapy.12 This treatment regimen—which consists of a PPI and amoxicillin for 5 days followed by a PPI, clarithromycin, and tinidazole for an additional 5 days—has demonstrated an eradication rate of 93.5% in a pooled analysis of 15 Italian studies including more than 1,800 patients.13 A subsequent systematic review and meta-analysis of 10 clinical trials (N=3,006 patients) that directly compared sequential therapy with clarithromycin-based triple therapy reported an odds ratio

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(OR) for eradication of 2.99 (95% confidence interval [CI], 2.47-3.62) in favor of sequential therapy, yielding a number needed to treat of 7.14 Among individuals with clarithromycin resistance, the OR for eradication was 10.21 (95% CI, 3.01-34.58) in favor of sequential therapy. However, 8 of the 10 clinical trials were performed in Italy, with the other 2 from Korea and China, calling into question the generalizability of the results. Indeed, subsequent studies from other parts of the world have yielded varying results with sequential therapy. For example, a multicenter clinical trial performed between 2009 and 2010 with 1,463 adults from 6 Latin American countries found 14 days of clarithromycin-based triple therapy marginally better than 10 days of sequential therapy, with an eradication rate of 82.2% versus 76.5% (95% CI, –0.04 to 11.6).15 A clinical trial in Turkey reported a cumulative eradication rate of only 66.5% in 200 adults receiving 1 of 2 14-day sequential therapies (either lansoprazole plus amoxicillin for 1 week followed by lansoprazole, clarithromycin, and metronidazole; or lansoprazole, clarithromycin, and tetracycline for the second week) as first-line therapy for H. pylorii infection.16 Furthermore, a large study from Taiwan found that preexisting resistance to clarithromycin or metronidazole reduced the efficacy of sequential therapy (Table 5) and that eradication rates might be improved by extending the duration of therapy to 14 days.17 A more recent systematic review and meta-analysis of RCTs through May 2013 (46 trials, N=13,532) comparing sequential therapy with either preexisting or new therapy has been published.18 In this study, the overall eradication rate of sequential therapy was 84.3% (95% CI, 82.1%-86.4%). Sequential therapy was superior to 7 days of clarithromycin-based triple therapy (relative risk [RR], 1.21; 95% CI, 1.17-1.25). However, sequential therapy was only marginally superior to 10 days of clarithromycin-based triple therapy (RR, 1.11; 95% CI, 1.04-1.19), and not superior to 14 days of clarithromycin-based triple therapy (RR, 1.00; 95% CI, 0.94-1.06) or quadruple therapy (RR, 1.01; 95% CI, 0.95-1.06). A meta-analysis of 6 RCTs in Korea (N=1,529) found 10 days of sequential therapy superior to clarithromycin-based triple therapy; however, the intention-to-treat eradication of sequential therapy was only 79.7% (95% CI, 76.8%-82.5%; n=754).19 A meta-analysis of 17 RCTs in Asia (N=3,419) found 10 days of sequential therapy superior to clarithromycin-based triple therapy with an eradication rate of 81.8% (95% CI, 78.9%-84.6%) for sequential therapy versus 74.3% (95% CI, 69.6%-78.8%) for triple therapy.20 A recent RCT from China underscored the potential negative effect of clarithromycin and metronidazole resistance on treatment efficacy of 10-day sequential therapy.21 This study, which included 280 patients from 4 centers, found 10 days of sequential therapy no better than clarithromycin-based triple therapy with an eradication rate of 72.1% (95% CI, 65%-79.3%) versus 66.4% (95% CI, 59.3%-74.3%). Moreover, clarithromycin and

Table 4. Effect of Prior Antibiotic Exposure on Risk for Antibiotic-Resistant Helicobacter pylori in a Population from the United Kingdom8 Patients, n (% With Antibiotic-Resistant H. pylori) Prior Antibiotic Exposure

Antibiotic Sensitivity

0 Courses

1 Courses

2+ Courses

RRa (95% CI)

Quinolone

Levofloxacin

114 (4)

7 (14)

11 (27)

1.8 (1.24-2.49)

Metronidazole

114 (28)

13 (38)

5 (100)

1.6 (1.46-1.75)

Clarithromycin

103 (7)

21 (19)

8 (25)

1.5 (0.92-2.41)

Erythromycin

Clarithromycin

104 (8)

15 (20)

13 (15)

1.1 (0.82-1.59)

Ratio of risk for being resistant per unit increase in number of courses. course es.

metronidazole resistance both independently predicted treatment failure with sequential therapy (OR, 8.34; 95% CI, 3.13-22.26 and OR, 7.14; 95% CI, 1.52-33.53, respectively). Patients with resistance to clarithromycin and metronidazole had a lower eradication rate (43.9%) than those with isolated resistance to clarithromycin (88.9%) or metronidazole (87.8%). Conversely, an RCT at a single center in Mumbai, India, involving 231 patients (enrolled between June 2011 and June 2012) found 10 days of sequential therapy superior to clarithromycin-based triple therapy, with an eradication rate of 88.2% (95% CI, 80.9%-93%) versus 79.1% (95% CI, 71.1%-85.4%).22 Unfortunately, no RCT has evaluated the efficacy of sequential therapy in the United States. Because of the divergent results from other countries and the lack of data from the United States, it is difficult to offer an unqualified endorsement to sequential therapy when considering treatment of patients in this country with H. pylorii infection. The ACG guidelines therefore offered cautious optimism for sequential therapy and recommended formal validation in the United States.1 The second Asia-Pacific Consensus also concluded that data in Asian populations were insufficient to recommend sequential therapy as a first-line eradication therapy for H. pylori.11 Given that the data suggest that sequential therapy is at least as effective, and, in selected populations, superior to clarithromycin-based triple therapy, the fourth Maastricht/Florence Consensus Conference recommendation that “In areas of low clarithromycin resistance, clarithromycin-containing treatments are recommended for ﬁrst-line empirical treatment,” seems appropriate.9 A recent clinical trial from Taiwan suggested that the sequence of the antibiotics in sequential therapy may not influence treatment efficacy.23 In this study, 122 adults were randomized to receive either sequential therapy (a 5-day dual therapy with pantoprazole plus amoxicillin, followed by a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole) or reverse sequential therapy (a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole,

followed by a 5-day dual therapy with pantoprazole plus amoxicillin). Eradication rates, by intention-totreat analysis, were 91.9% (95% CI, 85.1%-98.7%) for sequential therapy and 96.7% (95% CI, 92.2%-101.2%) for reverse sequential therapy, both yielding 100% eradication rates in strains resistant to clarithromycin. Another treatment regimen primarily developed to address the complexity of sequential therapy is that of non-bismuth quadruple therapy, or so-called “concomitant therapy.” This regimen consists of a PPI, amoxicillin, clarithromycin, and imidazole given concomitantly for 3 to 10 days. The initial clinical trial from Germany reported an eradication rate of 91% in 46 patients receiving a 5-day concomitant first-line therapy consisting of omeprazole, clarithromycin, metronidazole, and amoxicillin.24 A meta-analysis of 19 clinical trials involving 2,070 patients infected with H. pylorii using concomitant therapy revealed a mean cure rate of 88%.25 In addition, the RCTs (N=984 patients) in which concomitant therapy was compared with clarithromycinbased triple therapy revealed a cure rate of 90% versus 78%, yielding an OR of 2.36 (95% CI, 1.67-3.34) in favor of the concomitant therapy.25 The most recently published prospective trial involving 777 patients from 16 centers in Spain found concomitant therapy superior to an optimized clarithromycin-based triple therapy (14 days of therapy and high-dose PPI therapy), with an intention-to-treat eradication rate of 90.4% (95% CI, 87%-93%) versus 81.3% (95% CI, 78%-86%).26 Nearly all studies were performed in Europe or Asia, with only a single study performed in Latin America, with treatment durations ranging from 5 to 14 days. A systematic review and meta-analysis that pooled data from 7 clinical trials with 2,412 adults provided additional insight into the efficacy of concomitant therapy compared with sequential therapy, and the effect of treatment duration as well as antibiotic resistance on the performance of concomitant therapy.27 In this study, concomitant therapy was not found to be superior to 10 days of sequential therapy, with a pooled

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Table 5. Effect of Clarithromycin and Metronidazole Resistance on the Efficacy of Sequential Therapy in a Taiwanese Population17 Eradication Rate Antibiotic Resistance Profile of H. pylori

14-d Sequential Therapy, N (%)a

10-d Sequential Therapy, N (%)

14-d Triple Therapy, N (%)b

Cla-S + Met-S

116/117 (99)

123/129 (95)

98/109 (90)

Cla-S + Met-R

30/33 (91)

29/37 (78)

39/42 (93)

Cla-R + Met-S

10/14 (71)

7/10 (70)

9/16 (56)

Cla-R + Met-R

0/1 (0)

3/7 (43)

2/4 (50)

Cla, clarithromycin; Met, metronidazole; R, resistant; S, sensitive a

Sequential therapy: lansoprazole 30 mg bid + amoxicillin 1 g bid for first 5 or 7 d followed by lansoprazole 30 mg + clarithromycin 500 mg bid + metronidazole 500 mg bid for the subsequent 5 or 7 d. b

Triple therapy: lansoprazole 30 mg + am amoxicillin moxicillin 1 g bid + clarithromycin n 500 mg bid for 14 d.

intention-to-treat eradication rate of 86.1% (95% CI, 79.6%-90.7%) for concomitant therapy compared with 83.6% (95% CI, 78.3%-88.3%) for sequential therapy, and an OR of 1.12 (95% CI, 0.80-1.57; P=0.526).27 However, when comparing 10 days of concomitant therapy with sequential therapy, eradication efficacy favored concomitant therapy, with an OR of 1.52 (95% CI, 0.982.35); 5 days of concomitant therapy favored sequential therapy, with an OR of 0.64 (95% CI, 0.31-1.32).27 Eradication rates of concomitant therapy were affected by antibiotic-resistance profiles of H. pylori, with an eradication rate of 100% in clarithromycin-resistant strains, 95.5% to 100% in metronidazole-resistant strains, and 66.7% to 100% in strains resistant to both clarithromycin and metronidazole.27 No difference was observed in the rate of adverse events (AEs; OR, 1.229; 95% CI, 0.971-1.556; P=0.086) or compliance (OR, 0.945; 95% CI, 0.722-1.237; P=0.681) between the 2 regimens.27 Similar to sequential therapy, no randomized trials evaluating concomitant therapy have been reported from North America. Given the lack of any clinical trials in North America, the ACG guidelines did not provide recommendations for the use of concomitant therapy in the United States. However, a recent large multicenter, randomized trial in Latin America found clarithromycin-based triple therapy to be superior to 5 days of concomitant therapy, with an eradication rate of 82.2% versus 73.6% (95% CI for difference, 2.6%-14.5%).15 Therefore, if concomitant therapy is used, durations of 10 to 14 days seem most appropriate. The fourth Maastricht/Florence Consensus Conference recommended the use of concomitant therapy if bismuth quadruple therapy was not available.9 A third treatment regimen, so-called “hybrid therapy,” combines sequential and concomitant therapies. This approach consists of a standard 14-day sequential regimen; however, amoxicillin is continued for the entire period, making this a “concomitant” therapy for the last 7 days of treatment. Hybrid therapy initially was found

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to achieve an intention-to-treat eradication rate of 97.4% (95% CI, 94.5%-100%) in a multicenter trial involving 117 Taiwanese adults who specifically received twice-daily doses of 40 mg of esomeprazole and 1 g of amoxicillin for the first 7 days, followed by twice-daily doses of esomeprazole (40 mg), amoxicillin (1 g), clarithromycin (500 mg), and metronidazole (500 mg) for 7 additional days.28 A subsequent clinical trial involving 396 Iranian adults found hybrid therapy (40 mg of pantoprazole and 1 g of amoxicillin twice daily for 14 days, plus 500 mg of clarithromycin and tinidazole, both twice daily, for the last 7 days) superior to 10 days of sequential therapy, with an intention-to-treat eradication rate of 89.5% (95% CI, 85.4%-93.6%) versus 76.7% (95% CI, 71%-82.4%).29 A multicenter trial involving 343 adults from areas in Italy and Spain with high rates of resistance to clarithromycin and metronidazole found similar rates of intention-to-treat eradication for hybrid therapy (40 mg of omeprazole and 1 g of amoxicillin twice daily for the first 7 days, followed by 40 mg of omeprazole, 1 g of amoxicillin, and 500 mg of clarithromycin and nitroimidazole, all twice daily, for the final 7 days) compared with 14 days of concomitant therapy, with rates of 90% (95% CI, 86%-93%) and 91.7% (95% CI, 87%-95%), respectively. In this study, 23.5% of patients had H. pylori strains resistant to clarithromycin (26% in Italy and 19.5% in Spain), 33% had H. pylori strains resistant to metronidazole (33% in Italy and 34% in Spain), and 8.8% had H. pylori strains resistant to both clarithromycin and metronidazole (7.1% in Italy and 11.5% in Spain).30 Conversely, a multicenter, open-label clinical trial involving 270 Italian adults found 14 days of hybrid therapy (20 mg of omeprazole and 1 g of amoxicillin twice daily for 7 days, followed by 20 mg of omeprazole, 1 g of amoxicillin, and 500 mg of clarithromycin and tinidazole twice daily for an additional 7 days) inferior to 10-day sequential therapy and 5 days of concomitant therapy, with an intention-to-treat eradication rate of

80% with the hybrid therapy compared with 91.1% and 85.5% with the sequential therapy and concomitant therapy, respectively.31 A meta-analysis of 10 RCTs involving 3,501 patients receiving hybrid, concomitant, or sequential therapy reported pooled intention-to-treat eradication rates of 86.6% (95% CI, 82.3%-91%) for the group receiving hybrid therapy, 86.7% (95% CI, 81%-92.3%) for the group receiving concomitant therapy, and 84.3% (95% CI, 79.1%-89.4%) for the group receiving sequential therapy.32 The pooled data analysis suggested that the differences between the 3 groups were not statistically significant, with an RR of 1.01 (95% CI, 0.97-1.04) in the sequential versus concomitant therapies, 1.02 (95% CI, 0.85-1.22) in the sequential versus hybrid therapies, and 1.03 (95% CI, 0.97-1.08) in the concomitant versus hybrid therapies.32 Data from an RCT conducted in the United States do exist for one first-line treatment regimen, “LOAD” therapy. This 4-drug combination consists of levofloxacin, omeprazole, nitazoxanide, and doxycycline administered for either 7 or 10 days and was superior to a 10-day course of amoxicillin, clarithromycin, and lansoprazole in an open-label, randomized study of 270 patients. Eradication rates of 89%, 90%, and 73% were reported with 7 days of LOAD therapy, 10 days of LOAD therapy, or triple therapy for 10 days, respectively.33 Other first-line levofloxacin-based triple therapies have been evaluated in clinical trials, yielding mixed results. At present, levofloxacin triple-drug regimens are largely reserved to salvage patients with persistent infection despite an initial course of therapy.34

Role of Probiotics in H. pylori Treatment The use of probiotics as an adjuvant therapy in the treatment of H. pylori infection is attracting increasing interest. Evidence has suggested an inhibitory effect of Lactobacillus and Bifidobacterium species on H. pylori.35 Furthermore, there has been a suggestion that these probiotic strains also may help to reduce the side effects of eradication therapies and improve patient compliance with therapy.35 An initial meta-analysis of 10 clinical trials of adjuvant probiotics demonstrated a pooled OR of 2.066 (95% CI, 1.398-3.055), favoring improved cure rates with probiotic supplementation. Probiotics also reduced the incidence of total side effects, with a pooled OR of 0.305 (95% CI, 0.117-0.793).35 The majority of these studies were performed in China and there was great variability in the probiotics used as well as the treatment regimen employed. A more recent systematic review and meta-analysis included 45 RCTs involving pooled data from 6,997 patients, with results demonstrating an improvement in eradication rates and a decrease in treatment-related AEs when adding a probiotic to eradication therapy.36 This analysis was confounded by substantial heterogeneity regarding the treatment regimen and probiotic used (Lactobacillus, Bifidobacterium, Streptococcus, Saccharomyces, and/or Enterococcus). Acknowledging these issues, probiotics

plus therapy was associated with an increased eradication rate by pooled per-protocol analysis (RR, 1.11; 95% CI, 1.08-1.15; P<0.001) as well as by pooled intention-totreat analysis (RR, 1.13; 95% CI, 1.10-1.16; P<0.001) and a decrease in overall AEs (21.44% vs 36.27%), with a significant reduction in the risk for AEs on pooled analysis (RR, 0.59; 95% CI, 0.48-0.71; P<0.001). However, there was no effect on patient compliance (RR, 0.98; 95% CI, 0.68-1.39; P=0.889).36 Although use of probiotics appears promising, many important questions remain unanswered, including the preferred probiotic supplement, optimum dose, time of dosing (before, during, or after eradication therapy), duration of therapy, and the cost-effectiveness of such adjuvant therapy. At present, no widely accepted guidelines exist regarding the use of adjuvant probiotics in the treatment of H. pylori infection.

Conclusion Clarithromycin-based triple and bismuth-based quadruple therapies for 10 to 14 days remain the most commonly prescribed first-line eradication regimens for H. pylorii infection. Ten- to 14-day sequential, 10- to 14-day concomitant, 14-day hybrid, and 10-day LOAD quadruple regimens are gaining popularity as alternative first-line treatments given the falling eradication rates of clarithromycin-based therapy. Evidence clearly indicates that the presence of clarithromycin-resistant H. pylori significantly reduces the efficacy of clarithromycin-based triple therapy and, to a lesser extent, sequential therapy. However, clarithromycin- and/or metronidazole-resistant H. pylorii appear to have much less effect on bismuth-based quadruple, concomitant, and hybrid therapies. Although rates of antibiotic resistance are available in many parts of Europe and Asia, this information is still lacking for most parts of the United States. In the absence of resistance data, it is critical for clinicians to ask patients about previous exposure to antibiotics such as macrolides and quinolones. In regions where clarithromycin resistance is known to be greater than 15% to 20%, or if a patient has a history of more than one previous course of macrolide antibiotics for any indication, clarithromycin-based triple therapy, and arguably sequential therapy, should be avoided in favor of bismuth-based, concomitant, hybrid, or LOAD quadruple therapies. Obtaining a history of allergy or intolerance to any of the commonly used antibiotics will also assist in the most appropriate choice of treatment regimen. Gone are the days when physicians can mindlessly prescribe clarithromycin-based triple therapy for all patients with H. pylorii infection. Although this regimen remains effective in specific circumstances, a strategy that uses information regarding prior administration of antibiotics, regional antibiotic susceptibility, and drug allergies can assist the clinician in making the best treatment choice for an individual patient.37 In this era of “superbugs” and epidemic Clostridium difficile infection, responsible care demands a fresh look at how we manage this common and important infection.

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