January 2014 by McMahon Group

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Volume 65, Number 1 • January 2014

The Lowdown on Burnout in Medicine

ACG 2013

ACG Abuzz With FMT

Resolutions ns for Mitigating Stress and Avoiding Burnout in 2014

BY DAVID WILD BY MONICA J. SMITH SAN DIEGO—A swath of studies presented at the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting demonstrated the possible spectrum of indications for fecal microbiota transplantation (FMT). The new data show promise for FMT in the treatment of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), and also demonstrated the safety and efficacy of the procedure in see FMT, page 26

New Oral HCV Drugs Show Lasting Efficacy BY DAVID WILD SAN DIEGO—Several novel treatments for hepatitis C virus (HCV) infection lead to durable sustained virologic responses (SVR), researchers told attendees of American College of Gastroenterology 2013 Annual Scientific Meeting. Investigators presented updated see HCV, page 23

SAN DIEGO— —T The preparation for a talk on avoiiding burnout and finding ballance took gastroenterologisst Christina Surawicz, MD, outside her comfort zone, but it gave herr time to reflect on herr own experience, whaat she sees in her peerrs and younger colleagues, and how doctors can help themselvees and each other establiish more manageable and rewarding work–life pattern ns. “I am not an expert on burnout, but I cllearly have experienced it, althoough I don’t think I recognized it at the time,” said Dr. Surawicz, a faculty member at the University of Washington School of M Medicine, di i iin S Seattle, ttl who h iis b based d att Harborview Medical Center.

‘Disclose-and-Investigate’ Approach To Malpractice Claims Pays Off

“The two maiin contributing factors were feeling that I d didn’t have any controol and that I didn’tt have any supporrt at work.”

‘Burrnout’ Deffined The term T “bu urnout” was coin ned by psychologistt Herbert Freudenb berger to describe the consequences of a combination of high ideals and severe stress, Dr. Surawicz told her coolleagues in a presentation at tthe American College of Gastrooenterology (ACG) 2013 Annual Scientifi fic Meeting. “A typical example is doctors and nurses n who may sacrifice ifi th themselves l ffor others, th and d often f end up see Burnout, page 32

I N S I D E EXPERTS’ PICKS Best of the ACG Annual Scientific Meeting: Part 2 .............................................................. page 19

BY TED BOSWORTH ORLANDO, FLA.—The gastroenterology division of a large institution that changed its approach to malpractice claims benefited enormously, according to a study that compared claims filed before and after the policy change. The comparison showed a reduction in the number of claims, a reduction in the costs per claim, a reduction in total costs for defending claims, and a reduction in the time see Malpractice Claims, page 36

Frank G. Gress, MD

Franklin Kasmin, MD

CLINICAL REVIEW see insert after page 48

The Heterogeneity of Cancer Offers Targeted Therapy Opportunities see pages 8-9

Approach to Hemorrhoids: A Primer for Gastroenterologists By Harry Sarles Jr., MD

Prateek Sharma, MD

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

‘Change’ May Be the Operative Word in Medicine in 2014 Hundreds of CPT Code Changes, Nearly One-Quarter for Upper GI Procedures Lucian Newman III, MD General Surgeon Gadsden, Alabama Each year, the American Medical Association (AMA) releases updates to reflect changes in the way physicians report the work they perform

via the Current Procedural Terminology (CPT) reporting system. Initially developed in 1966 as a way to report work done by providers, it was modified in 1970, and by 1983 was mandated by Medicare as the system to be used to report the work performed by physicians and nonphysicians alike. The original intent was not meant to be a vehicle to bill insurance

carriers, but that is its basis now. This year, the AMA announced 335 changes to the CPT that include roughly 9,700 entries. The changes involve code additions, deletions and revisions. As a historical comparison, in 2010 there were 219 new codes, 141 revisions and 63 deletions. In 2012, there were 278 new codes, 139 revisions and 98 deletions.

Each modification is intended to reflect changes in the way we practice, adopting new approaches accordingly. The immense undertaking is broken down annually to address the items that need critical attention. Nearly 25% of the 2014 CPT update is devoted to upper endoscopy, while lower gastrointestinal (GI) procedures will be addressed in 2015. It would be prudent for all to understand the process by which these changes occur. The CPT exists to create a consistent system to report work to Medicare and Medicaid, as well as most private third-party payors. In this manner, a fee schedule is produced for reimbursement. The CPT is maintained by a committee that includes 11 physicians who are nominated by the representative medical societies. As changes in practice require CPT changes, the work group reviews these ideas to make recommendations to the Relative Value Scale Update Committee (RUC). This committee is composed of 31 members, some of whom are nominated by a broad cross section of medical specialty societies (Table, page 13). The criteria for review are known as screens and include site-of-service anomalies, fast-growing procedures and new technologies, among others. The reviews may look at low-value/high-frequency codes, bundling issues and unused codes, as well as any codes that influence the balance of the CPT process. The resource-based relative value scale (RBRVS) system is also pertinent to discuss. In the RBRVS system, payments for services are determined by the resource costs needed to provide them. The cost of providing each service is divided into three components: physician work, practice expense and professional liability insurance. Payments are calculated by multiplying the combined costs of a service by a conversion factor (a monetary amount that is determined by the Centers for Medicare & Medicaid Services). Payments are also adjusted for geographic differences in resource costs. Specifically, 2014 includes changes to upper endoscopy, abscess drainage with image guidance, breast biopsies with image guidance, radiological and cardiology embolization procedures, and molecular pathology diagnostic codes. The gastroenterology code changes include new codes, revised codes and the addition of sedation options. The focus on upper GI procedures separates rigid and flexible approaches to therapeutic interventions. Newer therapeutic options see Coding Update, page 13

FROM THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Among the Tried-and-True, 2014 Will Feature Something New Cynthia J. Gordon, PhD Managing Editor Gastroenterology & Endoscopy News Happy New Year from Gastroenterology & Endoscopy News!! With the new year under way, it seems appropriate to outline some of our plans for 2014: Among our features, will be some things old, and some things new. Among the new in 2014, we present “Endoscopy Suite.” This column will zoom in on endoscopy, focusing on coverage of new research in endoscopic procedures, new devices and imaging tools, novel techniques used in clinical practice, trends in coding for procedures, the business of managing an endoscopy practice, a spotlight on practices throughout the country, a historical look at endoscopy through the ages and more. All in all, we think this new column will be pretty “sweet”! Also new in 2014, we will feature a quarterly “Opinion” column from our contributor, private practice gastroenterologist Nicholas V. Costrini, MD, PhD, MBA, based in Savannah, Ga. See the first installment on page 6 of this issue (“Dear Professor Flexner: Medicine Is a Business, as Well as a Public Trust”). Our perennial features in 2014 will include: • “Experts’ Picks,” featuring expert selections of the

best abstracts from gastroenterology conferences held throughout the year (see page 19 of this issue for this year’s first installment); • “Clinical Reviews,” review articles featured nearly every month, written by leaders in the field (see “Approach to Hemorrhoids: A Primer for Gastroenterologists,” by Harry Sarles Jr., MD, included as an insert after page 48 of this issue); • “FDA Update & Product News,” providing current coverage of drug and device approvals (coverage begins on page 43 of this issue); • “Hepatology in Focus,” our quarterly focus on all things hepatology (first installment coming in February); and • “Expert Roundtable,” a series of panel discussions covering provocative topics in gastroenterology and beyond (first installment scheduled for April 2014). We also plan to add more new features based on feedback we receive from you throughout the year. Watch for reader surveys coming to you with your print issue in the months ahead. We want to make sure we continue to provide you with the most relevant and useful information we can.

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publish articles in i advance of the prin nt issue and breakingg news on a varietyy of topics. There, you can sign up p to receive our free weekly e-newsletters, delivered directly to your email. Also, follow us in real time on Twitter at @gastroendonews. In 2014, we anticipate adding even more online features, including more breaking news, a community of gastroenterology bloggers and a video channel, featuring a collection of gastroenterology-related videos.

Stay Current in 2014 We’ve resolved to make 2014 a dynamic year, with features we hope you’ll find valuable and compelling. So, resolve to stay current this year: Don’t miss an issue off Gastroenterology & Endoscopy News, and visit gastroendonews.com today! ■

Gastroenterology & Endoscopy Newss also has a thriving online community, gastroendonews.com, where we

Contact the editor at cgordon@mcmahonmed.com.

Vol. 65, No. 1 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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FREDRIC DAUM, MD Mineola, New York

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Dear Professor Flexner: Medicine Is a Business, as Well as a Public Trust gaps model of service quality. To those gastroenterologists who believe we are already on top of our game in these matters, consider this: When we built our endoscopy units over the past two decades, we followed the recommendations of the endoscopy vendors. That would It has been a century since the medibe like Delta Airlines asking Goodyear Tire Company cal community has faced social and how many tires it needed! It is not surprising that, by professional issues that were destined my assessment, 25% endoscopy of units overestimated to alter the course of health care for generations. In 1910, Embracing the Business of Medicine their needs for square footage and/or equipment. It is Abraham Flexner presented his damning appraisal of At present, the central driver of the future of health noteworthy that a similar number of units closed durthe state of the nation’s medical schools and made rec- care is value. The traditional practices of fee-for-service ing the economic downturn. This is a result of a lack of ommendations for change. These changes, outlined in medical care, silo health care and individual doctor– understanding of the health care business environment. the Flexner Report, were widely accepted, as they were patient relationships fail to offer definable value. To The best argument for optimism regarding the future true and fit well with the social and political of health care is that the myriad of challenges environment of the time. Whereas most medical can be met by applying some, or other, of the For Flexner, hospitals, physicians and health care were a schools in the mid-19th century existed as a colbusiness concepts outlined above. The current public trust; for a hospital to operate as a business was lection of for-profit enterprises that distributed health care crisis, purported in doctors’ lounges diplomas in return for a healthy sum, Flexner to be so unique to our profession, has in fact in conflict with the goal of public welfare. demanded that schools meet specific educational been managed hundreds, if not thousands, of standards and that faculty devote their time times in corporate America. The public and almost exclusively to teaching and research the government demand quality and value in a activities. Another visionary, Sir William Osler, variety of arenas. That the medical profession the “father of modern medicine,” considered should be offended by such demands is a source patient care to be the highest interest of medical of humor. education. Osler sought to expose medical stuEvolution in health care requires that physidents to clinical care through his establishment cians acquire requisite business skills, and that of the medical residency program. evolution is beginning. In 1993, five medical Regarding the points of money and business schools recognized that business skills would in medicine, Flexner and Osler agreed: Both be required in medicine, and the MD–MBA abhorred any thought of entrepreneurial intercombined degree program was born. Today, ests for physicians. (They did, however, enjoy 65 leading U.S. medical schools offer the comthe philanthropy of business titans John D. bined degree (usually as five-year program), and Rockefeller and Andrew Carnegie.) For Flexner, this year, 550 graduates will have the tools to hospitals, physicians and health care were a pubinfluence, guide and coordinate survival, and lic trust; for a hospital to operate as a business indeed achievement, in the private and public was in conflict with the goal of public welfare. sectors of medicine. Flexner would be reassured One of the harshest criticisms in the Flexner to know that the vast majority of MD–MBA The Flexner Report was so scathing in regard to the Report was that medical schools operated priprograms recognize that medicine is a pubinfluence of money, profit and self-interest in medicine, marily for profit, and secondarily for the health lic trust, and they are motivated as he would that for the next 100 years, no dean, professor, department and welfare of patients. hope. The scope of this combined degree is After publication of the report, the number of covered in the superb text “Physicians’ Pathway head, resident, intern, medical student—even hospital medical schools operating at the time dropped to Non-Traditional Careers and Leadership cafeteria attendant—would dare mention the ‘M word’ for from 155 to 31. Only schools meeting the Opportunities,” by Drs. R.D. Urman and J.M. fear of being subjected to the ‘wrath of Abraham.’ new standards of performance remained; othEhrenfeld. It is a handbook that the dinosaurs ers became extinct. The Flexner Report was so would have found very valuable 65 million years scathing in regard to the influence of money, profit and revolutionize medicine in line with the themes of 21st- ago when they sensed trouble was coming! [See “Private self-interest in medicine, that for the next 100 years, no century health care requires that physicians adapt in a Practice Is a Dinosaur and the ACA Is an Asteroid,” by dean, professor, department head, resident, intern, medi- way that respects Flexner’s caution regarding the fiscal Nicholas V. Costrini, MD, PhD, MBA. Gastroenterology cal student—even hospital cafeteria attendant—would motivations of medicine while embracing the business & Endoscopy News August 2013;64:7.] dare mention the “M word” for fear of being subjected of medicine practically, academically and with the intent If a physician looks at the Affordable Care Act from a to the “wrath of Abraham.” of best serving the public trust. The evolution of medi- business perspective, “evidence-based medicine” reveals Considering the avoidance of business-related matters by cine is this: Health care is a business, and the practice itself to be “process-driven quality”; the goals of improvseveral generations of medical educators, physicians and of medicine requires requisite business skills. Failure to ing coordination of care, reducing redundancy and students, it is not surprising that the medical profes- embrace this concept is a failure to both the medical eliminating waste might be called “value chain managesion now finds itself ill-equipped to face the current profession and the public trust. This is evident, given the ment.” If these are the rules of the road in the future challenges in health care. Addressing these challenges current fiscal dilemmas in health care. of health care, it is necessary for engaged physicians to requires—you guessed it—business skills! In order Gastroenterologists are comfortable with the fol- embrace these topics, just as they embraced the “Physito define and direct the future of health care, private lowing terms: Barrett’s metaplasia, Crohn’s disease, cal Diagnosis” course during their training. practice, academic research and the very important adenoma, endoscopic retrograde cholangiopancreatograIf physicians are serious about survival, better business American system of innovative health care solutions phy, and endoscopic ultrasound. Physicians who intend skills are vital. Of course, we could ignore the facts and in the private sector, physicians must possess business to survive and thrive in the coming decades will become choose the other option: extinction. ■ savvy. In his seminal text on the history of medical equally comfortable with the following terms: non-mareducation, “Time to Heal: American Medical Education ket business environment and strategy, core competency, Dr. Costrini can be reached via email at from the Turn of the Century to the Era of Managed service recovery strategy, value chain management and ncostrini@georgiagi.com. Nicholas V. Costrini, MD, PhD, MBA Gastroenterologist in solo practice Georgia Gastroenterology Group, PC Savannah, Georgia

Care,” Kenneth Ludmerer opines that although Flexner made recommendations in his report that were necessary at that time, he could not have predicted the issues facing society, government and medicine today. Mr. Ludmerer said that all matters must be addressed with the best interests of the public—i.e., the consumer—as the primary motivator of adaptation and change.

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

The Heterogeneity of Cancer Offers Targeted Therapy Opportunities Faculty Andrea Califano, PhD Chair, Columbia University Department of Systems Biology Director, JP Sulzberger Columbia Genome Center Associate Director, NCI-Designated Herbert Irving Comprehensive Cancer Center Clyde and Helen Wu Professor of Chemical Systems Biology Columbia University and NewYork-Presbyterian/Columbia University Medical Center New York, New York

Mark A. Rubin, MD Director, The Institute for Precision Medicine Vice Chair for Experimental Pathology Director, Translational Research Laboratory Services Homer T. Hirst III Professor of Oncology Weill Cornell Medical College and NewYork-Presbyterian/Weill Cornell Medical Center New York, New York

t NewYork-Presbyterian Hospital, initiatives to tailor cancer therapy to the specific genomic and molecular features of a patient’s tumor are advancing rapidly in the clinic. The Institute for Precision Medicine was created by Weill Cornell Medical College and NewYork-Presbyterian/ Weill Cornell Medical Center specifically with this mandate in mind. At NewYork-Presbyterian/Columbia University Medical Center and elsewhere on the Columbia University campus, meanwhile, pioneering work characterizing the interplay of genetic characteristics and molecular events in cancer cell pathology is providing a new path to therapies for challenging cancers in trial-eligible patients. “We are trying to understand cancer by looking at the regulatory networks within the cell,” explained Andrea Califano, PhD, chair, Columbia University Department of Systems Biology. “Integrative network-based association studies [INAS] are for the first time allowing us to separate the handful of driver events from the thousands of transcriptional, posttranscriptional, and metabolic events that could be potentially linked to a given cancer. This is an important departure from genome-wide association studies [GWAS], which look linearly at the germline DNA for common variants associated with cancer growth.” Dr. Califano emphasized, “Cell regulation is not generally a linear phenomenon.”

Targeting Mutations Individualized cancer care, foreseen for a decade or more, is already underway, and the NewYork-Presbyterian initiatives represent bold next steps. In the Precision Medicine Clinic of the Institute for Precision Medicine, whole-exome

genome sequencing is being performed for patients with microarrays, and expression of cloned DNA—to isolate the advanced cancer to identify targetable mutations. The events unique to the growth of a cancer type. This ongoing immediate effect is the opportunity to identify one of a work has already allowed Dr. Rubin to publish findings on an growing number of targetable mutations to which treat- array of novel biomarkers for aggressive forms of prostate ment can be directed. At the same time, this sequencing will and other cancers. generate its own library of recurring mutations for which a “We have started sequencing patients with advanced new generation of targeted therapies might be developed. bladder, prostate, lung, and brain cancers, and are per“A patient’s genome can now be sequenced in a mat- forming real-time analyses that we hope will guide us in ter of days at an acceptable cost,” said Mark A. Rubin, MD, understanding events that confer or inhibit susceptibility director of the Institute for Precision Medicine. “This has to highly targeted therapies,” Dr. Rubin said. These princibeen a key advance with far-reaching implications.” This ples extend to many other cancer types, and the Institute not only means identifying and developing therapies for for Precision Medicine provides the framework for expandevents responsible for the development of malignancy, but ing this approach. also developing therapies for the genetic and molecular This is not theoretical. Dr. Rubin noted that the work events that permit a tumor to regrow when initial treat- with sequencing in advanced prostate cancer has already ments lose efficacy. It is reasonable to expect both of these revealed actionable information that may provide opportutypes of therapies to be targetable. nities to improve outcome. The challenge will be to develop “Next-generation sequencing will allow us to look for clinical trials around these novel discoveries. As data genermechanisms of growth when treatments fail, creating sec- ated by serial sequencing of advanced cancers accrue, the ond opportunities to understand and inhibit tumor growth,” opportunity for the Institute for Precision Medicine to fulfill explained Dr. Rubin, who is also director of Translational its mission increases. These data will capture key genetic and Research Laboratory Services at NewYork-Presbyterian/Weill molecular drivers of cancer from which those most relevant Cornell. He co-led the team that characterized the fusion of to an individual patient can be identified and targeted. TMPRSS2 and ETS transcription factors, which is now recognized as one of the earliest events of prostate cancer Regulatory Network Models invasion. More recent work has defined the landscape of The heterogeneity of cancer underlies the efforts to better prostate cancer mutations. individualize care on both campuses of NewYork-Presbyterian The work at the Institute for Precision Medicine will not Hospital. Within cancer types further stratified by histology, only address cancer but also other diseases, such as genetic, stage, or other broad characteristics, mechanisms of growth cardiovascular, and neurodegenerative disorders, for which can differ, which explains the variability in response to thergenomic sequencing may provide new insights into pre- apy. Information gained from sequencing studies suggests vention and treatment. In many ways, the advanced work in that therapy needs to be further individualized even among understanding the signals that initiate abnormal cell growth patients whose cancer has emerged from the same genetic in cancer is informing research in other diseases. The efforts pathways. This is because additional heterogeneity in drivto control tumor growth by identifying and then suppress- ers of growth is produced by a complex interaction between ing the underlying molecular signals have major implica- culprit genes and the molecular events that follow. Drilling tions for understanding a full spectrum of disease states. As down to key and targetable drivers of growth in individual opposed to cytotoxic therapies designed to eradicate can- patients is the focus of the work at NewYork-Presbyterian/ cer cells, the inhibition of cancer growth Columbia and Columbia University, where involves understanding its biolDr. Califano is evaluating regulatory A large ogy at a fundamental level. networks through INAS. analysis of tissue samples The hope is that, through “Regulatory network increased understandmodels attempt to from patients with neuroendocrine ing, better and more understand the celtumors of the gastrointestinal tract was precise therapies can lular machinery that conducted specifically to develop an integrative be initiated. connects the genetic In advance of the mutations in a cancer network-based association study capable founding of the Institute patient with the abnorof isolating targetable drivers of for Precision Medicine, Dr. mal behavior of their cells. malignancy. Rubin participated in and led These models take into considthe types of translational research eration the influence of genetics and teams on which these advances depend. It epigenetics to identify the unique vulnerabiliis complex work that requires collaboration between clini- ties of the cancer cell,” explained Dr. Califano, who also serves cians, pathologists, computational biologists, and basic sci- as the associate director of the NCI-designated Herbert Irving entists. The data are collated from multiple strategies—such Comprehensive Cancer Center at NewYork-Presbyterian/ as laser capture microdissection, high-throughput tissue Columbia. He suggested a parallel to INAS might be

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

continue to produce new factors to consider, and appear to be important in the context of genetic susceptibility as well as in the microenvironment of the cell at risk. Yet, within this overwhelming number of factors with potential relevance to cancer development, the final pathways to oncogenesis in the individual patient appear to be much smaller, at least in some cancers. As an example, Dr. Califano noted that there are dozens of genetic alterations associated with glioma but a much more limited number of molecular subtypes. In cancers like these, inhibition of the final common pathway, or cancer bottleneck, may benefit a large subset of patients with very different mutations. The opportunity for benefit in both cases depends on improved characterization of cancer—which appears to be possible with INAS—and then individualization of therapy. The concept of individualized therapy is already well established in a few malignancies. For example, tissue profiling is performed routinely in patients with non-small cell lung cancer because of the relevance of specific biological markers to drug selection. However, as the signaling systems and mechanisms of cancer are better underFigure. A Columbia Systems Biology study, led by Dennis Vitkup, PhD, identified metabolic stood, new targets for treatment will be identified and expression changes in cancer as well as hundreds of potential drug targets. Up-regulation is in the role of individualized therapy will expand. The work red, down-regulation is in blue. underway at NewYork-Presbyterian Hospital is at the foreNature Biotechnology. 2013;31:522-529. front of this effort. “The foundation of the Institute for Precision Medicine is conceptualized as accessing the blueprint of a complex elec- downstream effects, the focus from INAS on likely targeta- an exciting step,” Dr. Rubin said. “We expect to contribute tronic circuit with millions of components to understand why ble drivers of cancer can be narrowed. substantially to the rapid advances being made in identifyit is broken and how to fix it. Rather than addressing oncogening cell signals that participate in human diseases, not just esis as a linear phenomenon stemming from a single gene Cancer Bottlenecks cancer. The Institute will allow us to readily translate some mutation, INAS understands cancer as a product of multiple, “What we are looking for are the critical bottlenecks in the of the advances into improved patient care and, we hope, complex, and nonlinear events dependent on multiple fac- complex mechanics of cancer that are essential to tumor sur- better outcomes.” tors and creating unique vulnerabilities, which can be tar- vival and can be targeted pharmacologically,” said Dr. Califano. Dr. Califano made a similar point. As the interplay between geted pharmacologically. As noted above, this is not just theoretical. A large anal- factors leading to malignancy are better understood, it has This approach circumvents the limitations of GWAS. ysis of tissue samples from patients with neuroendocrine become clear that tumors that appear virtually identical are Although GWAS has identified mutations closely associ- tumors of the gastrointestinal tract was conducted spe- driven by very different signaling mechanisms within the ated with increased cancer risk, not all patients with a specifically to develop an INAS capable of isolatcell. Targeted therapies that are effective for cific mutation develop cancer or develop cancer via the exact ing targetable drivers of malignancy. one individual may therefore not have same set of underlying mechanisms. For instance, therapies The work allows simultaneous, similar efficacy in another. As a that are highly effective in a patient with a specific driver interactive signaling sysresult, cancer therapy is likely As the signaling systems and mutation may fail completely in another patient with the tems to be considered, to become increasingly same exact mutation. The complexity of the mechanics of which is likely to be individualized as more mechanisms of cancer are better cancer is further underlined by the fact that genomic altera- more representative of details about key steps understood, new targets for treatment will tions in individual tumor subclones are continuously evolv- cell biology than linear in the signaling process be identified and the role of individualized ing and being selected for, even once the malignancy is step-by-step signaling are isolated. established. This explains loss of response to treatment over pathways. “The regulatory nettherapy will expand. time and emphasizes the need for individualized treatment. “Pathway models are easwork model provides a Although the changes in activated and deactivated ier to conceptualize and lend framework to sort out the key genes, protein expression, and other molecular events themselves more easily to validation targets in complex processes depenpotentially associated with cancer in any single patient when a change in the pathway leads to a change dent on multiple factors,” Dr. Califano said. “In are vast, Dr. Califano pointed out that they are not ran- in cell function. However, individual transcription factors may most cases, sustained control of cancer is not likely to be dom. Rather, the promotion of malignancy can be traced regulate hundreds of thousands of cell context-dependent achieved by suppressing the activity of a single gene but back to a handful of driver genes, or master regulators of targets for which ultimate function is determined by syn- will require a combination of strategies against multiple cancer, that produce specific behavior. These genes are ergistic interactions between 2 or more genes,” Dr. Califano pathways. We think a better understanding of the cellular frequently not the ones that are mutated but are those explained. This complexity may explain why single pathways machinery will expand the opportunities to adapt treatdownstream from the mutated genes. By attempting to have proven incomplete for understanding cancer biology. ment to the specific features of the malignancy we are tryreconstruct gene-regulatory networks and understand the He noted that efforts to better characterize oncogenesis ing to control.”

Image courtesy of Dennis Vitkup, PhD

Supported by

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

12 Reasons To Reject the Central Authority of Health Care Re: “Private Practice Is a Dinosaur and the ACA Is an Asteroid,” by Nicholas V. Costrini, MD, PhD, MBA. Gastroenterology & Endoscopy News August 2013;64:7. Dr. Costrini waxes poetic, and I’m sure has good intentions, but I must dissent. The whole concept that a central authority or insurance company could ever provide what individual patients need is absurd. We were all trained for years to think

for ourselves, to treat each patient as an individual and to work within a framework that has evolved over centuries for the benefit of society. I could go on for pages, but consider the following consequences of what Dr. Costrini advocates, only to get worse every year:

1. We are required to get prior authorization for most things we do, including procedures, imaging, ultrasound, follow-up visits, etc. This is a major barrier to providing care. 2. It takes double the number of employees compared with 20 years ago to obtain authorizations, verify insurance, process appeals, etc. This increases overhead, and benefits no one.

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Web Comment 3.

Central authorities have given us the requirement of performing a comprehensive history and physical examination within 30 days of an esophagogastroduodenoscopy and so forth—a waste of patients’ time and money, and a burden that has not improved outcomes. 4. HIPAA requires patient privacy, but the government won’t allow a patient to be moved to a private procedure room until an assessment is completed in a public preoperative area. 5. We are told we will be paid on outcomes that are childish and short-term, or by the nebulous “patient satisfaction” metric. 6. Electronic medical records are encouraged, which increase staff expenses, make us less efficient, and decrease face-to-face time with patients. 7. Accountable care organizations don’t save money, and capitation schemes don’t work for specialists. 8. Internists don’t have time to go to hospitals to see their patients and/or delegate responsibilities to hospitalists who don’t know the patients, all because they aren’t paid enough to be able to leave the office. 9. Primary care doctors are using specialists for simple matters because of a lack of time in the office. 10. Physician assistants and nurse practitioners see many of primary care patients, and many patients have never seen an MD. 11. Fees paid by central authorities bear no relationship to practice costs, and economies of scale in large groups are a fallacy. 12. There is no human being available to talk to at the central authority who will discuss variation from the draconian list of criteria for payment of tests and procedures that are indicated but don’t conform to outdated guidelines. That’s the short list. We physicians have a responsibility to care for our patients efficiently and compassionately. The health care of the future will not do that. There is no reason why physicians cannot work for a fair fee determined by the level of service we provide. Any other scheme will lead us further into oblivion. “felde” September 26, 2013

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Hospital Employment: Look Before You Leap Frederick L. Greene, MD Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina It should not be surprising that in this era of shaky economic growth, funding sequestration, Congressional discord over the Affordable Care Act (ACA) and government closings, a majority of acute care hospitals are facing a precarious future, with the specter that many will be downsized or not survive at all. Many institutions have taken drastic steps to reduce their budgetary shortfalls by cutting payrolls through layoffs of physician and nonphysician personnel alike. Falling insurance payments and reduced inpatient visits, specifically caused by reductions in elective surgical procedures, have triggered these events. In 2013, health care institutions reported more than 41,000 layoffs, exceeded only by personnel reductions in the financial and industrial sectors. Even with the presumed positive effect of the ACA that launched on Oct. 1, 2013—creating opportunities for increased coverage for at least 30 million uninsured Americans—the negative effects of a poor economy and reduced payments by programs such as Medicare and Medicaid serve to add to an already shaky hospital-based economy. Increased layoffs will continue until some economic upturn is noted. These layoffs will affect all segments of health care workers. There are several major factors at play that create economic uncertainty for hospital solvency: • The Centers for Medicare & Medicaid Services and private insurers are restricting hospital reimbursement. The creation of funding sequestration by legislative fiat has reduced Medicare reimbursement by 2%. • Using benchmarks of quality care including hospital readmission rates, a number of hospitals have already witnessed and will be targeted for more reductions in Medicare payments. • Research dollars aimed at academic centers have been reduced by 5% as a byproduct of sequestration, resulting in the layoff of those supporting research efforts. • The overall number of inpatient hospital days fell by 4% between 2007 and 2011 as a result of the economic downturn and reduced numbers of elective surgical procedures. • With increased numbers of “baby boomers,” a greater segment of the

population consuming health care is being reimbursed at Medicare rates, which are lower than private insurance. • Hospitals depending on Medicare and Medicaid dollars for support of physicians-in-training (disproportionate share funding) will be especially at risk because this traditional economic support is slated to end or to be severely limited in the very near future. This will especially weaken

“safety net hospitals” that depend on residents to provide a significant portion of patient care. These negative factors should be of particular concern for surgeons who already have joined or are considering becoming employees of hospitals. Hospital-employed physicians are not immune to the economic exigencies that institutions are facing. All physicians need to understand the factors that are negatively affecting the hospital margin.

My concern is there will continue to be a continuous erosion of hospital finances, despite the strong lobbying activity of physicians and hospital associations. Physicians contemplating employment by hospitals need to be acutely aware of these factors and at least should be able to ask the right questions during contractual discussions and be capable of understanding the metrics that represent the bellwethers of hospital economics and success. ■

NEW from Amneal Pharmaceuticals

Esomeprazole therapy at an easy-to-swallow price Esomeprazole therapy is now available as Esomeprazole Strontium delayed-release capsules 49.3 mg. This strontium salt is a pharmaceutical alternative with the same indication in adults as Nexium® (esomeprazole magnesium) delayed-release capsules; it is not approved for patients under 18 years old. Esomeprazole Strontium provides the same dose of esomeprazole therapy as Nexium® 40 mg and may likely deliver cost savings to patients.

INTRODUCING

ESOMEPRAZOLE STRONTIUM Learn more at esomep.com Indications and Usage Esomeprazole Strontium is a proton pump inhibitor (PPI) indicated for adults for: O Treatment of gastroesophageal reflux disease (GERD) O Risk reduction of NSAID-associated gastric ulcer O H. pylori eradication to reduce the risk of duodenal ulcer recurrence O Pathological hypersecretory conditions, including Zollinger-Ellison syndrome The safety and effectiveness of esomeprazole strontium have not been established in pediatric patients. Esomeprazole strontium is not recommended for use in pediatric patients. The safety of esomeprazole strontium has not been studied in patients with severe renal impairment. Esomeprazole strontium is not recommended for use in patients with severe renal impairment. Nursing mothers should consider discontinuing esomeprazole strontium. There are no studies in pregnant women. Esomeprazole Strontium should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Important Safety Information Esomeprazole strontium is contraindicated in patients with known hypersensitivity to PPIs. Hypersensitivity reactions, e.g., angioedema and anaphylactic shock have been reported with esomeprazole use. Symptomatic response to therapy does not preclude the presence of gastric malignancy. Atrophic gastritis has been noted occasionally in biopsies from patients treated long-term with omeprazole. PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. All trademarks are property of their respective owners. Products are not to scale and color may vary. ©2014 Amneal Pharmaceuticals LLC. All rights reserved. ESPA-0114bMD

Avoid concomitant use of esomeprazole strontium with clopidogrel, because the metabolism of clopidogrel can be impaired. When using esomeprazole strontium consider alternative anti-platelet therapy. Long-term and multiple daily dose PPI therapy may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine. Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. Serious events included tetany, arrhythmias, and seizures, and may require discontinuation of the PPI. Most common adverse reactions in adults (≥18 years) (incidence ≥1%) are headache, diarrhea, nausea, ﬂatulence, abdominal pain, constipation, and dry mouth. Avoid concomitant use of esomeprazole strontium with drugs which induce CYP2C19 or CYP3A4, such as with St. John’s Wort or rifampin, due to the potential substantial reduction in esomeprazole levels. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Esomeprazole may interfere with the absorption of drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, and digoxin). Drug-induced decreases in gastric acidity may increase serum chromogranin A (CgA) levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment before assessing CgA levels. Concomitant use with atazanavir and nelﬁnavir is not recommended; Concomitant use of saquinavir with PPIs is expected to increase saquinavir concentrations, which may increase toxicity.

Please see the Brief Summary of the full Prescribing Information on the next page.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Universal Health Care, for a Price Re: “The U.S. Trillion-Dollar Medical Bill: 99.6% Is Not Related to Colonoscopy,” by Victoria Stern. Gastroenterology & Endoscopy News December 2013;64:1,8,10,13-14,27,34. Hear, hear! Finally, a real article on the root problem of our health care issues: unabated price gouging and collaboration between insurance companies, Big Pharma and hospitals/clinics. The Obamacare fiasco may shed light on the health care industry, but it does nothing to fix the real problems behind it. All it did was cost millions to taxpayers and enslave millions to

BRIEF SUMMARY

ESOMEPRAZOLE STRONTIUM delayed-release capsules 49.3 mg For oral use only Rx Only BRIEF SUMMARY of Prescribing Information INDICATIONS AND USAGE Treatment of GERD in Adults: Esomeprazole strontium is indicated for the short-term treatment (4 to 8 weeks) for healing and symptomatic resolution and maintenance (controlled studies do not extend beyond 6 months) of confirmed erosive esophagitis (EE), the short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults. Risk Reduction of NSAID-Associated Gastric Ulcer in Adults, H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults, and Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome in Adults. CONTRAINDICATIONS Esomeprazole strontium is contraindicated in patients with known hypersensitivity to proton pump inhibitors (PPIs). Hypersensitivity reactions, e.g., angioedema and anaphylactic shock, have been reported with esomeprazole use. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with esomeprazole strontium, refer to the CONTRAINDICATIONS section of their package inserts. WARNINGS AND PRECAUTIONS Concurrent Gastric Malignancy: Symptomatic response to therapy with esomeprazole strontium does not preclude the presence of gastric malignancy. Atrophic Gastritis: Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer. Clostridium difficilee Associated Diarrhea: Published observational studies suggest that PPI therapy like esomeprazole strontium may be associated with an increased risk of Clostridium difficilee associated diarrhea. This diagnosis should be considered for diarrhea that does not improve. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Clostridium difficilee associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with esomeprazole strontium, refer to WARNINGS and PRECAUTIONS sections of those package inserts. Interaction with Clopidogrel: Avoid concomitant use of esomeprazole strontium with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole strontium, consider alternative anti-platelet therapy. Bone Fracture: Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. Hypomagnesemia: Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. Concomitant Use of esomeprazole strontium with St. John’s Wort or Rifampin: Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of esomeprazole strontium with St. John’s Wort or rifampin. Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Concomitant Use of esomeprazole strontium with Methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients.

Web Comment health care giants with threat of jail or wage garnishments. … When I am forced to go to China to give birth to a child, something is wrong in the United States: Five days in a hospital cost $500 for child delivery—in the United States, the same procedure, for a two-day stay, is $20,000?! I refuse to go into debt because of a corrupt medical industry. “barga” December 12, 2013

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of esomeprazole strontium has been established from adequate and wellcontrolled studies of esomeprazole magnesium. Adults: The safety of esomeprazole magnesium was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6-12 months. In general, esomeprazole magnesium was well tolerated in both short and long-term clinical trials. The safety in the treatment of healing of erosive esophagitis was assessed in 4 randomized comparative clinical trials, which included 1,240 patients on 22.3 mg of esomeprazole magnesium (equivalent to 20 mg of esomeprazole), 2,434 patients on 44.6 mg of esomeprazole magnesium (equivalent to 40 mg of esomeprazole), and 3,008 patients on 20 mg of omeprazole daily. The most frequently occurring adverse reactions (≥1%) in all three groups were headache (5.5%, 5%, and 3.8%, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking esomeprazole magnesium or omeprazole. Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence <1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors; Cardiovascular: flushing, hypertension, tachycardia; Endocrine: goiter; Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting; Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased; Metabolic/ Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect; Reproductive: dysmenorrhea, menstrual disorder, vaginitis; Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis; Skin/Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria; Special Senses: otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria; Visual: conjunctivitis, vision abnormal. Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration. In two placebo-controlled studies, 710 patients were treated symptomatic GERD and the most common adverse reactions possibly or probably related to esomeprazole magnesium were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%). Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with esomeprazole magnesium plus amoxicillin and clarithromycin, no additional adverse reactions specific to these drug combinations were observed. Adverse reactions that occurred were limited to those observed when using esomeprazole magnesium, amoxicillin, or clarithromycin alone. The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea (9.2%), taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse reactions were observed at higher rates with triple therapy than were observed with esomeprazole magnesium alone. For more information on adverse reactions with amoxicillin or clarithromycin, see their package inserts, refer to ADVERSE REACTIONS sections. Postmarketing Experience The following adverse reactions have been identified during post-approval use of esomeprazole magnesium. Because these 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. These reports are listed below by body system: Blood and Lymphatic: agranulocytosis, pancytopenia; Eye: blurred vision; Gastrointestinal: pancreatitis, stomatitis, microscopic colitis; Hepatobiliary: hepatic failure, hepatitis with or without jaundice; Immune System: anaphylactic reaction/ shock; Infections and Infestations: GI candidiasis; Clostridium difficilee associated diarrhea; Metabolism and nutritional disorders: hypomagnesemia; Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture; Nervous System: hepatic encephalopathy, taste disturbance; Psychiatric: aggression, agitation, depression, hallucination; Renal and Urinary: interstitial nephritis; Reproductive System and Breast: gynecomastia; Respiratory, Thoracic, and Mediastinal: bronchospasm; Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal).

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Coding Update continued from page 3

are described. As always, the exact description by the physician is required to bill the specific code. All too often, the report produced by the proceduralist is not specific enough to distinguish between the CPT codes. Imaging services, in general, will face substantial cuts in 2014. It is anticipated that radiation therapy centers will be cut by approximately 13%, diagnostic testing by 7%, radiation oncology by

5%, interventional radiology by 3% and nuclear medicine by 3%. As expected, when changes occur, there are intended and unintended consequences. For example, the American Society of Breast Surgeons and the Society of Breast Imaging have opposed the reductions that will affect physicians in non-facility settings. The new payment bundling system will include the biopsy and the localization service together,

DRUG INTERACTIONS Interference with Antiretroviral Therapy: Concomitant use of atazanavir and nelfinavir with PPIs is not recommended. Coadministration of atazanavir with PPIs is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Coadministration of saquinavir with PPIs is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. Reduced concentrations of atazanavir and nelfinavir:: For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmaxx by 37% and 89% and Cmin by 39% and 75%, respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmaxx by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Increased concentrations of saquinavir:: For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmaxx by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily coadministered days 11 to 15. Clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with esomeprazole. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. Drugs for Which Gastric pH Can Affect Bioavailability: Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g. ketoconazole, atazanavir, iron salts, and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Esomeprazole is an enantiomer of omeprazole. Coadministration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin. Patients may need to be monitored when digoxin is taken concomitantly with esomeprazole. Effects on Hepatic Metabolism/Cytochrome P-450 Pathways: Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitroo and in vivoo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, quinidine, clarithromycin, or amoxicillin. Although drug interaction studies have not shown that esomeprazole has a clinically significant interaction with warfarin, post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of esomeprazole strontium with clopidogrel. When using esomeprazole strontium, consider use of alternative anti-platelet therapy. Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in a cross-over study, increased Cmaxx and AUC of cilostazol by 18% and 26% respectively. Cmaxx and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Coadministration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. A dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John’s Wort, an inducer of CYP3A4. In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (Cmaxx and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmaxx and AUC decreased by 49.6 % and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with esomeprazole strontium. Interactions with Investigations of Neuroendocrine Tumors: Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels, which may interfere with investigations for neuroendocrine tumors. Tacrolimus: Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus. Combination Therapy with Clarithromycin: Coadministration of esomeprazole,

resulting in a lower total reimbursement. If insufficient reimbursement is the result, the fear is that more invasive open biopsies will be done. The take-home message is that as medicine changes, our ability to differentiate between approaches becomes more difficult. We are moving to ICD-10 in 2014, and similarly, diagnostic specificity is paramount. ICD-10 PCS [procedure

clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin. Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see WARNINGS and PRECAUTIONS in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for coadministration with certain drugs [see CONTRAINDICATIONS in prescribing information for clarithromycin]. Methotrexate: Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted. SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate and well controlled studies of esomeprazole strontium delayed-release capsules in pregnant women. Teratogenicity was not observed in an embryofetal developmental study in rats with either esomeprazole strontium or esomeprazole magnesium at equimolar oral doses up to 280 mg esomeprazole/kg/day (about 57 times the daily maximum recommended human dose (MRHD) of 40 mg on a body surface area basis). When administered as either the strontium or magnesium salt, changes in bone morphology and physeal dysplasia were observed in pre- and postnatal developmental toxicity studies in rats at doses equal to or greater than 138 mg esomeprazole/kg/day (approximately 33.6 times the daily MRHD of 40 mg on a body surface area basis). Because of the observed effect at the high doses of esomeprazole strontium on developing bone in rat studies, esomeprazole strontium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Limited published data indicate that esomeprazole and strontium are present in human milk. Because of the effect of esomeprazole strontium observed at high doses on developing bone in rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of esomeprazole strontium delayed-release capsules have not been established in pediatric patients. Strontium is known to compete with calcium for intestinal absorption and is incorporated into bone. Use in pediatric patients is not recommended because adequate safety studies have not been performed. Geriatric Use: No overall differences in safety and efficacy were observed between the elderly and younger individuals, 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. Use in Patients with Renal Impairment: No dosage adjustment is necessary in patients with mild to moderate renal impairment. The pharmacokinetics and safety of strontium in patients with severe renal impairment has not been studied and, therefore, use in this patient population is not recommended. OVERDOSAGE A single oral dose of esomeprazole at 510 mg/kg (about 103 times the human dose on a body surface area basis), was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions. The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg of esomeprazole were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert - ADVERSE REACTIONS). No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose contact a Poison Control Center at 1-800-222-1222. Please see package insert for full prescribing information. More detailed information is available upon request. For more information about esomeprazole strontium contact: Amneal Pharmaceuticals at 1-877-835-5472. Date of Issue: December 2013 Licensed from: Hanmi Pharm. Co. Ltd., Seoul, Korea Distributed by: Amneal Pharmaceuticals, Glasgow, KY 42141

Table. Current Composition of the RUC • Chair • American Medical Association representative • CPT Editorial Panel representative • American Osteopathic Association representative • Health Care Professionals Advisory Committee representative • Practice Expense Review Committee representative • Anesthesiology • Cardiology • Dermatology • Emergency medicine • Family medicine • General surgery • Geriatric medicine • Infectious diseasea • Internal medicine • Neurology • Neurosurgery • Obstetrics/Gynecology • Oncology/Hematologya • Ophthalmology • Orthopedic surgery • Otolaryngology • Pathology • Pediatrics • Pediatric surgerya • Plastic surgery • Primary carea • Psychiatry • Radiology • Thoracic surgery • Urology CPT, Current Procedural Terminology; RUC, Relative Value Scale Update Committee a

Indicates rotating seat

Source: American Medical Association, www.ama-assn.org

coding system] is the facility analog to the physicians’ CPT. It also requires documentation to generate accurate reimbursement. Adopting a strategy to survive professionally in the future seems imperative. Software solutions are being developed to help in these endeavors. ■ Dr. Newman is founder and CMO of ComplyMD (complymd.com), a company that provides procedural documentation solutions.

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CDC Reports Top Achievements in 2013, Predicts Top Health Threats in 2014 As 2013 came to a close, the Centers for Disease Control and Prevention (CDC) issued a progress report on the top health concerns it managed in 2013 and what the agency expects will be the top health threats in 2014. The agency noted that its most important achievements in 2013 were the outbreaks that didn’t happen, the diseases that were stopped before they crossed U.S. borders and the lives saved from preventable chronic diseases and injuries. “While our biggest successes may be the bad things that did not happen, careful assessment of what we did well—and what we might do better—is essential for continued success,” said CDC director Tom Frieden, MD, MPH.

2013, which prevented the 1 millionth baby from being infected with HIV. The program counts 6.7 million people on treatment, with HIV incidence falling in nearly all PEPFAR countries. • CDC estimates of foods that are causing foodborne illnesses in the United States, helping regulators,

industry and consumers effectively prevent food contamination. • The newly discovered Heartland virus that infected two men from northwestern Missouri, which CDC scientists traced to populations of lone star ticks in the region. • Identification of a new poxvirus related to smallpox that sickened

New Challenges Ahead Looking ahead, a major priority for the CDC is to improve the nation’s ability to detect diseases, both at home and abroad. The CDC and its partners are building a global health security infrastructure that can be scaled up

Read the No. 1 publication in the

Looking Back The CDC’s report of its top 2013 accomplishments included: • New Advanced Molecular Detection technologies and methods that can detect disease outbreaks sooner, stop them faster and prevent them better. These technologies, for example, allowed the CDC to quickly track and trace a Listeria outbreak from contaminated cheese. • Progress in heart attack and stroke prevention through the Million Hearts® initiative, including: » The “Tips from Former Smokers” campaign, which outpaced the CDC’s own ambitious goals. » Publication of the FDA’s tentative determination that partially hydrogenated oil—the primary source of dietary trans fats—is not “generally recognized as safe.” Its removal from the food supply could save up to 7,000 lives and prevent up to 20,000 heart attacks per year. » Improvements in knowledge about blood pressure control and efforts to educate federal, state and local partners on effective approaches. • The CDC’s National Healthcare Safety Network, which more than 12,000 facilities now use to track hospital-acquired infections. Since 2008, bloodstream infections in patients with central lines have decreased by 44% and surgical site infections have decreased by 20%. • The U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), marking its 10th anniversary in

shepherds in Akhmeta, located in the nation of Georgia. • Two new antibiotic regimens, identified by CDC researchers, that use existing drugs to successfully treat gonorrhea infections.

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to deal with multiple emerging health threats. According to the CDC, only one in five countries can rapidly detect, respond to or prevent global health threats caused by emerging infections. Improvements overseas, such as strengthening surveillance and lab systems, training disease detectives and building facilities to investigate disease outbreaks can make the world and the United States more secure. The CDC reported that health security threats come from at least five sources:

1. The emergence and spread of new microbes; 2. The globalization of travel and food supply; 3. The rise of drug-resistant pathogens; 4. The acceleration of biologic science capabilities and the risk that these capabilities may cause the inadvertent or intentional release of pathogens; and 5. Continued concerns about terrorist acquisition, development and use of biological agents.

In addition to global health security, another CDC priority for 2014 is combating the spread of antibioticresistant bacteria. Several multidrugresistant superbugs already threaten a throwback to the preantibiotic era, the agency said. “There may be a misconception that infectious diseases are over in the industrialized world. But in fact, infectious diseases continue to be, and will always be, with us,” Dr. Frieden said. “With patterns of global travel and trade, disease can spread nearly

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anywhere within 24 hours,” he added. “That’s why the ability to detect, fight and prevent these diseases must be developed and strengthened overseas, and not just here in the United States.” Other CDC initiatives for 2014 include investigating the slow uptake of the human papillomavirus vaccine, the growing epidemic of prescription opiate addiction, emerging threats of infectious disease and creating the final push for global polio eradication. ■

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For more than three decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician. 1978 —

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ACG 2012

IBS No Longer Only Functional Disorder

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search

BY DAVID WILD BY CHRISTINA FRANGOU LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8

Mesalamine Elicits Response in IBS BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search. The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training. With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy Newss summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

MDs and DOs Plan Unified Accreditation System For Graduate Medical Education ............... page 5

EXPERT REVIEW: Sexual Misconduct by Professionals: A New Model of Understanding

COMPILED AND WRITTEN BY DAVID WILD Gastroenterology & Endoscopy Newss asked several experts to select their favvorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scien ntific Meeting. Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the Decemberr 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14

BY GREGORY E. SKIPPER, MD, AND STEPHEN SCHENTHAL, MD..................... page 29

EXPERT REVIEW: Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD .................................................................. page 33

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Experts’ Picks:

Best of the ACG Annual Scientific Meeting: Part 2 COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy News asked several experts to sift through the mounds of top-notch studies presented at the American College of Gastroenterology 2013 Annual Scientific Meeting. They did the work; here are their selections.

Frank G. Gress, MD Professor of Medicine Clinical Chief, Division of Digestive Diseases Chief, Interventional Endoscopy Columbia University Medical Center New York, New York

Female Gender Impacts Mortality and Length of Stay in Acute Pancreatitis in the United States: A Report of the National Inpatient Sample (McNabb-Baltar J et al)

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In this study, researchers set out to compare rates of inhospital mortality and hospital lengths of stay in men and women who presented to the emergency department with acute pancreatitis (AP) as their primary diagnosis. Using data from the Health Care Utilization Project Nationwide Inpatient Sample (NIS), they identified 2,844,497 adult patients who fit these criteria.

‘Female gender appears to impart a less severe course of acute pancreatitis, including lower rates of in-hospital mortality and shorter lengths of stay.’ —Frank G. Gress, MD

The investigators observed a near-even gender distribution in the study population. They found that 2.7% of patients (48.2% women) died during hospital admission. Among the patients who died, 14.3% had biliary pancreatitis and 8.3% had alcoholic pancreatitis. Men who died during admission were more likely than women to have alcoholic pancreatitis (23% vs. 7.5%, respectively; P<0.001), whereas women who died were more likely than men to have biliary pancreatitis (32.5% vs. 18.3%, respectively; P<0.001). Additionally, 8.4% of men had underlying chronic pancreatitis compared with 5.5% of women (P<0.001). Women had more comorbidities, as measured by the Charlson Comorbidity Index, the researchers found. Multivariate analyses controlling for race, comorbidities, insurance coverage and socioeconomic status

revealed that women were significantly more likelyy than men to survive their in-hospital stay (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.32-1.36; P<0.001). Women also were significantly more likely to reequire fewer than seven days of in-hospital care (OR, 1.03; 95% CI, 1.02-1.03; P<0.001). Dr. Gress: This well-done study looked at the effect of gender on inpatient mortality and length of sttay in patients presenting with acute pancreatitis. Usingg data from the NIS, researchers determined that genderr represents an independent predictor of in-hospital moortality and length of stay. Female gender appears to im mpart a less severe course of AP, including lower rates of inhospital mortality and shorter lengths of stay. A Prospective Study of the Risk of Bacteremia in Directed Cholangiosco opic Examination of Common Bile Duct (CBD) (Othman M et al) This prospective, nonrandomized study documented the rate of bacteremia and subsequent infectious complications after endoscopic retrograde cholangiopancreatography (ERCP)-directed cholangioscopy. Researchers examined 46 patients who underwent the procedure for examination of the CBD, none of whom had an ongoing infection before the procedure or had recently taken antibiotics. None of the patients were administered antibiotics either before or immediately after the procedure. The investigators examined blood samples before the procedure and then five and 30 minutes after the procedure. Patients also were examined 24 hours and one week after the procedure. According to the researchers, six patients (13%) were found to have bacteremia five minutes after the procedure: Blood cultures taken five minutes after the procedure revealed the presence of Escherichia coli in two patients, Clostridium perfringens in one, Enterococcus faecium in one, Enterococcus avium in one and Morganella morganii in one. Blood cultures taken 30 minutes after the procedure were positive for bacteremia in two patients, including Staphylococcus capitis in one patient who had tested negative five minutes after the procedure. Additionally, one of the patients who tested negative at five and 30 minutes postprocedure was found to have Klebsiella pneumonia at 24 hours postprocedure. Three patients (6.5%) required readmission due to cholangitis. Findings showed that 36.4% of patients (four of 11) who had cholangioscopy with biopsy developed bacteremia compared with 5.7% (two of 35) who did not undergo biopsy (P<0.023). One of eight patients who underwent laser lithotripsy had a positive blood culture.

63.

Dr. Gress: T This prospective study determined the frequency of bacteremia and subsequent infectious complications after ERCP with direct cholangiography, and showed a bacteremia rate of 13% and a cholangitis rate of 6.5%. Additionally, the rate of bacteremia was significantly higher in patients who underwent biopsy. The take-home message is that preprocedure antibiotics should be administered in patients undergoing ERCPguided cholangiography. ■ Dr. Gress reported no relevant conflicts of interest.

Franklin Kasmin, MD Assistant Professor of Medicine Albert Einstein College of Medicine Yeshiva University New York, New York

Intestinal Metaplasia of the Stomach Is Associated with an Increased Risk of Gastric Cancer in a Western Population (Bleibel W et al)

Researchers at the University of Virginia set out to document the incidence of and risk factors for gastric cancer in patients with or without intestinal metaplasia of the stomach. To this end, they examined the electronic medical records of 675 patients who had endoscopically proven intestinal metaplasia of the stomach and compared them with 1,273 patients who had normal gastric see Best of ACG, page 20

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Best of ACG continued from page 19

biopsies. Patients with intestinal metaplasia of the stomach were older than those in the control group (61 vs. 44 years; P<0.0001) and were followed for a longer period of time (5.3 vs. 3.1 years). The investigators found that 2.1% of patients (14 of 675) with intestinal metaplasia of the stomach subsequently developed gastric cancer compared to 0.1% of patients (one of 1,273) in the control group (P<0.0001). The mean time to gastric cancer diagnosis following a diagnosis of intestinal metaplasia of the stomach was four years (±3.5 years). Biopsy findings showed that 17.5% of patients with intestinal metaplasia of the stomach had Helicobacter pylorii compared with none of the patients in the control group (P=0.001). P

‘My take on this data is that individuals with gastric intestinal metaplasia and H. pylori should be aggressively treated to eradication, and should perhaps undergo surveillance.’ —Franklin Kasmin, MD

Univariate analyses revealed that intestinal metaplasia of the stomach was associated with a 15.7-fold increase in risk for gastric cancer (hazard ratio [HR], 15.7; 95% CI, 2-122.81; P<0.009), and H. pylori infection increased the risk for gastric cancer by 3.4 (HR, 3.4; 95% CI, 1.02-10.99; P<0.05). However, intestinal metaplasia of the stomach was the only factor independently associated with an increased risk for gastric cancer in multivariate analyses (HR, 11.23; 95% CI, 1.35-93.40; P<0.025). Dr. Kasmin: Metaplasia is the replacement of native histologic tissue with a new histologic variant, typically from a discretely separate site of the body. Barrett’s esophagus (BE) is a metaplastic variant that we are all familiar with and that we know can change to a neoplastic or malignant form. Why should gastric intestinal metaplasia be any different? This study indicates that, indeed, there may not be a difference, and that intestinal metaplasia of the stomach—especially in the presence of H. pylori—should i be considered a risk factor for gastric cancer. This makes sense to those of us who have repeatedly diagnosed gastric cancer in the setting of diffuse gastric intestinal metaplasia elsewhere in the stomach. We also recognize the increasing incidence of cancer of the gastroesophageal junction, and we wonder if that disease sometimes arises from cardia intestinal metaplasia we see distal to BE. My take on this data is that individuals with gastric intestinal metaplasia and H. pylorii should be aggressively treated to eradication, and should perhaps undergo surveillance. More data from additional trials may ultimately suggest that we should perform surveillance of all patients with gastric intestinal metaplasia, or even ablation. We’ll see.

Improved Detection and More Accurate Surveillance Intervals with Fuse™ Colonoscopy (Rex DK et al)

14.

tandem studies showed us that perhaps the adenoma miss rate was higher than 5%. How shocking it is that a miss rate of 42.5% was detected in this tandem study, presumably as endoscopists were carefully doing their best with the standard colonoscope, as they knew they were participating in a trial! ■

Investigators assigned 185 patients to undergo tandem conventional colonoscopy and Fuse Full Spectrum Endoscopy (EndoChoice) colonoscopy, a new technology that provides a 330-degree field of view of the gastrointestinal tract. Approximately half of the patients Dr. Kasmin reported no relevant conflicts of interest. underwent Fuse colonoscopy first, followed by conventional colonoscopy; the other half underwent the procedures in reverse order. Roughly 56% of patients were being screened for colorectal cancer (CRC), 19.5% were Prateek Sharma, MD undergoing surveillance colonoscopy and 24.9% were undergoing diagnostic colonoscopy. Professor of Medicine In 15 of the patients who underwent conventional University of Kansas Medical School colonoscopy first, subsequent Fuse colonoscopy detected Kansas City, Kansas additional adenomas. This led endoscopists to revise their surveillance interval recommendations from 10 years or five to 10 years with conventional colonoscopy to five to 10 years or three years in eight patients, and from 10 years to three years in one patient who was found to have a large adenoma with Fuse colonoscopy Incidence of Colorectal Cancer after a but not with conventional colonoscopy. Notably, recomNegative Colonoscopy (Fujii L et al) mended surveillance intervals were never revised when Fuse colonoscopy was conducted first. This systematic literature review included 15 cohort Among the 67 patients older than 50 years who studies published before March 1, 2013 that reported underwent conventional colonoscopy first, that approach incidence rates of CRC in average-risk patients foldetected 23 adenomas; subsequent Fuse colonoscopy lowing a negative screening colonoscopy. Researchers revealed 17 additional adenomas, translating to a 42.5% compared these CRC rates to the incidence of CRC adenoma miss rate with conventional colonoscopy. Five in a similar cohort of average-risk adults in the Surolder patients whose initial conventional colonoscopy veillance, Epidemiology, and End Results (SEER) detected no adenomas were found to have adenomas database (2000-2002). Patients had a mean age of 60.5 with subsequent Fuse colonoscopy. years (±6 years) and were followed from 1.6 to 11.2 Among 80 patients who underwent Fuse colonoscopy years after having a negative colonoscopy. first, 58 adenomas were detected; subsequent convenPooled data from the 15 cohort studies revealed an tional colonoscopy uncovincidence of 0.5 CRC ered an additional five cases per 1,000 patientadenomas, translating to years after negative a 7.8% miss rate for Fuse screening colonoscopy ‘Wow! What a dramatic set of colonoscopy (P<0.0001 in average-risk patients findings. It seems clear that widefor adenoma miss rate in (95% CI, 0.1-0.86 per angle colonoscopy will become a older patients who under1,000 patient-years), went Fuse colonoscopy translating to a 0.05% desirable new standard, and this vs. conventional coloannual risk for CRC folnew technology will be rapidly noscopy). Patients who lowing a negative colowere determined to be noscopy. The five- and adapted, with other endoscope adenoma-free upon ini10-year risk for CRC in makers creating their own widetial Fuse colonoscopy did this average-risk populaview solutions.’ not have any additional tion after negative screenadenomas detected with ing colonoscopy was —Franklin Kasmin, MD subsequent conventional 0.25% and 0.5%, respeccolonoscopy. tively, compared with a 0.6% and 1.5% five- and Dr. Kasmin: Wow! What a dramatic set of find10-year risk, respectively, in average-risk, CRCings. It seems clear that wide-angle colonoscopy free, 60-year-old adults in the SEER database. will become a desirable new standard, and this Pooled analysis of four of the studies that included new technology will be rapidly adapted, with other standardized incidence ratios revealed that those who endoscope makers creating their own wide-view solu- had a negative index colonoscopy were 57% less likely tions. This is great news for patients! There is not only to develop subsequent CRC than the average-risk genincreased polyp detection rates with this new technol- eral population in the SEER database (OR, 0.43; 95% ogy, but also an improved ability to navigate turns and CI, 0.22-0.86). manipulate the instrument tip as one moves around Incidence of CRC after a negative colonoscopy was colonic folds to approach a lesion therapeutically. not influenced by the setting in which colonoscopy was What is most sobering about this study is the miss conducted, what country it was performed in, whether rate with standard colonoscopy: In the 1990s and ear- or not it was conducted by a gastroenterologist or lier, we thought that missed polyps were a rarity. Then, see Best of ACG, page 22

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Best of ACG continued from page 20

whether the patient presented with symptoms at the time of colonoscopy. Dr. Sharma: As the role of colonoscopy in CRC screening continues to be questioned, data showing its effectiveness is very important. In this meta-analysis, the authors were able to show that the risk for CRC is extremely low in patients who have undergone a screening colonoscopy compared with

the risk for CRC in the general population. Although there was no comparator group as part of the study, these data do support the positive effect of colonoscopy in screening for CRC. Gender Disparities in Remission of Esophageal Intestinal Metaplasia after Radiofrequency Ablation (Qumseya BJ et al) In this study, researchers set out to examine potential gender-based differences in the efficacy of radiofrequency ablation

49.

(RFA) for the treatment of BE. This retrospective, observational study examined 257 patients with BE, 26 of them women, treated with RFA at a tertiary care center between 2005 and 2012. Patients were similar in age, race and history of cigarette smoking. There also were similar numbers of patients who had previously undergone endoscopic mucosal resection and pre-RFA biopsy. The investigators found that women underwent fewer RFA sessions compared with men (P=0.027). P The median time to complete remission of intestinal

metaplasia was 24 months for women (95% CI, 10.3-60.2 months) compared with 11.7 months for men (95% CI, 10-15 months). Statistical analyses controlling for possible confounding factors showed that over 60 to 80 months of follow-up, women were 55% less likely than men to achieve complete remission of intestinal metaplasia (HR, 0.45; 95% CI, 0.25-0.82; P P=0.009).

‘In this study, researchers showed that women with BE who underwent endoscopic treatment had lower rates of complete eradication.’ —Prateek Sharma, MD

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Dr. Sharma: The initial goal of endoscopic therapy in patients with BE who are deemed as candidates for such therapy is to achieve complete eradication of all endoscopic and histologic evidence of intestinal metaplasia. Knowledge of specific factors that can affect the rate of efficacy are important. In this study, researchers showed that women with BE who underwent endoscopic treatment had lower rates of complete eradication. These results are somewhat surprising, given that both BE and cancer are male-predominant diseases. Given the small number of women in this study, larger studies should evaluate gender and other factors that may be associated with complete eradication of BE. ■

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Dr. Sharma has received grants from Cook Medical, NinePoint Medical, Olympus and Takeda Pharmaceuticals.

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HCV continued from page 1

findings from five pivotal trials of sofosbuvir, ABT-450, ABT-267 and ABT-333, and said regimens including these drugs led to SVR rates at 24 weeks similar to those observed at 12 weeks. These agents “have important implications, both on an individual level and a societal level,” said Zobair Younossi, MD, MPH, vice president for research, Inova Health System, and chairman, Department of Medicine, Inova Fairfax Hospital, Falls Church, Va. “These future treatments for hepatitis C are shorter in duration; they can be administered as part of a regimen that is potentially all-oral; they require less clinician and lab monitoring; and they are associated with improved quality of life and job functioning,” said Dr. Younossi, who was involved in some of the research. “As these highly effective and well-tolerated regimens are developed, approved and made available to patients with hepatitis C, they have the potential to reduce the incidence of cirrhosis and liver cancer, which is the only solid organ tumor that’s increasing in incidence in the United States.”

NEUTRINO The Phase III NEUTRINO study included 292 patients with HCV genotype 1, 28 with HCV genotype 4 and seven patients with HCV genotype 5/6, all of whom were treatment-naive. Patients underwent 12 weeks of openlabel treatment with 400 mg of sofosbuvir, a pangenotypic HCV NS5B polymerase inhibitor, administered once daily, along with ribavirin (RBV; 1,000-1,200 mg, twice daily) and pegylated interferon (PEG-IFN) alfa-2a (180 mcg per week). Seventeen percent of patients had compensated cirrhosis, and 29% had the interleukin-28 (IL28)-B CC C genotype. Nearly all patients—91%—achieved SVR at weeks 12 and 24. SVR rates at week 24 among patients with and without cirrhosis were 80% and 93%, respectively. At week 24, SVR rates were 90% among patients with HCV genotype 1, 96% for genotype 4 and 100% for genotype 5/6. None of those who relapsed before week 12 developed HCV NS5B S282T resistance. Adverse events (AEs) led to treatment discontinuation in 2% of patients and included fatigue (59%), headache (36%), nausea (34%) and insomnia (25%). One percent of patients experienced serious AEs.

RBV (1,000-1,200 mg per day) or PEGIFN (180 mcg, weekly) and RBV (800 mg, twice daily) for 24 weeks. Approximately 20% of patients in each group had cirrhosis. Approximately 67% of patients in both treatment groups achieved SVR at week 12. One sofosbuvir recipient experienced virologic breakthrough compared with 18 patients in the PEG-IFN/RBV treatment arm. Virologic relapse occurred within 12 weeks after treatment in 29% and 20% of patients in the sofosbuvir/RBV and PEGIFN/RBV treatment arms, respectively.

In the sofosbuvir/RBV treatment group, 97% and 56% of patients with HCV genotype 2 and 3, respectively, achieved SVR at week 12. In the PEGIFN/RBV group, 78% and 63% of patients with HCV genotype 2 and 3, respectively, achieved SVR at week 12. Overall, 47% and 38% of patients in the sofosbuvir/RBV and PEG-IFN/RBV treatment arms, respectively, achieved SVR at week 12. Two sofosbuvir recipients and three patients in the PEG-IFN/ RBV treatment arm relapsed after achieving SVR at week 12.

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AEs occurred in 86% of patients in the sofosbuvir/RBV treatment group, including fatigue (36%), headache (25%), nausea (18%), insomnia (12%), irritability (10%) and anemia (8%). Three percent of patients in this group experienced serious AEs; 9% had hemoglobin levels lower than 10 g/dL; and 1% discontinued treatment.

FUSION This placebo-controlled, double-blind, Phase III study of dual therapy with see HCV, page 24

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A variety of gastrointestinal conditions will be discussed,, including Barrett’s esophagus, luminal neoplasia, gastro-intestinal bleeding, colon polyps, pancreaticobiliary diseases and endoscopic complications.

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FISSION This Phase III trial included 499 treatment-naive patients with HCV genotype 2 or 3. Patients were randomized to receive open-label treatment for 12 weeks with sofosbuvir (400 mg, daily) and

Registration opens January 8, 2014. Visit www.asge.org for more information or to download a full brochure with agenda.

ACG 2013

HCV continued from page 23

sofosbuvir 400 mg daily and RBV (1,0001,200 mg, twice daily) included 201 treatment-experienced patients with HCV genotype 2 (37%) or 3 (63%). Thirty percent had the IL28B CC C genotype, 34% had compensated cirrhosis, 75% were prior relapsers and 25% were prior null responders. Patients were randomized to receive 12 weeks of active treatment followed by four weeks of placebo, or 16 weeks of active treatment.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

In the 16-week treatment group, 100% of HCV genotype 2 patients without cirrhosis and 78% of those with cirrhosis achieved SVR at week 12. In the 12-week treatment group, 96% and 60% of HCV genotype 2 patients without and with cirrhosis, respectively, achieved SVR at week 12. Among HCV genotype 3 patients, SVR at week 12 was achieved by 63% of noncirrhotic patients and 61% cirrhotic patients in the 16-week treatment group, and in 39% of noncirrhotic and 19% of cirrhotic patients in the 12-week treatment

group. One patient in each treatment arm relapsed between 12 and 24 weeks post-treatment. Five percent and 3% of patients in the 12- and 16-week treatment groups, respectively, experienced serious AEs that did not require drug discontinuation. Five percent and 11% of those in the 12- and 16-week groups, respectively, experienced a drop in hemoglobin to below 10 g/dL; 2% of patients in the 12-week group had hemoglobin levels below 8.5 g/dL. Common AEs in the 12- and 16-week groups included fatigue

(45% and 47%, respectively), headache (25% and 33%, respectively), insomnia (20% and 29%, respectively), nausea (21% and 20%, respectively), irritability (15% and 11%, respectively), cough (10% and 13%, respectively) and diarrhea (15% and 6%, respectively).

POSITRON Researchers randomized 278 patients with HCV genotype 2 or 3 for whom treatment with PEG-IFN was not an option to receive 12 weeks of treatment with sofosbuvir (400 mg, daily) and

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L k ffor more coverage off hepaLook h titis C virus (HCV) infection and other topics in hepatology in the February 2014 issue of Gastroenterology & Endoscopy News. The February issue will feature our quarterly “Hepatology in Focus” section, with coverage from the American College of Gastroenterology 2013 Annual Scientific Meeting and The Liver Meeting 2013, including: • “Experts’ Picks,” featuring the best abstracts from The Liver Meeting 2013; • Findings on the role of emergency departments in screening patients for HCV infection; • More new data on emerging interferon-free treatments for HCV infection; and • Statistics on organ donation rates and HCV reinfection in liver transplant recipients.

Don’t miss the February 2014 issue of Gastroenterology & Endoscopy News!

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Faldaprevir an Anticipated Addition to HCV Treatment Armamentarium BY DAVID WILD SAN DIEGO—Treatment with faldaprevir, a oncedaily hepatitis C virus (HCV) NS3/4A protease inhibitor, in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) led to sustained virologic response (SVR) rates at week 12 in 80% of patients with HCV genotype 1, findings from a large, randomized placebo-controlled trial of the drug revealed. Co-investigator Christophe Moreno, MD, PhD, head of the Liver Unit, Erasme University Hospital, Brussels, Belgium, presented findings from the multicenter international STARTVerso 1 trial of 652 treatment-naive patients with HCV genotype 1 at the American College of Gastroenterology 2013 Annual Scientific Meeting (abstract

RBV (1,000-1,200 mg, twice daily), or a matching placebo alone. In the sofosbuvir group, 78% of patients achieved SVR at weeks 12 and 24 compared with 0% in the placebo group. Among patients in the sofosbuvir group, 93% and 61% of those with HCV genotype 2 and 3, respectively, achieved SVR at weeks 12 and 24. Additionally, 92% and 94% of noncirrhotic and cirrhotic patients with HCV genotype 2, respectively, achieved SVR at weeks 12 and 24, and 68% and 21% of noncirrhotic and cirrhotic patients with HCV genotype 3, respectively, had SVR at weeks 12 and 24. Serious AEs occurred in 5% and 3% of sofosbuvir and placebo recipients, respectively. Additionally, 2% and 4% of sofosbuvir and placebo recipients, respectively, discontinued treatment. The nature and incidence of common AEs were similar to those observed in the FISSION study. Seven percent of sofosbuvir recipients experienced hemoglobin levels below 10 g/dL; fewer than 1% of sofosbuvir recipients had hemoglobin levels below 8.5 g/dL.

AVIATOR In this open-label study, researchers randomized 247 patients with HCV genotype 1 and without cirrhosis to receive treatment with either 12 or 24 weeks of a four-drug regimen including ABT-450, an oral HCV NS3/4A protease inhibitor, at 100 or 150 mg once daily administered with ritonavir 100 mg; ABT-267, an HCV NS5A inhibitor, at 25 mg once daily; ABT-333, a non-nucleoside HCV polymerase inhibitor, at 400 mg twice daily; and RBV, at 1,000-1,200 mg, twice daily. Eighty patients were treatmentnaive, and 45 were prior null responders. Nearly two-thirds of patients had HCV genotype 1a, and 37.4% had a fibrosis score of F2 or higher.

37). Dr. Moreno and his colleagues randomized patients to receive PEG-IFN and RBV in combination with once-daily faldaprevir 240 mg for 12 weeks (n=261), once-daily faldaprevir 120 mg for 12 or 24 weeks (n=259), or placebo for 24 weeks (n=132). Faldaprevir recipients who achieved a treatment response at weeks 4 and 8 could discontinue all treatment at week 24; those who did not exhibit an early response to treatment received 48 weeks of treatment with PEG-IFN and RBV. About half of the patients in the study were men; 78% were white; 20% were Asian; 17% had fibrosis scores of 3 or greater; 39% had the interleukin-28 (IL28)-B CC genotype; and 66% had HCV genotype 1b. Among patients who were treated with faldaprevir, 79% and 80% of patients in the 120- and

Researchers found that 99% of treatment-naive patients and 93% of null responders in the 12-week treatment arm achieved SVR at week 12; 96% and 93% of those patients, respectively, had SVR at week 24. In the 24-week treatment arm, SVR rates at weeks 12 and 24 were 93% and 90%, respectively, for treatmentnaive patients, and 98% and 95%, respectively, for null responders. Treatment response was not affected by baseline HCV RNA levels, fibrosis stage or HCV genotype. Three prior null responders in the 12-week treatment group and one in the 24-week group experienced viral breakthrough. AEs that occurred in more than 10% of patients included asthenia and fatigue. Six patients experienced grade 3 to 4 total bilirubin abnormalities, and one patient had grade 3 to 4 alanine aminotransferase abnormalities. Four patients discontinued treatment due to AEs.

Analysis Kris Kowdley, MD, director of the Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, was involved in all five studies and said these updated findings confirm what has already been suspected. “These new agents will change the paradigm for treatment of HCV,” Dr. Kowdley said. “We still have some work to do, especially in HCV genotype 3 patients where response rates are not as impressive. … But we are heading toward all-oral regimens that are effective in both prior null responders and treatmentnaive patients, and in some cases, can be as brief as eight weeks.” ■ The NEUTRINO, FISSION, POSITRON and FUSION studies were presented in abstract 38; AVIATOR was included in abstract 39.

240-mg groups, respectively, achieved SVR at week 12 compared with 52% of placebo recipients (P<0.0001 for both treatment groups vs. placebo). SVR rates at week 12 among IL28B CC patients in the 120- and 240-mg faldaprevir groups were 90% and 95%, respectively, compared with 71% of IL28B non-CC patients in either treatment group. Between 87% and 89% of faldaprevir recipients had early treatment success and stopped all treatments at 24 weeks. Of these early responders, 86% and 89% achieved SVR at week 12. Dr. Moreno has served as a board member for BristolMyers Squibb, Gilead, Janssen and MSD, and has received research grants from Gilead, Janssen, MSD, Novartis and Roche Pharmaceuticals.

Dr. Kowdley has received grant or research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead/Pharmasset, Intercept, Janssen, Merck & Co., Mochida and Vertex Pharmaceuticals; he has served as a scientific consultant for Novartis; and as an

advisory board member for AbbVie, Gilead, Merck and Vertex. Dr. Younossi has served as a consultant and/or an advisory board member for Bristol-Myers Squibb, Conatus Pharmaceuticals, Enteron, Gilead, Merck, Tibotec/ Janssen and Vertex Pharmaceuticals.

ACG 2013

FMT continued from page 1

immunocompromised patients with Clostridium difficile infection (CDI). “FMT is an exciting area full of promise, and these abstracts have explored some of the many opportunities for applying the treatment,” said Brian Lacy, PhD, MD, who was not involved in the research presented at the ACG meeting.

‘FMT is an exciting area

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

the procedure, Dr. Brandt reported. Additionally, frequency of diarrhea dropped from a mean of 8.2 times daily to 3.6 times daily after the procedure, and no patients reported increased frequency of diarrhea following FMT. Of 14 patients with pre-FMT rectal bleeding, symptoms resolved completely in 29%, decreased in 43% and did not change in 21%, Dr. Brandt found. FMT also was associated with decreased abdominal pain, increased or sustained weight, reduction or discontinuation of corticosteroids and

discontinuation of anti–tumor necrosis factor therapy in one of four patients. The greatest improvement occurred in four patients with UC with concomitant CDI, Dr. Brandt said. “All of these patients were able to discontinue maintenance medications, including steroids, 6-mercaptopurine or both.” In a separate safety analysis of FMT in the same population (abstract P1659), the only FMT-related adverse event (AE) was transient worsening of abdominal distension, which occurred in three patients, Dr. Brandt reported.

FMT in IBS Dr. Brandt’s data also suggested FMT could be useful in treating patients with IBS (abstract P1688). As Dr. Lacy told Gastroenterology & Endoscopy News, this is the first study to examine FMT in the context of IBS. “There is growing interest in the use of FMT for IBS, and the rationale for its use is sound, since some IBS patients respond to probiotics or antibiotics,” said Dr. Lacy, who is professor of medicine and chief of the Section of Gastroenterology and Hepatology, Geisel School of

full of promise, and these abstracts have explored some of the many opportunities for applying the treatment.’ —Brian Lacy, PhD, MD

In Active, Mild to Moderate Ulcerative Colitis (UC)1

A sizeable chunk of the new data derives from the clinical experience of Lawrence J. Brandt, MD, professor of medicine and surgery at Albert Einstein College of Medicine and emeritus chief of the Division of Gastroenterology at Montefiore Medical Center, New York City. Dr. Brandt began conducting FMT in selected patients before the FDA’s tightening of rules regarding use of the procedure (see “FDA Moves To Regulate Fecal Microbial Transplantation,” Gastroenterology & Endoscopy News July 2013;64:7).

FMT in IBD In one case series from Dr. Brandt (abstract P1629), 16 patients who had IBD for an average of 7.5 years (range, 1-33), including 14 patients with ulcerative colitis (UC) and two with Crohn’s disease (CD), received colonoscopyadministered FMT, followed by several months of scheduled, self-administered stool suspension enemas in a tapered fashion. According to Dr. Brandt, after a mean follow-up of 14 months (range, 4.5-30 months), 63% of patients (10 of 16) reported a lower frequency of disease flares than before FMT. Three patients reported no relapses after a mean of 21 months (range, 8-30 months) following FMT, and none experienced more frequent disease flares than they had before

INDICATIONS AND USAGE UCERIS ® is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage of UCERIS is one 9-mg tablet to be taken once daily in the morning with or without food for up to 8 weeks.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS UCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS. WARNINGS AND PRECAUTIONS • Hypercorticism and adrenal suppression: Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. • Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. • Immunosuppression: Potential worsening of infections (eg, existing tuberculosis, fungal, bacterial, viral, or parasitic

infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. • Increased systemic glucocorticoid susceptibility: Reduced liver function affects the elimination of glucocorticosteroids. • Other glucocorticoid effects: Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Most common adverse reactions (incidence ≥2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. DRUG INTERACTIONS Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. USE IN SPECIFIC POPULATIONS Hepatic impairment: Monitor patients for signs and/or symptoms of hypercorticism.

The Important Safety Information does not include all of the information needed to use UCERIS safely and effectively. Please see Brief Summary of Prescribing Information on the following page and Full Prescribing Information at www.UCERIS.com.

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Medicine, Dartmouth–Hitchcock Medical Center, Lebanon, N.H. Dr. Brandt reported outcomes from nine patients with diarrhea-predominant IBS (IBS-D), three with constipationpredominant IBS (IBS-C) and one with mixed-type IBS (IBS-M). Most patients received a single fecal transplant. The mean duration of IBS before FMT was 73 months (range, 12-180 months), and patients had failed to respond to prior treatment with antibiotics, antidepressants, anti- or pro-motility agents, dietary interventions or probiotics.

Questionnaires that patients completed an average of 11 months after the procedure (range, 6-18 months) revealed that 70% of FMT recipients had complete or partial resolution of IBS symptoms, with the remainder reporting no change in symptoms. Among a subgroup of patients with pre-FMT abdominal pain, 73% said this symptom resolved or diminished after FMT. Additionally, 50% of those with pre-FMT bloating experienced symptom resolution or relief and 41% and 66% of those with preFMT flatus and dyspepsia, respectively,

experienced complete resolution or partial relief of those symptoms. The procedure also markedly decreased the frequency of constipation in patients with IBS-C, reduced the frequency of diarrhea in those with IBS-D, and relieved both symptoms in the patient with IBS-M. Furthermore, most patients in the study experienced improved global wellbeing after FMT, and there were no reported AEs. The small case series is “a start,” commented Dr. Lacy, and more research on the efficacy of FMT for IBS is warranted.

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and placebo at 8 weeks—10.2% vs 10.5%, respectively1‡ CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index [EI] score) after 8 weeks of treatment.1 *Some restrictions apply. Please see the eVoucherRx™ and Instant Savings Card Program brochure for Terms and Conditions. Santarus reserves the right to modify or cancel these offerings at any time. † Source: RelayHealth, June 2013. ‡ In a pooled analysis of 2 Phase III clinical trials.1,2 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. Data on file. Santarus, Inc. 3. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. UCERIS is a registered trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd. eVoucherRx™ is a trademark of RelayHealth.

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“There needs to be a placebo-controlled trial, and also ideally, a head-tohead trial comparing FMT with standard therapy,” Dr. Lacy said.

FMT in Immunocompromised Patients Although FMT is now an accepted treatment for refractory CDI, findings from a multicenter study presented by Colleen Kelly, MD, clinical assistant professor of medicine, Department of Gastroenterology, Brown Alpert Medical School, see FMT, page 28

ACG 2013

FMT continued from page 27

Providence, R.I., are the first to document the procedureâ&#x20AC;&#x2122;s safety and efficacy in patients with CDI with compromised immune system functioning (abstract 10). Dr. Kelly and her colleagues at 16 research centers reviewed data from 66 immunocompromised patients, including 61 adults and five children, who received FMT for refractory, recurrent, or refractory and recurrent CDI. Patients, most of whom received FMT as an outpatient BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections. Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTN BOE "ESFOBM 4VQQSFTTJPO t 4ZNQUPNT PG TUFSPJE XJUIESBXBM JO UIPTF QBUJFOUT USBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t *ODSFBTFE 4ZTUFNJD (MVDPDPSUJDPTUFSPJE 4VTDFQUJCJMJUZ t 0UIFS (MVDPDPSUJDPTUFSPJE &GGFDUT Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1. Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

Headache Nausea Decreased Blood Cortisol Upper Abdominal Pain Fatigue Flatulence Abdominal Distension Acne Urinary Tract Infection Arthralgia Constipation

UCERIS 9 mg (N = 255) n (%) 29 (11.4) 13 (5.1)

UCERIS 6 mg (N = 254) n (%) 37 (14.6) 12 (4.7)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3)

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

8 (3.1) 6 (2.4) 6 (2.4) 6 (2.4) 5 (2.0) 5 (2.0) 5 (2.0)

5 (2.0) 8 (3.1) 4 (1.6) 2 (0.8) 1 (0.4) 5 (2.0) 1 (0.4)

5 (1.9) 5 (1.9) 2 (0.8) 5 (1.9) 1 (0.4) 4 (1.6) 2 (0.8)

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JANUARY 2014

procedure, were followed for a mean of 12 months after FMT (range, 3-51 months). Compromised immunity resulted from immunosuppressive IBD therapy in 48% of patients, solid organ transplant in 21%, the presence or treatment of chronic conditions other than IBD in 18%, cancer treatments in 9% and HIV in 3%. Dr. Kellyâ&#x20AC;&#x2122;s team found that CDI resolved in 89% of patients after one or two FMTs, confirming the efficacy of the procedure. They also found that 14% of patients experienced a serious AE within 12 weeks of FMT, although not all were 0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

0WFSBMM Mood changes Sleep changes Insomnia Acne Moon face Fluid retention Hirsutism Striae rubrae Flushing

UCERIS 9 mg (N = 255) n (%) 26 (10.2) 9 (3.5) 7 (2.7) 6 (2.4) 6 (2.4) 3 (1.2) 2 (0.8) 1 (0.4) 0 0

UCERIS 6 mg (N = 254) n (%) 19 (7.5) 10 (3.9) 10 (3.9) 6 (2.4) 2 (0.8) 3 (1.2) 3 (1.2) 0 0 1 (0.4)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3) 12 (4.7) 8 (3.1) 5 (1.9) 4 (1.6) 3 (1.2) 0 2 (0.8) 3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1. In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4)

0WFSBMM Insomnia Mood changes Moon face Sleep changes Acne Hirsutism Flushing Fluid retention

UCERIS 6 mg (N = 62) n (%) 9 (14.5) 4 (6.5) 4 (6.5) 3 (4.8) 3 (4.8) 3 (4.8) 3 (4.8) 1 (1.6) 1 (1.6)

Placebo (N = 61) n (%) 7 (11.5) 4 (6.6) 2 (3.3) 3 (4.9) 3 (4.9) 0 0 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide. Because these 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. Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects:: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

AEs deemed treatment-related: These included two deaths, one due to worsening of preexisting pneumonia and another due to aspiration during colonoscopy-administered FMT. Seven patients required hospitalization due to diarrhea, IBD flare, IV catheter sepsis or hepatic encephalopathy. Also, two cases of worsened diarrhea were not associated with a pathogen and did not require hospitalization. Four patients experienced mild abdominal discomfort shortly after the FMT, and one patient suffered a minor mucosal tear related to colonoscopic FMT administration. Two patients with to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

â&#x20AC;&#x2DC;This high-risk population of immunocompromised patients â&#x20AC;Ś experienced few serious AEs and, importantly, did not have infectious complications related to FMT.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Colleen Kelly, MD Similar to findings from Dr. Kellyâ&#x20AC;&#x2122;s group, Dr. Khannaâ&#x20AC;&#x2122;s team discovered that FMT was highly effective in treating CDI, with 92% of patients experiencing complete or partial relief of CDI-related symptoms a median of two weeks after FMT (range, 1-14 days). Laboratory tests confirmed that 85% of patients had complete clearance of C. difficile, Dr. Khanna reported. Also, there were no AEs related to FMT, the researchers found. Unlike Dr. Brandtâ&#x20AC;&#x2122;s data, which showed relief of symptoms in patients with IBD after FMT, Dr. Khannaâ&#x20AC;&#x2122;s team did not find the procedure to relieve IBD symptoms. In fact, Dr. Khanna found that 46% of patients in the study required higher doses of their IBD medications after the procedure. Dr. Khanna acknowledged that identifying which symptoms are related to CDI and which are related to IBD was difficult because the two diseases have similar presentations. However, exacerbations of see FMT, page 31

UCERISâ&#x201E;˘ is a trademark of Santarus, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273. ÂŠ 2013 Santarus, Inc.

UC required a colectomy, although the colectomies were unrelated to FMT and were conducted more than 100 days following the procedure, Dr. Kelly said. â&#x20AC;&#x153;This high-risk population of immunocompromised patients, including some severely immunocompromised patients, experienced few serious AEs and, importantly, did not have infectious complications related to FMT,â&#x20AC;? Dr. Kelly concluded. A separate study looked at the safety and efficacy of FMT in 13 patients with IBD and CDI, including some immunocompromised individuals (abstract P1657). The prospective study, led by Sahil Khanna, MD, assistant professor of medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn., included seven patients with CD and six patients with UC who had refractory CDI following a median of five prior treatments. At the time of FMT, six patients were receiving treatment with 5-aminosalicylic acid, six were being treated with biologics, three were receiving immunomodulators and five were receiving corticosteroids; none of the treatments were discontinued in advance of FMT. Study participants ranged in age from 21 to 48 years and had IBD for a median of three years before FMT.

1-UCE13033 V1

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

FMT Stands Up To Antibiotics in Cost-Effectiveness Model BY MONICA J. SMITH

‘FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence.’

SAN DIEGO—Fecal microbiotta transplant (FMT) has been rapidlyy gaining ground as a treatment for re ecurrent Clostridium difficile infectio on (CDI), showing in one study after another to be safe and often more effective than conventional therapiess. A new study presented at the American College of Gastroenterolog gy 2013 Annual Scientific Meeting supports the cost-effectiveness off this procedure as well. The growing incidence off CDI and the high cost of drugs used to treat it has resulted in so oaring health care costs related to management of the infection. CDI has become particularly more difficult to manage since the emerg gence of the 027 strain, which has resulted in lower cure rates and inc creased resistance to treatmentss. Additionally, the rate of recurrrence is growing: As many as one--third of patients experience a rec currence after an initial infection, an nd up to two-thirds of those patientts experience further recurrent infe ections. “All of this has resulted in a high economic burden of over $1 billion annually,” said Gauree G. Konijeti, MD, MPH, a fellow in gastroenterology and hepatology at Massachusetts General Hospital and Harvard Medical School, in Boston. “We manage an initial infection with metronidazole or vancomycin, and recurrences with either of these two antibiotics or fidaxomicin,” Dr. Konijeti said. “FMT has emerged as a highly effective therapy because of high cure rates and low rates of recurrence.” Given that background, Dr. Konijeti and her colleagues constructed a decision-analytic model to compare the cost-effectiveness of four treatments for recurrent CDI: metronidazole, vancomycin, fidaxomicin and FMT. The model used a patient cohort with a median age of 65 years with mild to moderate CDI. Potential outcomes following treatment were cure without recurrence, cure with recurrence or nonresponse. The cost of FMT was modeled to include the cost of donor testing, recipient testing, FMT preparation and instillation, four-day preprocedural treatment with vancomycin and the cost of the procedure itself (administration

—Gauree G. Konijeti, MD, MPH

‘FMT also dominated metronidazole and fidaxomicin, which means that it was both more effective and less costly than the either of those two antibiotics.’ —Gauree G. Konijeti, MD, MPH via colonoscopy, upper endoscopy or enema). The researchers devised a clinical scenario in which two additional recurrences occurred following the first recurrence of CDI. Based on clinical practice guidelines, patients who received metronidazole for a first CDI recurrence were given vancomycin for a second recurrence and a vancomycin pulse/taper for a third recurrence. Those given vancomycin or fidaxomicin for a first recurrence received a vancomycin pulse/ taper for a second recurrence and FMT for a third. Patients who received FMT for a first recurrence underwent FMT again for a second recurrence and a vancomycin pulse/taper for a third. In the primary analysis, FMT administered via colonoscopy was the most cost-effective strategy, showing an incremental cost-effectiveness ratio (i.e., the additional cost per additional unit of effectiveness gained) of approximately $38,000.

“FMT also dominated metronidazole and fidaxomicin,, which means that it was both more effective and less costly than the either of those two antibiotics,” Dr. Konijeti said. The researchers also looked at the cost of FMT delivered via duodenal infusion and enema, but they found both strategies to be costprohibitive, mainly because of lower one-time infusion cure rates. They acknowledged that if cure rates with these techniques could be brought up to 89%, these two delivery strategies would be preferable to treatment with antibiotics as well. Sensitivity analyses revealed that FMT via colonoscopy would remain the preferred strategy if the CDI recurrence rate following the procedure were lower than about 10%; for recurrence rates higher than 10%, the preferred strategy would be vancomycin. Vancomycin was the most costeffective initial treatment in situations where FMT was not available. In this scenario, competing antibiotic therapies with an efficacy similar to fidaxomicin would need to cost less than about $1,500 to be considered cost-effective. “In summary, a strategy consisting of first-line treatment with

FMT colonoscopy for an initial recurrence of CDI appeared costeffective at conventional con willingness-to-pay th hresholds,” Dr. Konijeti said. “Guideline es should consider earlie er use of FMT in the treatm ment of CDI, and future studies should inc corporate FMT fo or comparative e effectiveness,” sh he concluded. The e study’s findings came as no surprise to Colleen Kelly, MD, clinical assistant profess sor of medicine, Brown Alpert Med dical School at Brown University, and a a gastroenterologist at the Center C for Women’s Gastrointes stinal Medicine, both in Providence, R.I. “Those of us s who do FMT have known its s cost-effectiveness, which is obv vious when you have such amazing cure rates compared to the other a agents, which are quite expensive,” sh he said. Dr. Kelly susp pects the cost advantage of FMT T in this study would have been even greater if the researchers us sed a population of sicker patients iin their model. “We see people who, with each case of CDI, get admitted to the hospital, with all the costs associated with that,” Dr. Kelly said. “If you looked at a more severely ill group of patients, I think you would find FMT even more cost-effective.” In the past year or so, Dr. Kelly has started administering FMT via sigmoidoscopy, both to avoid the cost associated with colonoscopy and to avoid subjecting patients to colonoscopy more often than necessary, especially if it meant scheduling a hospital-based procedure. Sigmoidoscopy offers several advantages over other modes of FMT instillation: Patients do not need to be sedated as they do with colonoscopy, and they are more likely to retain the dose long enough for it to take effect, which can be difficult to achieve with an enema. “It doesn’t have to be all or nothing—full colonoscopy or enema,” Dr. Kelly said, referring to the costeffectiveness of sigmoidoscopy. “Also, we’re hoping that some of the oral formulations [being investigated] will remove that whole cost from the picture.”

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H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28). But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated. The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

tor

Ma Vis it y DD 19- us W 21, bo 2 oth 013 15 31

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA). “This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer.................................................«>}iÊÓ{

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

PRODUCT ANNOUNCEMENT

Ulcerative Colitis:

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

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

BRIAN BOSWORTH, MD

see page 63 for product information

he e greatest ch hallenge for clinicians who

treat patients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of IBD using 5-aminosalicylic acid (5-ASA) agents.

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

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

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

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2013

FibroScan® Cleared by the FDA For Sale in the United States

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Popular IBD Diet Associated With Increased Microbial Diversity BY DAVID WILD SAN DIEGO—The specific carbohydrate diet (SCD), popular among patients with inflammatory bowel disease (IBD), is associated with distinct changes in the intestinal microbiome, researchers at Rush University have found. The trademarked SCD, as described by Elaine Gottschall, MSc, in her book, “Breaking the Vicious Cycle” (The Kirkton Press; 2012), is “predicated on the understanding that ulcerative colitis, Crohn’s disease, irritable bowel syndrome and gluten therapy resistant celiac [disease] are the consequence of an overgrowth and imbalance of intestinal microbial flora.” Ece Mutlu, MD, associate professor of medicine, Rush University Medical Center, Chicago, and her

colleagues analyzed fecal samples from 20 patients with IBD who reported following the SCD and 20 patients with IBD who did not adhere to the diet: Each group included 10 patients with Crohn’s disease and 10 patients with ulcerative colitis. Some patients were receiving immunosuppressant medications at the time of fecal sample analysis. Dr. Mutlu and her team performed 16S rDNA pyrosequencing and found that individuals in the SCD group had greater intestinal bacterial diversity compared with those in the control group, in addition to having a differing microbiome composition. The study was not designed to measure endoscopic and clinical disease activity, but Dr. Mutlu told Gastroenterology & Endoscopy News that she observed symptom relief in some patients following the diet.

“I have observed that a small number of my own IBD patients drastically improved on the SCD and achieved complete long-term mucosal healing, or were able to reduce or discontinue immunosuppressants for several years.” These anecdotal observations and the findings from the study justify further investigation of the diet’s effect, said Dr. Mutlu, who presented the study at the American College of Gastroenterology 2013 Annual Scientific Meeting (poster 1619). “A longitudinal study following IBD patients before the start of the diet, and during and after the SCD, would have been much harder for us to complete, but I think this should be done going forward and it could help us learn a lot more in the future.”

FMT continued from page 28

IBD symptoms were most likely related to CDI, he said, noting that CDI is associated with IBD exacerbations. Additionally, many of the patients had active IBD before the procedure. Dr. Lacy said that previous case reports have demonstrated serious AEs

following manipulation of the intestinal microbiome in immunocompromised patients, including two fungemiarelated deaths following probiotic use and an increased risk for diabetes and autoimmune and connective tissue diseases with FMT. The new data on the

safety of FMT in immunocompromised patients are important, in light of those reports, Dr. Lacy said. Although both of the new studies have weaknesses in their design, “they are the only studies to date to have looked at immunocompromised

patients who underwent FMT, and they show that it was safe and effective in treating CDI.” ■ None of the researchers featured in this article reported any relevant financial conflicts of interest.

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Burnout continued from page 1

feeling burned out—exhausted, listless and unable to cope.” Three components of burnout, Dr. Surawicz said, include: 1. Emotional exhaustion, “when we feel overworked and overextended”; 2. Depersonalization, “when we become unfeeling in our response to our patients or peers and treat them as objects rather than as humans”; and 3. “A decreased sense of personal accomplishment and success.” The scale most commonly used to measure burnout is the 22-item Maslach Burnout Inventory. But according to a 2009 paper from Mayo researchers (West CP et al. J Gen Intern Medd 2009;24:13181321), two items alone can predict burnout in medical professionals fairly accurately: 1. “I feel depleted and burned out from my work.” 2. “I have become more callous toward people since I started this job, treating them as objects instead of humans.”

‘By and large, the major contributor to burnout in the gastroenterologists we surveyed was emotional exhaustion, which was seen in 30% to 63% of respondents, with the highest proportion seen in junior attendings who identified themselves as interventional endoscopists.’ —Rajesh N. Keswani, MD

“In a paper where those questions were found to correlate pretty well with the 22-item score, [the authors] made the point that nobody ever put ‘never,’ ” Dr. Surawicz said. “The 90% correlation was with people who said they had these feelings several times a week, not several times a year.”

Burnout Buzz Lately, burnout has been receiving a lot of buzz. Coverage in the lay media and medical literature alike suggest that physicians are experiencing it in epidemic proportions. Some data indicate that up to 44% of physicians experience burnout, and that youth is not a predictor of resilience.

“In mediical students, 28% to 40% experience burnout; medical residents experiience it at rates of 27% to 75%, dep pending on the specialty; and th he greatest risk is in our youngger colleagues,” Dr. Surawiccz said. She nooticed this trend seveeral years ago when she developed a worrkshop on wellness. “I wass nervous that the topic might be seen as too ‘touch hy-feely,’ but there was a record turn nout for the workshoop, and it was youngeer faculty. That was when I realized that this was much more of a prroblem for our younger collleagues than for those of us who are older.” More than one-third of gastroeenterologists have reported experiencing burnout (Medscape Physician Lifestyle Report, 2013, availaable at www.medscape.com/ sites/publicc/lifestyle/2013). A recent survey of members of the American Society forr Gastrointestinal Endoscopy may provide some insight into why some gastroenterologists t t l i t may be particularly vulnerable to burnout (Keswani RN et al. Am J Gastroenterol 2011;106:1734-1740). “Stress levels were uniformly high, although highest in those who practiced interventional gastroenterology, and in the more junior attendings,” said the study’s lead author, Rajesh N. Keswani, MD, assistant professor in medicinegastroenterology and hepatology, Northwestern University Feinberg School of Medicine, Chicago. “By and large, the major contributor to burnout in the gastroenterologists we surveyed was emotional exhaustion, which was seen in 30% to 63% of respondents, with the highest proportion seen in junior attendings who identified themselves as interventional endoscopists.” The survey indicated that younger attending physicians tended to have higher levels of burnout. Dr. Keswani found burnout in interventional gastroenterologists was associated with younger age, male gender, being foreign-born, working more hours, having less leisure time and experiencing procedure-related worries. Stress among noninterventional gastroenterologists was associated with others

D fi i Burnout: Defining B t Three Components Emotional exhaustion: feeling overworked and overextended Depersonalization: becoming unfeeling toward patients or peers, and treating them as objects rather than as human beings A decreased sense of personal accomplishment and success

questioning their endoscopic skills and being pressured by nurses to perform procedures more quickly. Interestingly, gastroenterologists who spent more time in direct clinical practice, as well as those in academic practice, reported experiencing lower levels of personal accomplishment. Procedural complications, Dr. Surawicz noted, also are a significant contributor to burnout. “Complications are inevitable, especially

if one does procedures, and all physicians feel terrible about them. Add a malpractice suit, and the stress is even higher,” she said. The consequences of burnout can be deep and long lasting to both the individual id l physician h i i and d the th profession. f i “We do not know the impact of stress and burnout in gastroenterologists, but prior studies have shown that higher levels of burnout tend to result in early retirement; thus, those physicians with the most experience may prematurely leave medicine,” Dr. Keswani said. “Even more concerning,” he added, “it has been suggested in the surgical literature that higher levels of burnout are associated with medical errors, although it’s unclear if the burnout was the cause of increased errors. It is imperative that we, as a discipline, address this issue, as it affects all facets of the field.”

Admitting Burnout One of the challenges to combating burnout is acknowledging it in the first place. “Physicians tend to deny their anxieties and fears, desires and fatigues. How well do we recognize burnout in ourselves and others? I think this is a huge challenge and an area where we need more help,” Dr. Surawicz said. “We should be able to recognize burnout in ourselves and our colleagues, we should be able to educate ourselves about the factors contributing to it, we should be able to support ourselves and

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Battling Burnout: Three Steps Step 1: Identify and balance personal and professional goals.

Step 2: Recognize stressors and shape your career.

Step 3: Nurture personal wellness strategies for diminishing the effects of stress.

our juniors and we should team with the nurses to eliminate some of the stress that they may inadvertently generate.” Felice Schnoll-Sussman, MD, who writes a blog on issues in work–life balance for the ACG, agreed that physicians tend to not always recognize burnout in themselves. “They may not have experienced it before in their lives,” she said. “They’re overachievers and are used to the stress of a demanding career.” She agreed with Dr. Surawicz that younger physicians might struggle with burnout to a greater degree. “It’s more obvious that those in their earlier/mid-career are dealing with these type of issues,” she said. However, differences in burnout observed in junior medical professionals compared with their more senior colleagues might stem from younger people feeling more comfortable talking about these concerns. “Although I have also heard from more senior colleagues that work–life balance issues are important, they are more skittish in discussing them openly,” Dr. Schnoll-Sussman said. “They were trained in a culture of ‘suck it up and deal with it,’ whereas younger people may feel more empowered to express their wants and needs.” Another thing that Dr. Schnoll-Sussman has noticed is that although her blog was initially intended to be part of a women’s forum, it has generated a lot of commentary, both online and in person, from her male colleagues. “We assumed that many of these issues were female-specific, but men are struggling as well,” she said. “My male colleagues are just as enthusiastic to talk about these concerns. It’s not what I expected, but it’s there.” Additionally, her blog has allowed some issues to surface that some physicians may have shied away from addressing publicly in the past. “The response validates that others are feeling this way. We’re getting a sense of commonality and exploring how we, as a society of physicians, can change. Are we looking at our careers

the wrong way? Are there things in our control that we can change?” Dr. Schnoll-Sussman asked. “As someone who has faced the challenge of work–life balance, I can honestly say that although I love being a physician and the nature of my career path, the daily demands of practice can at times be daunting,” said Dr. Schnoll-Sussman, who is an associate professor of clinical medicine at Weill Cornell Medical College and director of research at The Jay Monahan Center for Gastrointestinal Health, both in New York City.

‘We assumed that many of these issues were female-specific, but men are struggling as well. My male colleagues are just as enthusiastic to talk about these concerns.’ —Felice Schnoll-Sussman, MD

Although working too many hours would seem an obvious precursor to burnout, not all studies have found a correlation. And some physicians, perhaps perversely, are inclined to wear exhaustion as a badge of honor.

“When you ask a physician ‘How is everything going?’ the word that means ‘good’ is ‘busy,’ ” Dr. Schnoll-Sussman observed. “It’s a weird mentality.” see Burnout, page 34

RESEARCH Advancing Genomic Medicine To Create Precision Therapies.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Burnout continued from page 33

Battling Burnout: Three Easy Pieces Although some studies have shown that burnout “correlates with stress, and stress is inevitable, it’s how we manage stress that makes a difference,” Dr. Surawicz said. With some knowledge, perspective and reflection, physicians can learn to mitigate stress and other factors that may contribute burnout.

‘For mid-career faculty, what

self-evaluation. “For mid-career faculty, what we’re really passionate about may have changed over the years,” Dr. Surawicz said. “Maybe it’s time to learn a new clinical skill. Maybe it’s time to start teaching— or stop teaching. Or maybe it’s being in a leadership role.” For Dr. Surawicz, taking on the role of assistant dean for faculty development in 2002 was profoundly energizing. “It gave me a steeper learning curve that really helped to change my professional life.”

we’re really passionate about may have changed over the years. Maybe it’s time to learn a new clinical skill. Maybe it’s time to start teaching—or stop teaching. Or maybe it’s being in a leadership role.’ —Christina Surawicz, MD

Dr. Surawicz cited a study by Shanafelt et al showing that higher quality-of-life scores were reported by surgeons who engaged in exercise and had seen their primary care physicians within the past year (Shanafelt TD et al. Ann Surg 2012;255:625-633). “They also combated burnout by finding meaning in their work, focusing on what was important and focusing on work–life balance,” she noted. Citing another article by Shanafelt (Balch CM, Shanafelt T. Adv Surg 2010;44:29-47), Dr. Surawicz distilled the authors’ recommendations for combating stress and burnout into three steps. Step 1: Identify and balance personal and professional goals.

“Do your professional and personal goals jibe? Do they need to be integrated … are they in completely separate spheres?” Dr. Surawicz asked. “The way we can think of this is ‘Why did I choose gastroenterology? What do I like most about my job? What motivates me professionally, and what do I want to have accomplished by the end of my career?’ ” Step 2: Recognize stressors and shape your career.

The idea behind this step is that you can enhance your work by focusing on what is most meaningful to you, by possibly avoiding procedures that make you uncomfortable or by getting enough training and experience in those areas so that you do feel comfortable. This step requires ongoing and objective

Step 3: Nurture personal wellness strategies for diminishing the effects of stress.

This means identifying what keeps you healthy, happy and sane, and honoring those practices with as little compromise as possible. For example, Dr. Schnoll-Sussman thrives on daily exercise. She seeks out local yoga classes whenever she is attending a conference or meeting away from home. “It’s part of my salvation; [it] helps me clear my mind and feel rejuvenated,” she said. “For a lot of people it’s the first thing they cut out, but potentially one of the things that could be most helpful for them.” Other strategies to promote personal wellness include healthy eating, exploring hobbies, nurturing relationships with friends and family, and for some, engaging in a spiritual community or practice.

‘For a lot of people [daily exercise] is the first thing they cut out, but potentially one of the things that could be most helpful for them.’ —Felice Schnoll-Sussman, MD

Some research has shown that mindfulness-based stress reduction (i.e., bringing one’s complete awareness to the present on a moment-to-moment basis) may be helpful as well. “This involves being nonjudgmental and consciously aware,” Dr. Surawicz explained. “It includes mindful meditation and can include narrative writing and appreciative inquiry.” In one study of primary care physicians, researchers reported significant improvements in well-being and attitudes toward patient-centered care among those who

Identifying Burnout: A Two-Item Test Two items from the 22-item Maslach Burnout Inventory can predict burnout in medical professionals: “I feel depleted and burned out from my work.”

“I have become more callous toward people since I started this job, treating them as objects instead of humans.”

Source: West CP et al. Single item measures of emotional exhaustion and depersonalization are useful for assessing burnout in medical professionals. J Gen Intern Med. 2009;24:1318-1321.

participated in a mindful communication program (Krasner MS et al. JAMA 2009;302:1284-1293). Another activity that may mitigate burnout is mentoring. “This has been suggested for use in other at-risk disciplines in the hopes of reducing burnout in both senior and junior colleagues,” Dr. Keswani said. Dr. Schnoll-Sussman has engaged in mentoring and counseling younger colleagues. “I think it’s really important to be available to them, especially in their first three years of practice,” she said. “Junior physicians stand on the shoulders of their mentors—you train the younger generation, and [their] success is [your] success.” Not all institutions may have a sufficient number of senior physicians to establish an appropriate mentoring program. In those cases, “it may be necessary to look to peer institutions,” Dr. Keswani said. “The major gastroenterology societies may play a vital role in this endeavor by connecting junior physicians with suitable mentors.” The ACG, for example, offers a program for pairing second- and third-year fellows with distinguished ACG members who act as mentors (http://gi.org/ fellows-in-training/mentoring-program). Dr. Surawicz noted that the ACG was an important resource for her in helping to combat burnout when she experienced it. “I’m thrilled that … the College is continuing to develop programs to improve our wellness,” she said.

Words To Live By Dr. Surawicz urged those who attended her talk to reflect on the epidemic of burnout among physicians, to support younger colleagues and to review their priorities and take control of their lives. She ended her presentation with two final thoughts. The first, often iterated

by ACG immediate past president, Ronald J. Vender, MD: “ ‘Remember that for each patient, their visit with you is probably the most important event of the day.’ ” The other, a quotation on the wall of her institution’s ICU, which she used in her 1999 ACG presidential address and later learned was attributable to Maya Angelou: “ ‘People will forget what you say. They may remember what you show them how to do, but they will never forget how you make them feel.’ ” ■

gastroendonews

Lowest volume of active prep solution— only 10 oz.

Superior

cleansing *

…that

patients preferred †

in clinical trials

*Demonstrated non-inferiority with both split-dose and day-before regimens, evaluated in randomized trials using the validated Aronchick scale. Superior cleansing efficacy of split-dose regimen demonstrated vs day-before regimen comparator (84% vs 74%, respectively, achieving “excellent or good” visualization). The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists. [Prepopik: n=256/304; comparator: n=221/297].1-3 SUPERIOR CLEANSING

PATIENT PREFERENCE

with the ACG-recommended split-dose regimen, assessed using validated scales*‡1,2

reported in clinical trials†1-3

Percentage of patients achieving excellent or good visualization in the split-dose trial

Patient reactions to bowel prep regimens in the split-dose trial

Colon segment

Prepopik

2L PEG+E plus 2x 5 mg bisacodyl tablets

Overall

84%

74%

(n=256/304)

Ascending Mid (Transverse and Descending)

Rectosigmoid

90%

(n=272/304)

92%

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79%

10%

86%

(n=255/297)

92%

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DIFFERENCE

(n=234/297)

(n=281/304) (n=281/304)

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(n=259/297)

Prepopik

99%

(n=304/305)

96%

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(n=290/302)

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(n=270/302)

89%

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91%

(n=267/292)

55%

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29%

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SPLIT-DOSE OR DAY-BEFORE REGIMEN4

INDICATION AND IMPORTANT SAFETY INFORMATION Prepopik ® for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. • Prepopik is contraindicated in the following conditions: patients with severely reduced renal function, gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should be advised on the importance of adequate hydration, and post-colonoscopy lab tests should be considered if a patient develops significant vomiting or signs of dehydration after taking Prepopik • Patients with electrolyte abnormalities should have them corrected before treatment. Use caution when prescribing for patients who are at risk for seizures, or arrhythmias, including those patients with a history of prolonged QT, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy. Caution should also be used in patients with impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function, electrolyte imbalance and/or water retention • Oral medication administered within one hour of the start of administration of Prepopik solution may be flushed from the GI tract and the medication may not be absorbed. Prior or concomitant use of antibiotics with Prepopik may reduce its efficacy. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of Prepopik to avoid chelation with magnesium. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with Prepopik may increase this risk • Prepopik should not be used if gastrointestinal obstruction or perforation is suspected. Prepopik is not for direct ingestion. Each packet must be dissolved in 5 ounces of cold water and administered at separate times, in addition to additional clear fluids, according to the dosing regimen. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common treatment-emergent adverse reactions (>1%) following Prepopik administration

Please see brief summary of Prescribing Information following this advertisement. †

The SEE CLEAR I and SEE CLEAR II studies were phase 3, randomized, multicenter, assessor-blinded, noninferiority studies in patients preparing for colonoscopy. The primary endpoints were evaluation of overall colon cleansing with Prepopik vs a comparator using modiﬁed Aronchick and Ottawa scales. Patients were also required to complete a questionnaire, which included the questions: “How easy or difﬁcult was it to consume the prescribed bowel preparation?” and “Would you ask your doctor for this preparation again if you needed another colonoscopy in the future?”1,3

‡

The Ottawa bowel preparation scale assesses bowel cleanliness by section, based on numeric scores of 0-4. A score of 0 denotes “excellent” cleansing with ascending numbers denoting “good,” “fair,” “poor,” and “inadequate.” Additional numeric value is assigned based on the amount of ﬂuid present (small, moderate, or large). [Prepopik: n=272/304; comparator: n=234/297].1,2

Visit prepopik.com/testimonials to hear what patients and healthcare professionals have to say about Prepopik! References: 1. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study [published online ahead of print]. Gastrointest Endosc. 2013. http://dx.doi.org/10.1016/j.gie.2013.02.024. 2. Data on ﬁle. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. 3. Katz PO, Rex DK, Epstein M, et al. A dual-action, low-volume bowel cleanser administered the day before colonoscopy: results from the SEE CLEAR II study. Am J Gastroenterol. 2013;108:401-409. http//dx.doi. org/10.1038/ajg.2012.441. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. PREPOPIK® is a registered trademark of Ferring B.V. © 2013 Ferring B.V. All rights reserved. PK/1219/2013/US(1)

Malpractice Claims continued from page 1

to claim resolution. Furthermore, the policy change appears to be generating improvements in quality of care. In July 2001, the University of Michigan Health System (UMHS), in Ann Arbor, replaced its traditional â&#x20AC;&#x153;deny-and-defendâ&#x20AC;? approach to claims of medical error with a â&#x20AC;&#x153;disclose-andinvestigateâ&#x20AC;? tactic. Previously, any malpractice claim was immediately referred to a trial attorney to prepare a defense.

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ JANUARY 2014

Reductions in malpractice claims were â&#x20AC;&#x2DC;reproduced in a dramatic way in our procedural-based specialty of gastroenterology.â&#x20AC;&#x2122; â&#x20AC;&#x201D;James M. Scheiman, MD

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Under the new system, a multidisciplinary team of physicians, nurses and administrators was created to review each claim. If the care provided was determined to have been unreasonable under accepted standards of care, this finding was openly disclosed, an apology was made to the patient and compensation was offered independent of the likelihood of the success of that claim in court. Alternatively, if the care provided was determined to have been reasonable in the eyes of the reviewers, the claim was defended as before. The success of the UMHS model has been published previously (Kachalia A et al. Ann Intern Medd 2010;153:213221). Comparing preimplementation and postimplementation data between 1995 and 2007 showed a 65% reduction in lawsuits (0.75 vs. 2.13 per 100,000 patient encounters), a 59% reduction in both total liability and patient compensation and a 61% reduction in noncompensation-related legal costs. Additionally, the median time from claim reporting to resolution was reduced from 1.36 to 0.95 years in the hospital-wide analysis.

â&#x20AC;&#x2DC;Dramaticâ&#x20AC;&#x2122; Results With these findings in mind, Megan A. Adams, MD, a fellow at the University of Michigan, and her colleagues conducted a follow-up study to determine whether the unique characteristics of the field of gastroenterologyâ&#x20AC;&#x201D;such as its procedural emphasis; large number of open-access procedures; and care of patients with unique diseases, such as functional bowel disordersâ&#x20AC;&#x201D;would affect the success of the program as it pertained to gastroenterology-related claims. Data from the new study were presented at the 2013 Digestive Disease Week meeting. The researchers found that reductions in malpractice claims were â&#x20AC;&#x153;reproduced in a dramatic way in our proceduralbased specialty of gastroenterology,â&#x20AC;? said James M. Scheiman, MD, professor of internal medicine at UMHS and senior author of the study. Dr. Scheiman cited data that suggested the overall effect of the policy was even greater for gastroenterology-related claims than it was systemwide. In a comparison of the 10-year preimplementation period with the 10-year postimplementation period, the absolute number of claims fell by around 25% even though the number of patient encounters increased by 72%. When the rate of claims per patient encounter was calculated, the reduction was significant (0.16% vs. 0.068% per 1,000 patient encounters, pre- vs. postimplementation, respectively; P P=0.001). The reduction in

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

the rate of claims was accompanied by a 54% reduction in total settlement dollars ($4.7 million vs. $2.1 million) and a 52% reduction in mean total dollars per claim ($167,309 vs. $81,107). The investigators categorized claims into three groups: those related to a delayed or missed diagnosis; those related to a gastroenterology procedure; and those related to improper management, treatment or monitoring. During the preimplementation period, which included 239,000 patient encounters, approximately 21% of claims were related to delayed or missed diagnosis; 34% were related to a gastroenterology procedure; and the remaining 45% involved alleged improper management, treatment or monitoring. In the postimplementation era, when the volume of patient encounters increased by 72% to 412,000, the proportion of claims related to gastroenterology procedural complications increased and the proportion related to delayed or missed diagnosis decreased. Dr. Adams said the costs per claim would have been reduced in all three groups except for a single large wrongful death claim that alleged a delay in diagnosis, which raised the average cost per claim in that category.

A large number of patients would not have brought a claim in the first place if there had been an acknowledgment of the error, an apology and reassurance that the error would not be repeated. nonprocedural specialties, so I am pleased but not surprised by the current findings,” Dr. Leffler said. “Although these new policies are more in line with the current focus in health care on quality and transparency, it is important to note that this is a dramatic change from behaviors of the past and there can be resistance from physicians, medical administrators and malpractice insurers. Our own current policy at Beth Israel Deaconess Medical Center is based on the Michigan model and although it is too early to know what benefits we may see, there appear to be few tangible downsides,” he added. Before a policy such as this can be put into place, Dr. Leffler said, “it is vital to have a coordinated agreement between all concerned parties, including physicians, medical administrators and malpractice insurers, and robust education to ensure that disclosure is carried out in a professional manner.” ■

Apology Accepted Notably, UMHS did not change their approach to medical errors primarily as a risk-management strategy; rather, Dr. Adams described it as “a part of the larger effort to address quality improvement.”

Dr. Scheiman reported financial relationships with AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim GmbH, McNeil Pharmaceuticals, Pozen Inc., ProStrakan, Stryker Endoscopy and Xlumena. Drs. Adams and Leffler reported no conflicts of interest.

‘One problem with the deny-and-defend approach is that it does not help to reduce errors and therefore may not best serve the

what is your

overarching goal of improving patient safety.’ —Megan A. Adams, MD When the multidisciplinary team reviews the malpractice claims, the goal is not only to identify and disclose errors but also to evaluate strategies to prevent the same errors from recurring. Dr. Adams described this as a “culture change,” with a profound shift in emphasis. “One problem with the deny-anddefend approach is that it does not help to reduce errors and therefore may not best serve the overarching goal of improving patient safety,” she said. Dr. Adams cited data suggesting that a large number of patients would not have brought a claim in the first place if there had been an acknowledgment of the error, an apology and reassurance that the error would not be repeated. Indeed, patients who are harmed by an error at

an institution employing a deny-anddefend approach receive only a fraction of the funds that the institution spends on defense. “Expenses generally outpace compensation. It is estimated that 54% of the cost of medical malpractice goes to administrative expenses, such as attorney fees, rather than to injured patients,” Dr. Adams said. Although claims data from UMHS— and the Gastroenterology Division specifically—validate medical error disclosure programs from a purely economic perspective, Dr. Adams stressed that patients may be the greater beneficiaries. Within the quality assurance programs that are now in place at most large institutions, a properly implemented medical

error disclosure program appears, from these data, to provide another avenue to identify and address problems to improve care and, as Dr. Adams suggested, “in doing so may help strengthen patient– provider relationships.”

Resistance to Change Asked to comment on these findings, Daniel A. Leffler, MD, director of quality assurance, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, said the Michigan initiative is well known among those with an interest in the area of medical errors and quality assurance. “Previous reports had suggested that thoughtful disclosure reduced malpractice risks in both procedural and

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IN THE TREATMENT OF CHRONIC HEPATITIS B (CHB) IN ADULTS WITH COMPENSATED LIVER DISEASE

TAKE A CLOSER LOOK AT LAMIVUDINE (LAM) RESISTANCE MORE THAN NEARLY Not an actual patient, but is representative of a real patient type. Models are used for illustrative purposes only.

50% 70% 70% 2%

of Americans living with CHB are Asian and Paciﬁc Islanders1

of Asian Americans were born or have parents born in countries where CHB is common1

of patients receiving lamivudine develop resistance at 5 years2

of patients in the United States use lamivudine; up to 88% in Asia3

Indication and Usage VIREAD® (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older. The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: s The indication in adults is based on data from treatment of subjects who were nucleoside–treatment-naïve and treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease s VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease s The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efﬁcacy

Important Safety Information BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS s Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases cases, have been reported with the use of nucleoside analogs, analogs including VIREAD, in combination with other antiretrovirals s Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted

Warnings and Precautions s New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of VIREAD. In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy. In patients at risk for renal dysfunction, including those

who previously experienced renal events while receiving adefovir dipivoxil, additionally monitor serum phosphorus, urine glucose, and urine protein. In patients with CrCl <50 mL/min, adjustt dosing interval and closely monitor renal function. Avoid concurrent or recent use with a nephrotoxic agent. Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in HIV-infected patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function s Coadministration with other products: – Do not use in combination with other products containing tenofovir disoproxil fumarate – Do not administer in combination with adefovir dipivoxil s Patients coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD s Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen in patients treated with VIREAD. C VIREAD Consider id assessmentt off BMD in i adult d lt andd pediatric di t i patients ti t who h have h a history of pathologic bone fracture or other risk factors for bone loss. In a clinical trial conducted in pediatric subjects 12 to <18 years of age with chronic hepatitis B, total body BMD gain was less in VIREAD-treated subjects as compared to the control group. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered

Adverse Reactions s In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). Other treatmentemergent adverse reactions reported in >5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash

TAKE A CLOSER LOOK AT VIREAD LAM-resistant VIREAD patients (Study 121) achieving viral suppression (HBV DNA <400 copies/mL) at 96 weeks of treatment 4,5 VIREAD

100 90

89%

(n=126)

Patients (%)

80 70 60 50 40

s As a secondary endpoint, no HBV resistance (0%) was detected at 96 weeks in CHB patients with LAM resistance4

30 20 10 0

Study 121 was a randomized, double-blind, active-controlled 96-week trial evaluating the safety and efﬁcacy of VIREAD (n=141) compared to an unapproved antiviral regimen (n=139) in subjects with CHB, persistent viremia (HBV DNA ≥1000 IU/mL), and genotypic evidence of LAM resistance. The primary endpoint in Study 121 was HBV DNA <400 copies/mL (69 IU/mL) at Week 96.4,5

12 16

Important Safety Information (cont’d) s In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (all grades) reported in ≥10% of patients treated with VIREAD were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%)

Drug Interactions s Didanosine: Coadministration increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy). Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD and in patients weighing <60kg, the didanosine dose should be reduced to 200 mg once daily when coadministered with VIREAD s HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations; use atazanavir given with ritonavir. Coadministration of VIREAD with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity s Drugs affecting renal function: Coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir

Dosage and Administration s Recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), for the treatment of chronic hepatitis B: one 300 mg tablet, once daily, taken orally, without regard to food s In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown

96 Weeks

s Safety and efﬁcacy in pediatric patients <12 years of age or weighing <35kg with chronic hepatitis B have not been established s The dosing interval of VIREAD should be adjusted (using recommendations in the table below) and renal function closely monitored in patients with baseline creatinine clearance <50 mL/min Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine clearance (mL/min)a ≥50 Recommended 300 mg dosing interval

Every 24 hours

30-49

Every 48 hours

10-29

Every 72 to 96 hours

Hemodialysis patients Every 7 days or after a total of approximately 12 hours of dialysisb

Calculated using ideal (lean) body weight. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

s The pharmacokinetics of tenofovir have not been evaluated in nonhemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients s No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in these patients s No data are available to make dose recommendations in pediatric patients with renal impairment

Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the adjacent pages. References: 1. CDC Web site. CDC Features-August 2011: Chronic hepatitis B and Asian & Pacific Islanders. Centers for Disease Control and Prevention. http://www.cdc.gov/Features/ChronicHepatitisB/. Accessed June 26, 2013. 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol.l 2012;57:167-185. 3. Data on file, Gilead Sciences, Inc. Gilead HBV LAM assessment, IMS MIDAS data. May 2013. 4. Data on file, Gilead Sciences, Inc. 0121 CSR. 5. VIREAD Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; October 2013.

VIREAD® (tenofovir disoproxil fumarate) tablets Brief summary of full Prescribing Information. Please see full Prescribing Information including Boxed WARNING. Rx only WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS @ Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals (See Warnings and Precautions) @ Severe acute exacerbations of hepatitis have been reported in HBVinfected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted (See Warnings and Precautions) INDICATIONS AND USAGE: VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: J The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease (See Adverse Reactions) J VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease (See Adverse Reactions) J The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy DOSAGE AND ADMINISTRATION: For the treatment of chronic hepatitis B the recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), is one 300 mg tablet, once daily, taken orally, without regard to food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients <12 years of age with chronic hepatitis B weighing <35 kg have not been established. Dose Adjustment for Renal Impairment in Adults: Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment. Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients (See Warnings and Precautions). No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose and urine protein should be performed in patients with mild renal impairment (See Warnings and Precautions). Dosage Adjustment for Adult Patients with Altered Creatinine Clearance

Recommended 300 mg dosing interval

Creatinine clearance (mL/min)a ≥50 30-49 10-29

Hemodialysis patients

Every 24 Every 48 Every 72 to hours hours 96 hours

Every 7 days or after a total of approximately 12 hours of dialysisb

a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis. The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be

suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Exacerbation of Hepatitis after Discontinuation of Treatment: Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD (See Adverse Reactions). It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs)) (See Drug Interactions). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Coadministration with Other Products: VIREAD should not be used in combination with the fixeddose combination products ATRIPLA®, COMPLERA®, STRIBILD® or TRUVADA® since tenofovir disoproxil fumarate is a component of these products. VIREAD should not be administered in combination with adefovir dipivoxil (See Drug Interactions). Patients Coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. Bone Effects Bone Mineral Density:: In clinical trials in HIV-1 infected adults, VIREAD was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD (See Adverse Reactions). Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected (See Adverse Reactions). The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Mineralization Defects:: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD (See Adverse Reactions). Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF (See Warnings and Precautions). ADVERSE REACTIONS: Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease: Treatment-Emergent Adverse Reactions:: In controlled clinical trials in subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with adefovir dipivoxil. Other treatmentemergent adverse reactions reported in >5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. No significant change in the tolerability profile was observed with continued treatment with VIREAD for up to 240 weeks. Laboratory Abnormalities:: in Studies 0102 and 0103 (0–48 Weeks) laboratory

Brief Summary (cont’d) abnormalities (Grades 3–4) reported in ≥1% of subjects treated with Viread (n=426) and adefovir dipivoxil (n=215), respectively, were: any ≥Grade 3 laboratory abnormality (19%, 13%); creatine kinase (M: >990 U/L; F: >845 U/L) (2%, 3%); serum amylase (>175 U/L) (4%, 1%); glycosuria (≥3+) (3%, <1%); AST (M: >180 U/L; F: >170 U/L) (4%, 4%); and ALT (M: >215 U/L; F: >170 U/L) (10%, 6%). Laboratory abnormalities (Grades 3–4) were similar in subjects continuing VIREAD treatment for up to 240 weeks in these trials. The overall incidence of on-treatment ALT flares (defined as serum ALT >2 × baseline and >10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and adefovir dipivoxil (2%). ALT flares generally occurred within the first 4-8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4-8 weeks without changes in study medication. The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults. Clinical Trial in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease:: In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus <2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score ≥10 and MELD score ≥14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain. One of 45 subjects experienced an ontreatment hepatic flare during the 48 week trial. Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B: Assessment of adverse reactions is based on one randomized study (0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults. In this study, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected (See Warnings and Precautions). Postmarketing Experience: The following adverse reactions have been identified during postapproval use of VIREAD. 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: allergic reaction, including angioedema, lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, asthenia. The following adverse reactions listed above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with VIREAD, Cmaxx and AUC of didanosine increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD. In patients weighing <60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). For additional information on coadministration of VIREAD and didanosine, please refer to the full Prescribing Information for didanosine.

HIV-1 Protease Inhibitors: VIREAD decreases the AUC and Cmin of atazanavir. Viread should not be coadministered with atazanavir without ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. Drugs Affecting Renal Function: Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (See Warnings and Precautions). In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with adefovir dipivoxil. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B:: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD. Geriatric Use: Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Impaired Renal Function: It is recommended that the dosing interval for VIREAD be modified in patients with estimated creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (See Dosage and Administration). For detailed information, please see full Prescribing Information. To learn more call 1-800-GILEAD-5 (1-800-445-3235) or visit www.VIREAD.com. COMPLERA, EMTRIVA, GSI, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Top 10 Stories of 2013 on GastroEndoNews.com 1.

Non-Celiac Gluten Sensitivity: Gastrointestinal Hip or Hype?

Food Allergy Explored in IBS

FDA Approves Delzicol for the Treatment of Ulcerative Colitis: Delzicol (Mesalamine) Capsules To Replace Asacol Tablets

By Brigid Duffy. Gastroenterology & Endoscopy News June 2013

Simeprevir Shines in Hep C Trial By David Wild. Gastroenterology & Endoscopy News July 2013

By Christina Frangou. Gastroenterology & Endoscopy News April 2013

Gastroenterology & Endoscopy News May 2013

Remission in IBD: The Pros and Cons of Discontinuing Treatment

IBS No Longer Only Functional Disorder

Approach to Hemorrhoids: A Primer for Gastroenterologists

By David Wild. Gastroenterology & Endoscopy News January 2013

By Monica J. Smith. Gastroenterology & Endoscopy News June 2013

Gastric Bypass Patients Often Relapse After Diabetes Remission By George Ochoa. Gastroenterology & Endoscopy News July 2013

New Colonoscope Offers Sweeping, 330-Degree Views of the Colon: Fuse Generates ‘Huge’ Interest at DDW Meeting By Audrey Andrews. Gastroenterology & Endoscopy News July 2013

By Harry Sarles Jr., MD. Gastroenterology & Endoscopy News January 2013

New in Colon Cancer Screening? 10. What’s The Latest in Imaging, Colonoscopes and Other Gadgets By Monica J. Smith. Gastroenterology & Endoscopy News March 2013

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BroadcastMed Soliciting Votes for Medical Video of the Year Digital medical broadcasting company, BroadcastMed, Inc., has created the “2013 Best of BroadcastMed” award to recognize the top online digital medical presentation created and posted in 2013. The medical community has been invited to review nine finalists and cast their votes for the best physician-directed learning initiative at bestof.BroadcastMed.com by Jan. 15, 2014. The winner will be announced on Jan. 20. The BroadcastMed.com digital library consists of 17 specialty-specific channels, including cardiology, gastroenterology, oncology and orthopedics, plus ORLive.com and more than 40 other affiliate channels. The award finalist in gastroenterology is “Ethical & Practical Issues in Organ Donation” from St. David’s HealthCare, in Texas. In this CME activity, Michael W. Rosson, RN, CPTC, discusses

ethical and practical issues in organ donation, federal regulations and Joint Commission standards. For every vote cast, BroadcastMed has promised to make a contribution to Doctors Without Borders, an international medical humanitarian organization that provides medical aid to people in need in more than 60 countries. “Through this initiative, we can leverage our position in the medical field to help those in need during this holiday season. At the same time, we’re able to provide expanded access to a broad range of trusted educational content physicians and professionals can use to positively impact the health and well-being of patients everywhere,” said Peter Gailey, president and co-founder, BroadcastMed. For more information, visit BroadcastMed.com.

Thank You for Reading! Based on a third-party readership audit performed by Kantar Media in December 2013, Gastroenterology & Endoscopy News ranks No. 1 in the following categories:

#1 in Total Readers #1 in Average Issue Readers #1 in Average Page Exposures Gastroenterology & Endoscopy News thanks each and every one of our readers for making us the best-read publication in the gastroenterology market! Our circulation, audited by BPA Worldwide, comprised more than 17,500 gastroenterology professionals as of July 2013, including: • 13,748 gastroenterologists • 1,588 colorectal surgeons • 1,059 pediatric gastroenterologists • 780 GI physician assistants • 210 GI nurse practitioners • 120 hepatologists We hope to continue to be your No. 1 source of gastroenterology information in 2014. Look for reader surveys coming to you over the next few months, where we hope you’ll share your feedback on how we can continue to provide you with the most relevant and useful information. Or, share your feedback with us right away: Send an email directly to the editor at cgordon@mcmahonmed.com today!

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

F D A U P D AT E & P R O D U C T N E W S May 3–6, 2014

Exhibit Dates: May 4–6, 2014 McCormick Place Chicago, ago, Illinois

Advisory Committee Recommends Approval of Investigational Biologic Vedolizumab for IBD On Dec. 9, an advisory committee to the FDA voted to recommend approval of vedolizumab for the treatment of adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). All 21 members of the committee voted to support approval of vedolizumab for UC, and 20 of 21 committee members voted to support approval for CD. The outcome of the advisory committee meeting is nonbinding and will be taken into consideration by the FDA when the agency makes its decision on the Biologics License Application (BLA) for vedolizumab, which was submitted by Takeda Pharmaceutical Company Limited in June 2013. “We are very pleased with the advisory committee’s recommendation,” said Asit Parikh, MD, PhD, vice president of general medicine at Takeda. “Many patients lose response to currently available treatments. Vedolizumab, … if approved, may offer an additional option for patients suffering from UC or CD.” During the advisory committee meeting, 13 members supported approval of vedolizumab for patients with UC who have failed to respond to treatment with steroids, immunosuppressants or tumor necrosis factor (TNF)-α antagonists, whereas eight committee members supported its approval for UC patients who have failed treatment with immunosuppressants or TNF-α antagonists, but not those who have failed to respond to steroids. Additionally, 14 committee members supported approval for patients with CD who have failed to respond to

treatment with steroids, immunosuppressants or TNF-α antagonists, whereas six supported its approval for CD patients who have failed immunosuppressants or TNF-α antagonists, but not for those who have failed to respond to treatment with steroids only. Vedolizumab is a humanized monoclonal antibody antagonist of α4β7 integrin. Vedolizumab inhibits binding of α4β7 integrin, which is expressed on a subset of circulating white blood cells, to intestinal mucosal addressin cell adhesion molecule 1, which is expressed in the blood vessels and lymph nodes of the gastrointestinal (GI) tract. This interaction plays a role in mediating the inflammatory process in UC and CD, and by inhibiting α4β7 integrin, vedolizumab may limit the ability of certain lymphocytes to infiltrate the GI tract. Vedolizumab has been studied in approximately 2,700 patients in nearly 40 countries, making this the largest Phase III clinical trial program conducted to date simultaneously evaluating both UC and CD patient populations, according to Takeda. The FDA requested feedback from its advisory committee on postmarketing risk mitigation strategies that might be needed to ensure the safety of vedolizumab. Takeda has said it plans to work with the FDA on an appropriate Risk Evaluation and Mitigation Strategy, known as REMS, for vedolizumab. For more information about vedolizumab, visit www.takeda. com.

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COLORECTAL CANCER:

The “Right” Perspective

Adenocarcinoma Detection and Prevalence in the Proximal Colon

Diagnoses of colorectal cancer (CRC) in the proximal (right) colon are recognized to be of increasing importance 1-3 • In a review of 9 population-based cancer registries of patients with CRC (N=243,861)1: — There was a relative increase of 18% in the proportion of right colon CRC cases from 1978 to 1998, while diagnoses in the left (distal) colon decreased1 • Right colon CRC is more common in the elderly,1,4,5 which is a growing percentage of the population6

Adenomas present special challenges in the right colon • “Endoscopically subtle” lesions* (Figure 17) are harder to detect and more common in the right colon8 • Cancers developing from serrated lesions are usually in the proximal region8 — Serrated adenocarcinoma represents up to 17.5% of most proximal CRCs (vs ≈7.5% of all CRCs)9 • Split-dose bowel preparations that improve cleansing may improve adenoma detection in the right colon8 — Ingestion of the second dose close to the time of colonoscopy clears mucus/chyme that tends to stick to the cecum/right colon8

Figure 1. Types of colorectal lesions* that are more difficult to detect7,8

*These include nonpolypoid (ﬂat, depressed) lesions and serrated lesions.8 Photographs shown to the left are from the cecum and were taken during a colonoscopy in a patient who had used a split-dose bowel preparation.7

Flat lesion

Serrated lesion

Importance of thorough adenoma detection during colonoscopy Adenoma detection rates (ADRs) ≥20% are signiﬁcantly associated with lower risk of interval colorectal cancer (Figure 2)10 Figure 2. Interval Colorectal Cancers Reported in a Colonoscopy-based Screening Program10*

Number of interval cancers†

35 33.6

30 25

*Results encompass the ﬁndings of 186 endoscopists in 45,026 patients. Each endoscopist had performed at least 30 screening examinations within the study period (October 2000– December 2004).

25.5 22.1

†Number of interval cancers/ 100,000 person-years of follow-up. A person-year represents one person at risk of development of CRC during a 1-year period.

15 10

‡ Proportion

2.4

5 0

<11%

11%-14.9% 15%-19.9% Adenoma detection rates‡

of subjects in whom at least one polyp was identiﬁed.

≥20%

Tracking ADR as a quality measure in colonoscopy will soon be required by law 11 Table. ACS/MSTF§ Colorectal Cancer Surveillance Guidelines12

Screening colonoscopy: adenoma ﬁndings

1-2 <1 cm tubular adenomas with low-grade dysplasia

3-10 adenomas; adenomas ≥1 cm; adenoma with villous features; high-grade dysplasia

>10 adenomas

Sessile adenomas removed piecemeal

Recommended timing of follow-up

5-10 years

3 years

<3 years; consider possibility of familial syndrome

2-6 months to verify complete removal

ACS, American Cancer Society; MSTF, Multi-Society Task Force on Colorectal Cancer.

References: 1. Rabeneck L, Davila JA, El-Serag HB. Is there a true “shift” to the right colon in the incidence of colorectal cancer? Am J Gastroenterol. 2003;98:14001409. 2. Kee F, Wilson RH, Gilliland R, et al. Changing site distribution of colorectal cancer. BMJ. 1992;305:158. 3. Cucino C, Buchner AM, Sonnenberg A. Continued rightward shift of colorectal cancer. Dis Colon Rectum. 2002;45:1035-1040. 4. Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57-64. 5. Strul H, Kariv R, Leshno M, et al. The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years. Am J Gastroenterol. 2006;101:255-262. 6. US Census Bureau. Unprecedented global aging examined in new Census Bureau report commissioned by the National Institute on Aging. http://www.census.gov/newsroom/releases/archives/aging_population/cb09-108.html. Published July 20, 2009. Accessed November 14, 2012. 7. Data on ﬁle. Braintree, MA; Braintree Laboratories, Inc.; 2012. 8. Lasisi F, Rex DK. Improving protection against proximal colon cancer by colonoscopy. Expert Rev Gastroenterol Hepatol. 2011;5:745-754. 9. Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology. 2007;50:131-150. 10. Kaminski MF, Regula J, Kraszewska E, et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. 2010;362:1795-1803. 11. GIQulC colonoscopy quality registry surpasses 100,000 cases: milestone underscores value of clinical benchmarking tool for gastroenterology practices [press release]. Bethesda, MD: American Society for Gastrointestinal Endoscopy. October 11, 2012. 12. Kaiser Family Foundation, American Cancer Society, National Colorectal Cancer Roundtable. Coverage of colonoscopies under the Affordable Care Act’s prevention beneﬁt. http://www.kff.org/healthreform/upload/8351.pdf. Published September 2012. Accessed November 12, 2012.

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May, 2013

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

FDA Approves Sovaldi as Part of First-Ever IFN-Free Treatment Regimen for Hepatitis C The FDA recently announced approval of sofosbuvir (Sovaldi, Gilead Sciences), a once-daily, oral nucleotide analog polymerase inhibitor, for the treatment of patients with chronic hepatitis C virus (HCV) infection. The drug is approved for use in combination with ribavirin for adults with HCV genotypes 2 or 3, and in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) for adults with HCV genotypes 1 or 4.

It may be used to treat patients with hepatocellular carcinoma awaiting liver transplantation to prevent HCV recurrence, and also in patients with HCV/HIV coinfection. Sofosbuvir is approved as part of a first-ever, all-oral treatment regimen for patients with HCV genotypes 2 or 3. The current standard of care for individuals with HCV infection involves up to 48 weeks of therapy with a PEGIFN/RBV–containing regimen.

Table. Recommended Regimen for Sofosbuvir Combination Therapy In Patients With HCV Infection or HCV/HIV-1 Coinfection HCV Genotype

Treatment Regimen

1 or 4

Sofosbuvir + PEG-IFN alfa + RBV 12

Sofosbuvir + RBV

HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin

“Today’s approval represents a significant shift in the treatment paradigm for some patients with chronic

Optimizing the Prevention and Management of Postsurgical Adhesions To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MN125” Release date: December 1, 2012

Chair

Jon Gould, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Faculty

Michael J. Rosen, MD Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

Statement of Need Adhesions are the most common complication of abdominopelvic surgery, developing postoperatively in 50% to 100% of all such interventions. They can lead to serious medical complications, substantial morbidity, high monetary costs, large surgical workloads, dangerous and difficult reoperations, and an increasing number of medicolegal claims. An official definition of the Sponsored by

Expiration date: September 1, 2014 condition has not been established, and an unequivocally effective prevention method has not been identified. A standardized classification for adhesion assessment and scoring also is lacking, as are guidelines for diagnosis and management. To close these gaps, clinician education is necessary.

Goal The goal of this educational activity is to provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation. 2 Summarize current strategies used to prevent postoperative adhesion formation. 3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Intended Audience The intended audience for this educational activity includes general surgeons, vascular surgeons, colon and rectal surgeons, critical care surgeons, surgical oncologists, trauma surgeons, and thoracic surgeons. Supported by an Educational Grant from

Duration of Therapy, wk

Estimated Time for Completion: 60 minutes Course Format Monograph (print and online)

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 the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

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Method of Participation There are no fees for participating in or receiving credit for this activity. To receive CME credit, participants should read the preamble and the monograph and complete the post-test and evaluation. A score of at least 70% is required to complete this activity successfully. Distributed via

hepatitis C,” said Edward Cox, MD, director of the Office of Antimicrobial Products, FDA Center for Drug Evaluation and Research, in a statement. “It is our hope that Sovaldi will mark the beginning of a new era in hepatitis C treatment,” said John C. Martin, PhD, chairman and CEO of Gilead Sciences, in a press release from the company. “Gilead is proud to have played a role in bringing about this important therapeutic advance.” Sofosbuvir is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme. Its approval came two weeks after the approval of simeprevir (Olysio, Janssen Therapeutics), an HCV NS3/4A protease inhibitor that is indicated for use in patients with HCV genotype 1 infection. Sofosbuvir’s approval primarily was based on data from four Phase III studies: NEUTRINO, FISSION, POSITRON and FUSION, which evaluated treatment with sofosbuvir, in combination with either RBV or RBV and PEG-IFN, for 12 or 16 weeks. Three of these studies evaluated sofosbuvir plus RBV in patients with HCV genotype 2 or 3 infection who were either treatment-naive (FISSION), treatment-experienced (FUSION) or PEG-IFN intolerant, ineligible or unwilling (POSITRON). NEUTRINO evaluated sofosbuvir in combination with RBV and PEG-IFN in treatmentnaive patients with HCV genotypes 1, 4, 5 or 6. In these studies, patients who received sofosbuvir achieved sustained virologic response (SVR) rates of 50% to 90% at week 12. Data from two additional Phase III studies of sofosbuvir showed that 84% of patients with HCV genotype 3 infection who were treated with sofosbuvir and RBV achieved SVR at week 12, and that patients with HCV genotypes 1, 2 or 3 who were coinfected with HIV-1 and treated with sofosbuvir and RBV achieved SVR rates of 76% to 92% at week 12 (VALENCE and PHOTON-1 studies, respectively). According to Gilead, nearly 3,000 patients to date have received at least one dose of sofosbuvir in Phase II or III clinical trials. Sofosbuvir was well tolerated; adverse events were see Sovaldi, page 47

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JANUARY 2014

Olysio, New Hepatitis C Therapy, Approved by FDA The FDA has approved a new protease inhibitor to treat adult patients with chronic hepatitis C virus (HCV) genotype 1 infection. Janssen Therapeutics’ Olysio (simeprevir) is approved for use in combination with pegylated interferon (PEG-IFN)-alfa and ribavirin for treatment-naive patients as well as patients for whom previous HCV antiviral therapies were ineffective. “Olysio is the third FDA-approved protease inhibitor to treat chronic HCV infection,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, in an FDA statement. “[It] provides health professionals and patients with a new, effective treatment for this serious disease.” In its approval, the FDA cited safety and efficacy data from more than 2,000 patients in several placebo-controlled clinical trials: QUEST-1 and QUEST-2, which included treatment-naive patients with compensated liver disease, and PROMISE, which included patients who relapsed or for whom earlier treatment with PEG-IFN had failed. All patients in these studies received PEG-IFN and ribavirin in combination with simeprevir or a placebo. In the QUEST trials, 80% of patients who were treated with simeprevir achieved sustained virologic response (SVR) compared with 50% of patients in the placebo group. Similarly, in the PROMISE study, 79% of patients in the treatment group achieved SVR compared with 37% of patients in the control group. Itching, nausea and skin rash were the most common adverse effects of treatment with simeprevir in clinical studies. The FDA also reported that some study participants who received simeprevir had

severe photosensitivity reactions that required hospitalization. Women who are pregnant or planning to become pregnant should avoid taking simeprevir, as it is associated with birth defects and fetal mortality. The efficacy of treatment with simeprevir in combination with PEGIFN and ribavirin is greatly reduced Olysio (simeprevir) is an HCV NS3/4A protease inhibitor approved for the treatment of chronic hepatitis C.

in patients with HCV genotype 1a who have the NS3 Q80K polymorphism. Physicians should screen for this polymorphism before initiating treatment with simeprevir. If the NS3 Q80K polymorphism is present, a different HCV therapy should be used. For more information, visit www. olysio.com. —Based on press releases from the FDA and Janssen Therapeutics

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Sovaldi continued from page 46

generally mild and resulted in few treatment discontinuations. The most common side effects reported in patients treated with sofosbuvir in combination with RBV were fatigue and headache. In patients treated with sofosbuvir, RBV and PEG-IFN, the most commonly reported side effects were fatigue, headache, nausea, insomnia and anemia. For more information, visit www. gilead.com. —Based on press releases from the FDA and Gilead Sciences

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Approach to Hemorrhoids A Primer for Gastroenterologists HARRY SARLES JR., MD Gastroenterologist Digestive Health Associates of Texas Dallas, Texas Disclosure—Dr. Sarles is a member of the advisory board of CRH Medical.

emorrhoids are normal vascular structures of the

anal canal. Often, they are the source of a variety of

troublesome symptoms, including bleeding, anal pruritus,

prolapse, and pain due to thrombosis of external hemorrhoids. Patients often mistake other anal or perianal problems for hemorrhoids, such as anal fissures, skin tags, hypertrophied anal papillae, anal cancer, and anal condylomata, as well as other infections. A good medical history and physical examination, including anoscopy or office proctoscopy, should guide the physician to the correct diagnosis; in cases of bleeding, a colonoscopy or sigmoidoscopy in addition to anoscopy is necessary to verify the source of the bleeding. It is the intent of this review to provide gastroentertologists with a general introduction to the nonsurgical management of hemorrhoids.

Anatomy Thomson, in his description of hemorrhoidal anatomy, noted a series of 3 cushions in the anal canal, located in the left lateral, right anterior, and right posterior positions. These hemorrhoidal cushions receive their blood supply primarily from the superior and middle hemorrhoidal arteries; the superior, middle, and inferior hemorrhoidal veins provide venous drainage. A sinusoidal pattern of arteriovenous communication is formed within the cushions, which explains why hemorrhoidal bleeding is arterial, rather than venous in nature.1 In addition to the vessels noted above, the hemorrhoidal cushions are also rich in muscular fibers, arising from the internal sphincter and the conjoined longitudinal muscle. These fibers help to anchor the cushions to the underlying muscular layer of the anorectum, and it is the breakdown of these supporting fibers that eventually leads to the changes that can cause hemorrhoidal symptoms.1,2 The cushions play an important role in the maintenance of rectal continence, as they provide 15% to 20% of the resting pressure at the anal verge.3

The epithelial layer of the anorectum is characterized by the relatively insensate columnar epithelium, which covers the internal hemorrhoidal cushions (mucosa) and the extremely sensitive squamous epithelium, which extends up into the anus (anoderm). The junction of these 2 epithelial layers is known as the dentate line, and is typically located approximately 3 cm inside the anal verge. This line marks the transition between the columnar epithelial–covered internal hemorrhoids and the squamous epithelial–covered external hemorrhoidal vessels.4-6

Pathophysiology There are a number of proposed mechanisms to explain the development of symptomatic hemorrhoids, including abnormal venous dilatation, abnormal distension of the arteriovenous anastomoses, downward displacement or prolapse of the hemorrhoidal tissue, or a breakdown of the connective tissue anchoring the hemorrhoidal cushions. Prolapse of hemorrhoidal tissue is what appears to lead to the development of symptoms. This prolapse allows for mucous deposition on the perianal skin, which causes itching, and leads to tissue friability and bleeding. Other symptoms include swelling of associated external disease and fecal soiling when the prolapsing tissue precludes complete closure of the anal opening.1,7 Internal hemorrhoids are covered by the mucosa; they reside proximal to the dentate line and are generally painless. External hemorrhoids are located distal

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to the dentate line and are covered by squamous epithelium; patients who experience pain as a result of hemorrhoids often have a thrombosed external hemorrhoid or an anal fissure. The causes of symptomatic hemorrhoids are not completely clear, but a number of factors, including lack of dietary fiber, constipation, straining on defecation, diarrhea, pregnancy, obesity, sedentary lifestyle, spending excess time on the commode, spinal cord injuries, and family history all have been suggested.8

Epidemiology It is difficult to quantify the incidence of hemorrhoidal disease, in large part because many patients do not seek medical care for their condition; additionally, some attribute almost any anorectal symptom to hemorrhoids. Estimates of the prevalence of hemorrhoidal disease in the United States range from 4.4% to 40%.9 Some research suggests that 75% of the population will experience symptomatic hemorrhoid disease at some point in their lives.10 Although these estimates vary widely, it seems clear that symptomatic hemorrhoids have a significant effect on health and well-being.

Grading of Hemorrhoidal Disease Banov et al11 developed a grading system for internal hemorrhoids based on the degree of prolapse. The grade of hemorrhoidal disease has some bearing on the treatment options available to a patient with internal hemorrhoids: • grade I: non-prolapsing internal hemorrhoids • grade II: prolapse of internal hemorrhoids during defecation with spontaneous reduction • grade III: prolapse of internal hemorrhoids during defecation that requires manual reduction • grade IV: prolapse and incarceration of internal hemorrhoids; hemorrhoids cannot be reduced

Diagnosis PATIENT HISTORY As previously stated, patients often attribute any anorectal symptom to hemorrhoidal disease, and although this may partly explain symptoms, it is important for the physician to determine whether there are other issues involved as well.5,12 Internal hemorrhoids are associated with painless bleeding, prolapse, mucus discharge, soiling, and symptoms of pruritus ani; these symptoms rarely cause significant pain. External hemorrhoids usually are asymptomatic, unless they become thrombosed. Pain with defecation is commonly due to the presence of an anal fissure, which is found in up to 20% of patients with hemorrhoids.13 The relationship between symptoms, defecation habits, bleeding, and a description of factors that might relieve or exacerbate a patient’s symptoms are important to consider in the medical history.

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PHYSICAL EXAMINATION A visual inspection of the perianal area will allow for the discovery and description of rashes, tags, fissures, fistulae, abscesses, neoplasms, condylomata, some cases of prolapse, and so forth. The left lateral decubitus position is preferred for the examination, as this position seems to be better tolerated than the prone, “jack-knife” position.14 A digital rectal examination will identify such things as scars, small fissures, and origins of fistulae. These clinical findings will be important in formulating a comprehensive treatment plan for the symptomatic patient.15

ENDOSCOPIC EXAMINATION Anoscopy is an accurate, efficient, inexpensive way to evaluate the anal canal quickly, with minimal discomfort to the patient. Flexible endoscopy frequently is performed to evaluate patients with symptoms of hemorrhoids, however, it is not as accurate as anoscopy. A prospective study showed that anoscopy revealed 99% of anorectal lesions, whereas endoscopy revealed 78% when performed with straight withdrawal of the endoscope, and 54% with retroflexion.16 The limitations of flexible endoscopy, along with increased cost and inconvenience to the patient, stress the need to consider anoscopy in the evaluation of hemorrhoidal disease.

Treatment CONSERVATIVE MEDICAL TREATMENT There are a number of over-the-counter preparations intended to treat patients with symptomatic hemorrhoids. These compounds contain ingredients such as antiseptics, astringents, topical anesthetics, and corticosteroids. There is not a lot of evidence to support the use of many of these products, and the potential negative effects of the long-term use of topical steroids should be considered.17 Common dietary and behavioral recommendations for patients with hemorrhoids include increasing the intake of dietary fiber, minimizing the amount of time spent on the commode, avoiding straining during defecation, and taking sitz baths several times a day. There is evidence to support these recommendations both for the treatment of symptomatic disease and in limiting the risk for recurrence.18 These measures are a reasonable first-line approach for patients with mild symptoms.

NONSURGICAL TREATMENT Sclerotherapy Sclerotherapy uses the injection of a sclerosant into the submucosa, beneath the hemorrhoid, to create an inflammatory reaction in the soft tissue that affixes the loose hemorrhoidal mucosa back to the underlying musculature. The procedure dates back to the 1800s. Some research shows sclerotherapy to be beneficial in patients with grade I and II hemorrhoids,19 whereas other research shows it to be no more beneficial than bulk laxatives.20 Potential complications of sclerotherapy include pain,

urinary retention, abscess, and impotence. Avoidance of these complications depends on precise placement of the injection.21 Rubber Band Ligation Rubber band ligation (RBL) is the most commonly performed nonsurgical procedure used in the treatment of hemorrhoids; it is performed in up to 80% of patients with hemorrhoids.22,23 Blaisdell first described a ligation technique using a silk suture in 1958,24 with Barron beginning to use rubber bands in 1963.25 Barron treated one column of hemorrhoids per session to minimize pain and post-banding complications. The process causes the banded tissue to necrose and slough, with the resultant inflammatory reaction causing refixation of the mucosa to the underlying tissue, eliminating hemorrhoidal prolapse. This mechanism of action is common among the nonsurgical treatments for hemorrhoids, stressing the importance of hemorrhoidal prolapse in the etiology of symptoms. RBL is a simple, inexpensive procedure, effective for grade I to III hemorrhoids.2 Patients undergoing RBL typically do not require bowel preparation, sedation, narcotics, or a significant recovery period; they are able to return to work immediately.5 One of the disadvantages of earlier RBL procedures was the need for 2 operators to perform the procedure, but this has since been overcome with the development of single-use, disposable devices that do not require an assistant.6,7 RBL leads to reconfiguration and reduction in the size of hemorrhoidal cushions, resulting in symptom resolution. Short-term success rates of up to 99% and longterm success rates of up to 80% have been described; however, there is a large range in the reported incidence of complications. The predominant issue in patients undergoing RBL is significant pain, with the incidence rates ranging from less than 1% to 50%, in some series.6,26 Other reported complications include bleeding, urinary retention, vasovagal reactions, and the very rare complication of sepsis. Based on the literature, the incidence of complications appears to be related to the techniques that are used to perform the banding. Endoscopic RBL has been shown to have excellent results, although the method is more expensive than the others and requires patient preparation as well as anesthesia.27 Endoscopic RBL also has been reported to be more painful than other banding techniques.28 Other common techniques use an anoscope to gain access to the hemorrhoids. There also is a procedure that allows for a “blind” placement of the band, obviating the need for an anoscope. The literature is confusing when it comes to where the band should be placed, as descriptions vary from “a few millimeters” above the dentate line29 to “at least 2 cm proximal” to the dentate line.30,31 I prefer a technique that involves placing the band at least 2 cm above the dentate line, as this technique has been associated with less pain.6 Controversy exists regarding the number of

hemorrhoids to treat during a single session. In the time since Barron’s original work was published,25 most researchers have recommended treating only one column of hemorrhoids per session in order to minimize the rate of complications. Other authors have suggested banding 2 or more columns per session in order to minimize the number of patient visits required; however, complication rates are higher when more bands are placed.32 I recommend banding a single hemorrhoid per session. Endoscopic band placement is effective but is more costly and is associated with higher rates of post-procedural pain compared with in-office band placement.24,33 Personally, I prefer the blind “touch” technique described by Cleator and Cleator.6 This technique allows placement of the band without an anoscope at 2 cm above the dentate line. Using this technique, the researchers demonstrated a 1% complication rate (primarily pain) and successful treatment of up to 99% of patients, with a recurrence rate of 5% at 2 years.5 Infrared Coagulation Neiger first described infrared coagulation (IRC) in 1979.34 The infrared coagulator is placed through an anoscope while infrared light is converted to heat in the hemorrhoidal tissue. The heat produces tissue destruction, protein coagulation, and inflammation, leading to scarring and tissue fixation. During the procedure, 3 to 4 pulses of energy are applied to the mucosa at the apex of the hemorrhoid, and 1 to 2 columns of hemorrhoids are treated at a time. Treatment is repeated every 2 to 4 weeks.24 Advantages of IRC include a relative lack of significant complications. Disadvantages include equipment costs, the need for repeated treatments, higher recurrence rates, and ineffectiveness in patients with more advanced disease.24,34 Direct Current Electrotherapy Direct current electrotherapy also uses a device that is inserted through an anoscope (Ultroid, Ultroid Technologies, Inc).35 This procedure uses direct current and rather than creating heat, it produces sodium hydroxide, creating the submucosal reaction that leads to scarring, which helps eliminate hemorrhoidal prolapse.7 Limitations of direct current electrotherapy include cost of the technology and amount of time required to treat the involved tissue. The length of the procedure depends on the grade of hemorrhoidal disease and the amount of current that the patient can tolerate, which ranges from 4:45 to 19:45.35 The procedure has been reported to cause significant pain in up to 20% of patients, resulting in termination of therapy; 16% of patients have prolonged post-procedural pain.36 Bipolar Diathermy and “Heater Probe” Coagulation These technologies may be used by way of anoscopy in order to control chronic hemorrhoidal symptoms. Both procedures generate heat, which causes coagulation of the target tissue leading to a fibrotic reaction with fixation of the treated tissue.32 The procedures have similar efficacy for the treatment

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of bleeding. In one study, the heater probe controlled the bleeding more quickly (76.5 vs 120.5 days) at the expense of more pain.37 The bipolar technology was associated with a higher overall rate of complications (11.9% vs 5.1%), including pain, bleeding, fissure formation, and spasm of the internal sphincter. Another study demonstrated symptomatic mucosal ulceration in 24% of patients treated with bipolar electrocoagulation, significant bleeding in 8%, and prolonged pain in 4%.36 Neither technology was able to reliably eliminate prolapsing tissue.29,36,37 Cryosurgery and Lord’s Stretch Procedure These techniques are mentioned for historical reference only, as neither is recommended. Cryosurgery is associated with significant post-procedure pain, along with foul-smelling discharge and prolonged recovery in several series.36 The “Lord’s Stretch,” a forceful dilatation of the anus in order to reduce elevated sphincter pressures was found to result in incontinence in a significant number of patients.38 Some have recommended that the procedure be abandoned.39

SURGICAL TREATMENT OPTIONS This review is intended to discuss nonsurgical options available for the treatment of symptomatic hemorrhoidal disease, and these approaches have proven effective in 80% to 99% of patients. A number of surgical options are available as well, but because of increased cost, pain, disability, recuperation time, risk for complications, and so on, surgical options should be reserved only for nonresponders and for patients with grade IV hemorrhoids or hemorrhoids with both internal and external components.40

Conclusions Symptomatic hemorrhoids are common and patients frequently visit a gastroenterologist for diagnosis and treatment. A number of effective nonsurgical approaches are available for these patients. RBL is the most commonly used office-based hemorrhoidal therapy. Information is presented here to aid the gastroenterologist in the evaluation and definitive treatment of patients with hemorrhoidal disease.

References 1. 2. 3.

5. 6. 7. 8.

Thomson WH. The nature of haemorrhoids. Br J Surg. 1975;62(7):542-552. Sardinha TC, Corman ML. Hemorrhoids. Surg Clin North Am. 2002; 82(6):1153-1167, vi. Lestar B, Penninckx F, Kerremans R. The composition of anal basal pressure. An in vivo and in vitro study in man. Int J Colorectal Dis. 1989;4(2):118-122. Wexner SD, Jorge JMN. Anatomy and embryology of the anus, rectum, and colon. In: Corman ML, ed. Colon and rectal surgery. 4th ed. Philadelphia, PA: Lippincott-Raven; 1998. Guttenplan M, Ganz RA. Hemorrhoids—office management and review for gastroenterologists. Touchgastroentorology.com; December 2011. Cleator IGM, Cleator MM. Banding hemorrhoids using the O’Regan disposable bander. US Gastroenterology Review. 2005:69-73. Corman ML. Hemorrhoids. In: Corman ML, ed. Colon and rectal surgery. 4th ed. Philadelphia, PA: Lippincott-Raven; 1998:147-205. Loder PB, Kamm MA, Nicholls RJ, Phillips RK. Haemorrhoids: pathology, pathophysiology and aetiology. Br J Surg. 1994;81(7):946-954.

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9. Ohning GV, Machicado GA, Jensen DM. Definitive therapy for internal hemorrhoids—new opportunities and options. Rev Gastroenterol Disord. 2009;9(1):16-26. 10. Baker H. Hemorrhoids. In: Longe JL, ed. Gale encyclopedia of medicine. 3rd ed. Detroit: Gale; 2006:1766-1769. 11. Banov L Jr, Knoepp LF Jr, Erdman LH, Alia RT. Management of hemorrhoidal disease. J S C Med Assoc. 1985;81(7):398-401. 12. Halverson A. Hemorrhoids. Clin Colon Rectal Surg. 2007;20(2):77-85. 13. Schubert MC, Sridhar S, Schade RR, Wexner SD. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009;15(26):3201-3209. 14. Alonso-Coello P, Castillejo MM. Office evaluation and treatment of hemorrhoids. J Fam Pract. 2003;52(5):366-374. 15. Beck DE. Evaluation of the anorectum during endoscopic examinations. Tech Gastro Endoscopy. 2004;6:2-5. 16. Kelly SM, Sanowski RA, Foutch PG, Bellapravalu S, Haynes WC. A prospective comparison of anoscopy and fiberendoscopy in detecting anal lesions. J Clin Gastroenterol. 1986;8(6):658-660. 17. Chong PS, Bartolo DC. Hemorrhoids and fissure in ano. Gastroenterol Clin North Am. 2008;37(3):627-644, ix. 18. Moesgaard F, Nielsen ML, Hansen JB, Knudsen JT. High-fiber diet reduces bleeding and pain in patients with hemorrhoids: a double-blind trial of Vi-Siblin. Dis Colon Rectum. 1982;25(5):454-456. 19. Khoury GA, Lake SP, Lewis MC, Lewis AA. A randomized trial to compare single with multiple phenol injection treatment for haemorrhoids. Br J Surg. 1985;72(9):741-742. 20. Senapati A, Nicholls RJ. A randomised trial to compare the results of injection sclerotherapy with a bulk laxative alone in the treatment of bleeding haemorrhoids. Int J Colorectal Dis. 1988;3(2):124-126. 21. Pilkington SA, Bateman AC, Wombwell S, Miller R. Anatomical basis for impotence following haemorrhoid sclerotherapy. Ann R Coll Surg Engl. 2000;82(5):303-306. 22. Kann BR, Whitlow CB. Hemorrhoids: diagnosis and management. Tech Gastro Endoscopy. 2004;6(1):6-11. 23. Corman ML, Veidenheimer MC. The new hemorrhoidectomy. Surg Clin North Am. 1973;53(2):417-422. 24. Blaisdell PC. Prevention of massive hemorrhage secondary to hemorrhoidectomy. Surg Gynecol Obstet. 1958;106(4):485-488. 25. Barron J. Office ligation of internal hemorrhoids. Am J Surg. 1963; 105:563-570. 26. Kumar N, Paulvannan S, Billings PJ. Rubber band ligation of haemorrhoids in the out-patient clinic. Ann R Coll Surg Engl. 2002;84(3):172-174. 27. Jutabha R, Jensen DM, Chavalitdhamrong D. Randomized prospective study of endoscopic rubber band ligation compared with bipolar coagulation for chronically bleeding internal hemorrhoids. Am J Gastroenterol. 2009;104(8):2057-2064. 28. Cazemier M, Felt-Bersma RJ, Cuesta MA, Mulder CJ. Elastic band ligation of hemorrhoids: flexible gastroscope or rigid proctoscope? World J Gastroenterol. 2007;13(4):585-587. 29. Daram SR, Lahr C, Tang SJ. Anorectal bleeding: etiology, evaluation and management (with videos). Gastrointest Endosc. 2012:76(2):406-417. 30. Madoff RD, Fleshman JW, Clinical Practice Committee, American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology. 2004;126(5):1463-1473. 31. Kaidar-Person O, Person B, Wexner S. Hemorrhoidal disease: a comprehensive review. J Am Coll Surg. 2007;204(1):102-117. 32. Lee HH, Spencer RJ, Beart RW Jr. Multiple hemorrhoidal bandings in a single session. Dis Colon Rectum. 1994;37(1):37-41. 33. Cataldo P, Ellis CN, Gregorcyk S, et al. Practice parameters for the management of hemorrhoids (revised). Dis Colon Rectum. 2005;48(2)189-194. 34. Neiger S. Hemorrhoids in everyday practice. Proctology. 1979;2:22-28. 35. Ultroid® Model 3053 Operating & Maintenance Manual. Ultroid Technologies, Inc., Rev 10.5.2010a:17. 36. Yang R, Migikovsky B, Peicher J, Laine L. Randomized, prospective trial of direct current versus bipolar electrocoagulation for bleeding internal hemorrhoids. Gastrointest Endosc. 1993;39(6):766-769. 37. Jensen DM, Jutabha R, Machicado GA, et al. Prospective randomized comparative study of bipolar electrocoagulation versus heater probe for treatment of chronically bleeding internal hemorrhoids. Gastrointest Endosc. 1997;46(5):435-443. 38. Lord PH. A new regime for the treatment of haemorrhoids. Proc R Soc Med. 1968;61(9):935-936. 39. The Standards Task Force. Practice parameters for the treatment of hemorrhoids. Dis Colon Rectum. 1990;33(11):992-993. 40. MacRae HM, McLeod RS. Comparison of hemorrhoidal treatments: a meta-analysis. Can J Surg. 1997;40(1):14-17.