October 2013

1978 —

P AC lease AA G b Vis i SL oo D b th t Us! # oo 10 0 th #4 9 41

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 10 • October 2013

Deep Sequencing of Microbiome in IBS Findings Support SIBO

Is It Time To Rethink CRC Screening?

Experts Make a Case for More Nuanced Risk Assessment

BY CAROLINE HELWICK

BY CAROLINE HELWICK ORLANDO, FLA.—In what appears to be the first largescale, deep sequencing of the duodenal microbiome of patients with irritable bowel syndrome (IBS), researchers have observed dramatic differences between patients with IBS and healthy controls, said Mark Pimentel, MD, see IBS Microbiome, page 10

FDA Flips on FMT

ORLANDO, FLA.—With — health care resources dwindling and the population aging, is it time for a more evidence-based, individualized approach to colorectal cancer (CRC) screening in the general population?

A strong case was made in a number of presentations at the 2013 Digestive Disease Week (DDW) meeting.

Why Risk-Based Screening?

After stating that the use of fecal microbiota transplantation (FMT) to treat Clostridium difficile infection would require an Investigational New Drug Application (IND), the FDA reversed course after a public outcry

Thomas Imperiale, MD, of Indiana University School of Medicine, Indianapolis, told DDW attendees that although CRC screening in average-risk individuals reduces CRC-related morbidity and mortality, it is inefficient and expensive. In a session dedicated to the topic, he pointed out that although many individuals at low risk for CRC are screened unnecessarily, many highrisk individuals are never examined.

A more tailored approach to CRC screening would adjust the intensity of screening

see FMT, page 4

see CRC Screening, page 25

Agency Swayed By Pleas From Doctors, Patients

BY GEORGE OCHOA

I N S I D E

AGA Asks: Are You Choosing Wisely?

HEPATOLOGY

I N

FOCUS

EXPER EXPERTS’ PICKS Best of Hepatology: A Survey of Recently Published Studies

Overutilization of Colonoscopy, CT Scans Questioned

........................................................................................ page 16

BY CAROLINE HELWICK The American Gastroenterological Association (AGA) and 24 other specialty societies have affirmed their commitment to quality care by partnering with the American Board of Internal Medicine Foundation’s Choosing WiselyŽ campaign, an initiative designed to engage physicians and patients in conversations

Jacqueline O’Leary, MD, MPH

Zobair Younossi, MD, MPH

see Choosing Wisely, page 30 ADVERTISEMENT

Corporate Spotlight Sandhill Scientific Inc see page 13

Sandhill Scientific Inc

13

Corporate Spotlight

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Innovation matters.

Parameters That Define a Successful Colonoscopy

Such has been the creed of Sandhill Scientific Inc, for the past 33 years, as a leading developer, manufacturer and marketer of gastrointestinal (GI) diagnostic devices. Initiating the business as the first U.S. supplier of ambulatory reflux monitoring and esophageal manometry systems, the innovative focus continues today, with a perpetual drive to deliver tomorrow’s leading-edge technologies.

Based in Highlands Ranch, Colo., Sandhill Scientific leverages the significant benefits of private employee ownership.

Sandhill employees take pride in their company because they own their company. From these entrepreneurial roots springs a focus on delivering products and services that optimally fulfill customer needs.

In our corporate office, Sandhill employs approximately 45 people, who are involved in sales, clinical education, technical support, engineering, quality control, finance and manufacturing. Sandhill’s consumable catheter manufacturing facility in Ho Chi Minh City, Vietnam, employs approximately 75 people. A worldwide distribution system markets and supplies Sandhill products in the United States and more than 55 countries.

Innovative Products As the first developer of impedance/pH reflux monitoring technologies, Sandhill is the worldwide leader in total reflux monitoring devices. Today’s state-of-the-art ZepHrŽ Impedance/pH Reflux Monitoring System, coupled with BioVIEWŽ analysis software and ComforTECŽ reflux monitoring catheters, sets the standard for usability, accuracy and clinical utility.

In the field of esophageal function testing, Sandhill created the world’s first combined impedance/manometry system for concurrent assessment of peristalsis and bolus transit. Today, high-resolution impedance manometry testing is the gold standard for assessment of esophageal and pharyngeal swallowing. With the recent introduction of the inSIGHT Ultima™ motility inSIGHT Ultima™ platform, procedure-specific diagnostic modules can be added to expand system functionality to anorectal manometry, anorectal biofeedback, sphincter of Oddi manometry and small bowel/colonic manometry.

Marking yet another technology innovation, Sandhill recently partnered with EchoSens, a French manufacturer, to become the exclusive U.S. distributor of the FibroScanŽ 502 Touch (www. fibroscan502touch.com), a noninvasive liver stiffness diagnostic system. The FibroScanŽ 502 Touch was cleared by the FDA in April 2013, and is being adopted widely in the hepatology and gastroenterology fields for both clinical and research applications. Based on the patented Vibration-Controlled Transient Elastography (VCTE™) technology, FibroScanŽ 502 Touch assesses shear wave speed in the liver (expressed in meters per second) and equivalent stiffness (expressed in kilopascals) in a simple, fast and noninvasive painless test. The FibroScanŽ 502 Touch is indicated for noninvasive measurement of shear wave

David A. Johnson, MD Professor of Medicine Chief of Gastroenterology Eastern Virginia Medical School Norfolk, Virginia

speed at 50 Hz in the liver, which is used to aid in the clinical management of patients with liver disease. FibroScanÂŽ has been validated in more than 700 peer-reviewed publications.

Moreover, the use of FibroScanÂŽ also is mentioned in international guidelines, including recommendations from the World Health Organization, the European Association for the Study of the Liver, the United Kingdom National Institute of Clinical Excellence, and the Asian FibroScanÂŽ Pacific Association for the Study of 502 Touch the Liver.

Introduction

Sandhill University In addition to product development, manufacturing and worldwide marketing, Sandhill places significant emphasis on clinician education. Under the banner of the industry-leading Sandhill University, comprehensive training and education programs are offered, covering the complete spectrum of the clinician’s needs. Hands-on clinical training courses are offered monthly at Sandhill’s headquarters in Colorado, where physicians and nurses are provided training in clinical applications and product operations.

A three-day, comprehensive esophageal course covers the areas of reflux monitoring and swallowing function testing. Two-day comprehensive anorectal manometry courses also are available.

The “Denver Course� is supplemented with a series of workshops held in major cities across the United States, Canada, Latin America, Europe and the Middle East. Sandhill University also provides web-based cybercoaching, allowing clinicians from around the world to review studies with a Sandhill clinical application expert.

Focus on the Future Perpetually focused on creating “what’s next,� Sandhill conducts product development research with clinical thought leaders around the world. As validated by more than 30 years of product innovation and 250 peer-reviewed publications, the Sandhill development team plays a key role in the evolution and utilization of endoscopic GI diagnostics.

Address Sandhill Scientific Inc 9150 Commerce Center Circle, No. 500 Highlands Ranch, CO 80129 Phone (800) 468-4556 (303) 470-7020 Fax (303) 470-2975 Web www.sandhillsci.com

Parameters That Define a Successful Colonoscopy

When used properly, colonoscopy is the most powerful strategy for the primary and secondary prevention of colorectal cancer (CRC). However, the efficacy and safety of this procedure is dependent on a variety of factors, including operator skill and experience, quality of examination, achievement of goal-directed end points, compliance with guideline recommendations, and multiple technical aspects regarding patient preparation for the procedure and the procedure itself.

As with other areas of clinical medicine, currently there is a concerted shift to define the critical aspects of quality delivery of colonoscopy in an effort to increase the related utility and optimize the effect, while simultaneously limiting unnecessary health care expenditures and patient risk. Future colonoscopy quality regulations may cause confusion among endoscopists, particularly long-practicing clinicians or those practicing individually outside of a hospital system.

Thus, standardizing the process for illustrating how value-based care is delivered and core capabilities are demonstrated may be beneficial for these practitioners.

Current Problems With Colonoscopy Quality Although removal of premalignant lesions via colonoscopy is the single most

effective strategy to prevent the development of CRC, a reported and notable percentage of patients who undergo screening colonoscopy still develop interval CRCs —a concept known as “incomplete protection.�

This deficiency is likely related to several different factors. Indeed, there is considerable evidence of variability among the type or defined quality of the endoscopists in terms of the technical performance of colonoscopy, thereby resulting in a suboptimal adenoma detection rate (ADR).4 This may be due to failure to achieve cecal intubation or rapid withdrawal, both of which may result in missed lesions or incomplete polypectomy.5 Proximal serrated lesions are responsible for a significant proportion of CRCs after the use of colonoscopy,6 but inadequate education and training in the recognition and pathophysiologic significance of such lesions also plays a likely role in suboptimal outcomes.6-8 The quality of bowel preparation has a major effect on the ability to perform a complete examination and on the duration of the procedure. Inadequate bowel preparation quality (defined as ability to exclude polyps smaller than 6 mm) occurs in approxJNBUFMZ PG DBTFT 9 Because inadequate bowel preparation quality can result in the need to cancel/reschedule procedures or change screening/surveillance recommendations for repeat examination, this is a major contributor to impairment of qualityrelated outcomes as well as to consequent related increased health care costs.

Finally, despite strong evidence suggesting that using appropriate screening and surveillance intervals results in improved patient outcomes and reduced costs, more UIBO PG BMM DPMPOPTDPQJFT QFSGPSNFE BSF in noncompliance with these recommended intervals. Clearly, this percentage should

Table 1. Quality Indicators for Colonoscopy Current ADR Appropriate use of surveillance/screening intervals Cecal intubation rates

Future Adequacy of bowel preparation Adequacy of polypectomy

Rate of interval cancers Rate of lost specimens Rate of surgical referrals Recognition of sessile serrated lesions

16

Current and Future Quality Measures The potential variability in endoscopists’ performance suggests that objective measures are needed to improve the quality of this procedure. Currently, widely accepted and often used quality measures include ADR, cecal intubation rates, and compliance with recommended screening and surWFJMMBODF JOUFSWBMT 5BCMF 5

0G UIFTF "%3 is probably the most widely used and studied, with clinical practice guidelines defining quality endoscopy as an ADR in a screening QPQVMBUJPO DPIPSU PG BU MFBTU JO NFO BOE BU MFBTU JO XPNFO These measures already are being used within voluntary central registries that are designed to

("4530&/5&30-0(: &/%04$01: /&84 t 0$50#&3

track colonoscopy quality to identify providers and programs that would benefit from specific quality improvement training.

However, medical societies already are looking beyond these established measures toward the next iteration of quality end points. For example, experts have noted that multiple (rather than solitary) adenomas usually are present in the colon and that an endoscopist who finds one adenoma per colonoscopy receives the same ADR quality assessment as another endoscopist who finds multiple adenomas. Because every adenoma carries some risk for malignancy, JU JT MJLFMZ UIBU UIFTF FOEPTDPQJTUT QSPWJEF different levels of CRC protection, although they receive an equal quality assessment via the ADR metric. Therefore, investigators have advanced the concept of tracking the “AD “ R-plus� rate—defined as the detection of more than one adenoma per colonoscopy—as a measure of quality.

Wang and colleagues demonstrated how the use of the ADR-plus rate could further differentiate quality performance among endoscopists who had the same conventional ADR score (Figure).

The recognition and management of sessile serrated lesions such as sessile serrated adenomas also is likely to emerge as an indicator of quality of colonoscopy. Such lesions tend to appear flat or depressed and covered

“ ll or None� “A

“Optimal�

“None and Done�

“One and Done�

TTeaching Non-T -Teaching

ADR-plus (rate of detection of multiple adenomas within one colonoscopy) Periprocedural management of antiplatelet and anticoagulant drugs

ADR, adenoma detection rate

see pages 14-15

be placed in context and on occasion, diverging from following guidelines should be individualized by the best recommendations of the clinician based on an individual patient. Nevertheless, guideline recommendations should be the overarching perspective and plan in general. Noncompliance with evidence-based guideline recommendations may result in overutilization, thereby increasing costs and needless risk for adverse events, or paradoxically to the underuse of colonoscopies, which results in the potential for missed cancers, which may be preventable lesions.

ADR-plus, mean beyond 1

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

ADR, %

Figure. Use of the ADR-plus rate to further differentiate quality performance among endoscopists with the same ADR score.

There is a wide distribution of endoscopists within the optimal, one and done, none and done, and all or none DBUFHPSJFT &OEPTDPQJTUT NFFUJOH UIF 64 .VMUJ 4PDJFUZ $3$ 5BTL 'PSDF 5 "%3 $SJUFSJPO GPS NFO DBO TUJMM vary widely in terms of total adenomas detected, here measured with ADR-plus, a metric independent of the ADR. The size of the circle reflects the total number of procedures performed by the endoscopist.

ADR, adenoma detection rate 3FQSJOUFE XJUI QFSNJTTJPO GSPN SFGFSFODF

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere.

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35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

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 Sttrategies 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

T

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

b

c

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

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

1

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

3

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

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OPINION

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

7

Nicholas V. Costrini MD, PhD, MBA Gastroenterologist in solo practice Georgia Gastroenterology Group, PC Savannah, Georgia

After reigning over the earth for more than 250 million years, it all came to an end 65 million years ago. The dinosaur was done, and many offer that an asteroid struck the Yucatan Peninsula causing immediate and longterm environmental changes that left only the lonely bird as an evolutionary footnote and paleontologic reminder of the dinosaur’s existence. Although the Yucatan disaster indeed may have been the final catastrophic extinction event, other ecologic forces were at play and also may have contributed to the demise of the dinosaur. Coconspirators in the probable 1 million-year pre-Yucatan dinosaur decline include the increasing mammal population; continental drift; decreasing sea levels; and volcanic eruption, resulting in blockage of sunlight. Researchers are not exactly sure what ended the dinosaur reign—it was probably a combination of events.

Interesting, but what does this have to do with the future of private practice gastroenterology?

Over the next several decades, the private practice of medicine, and more specifically, the high-volume, highreimbursement subspecialty private practices, such as gastroenterology, will be like the lonely bird. They will be present, but mostly will be a reminder of a medical and sociologic past and no longer will dominate medical care. Numerous factors will contribute to the future of how medical care will be delivered. As in the natural world, these factors should not be judged as good or bad, but rather as evolutionary events that, in their totality, will change the nature of things, namely medical care. If mammals replaced the dinosaur as the higher life form, we can hope that the evolution of medical care will offer a better form of health care than currently exists.

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.

Dear Dr. Costrini,

Dr. Costrini, I just read your article in Gastroenterology & Endoscopy News. I want to compliment you on the beautifully written article. I am part of a large gastroenterology private practice, and have no plans to merge with hospital systems. I therefore agree with some, and

-/," / ," " 9ÊEÊ "- "*9Ê 7-ÊUÊ 1 1-/ÊÓä£Î

Private Practice Is a Dinosaur and the ACA Is an Asteroid

Dinosaurs Not Dead Yet!

I read your opinion in Gastroenterology & Endoscopy Newss about the imminent demise of gastroenterology private practice. It was beautifully written and was very insightful. I am three years out of my gastroenterology fellowship, and so I guess I am of the millennial generation! I could easily relate to, and completely agree with, your opinion on the changing priorities in our lives, and also the fact that the change is, in many ways, inevitable.

I just wanted to thank you for reminding all of us to appreciate our interaction with our fellow beings, and wish you the very best!

Sincerely, A young ground-dweller in awe of the bird soaring high!

Mohit Jindal, MD Gastroenterologist, large, multi-specialty group practice Terre Haute, Indiana

OPINION

disagree with other, aspects of your article, but overall I was very impressed with the way it was written. It is rare to read an article in the medical literature where the literary aspect is as good as its content.

Congratulations!

The Decline of Private Practice Although many consider the Patient Protection and Affordable Care Act (ACA) as the primary threat to the existence of private gastroenterology practice, I offer that it is an important, but not the only, cause of the decline of the private health care sector. In fact, the ACA became possible only as a result of the antecedent conspirators against private medical practice.

The first of these factors is the disposition of the modern workforce. Private practice is a self-driven, work ethic– dependent, professional-life priority venture. It represents the ethics, values and priorities of traditional American life. The sociologic and personal credo of making success, work and achievement the highest priority, with family, personal life, rest, balance and quality of life following that lead, has been challenged by the millennial generation. Any human resource executive, practice manager or division chief will tell you this. Millennials are smart, fast, eager, group-oriented and most importantly, place the highest priority on quality of life and balance of personal and work arenas. The new generation of physicians has no desire to accept the challenges, workload, fatigue and emotional stress of private medical practice. The demands of private practice, independent of financial considerations, do not match their view of the role of work in their lives.

Over the past decade, the percentage of graduating, subspecialty physicians seeking or accepting positions in solo or small private practices has dwindled to single digits, and

Ravi Ravinuthala, MD, MRCP (UK) Director, Liver Clinic at Ohio GI Medical Director, Mercy Health Liver Center Associate Professor of Medicine Division of Gastroenterology University of Kentucky and University of Cincinnati Cincinnati, Ohio

Over the next several decades, the private practice of medicine, and more specifically, the high-volume, high-reimbursement subspecialty private practices, such as gastroenterology, will be present, but mostly will be a reminder of a medical and sociologic past and no longer will dominate medical care. the ACA has not yet been minimally implemented. The millennial generation is a major factor that is reducing the viability of the private practice future.

Second, there are shifting demographics. The United States has come to the economic brink of disaster with the rising costs of caring for its citizens. In the coming decades, the population of the then-elderly will grow to such a point that the costs of care will be unsustainable.

It is worth stating that the additional covered lives with the ACA will represent only 15% of the added population needing care in the next four or more decades.

Third, efforts to contain costs by statewide universal health care systems, health management organizations, vertically integrated medical systems and so on, have been present for decades and have served as a prelude to the ACA. Finally, the ACA is here because the country has accepted the gradually evolving political and sociologic concept of the rest of the modern world—that it must have universal health care, and it must find a way to pay for it. This realization—like the rise of the mammal, the shift of the continents and the effect of volcanic gases—paved the way for the exclamation point of the Yucatan asteroid of private practice, namely the ACA.

The Rise of the ACA The ACA seeks to eliminate private practice because that form of medical delivery—namely fee-for-service, individual doctor–patient relationships and owner– entrepreneurial status—cannot be aligned with its goals, which are to organize care around patient populations with large health care systems; to control costs by various maneuvers, such as accountable care organizations, bundling and shared financial risk by clinicians; and to reduce subspecialty care in general. The mechanics of the ACA also promote the extinction of private practice in two obvious ways: 1. the burden of cost and regulatory compliance with electronic health management systems, which are

demanded in the still-elusive names of quality and value, and 2. the reduction in reimbursements for high-cost and high-volume procedures.

The business of medicine—the individual entrepreneurial focus of private practice—will succumb to the reality that the cost of running a private business will not be supported by the reimbursements allowed by the ACA. Over the past decade, gastroenterologists have worked harder and longer hours, and have performed perhaps 30% more relative value units annually in order to keep their salaries high and pay the bills. There is no longer a place to go, a way to run faster. And the new generation of doctors would not choose these routes anyway, nor should they. In this respect, the ACA will succeed because the new generation of doctors has evolved in a way that makes the legislation tailor-made for their priorities.

This is not a criticism. As in the natural world, change happens. The current flow of private physicians into larger groups is consistent with the priorities of younger physicians, the economic realities of older physicians, the intent of the ACA and the means to cope with the regulatory requirements of a government-directed health care system.

The idea that doctors are joining hospitals simply for large signing bonuses dismisses the larger social, political and economic realities of the evolving medical landscape. I would encourage gastroenterologists to join the new order: Do not push harder or run faster, but rather find ways to integrate; reduce office and personnel costs; continue to view your profession in evolutionary terms; and above all, take time to appreciate your contributions to your fellow man. The public does.

In the process, however, if you choose to be a bird and remain solo or in a small group practice, you can tell the next generation what it was like to rule the earth. They will be in awe, but will not understand.

■ Dr. Costrini can be reached via email at drcostn@gmail.com.

Dear Dr. Costrini, I enjoyed reading your article in the opinion section of Gastroenterology & Endoscopy News. I am a gastroenterologist in practice with my son in Brooklyn, N.Y. My practice has been in the same location for more than four decades. I am 72 years old; my son is 37. I started my practice working with my father who was in solo practice and loved the practice of medicine. As you mentioned, times have changed drastically, and I am not sure for the better. The relationships that develop with patients in a small practice have been

very rewarding for me, and I continue to lament the changes taking place.

It would be nice to form an organization of likeminded physicians to carry on what I felt was the best way to deliver meaningful care to our patients.

Although we may be indeed dinosaurs, I don’t believe we should become extinct.

Bill Erber, MD Gastroenterologist, private practice Brooklyn, New York

FMT continued from page 1

and announced it would not require INDs for this therapy, at least for the time being.

In a guidance dated July 2013, the FDA said it intended “to exercise enforcement discretion,” regarding the IND requirements, which, according to FDA spokesperson Morgan Liscinsky, means INDs will not be required.

“If practitioners are using FMT to treat C. difficile infection that is not responsive to standard therapies and they obtain informed consent, [the] FDA will not enforce the IND requirements,” Ms. Liscinsky told Gastroenterology & Endoscopy News. “However, if a practitioner would like to submit an IND, they may do so, and [the] FDA will work with them.”

The FDA guidance states that informed consent “should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational, and a discussion of its potential risks.”

‘Several of us who were doing FMT for C. difficile infection had been writing to the FDA, asking them to change their policy.’

—Lawrence J. Brandt, MD

“I applaud the FDA’s behavior in altering their ruling to allow FMT to go forward with much less severe restriction,” said Lawrence J. Brandt, MD, professor of medicine and surgery, Albert Einstein College of Medicine, New York City. “It’s not that frequent

that a governmental agency changes its direction, and here we have a reversal of course that I think has to be applauded and recognized for the benefit I think it will allow. This is a happy conclusion to what was a long and painful process for most of us who had been doing FMT,”

said Dr. Brandt, who is also emeritus chief of the Division of Gastroenterology, Montefiore Medical Center, New York City.

“Several of us who were doing FMT for C. difficile infection had been writing to the FDA, asking them to change their policy,” Dr. Brandt said. “After several months of physicians and patients calling them, and their becoming aware of the fact that this was a procedure that was in great need [in order to] help a lot of people, they called a public conference on May 2-3. That conference had maybe five or six of us as panelists who were actively working in the field, and an audience of professional, as well as lay people. I was one of the more outspoken panelists,” he said.

The workshop influenced the FDA to change its policy because—according to the guidance—physicians and scientists “expressed concern to the FDA that see FMT, page 6

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

FMT continued from page 4

FMT is not appropriate for study under the agency’s IND regulations.”

Dr. Brandt recalled that he told the FDA: “I have the highest regard for the reasons why you went about making your judgment that the use of FMT should require an IND, namely that you are concerned about the safety and well being of the patients who might potentially receive this treatment. But thousands of FMTs have been done, and the incidence

‘This is a happy conclusion to what was a long and painful process for most of us who had been doing FMT.’ —Lawrence J. Brandt, MD

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of severe acute adverse effects [AEs] is virtually zero. Your major concern is that by doing a fecal transplant, you might be predisposing the recipient of the stool to develop all or some of the diseases that the donor’s microbiota might predispose that donor to develop over the next 10 or 20 years. Because of that major concern, you are preventing hundreds to perhaps thousands of people from getting FMT and, I believe, that more people are going to die as a result of that judgment than will ever be hurt by fecal transplant,” Dr. Brandt said.

Dr. Brandt’s concerns, and those of others on the panel, were persuasive enough to convince the FDA to reverse its previous decision.

“Understanding that C. difficile infection can be very serious, often with few or no other treatment options for patients, [the] FDA listened to the concerns expressed to us that the IND requirements may impact such patients getting the treatment quickly, and therefore determined that it would exercise enforcement discretion for the use of FMT for these specific patients,” Ms. Liscinsky said.

Concerning the “potential risks” of FMT that physicians should inform their patients about, Dr. Brandt said, “The FDA does not mandate what risks you have to tell the patient about, and in fact there are only theoretic risks, none of which have been proven. There are very few acute serious AEs of FMT. Most commonly, patients develop transient gas, bloating, cramps and perhaps constipation that lasts for several days,” he said.

“Remember we’re not going to be doing fecal transplants forever,” Dr. Brandt added, “because there already are substitutions for FMT that are coming onto the radar. Two examples are a prepared mixture of 33 species of bacteria, and freshly donated and then filtered and frozen material from a highly vetted set of donors. Both are considered safer in terms of infection risk than [using] whole stool.”

The FDA still plans to develop a policy for the study and use of FMT, according to the agency.

“FDA intends to exercise this discretion on an interim basis while the agency develops appropriate policies for the study and use of FMT products under IND,” the guidance states.

Asked how long this interim period will last, Ms. Liscinsky wrote, “[W]e cannot predict a specific issue date.” ■ Dr. Brandt and Ms. Liscinsky reported no relevant financial conflicts of interest.

7

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Massive Project Aims To Profile the ‘American Gut’

BY DAVID WILD Organizers of the “citizen science” initiative, the American Gut Project, have to date enlisted 3,500 participants from around the globe to mail in samples of their stool for analysis.

The project is a pioneering collaboration between researchers and laypeople that could provide important insights into the human microbiome.

“We are looking for correlations between the gut microbiota and diet, drugs, disease status, geography, age and other variables,” said lead investigator Rob Knight, PhD, associate professor in the Department of Chemistry and Biochemistry at the University of Colorado at Boulder. “Our dream would be to enroll 100,000 subjects and collect at least 100 time points per subject.”

‘We are looking for

they also can add oral, vaginal and skin swabs, and can even swab their pets to determine whether there is an association between pet microbes and their own microbiome.

Of particular interest to the gastroenterology community, Dr. Knight’s team will be testing all samples received for fecal biomarkers of inflammatory bowel disease, colorectal cancer and other digestive illnesses.

“Linking the microbial profiles with these digestive diseases is a key goal of American Gut and ties in with our CCFA [Crohn’s and Colitis Foundation of America]-funded projects,” said Dr. Knight. “In those projects, we are using the same protocols.”

A handful of gastroenterologists are among the several dozen academic and industry collaborators involved in the project. Dr. Knight said the gastroenterologists will help

analyze the data and provide recommendations on how later phases of the study should be designed. Their recommendations will be based on hypotheses generated from earlier phases of the open-ended project, Dr. Knight said.

Gary Wu, MD, professor of medicine in the Division of Gastroenterology at the University of Pennsylvania Perelman School of see American Gut, page 8

you’ve

met Mr. I’D-RATHER-KEEPMY- INDEPENDENCETHAN-KEEP-MY-NEXTDOCTOR’S-APPOINTMENT.

correlations between the gut microbiota and diet, drugs, disease status, geography, age and other variables. Our dream would be to enroll 100,000

mild to NOW his moderate active meet uc THERAPY

subjects and collect at least 100 time points per subject.’

—Rob Knight, PhD

GIAZO IS THE ONLY BID 5-ASA APPROVED TO INDUCE REMISSION IN MEN WITH MILD TO MODERATE ACTIVE ULCERATIVE COLITIS.1 INDICATION Dr. Knight’s team will be analyzing, sequencing and classifying bacteria, fungi and viruses that reside in the gastrointestinal tracts of study participants. Along with the stool samples, the researchers are collecting detailed demographic and dietary data from study participants. As an added cost to the $99 basic stool test kit that participants receive when they voluntarily sign up to participate,

PROVEN EFFICACY 57% of male patients on GIAZO achieved clinical improvement compared to 20% on placebo1

GIAZO® (balsalazide disodium) is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older.

Safety and effectiveness of GIAZO beyond 8 weeks have not been established.

CONTRAINDICATION GIAZO® (balsalazide disodium) tablets are contraindicated in patients with hypersensitivity to salicylates, aminosalicylates, or their metabolites or to any of the components of GIAZO tablets.

Reference: 1. GIAZO Prescribing Information, 2012. Salix Pharmaceuticals, Inc.

Please see Brief Summary of complete Prescribing Information, including Important Safety Information on the opposite page.

Please see complete Prescribing Information available at giazo.com.

GIAZO® is a registered trademark of Salix Pharmaceuticals, Inc. ©2013 Salix Pharmaceuticals, Inc. All rights reserved. BZ 13/53

Learn more at giazo.com

8

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

American Gut continued from page 7

Medicine in Philadelphia, is one of the project collaborators. Although he has not yet actively been involved in the project, he said he is excited about the project’s engagement of both scientists and citizens.

“That people can send in their own samples and receive their own analyses makes the scientific advances in the microbiome more tangible to the general public,” said Dr. Wu. “The

more informed the general public is about scientific advances in health, the better.”

The study’s public accessibility stands in stark contrast to the esoteric way most academic research studies are conducted. From its use of indiegogo.com, a crowd-sourced funding website, and the use of social media, to the recruitment of public personalities like athlete Dean Karnazes, and celebrity author Michael Pollan, the project’s coordinators are making every effort to engage with the public.

Ultimately, Dr. Knight hopes, stool samples and data from other studies will be included, although limitations imposed by the institutional review board are currently a barrier to doing so.

“We are very interested in leveraging clinical studies where people can consent to release data, and I hope projects like American Gut will help break down the prohibitive barriers that currently prevent doing this,” said Dr. Knight. “In terms of incorporating samples from other trials, there

is the challenge of reconciling data sets that are collected using different primers and different DNA extraction protocols. But we’re trying to develop improved methods to do so.”

Specimens and DNA will be banked for further analyses at a later date, as new technologies emerge, Dr. Knight said. He is also planning to preserve live cells as techniques become cost-effective.

‘That people can send in their own samples and receive their own analyses makes the scientific advances in the

groups were gastrointestinal disorders, which were mainly associated with symptoms of ulcerative colitis.

Adverse reactions occurring in at least 2% of male patients and at a rate numerically higher than placebo in the placebocontrolled trial are listed in Table 1.

The following is a brief summary only. See complete Prescribing Information on www.Giazo.com.

INDICATIONS AND USAGE GIAZO is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older.

Limitations of Use: • Effectiveness of GIAZO in the treatment of female patients was not demonstrated in clinical trials.

• Safety and effectiveness of GIAZO therapy beyond 8 weeks have not been established.

CONTRAINDICATIONS GIAZO is contraindicated in patients with hypersensitivity to salicylates, aminosalicylates or their metabolites, or to any of the components of GIAZO tablets.

WARNINGS AND PRECAUTIONS Exacerbations of Ulcerative Colitis Balsalazide is converted to mesalamine, which has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis.

In controlled clinical trials with GIAZO in adults with ulcerative colitis, 7% of male patients reported exacerbation of the symptoms of ulcerative colitis. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with GIAZO. Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis and renal failure, has been reported in patients given products that release mesalamine in the gastrointestinal tract. Evaluate renal function prior to initiation of GIAZO therapy and periodically while on therapy. Exercise caution when using GIAZO in patients with known renal dysfunction or a history of renal disease.

Use in Hepatic Impairment There have been reports of hepatic failure in patients with preexisting liver disease who have been administered mesalamine.

Because balsalazide is converted to mesalamine, use caution and consider liver function testing when administering GIAZO to patients with liver disease.

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 data described below reflect exposure of GIAZO in 565 ulcerative colitis patients with mildly to moderately active disease. GIAZO was evaluated in one placebo-controlled trial (168 treated with GIAZO), one active-controlled trial (210 treated with GIAZO); and a subset of these patients also participated in an uncontrolled, open-label, extension study (additional 187 treated with GIAZO). The population studied had a mean age of 43.1 (range: 18-80) years; approximately 94% of patients were < 65 years old, 49% were male, and 84% were white.

In the placebo-controlled trial, the most common adverse reactions with GIAZO in male patients were headache, nasopharyngitis, anemia, diarrhea, fatigue, pharyngolaryngeal pain, and urinary tract infection. 10% of patients in the GIAZO group and 13% of patients in the placebo group discontinued treatment due to an adverse reaction. The majority of adverse reactions were mild to moderate in severity. The most common serious adverse reactions in both the placebo and GIAZO

Table 1: Adverse Reactions Experience by at least 2% of GIAZO-Treated Male Patients and at a Rate Numerically Greater than Placebo in a Placebo-Controlled Trial

Adverse Reaction Anemia Diarrhea Pharyngolaryngeal Pain Urinary Tract Infection Arthralgia Insomnia Musculoskeletal Pain

GIAZO 6.6 g/day N=82 3.7% 3.7% 3.7% 3.7% 2.4% 2.4% 2.4%

PLACEBO N=37 0% 0% 0% 0% 0% 0% 0%

Data collected from all three trials (placebo-controlled, active-controlled, and open-label) showed that female patients reported adverse reactions more frequently than did male patients (76% and 66%, respectively).

The following adverse reactions, presented by body system, were reported by less than 1% of GIAZO-treated ulcerative colitis patients in controlled trials.

Cardiovascular and Vascular: increased blood pressure, increased heart rate Dermatological: erythema nodosum, rash Respiratory, Thoracic and Mediastinal Disorders: dyspnea Gastrointestinal Disorders: abdominal pain, constipation, defecation urgency, diarrhea,dry mouth, hard feces, flatulence, gastroesophageal reflux disease, vomiting Hepatobiliary Disorders: increased aspartate aminotransferase Infections and Infestations: gastroenteritis, upper respiratory infection Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, myalgia Nervous System Disorders: dizziness, lethargy General Disorders and Administrative Site Disorders: face edema, fatigue, malaise, pain,pyrexia, swelling POSTMARKETING EXPERIENCE Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to products which contain or are metabolized to mesalamine, including balsalazide.

Cardiovascular and Vascular: myocarditis, pericarditis, vasculitis Respiratory: alveolitis, pleural effusion, pneumonia (with and without eosinophilia) Gastrointestinal: pancreatitis Renal: interstitial nephritis, renal failure.

Hepatobiliary Disorders: elevated liver enzymes (AST, ALT, GGT, LDH, alkaline phosphatase), elevated bilirubin, jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure, Kawasaki-like syndrome including hepatic dysfunction. Some of these cases were fatal.

Dermatological: alopecia, pruritus DRUG INTERACTIONS Based on in vitro studies, balsalazide and its metabolites [5-aminosalicylic acid (5-ASA), N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), 4-aminobenzoyl-ß-alanine (4-ABA), and N-acetyl-4-aminobenzoyl-ß-alanine (N-Ac-4-ABA)] are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies were performed in rats and rabbits at oral doses up to 2 g/kg/day, 2.5 and 4.9 times the recommended human dose based on body surface area for the rat and rabbit, respectively, and revealed no evidence of impaired fertility or harm to the fetus due to balsalazide disodium. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug

should be used during pregnancy only if clearly needed.

Mesalamine, a metabolite of GIAZO, is known to cross the placental barrier.

Nursing Mothers It is not known whether balsalazide disodium or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GIAZO is administered to a nursing woman.

Pediatric Use Safety and effectiveness of GIAZO tablets in pediatric patients have not been established.

Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products. GIAZO is converted into mesalamine in the colon.

Caution should be taken to closely monitor blood cell counts during therapy.

the general public. The more informed the general public is about scientific advances in health, the better.’

—Gary Wu, MD

Clinical trials of GIAZO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing GIAZO. OVERDOSAGE No case of overdose has been reported with GIAZO. GIAZO is an aminosalicylate, and symptoms of salicylate toxicity include: hematemesis, tachypnea, hyperpnea, tinnitus, deafness, lethargy, seizures, confusion, or dyspnea. Severe intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) involvement. There is no specific antidote for balsalazide overdose. Proper medical care should be sought immediately with appropriate supportive care, including the possible use of emesis, cathartics, and activated charcoal to prevent further absorption.

PATIENT COUNSELING INFORMATION • Instruct patients not to take GIAZO if they have a hypersensitivity to salicylates (e.g., aspirin).

• Instruct patients to take GIAZO with or without food.

• Advise patients who need to control sodium intake that the recommended dosing of GIAZO (6.6 g/day) provides about 756 mg of sodium per day.

• Instruct patients to contact their health care provider if they experience a worsening of their ulcerative colitis symptoms, because it could be due to a reaction to GIAZO. • Instruct patients to make sure they let their health care provider know: ż If they have or are later diagnosed with renal dysfunction.

Damage to the kidney has been observed in some people given medications similar to GIAZO. ż If they have or are later diagnosed with liver disease.

Worsening liver isease has been observed in some people given medications similar to GIAZO. HOW SUPPLIED GIAZO is available as oval, yellow, film-coated tablets containing 1.1 g balsalazide disodium, with BZT debossed on one side of the tablet.

NDC 65649-102-02 Bottles of 180 tablets STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature.

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.

To report adverse events, a product complaint, or for additional information, call 1-800-508-0024.

Manufactured for: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 www.salix.com GIAZO is a registered trademark of Salix Pharmaceuticals, Inc.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GIA-RALAB4-072013

microbiome more tangible to

Balfour Sartor, MD, distinguished professor in the Departments of Medicine (Gastroenterology and Hepatology) and Microbiology and Immunology, University of North Carolina School of Medicine at Chapel Hill, who is not involved in the project, said American Gut could yield important insights into the microbiome, particularly in the hands of Dr. Knight, whom he called an “outstanding researcher.”

“This could be a dynamite way of getting information from a very large population,” he said. “My only concern is that there may be gaps in the collected data.”

For more information on American Gut, visit americangut.org.

■ None of the researchers mentioned in this article reported any conflicts of interest.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

9

Ideas About Gut Microbiome and Diet Becoming Mainstream

BY DAVID WILD ORLANDO, FLA.—A growing body of evidence highlighting the interaction between diet, the microbiome and various aspects of health may one day yield dietbased interventions for common diseases, new research, presented at the 2013 Digestive Disease Week (DDW) meeting, has shown.

composition, metabolism and physiology, and can affect an individual’s behavioral responses to food and eating, Dr. Wu said.

In 2011, Dr. Wu and other researchers from the Human Microbiome Project published seminal results from COMBO (Cross-Sectional Study of Diet and Stool Microbiota) showing that individuals have small differences in the composition of their microbiome and tend to have one of three broad “enterotypes” (Wu GD

‘We are now beginning to consider that what we eat not only alters the composition of our gut microbiota in

Inflammatory Bowel Disease

several ways, but that foods can also act as a substrate

The widespread use of elemental and defined-formula diets for individuals with inflammatory bowel disease offers a rare opportunity to study the correlation between diet, the microbiome and disease prospectively and in a real-world environment, Dr. Wu said. He and his colleagues are currently examining data from PLEASE (Pediatric Longitudinal Study of Elemental Diet and Stool Microbiota Composition), which is funded by the National Institutes of Health’s Human Microbiome Project.

“Our hypothesis is that there are elemental diet-induced alterations in the gut that are associated with therapeutic efficacy,” Dr. Wu said. “We’re also

for these microorganisms to produ uce small molecules that can impact the host.’

—Gary D. Wu, MD

“We are now beginning to consider that what we eat not only alters the composition of our gut microbiota in several ways, but that foods can also act as a substrate for these microorganisms to produce small molecules that can impact the host,” said Gary D. Wu, MD, professor of medicine in the Division of Gastroenterology University of Pennsylvania Perelman School of Medicine, Philadelphia, who spoke about the subject to DDW attendees.

Dr. Wu’s research is leading to significant revisions of prevailing and limited views about the health effects of food, which until now have been primarily attributed to nutritive components, and it is becoming clear that metabolism by intestinal microorganisms plays a critical intervening role.

For example, Dr. Wu said, the well-documented risk for cardiovascular disease that is linked to high consumption of red meat has been thought to be largely due to its high content of saturated fat. However, earlier this year, Koeth et al showed that intestinal bacteria metabolize meat-derived L-carnitine into atherosclerosis-promoting trimethylamine N-oxide (Koeth RA et al. Nat Medd 2013;19:576585). Furthermore, they found that high plasma levels of an L-carnitine–derived metabolite produced by gut microbiota are associated with increased rates of cardiovascular disease, myocardial infarction and death.

Temporal Associations Studies that document diet-induced microbial changes throughout the lifespan are critical, Dr. Wu said, especially within the context of the growing link between diet, the microbiome and health and disease.

Dr. Wu pointed to results published last year showing that diet influences the microbiome from the time of birth. Those findings revealed that breast-fed infants have higher populations of Bifidobacteria, Lactobacillus and Staphylococcus, whereas formula-fed infants have smaller populations of Bifidobacteria and Lactobacillus and larger populations of Clostridium, Bacteroides, Enterobacteriaceae and Enterococcus (Thompson AL. Am J Hum Bioll 2012;24:350-360). These early microbial differences have implications for growth, body

10 days are needed, another study has suggested that significant alterations can be achieved within one year. The study was a longitudinal investigation of elderly individuals residing in either the community or in long-term care (Claesson MJ et al. Nature 2012;488:178-184). Microbiome analyses revealed profound changes within one year from moving from one living environment to another, and less diverse gut microbial populations among those living in long-term residential care. Those in residential care environments also were sicker, more frail, less nourished and had more inflammation, Dr. Wu said.

‘Ultimately, we should be able to alter our patients’ diets to change the populations of proinflammatory and anti-inflammatory bacteria and potentially manage chronic disease this way.’

—Mark Silverberg, MD, PhD

et al. Science 2011;334:105-108). They characterized the different enterotypes according to the balance of Bacteroides, which are associated with long-term protein and fat intake, and Prevotella, which are linked to diets with high amounts of simple carbohydrates. Research presented last year at the International Human Microbiome Congress showed that a Bacteroides-dominated enterotype is associated with obesity and metabolic alterations.

Other findings by Dr. Wu and his colleagues suggest that enterotypes can be altered through diet, but this takes time. In the CaFE (Controlled Feeding Experiment) study by the Human Microbiome Project, 10 healthy volunteers were monitored in a highly controlled inpatient setting and randomized to either a high- or low-fat diet for 10 days. Dr. Wu and his colleagues found that although specific diets led to small but “very significant” microbial alterations within 24 hours, the broader gut microbial composition remained fundamentally similar during and after the 10-day study (Wu GD et al. Science 2011;334:105-108).

“Enterotypes are associated with long-term diets but not with recent diet patterns,” Dr. Wu said.

Precisely how long does it take to meaningfully alter the balance of gut microorganisms?

Although the CaFE study indicated that more than

including a second group of patients treated with an anti–TNF [tumor necrosis factor]-α agent to compare changes in their microbiome.”

Mark Silverberg, MD, PhD, a gastroenterologist and associate professor of medicine at the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto, Canada, applauded Dr. Wu for his significant contributions to two main lines of inquiry in the study of the intestinal microbiome.

“We’re always asking ‘who are they?’ and ‘what are they doing?’ ” said Dr. Silverberg, referring to the types and function of intestinal microorganisms.

Dr. Silverberg’s own team is examining the relationship between diet and Crohn’s disease, with a focus on how diet affects the risk for disease recurrence after ileal resection. Preliminary findings based on a small group of subjects identified several foods, beverages and nutrients that seem to correlate with delayed postoperative recurrence.

“Ultimately, we should be able to alter our patients’ diets to change the populations of proinflammatory and anti-inflammatory bacteria and potentially manage chronic disease this way,” Dr. Silverberg said.

■ Drs. Wu and Silverberg reported no conflicts of interest.

10

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

IBS Microbiome continued from page 1

director, GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, who described the study at the 2013 Digestive Disease Week meeting.

Individuals with diarrhea-predominant IBS (IBS-D) were found to have significant alterations in duodenal microbial composition, characterized by a greater bacterial number, reduced microbial diversity and overrepresentation of Escherichiaa and Aeromonas species, Dr. Pimentel and his colleagues found.

‘The small bowel flora of [patients with] IBS contained a greater number of bacteria, with a lower diversity.’

—Mark Pimentel, MD

Why the Duodenum?

Both the microbiome project and early sequencing work in healthy individuals and those with IBS focused on colonic flora or stool; however, Dr. Pimentel maintained the duodenum may be a better site for sampling.

“Sequencing of stool does not represent the entire digestive tract.” For one thing, Dr. Pimentel said, stool contains dead bacteria. “You are amplifying DNA of organisms that are no longer metabolically active,” he explained.

“Our group also recently showed that stool flora in humans more closely resembles rodent stool flora than the flora in the human small intestine. … So, to imply that the human gut microbiome is totally represented by stool is probably not accurate because the small intestine has a completely different signature of microorganisms.”

Dr. Pimentel and his colleagues recently validated small intestinal bacterial overgrowth (SIBO) in patients with IBS based on coliform culture and single-organism polymerase chain reaction (PCR). His current study is the first of its kind to examine the duodenal microbiology of IBS using a new long-read, deep-sequencing approach that allows for sensitive, high-resolution microbial identification, he said.

The researchers isolated DNA from duodenal aspirates in patients with IBS-D and healthy controls and performed high-resolution, high-sensitivity sequencing. Sequence reads were aligned to the Greengenes Database for taxonomic identification, and the relative abundance of each genus was assessed. Researchers then compared the duodenal flora signatures in patients with IBS-D and healthy controls, and validated findings by quantitative PCR using genus-specific primers.

“The small bowel flora of [patients with] IBS contained a greater number of bacteria, with a lower diversity,” Dr. Pimentel reported.

Agilent plots of IBS patients and healthy controls revealed definitively higher peaks in IBS patients and more total organisms, whereas controls had more peaks of lesser magnitude. Sequencing revealed that total duodenal bacterial counts were higher in patients with IBS-D than in healthy controls, supporting the SIBO hypothesis (P<0.05). Furthermore, the diversity of small bowel microbial populations in patients with IBS-D was strikingly lower, with significantly enriched populations of Aeromonass (P P=0.0046) and Escherichiaa (P P=0.022), but significantly underrepresented populations of Lactococcus (P=0.032), P Acinetobacterr (P P=0.034) and Chryseobacterium (P=0.003).

P Samples from healthy controls were more diverse, Dr. Pimentel said.

Quantitative PCR was conducted on a large number of samples (patients with IBS-D, healthy controls and patients with non-IBS gastrointestinal [GI] disease), revealing significantly higher levels of E. colii in IBS-D patients compared with the other two groups (P<0.001).

Additionally, elevations in Aeromonas species were seen in

patients with IBS-D, and the ratio of E. colii to Aeromonass was significantly lower in patients with IBS-D (0.17) compared with patients with non-IBS GI disease (0.38; P<0.05).

Inflammation and SIBO J. Marc Rhoads, MD, of the Department of Pediatrics–Gastroenterology, University of Texas Medical School, Houston, commented on the study for Gastroenterology & Endoscopy News.

“It is interesting that the gram-negative bacteria that the researchers identified in some of the duodenal cultures may be proinflammatory,” Dr. Rhoads said. “The two species that [Dr. Pimentel’s group] have cultured from the duodenum are both implicated as possible causes of abdominal pain in babies with colic, reported by other investigators [E. coli; Savino F et al. Acta Paediatrr 2009;9:1582-1588] and by our group [Klebsiella; Rhoads JM et al. J Pediatrr 2009;155:823-828]. Colic is a condition that is similar in some ways to IBS, but in my opinion, is more severe.”

“It’s not a surprise,” Dr. Rhoads added, “that different organisms were identified by molecular techniques in the duodenum when compared to organisms isolated using older culture techniques. For example, in IBS

patients, Dr. Pimentel’s group found more Aeromonas and fewer Chryseobacteria than were seen in the nonIBS population. The fewer Lactobacillii in the duodenal aspirates in IBS patients also is not surprising because these are generally anti-inflammatory. We have strong data from rodent models of necrotizing enterocolitis to show this [Liu Y et al. PLoS Onee 2013;8:e56547; Liu Y et al. Am J Physiol Gastrointest Liver Physiol 2012;302:G608-G617].”

“Dr. Melissa Van Arsdall of our group has begun similar studies in pediatric patients because we have found that many with functional gastrointestinal disorders have elevated fasting breath H2 values or abnormal responses to an oral glucose breath test. We think that overgrowth may be important in a subgroup of children with abdominal pain,” he said.

“Overall, this line of investigation helps support these researchers’ previously controversial hypothesis that adults with IBS often have SIBO. I think no one knows how prevalent the problem is—it may be a significant subgroup,” Dr. Rhoads concluded.

■ Dr. Pimentel has served as a consultant for Salix Pharmaceuticals and has received grants or research support from Salix and the Seaver Foundation. Dr. Rhoads has received a research grant from BioGaia, Inc.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Sandhill Scientific Inc

13

Corporate Spotlight

Innovation matters.

Such has been the creed of Sandhill Scientific Inc, for the past 33 years, as a leading developer, manufacturer and marketer of gastrointestinal (GI) diagnostic devices. Initiating the business as the first U.S. supplier of ambulatory reflux monitoring and esophageal manometry systems, the innovative focus continues today, with a perpetual drive to deliver tomorrow’s leading-edge technologies.

Based in Highlands Ranch, Colo., Sandhill Scientific leverages the significant benefits of private employee ownership.

Sandhill employees take pride in their company because they own their company. From these entrepreneurial roots springs a focus on delivering products and services that optimally fulfill customer needs.

In our corporate office, Sandhill employs approximately 45 people, who are involved in sales, clinical education, technical support, engineering, quality control, finance and manufacturing. Sandhill’s consumable catheter manufacturing facility in Ho Chi Minh City, Vietnam, employs approximately 75 people. A worldwide distribution system markets and supplies Sandhill products in the United States and more than 55 countries.

Innovative Products As the first developer of impedance/pH reflux monitoring technologies, Sandhill is the worldwide leader in total reflux monitoring devices. Today’s state-of-the-art ZepHr® Impedance/pH Reflux Monitoring System, coupled with BioVIEW® analysis software and ComforTEC® reflux monitoring catheters, sets the standard for usability, accuracy and clinical utility.

In the field of esophageal function testing, Sandhill created the world’s first combined impedance/manometry system for concurrent assessment of peristalsis and bolus transit. Today, high-resolution impedance manometry testing is the gold standard for assessment of esophageal and pharyngeal swallowing. With the recent introduction of the inSIGHT Ultima™ motility inSIGHT Ultima™ platform, procedure-specific diagnostic modules can be added to expand system functionality to anorectal manometry, anorectal biofeedback, sphincter of Oddi manometry and small bowel/colonic manometry.

Marking yet another technology innovation, Sandhill recently partnered with EchoSens, a French manufacturer, to become the exclusive U.S. distributor of the FibroScan® 502 Touch (www. fibroscan502touch.com), a noninvasive liver stiffness diagnostic system. The FibroScan® 502 Touch was cleared by the FDA in April 2013, and is being adopted widely in the hepatology and gastroenterology fields for both clinical and research applications. Based on the patented Vibration-Controlled Transient Elastography (VCTE™) technology, FibroScan® 502 Touch assesses shear wave speed in the liver (expressed in meters per second) and equivalent stiffness (expressed in kilopascals) in a simple, fast and noninvasive painless test. The FibroScan® 502 Touch is indicated for noninvasive measurement of shear wave

speed at 50 Hz in the liver, which is used to aid in the clinical management of patients with liver disease. FibroScan® has been validated in more than 700 peer-reviewed publications.

Moreover, the use of FibroScan® also is mentioned in international guidelines, including recommendations from the World Health Organization, the European Association for the Study of the Liver, the United Kingdom National Institute of Clinical Excellence, and the Asian FibroScan® Pacific Association for the Study of 502 Touch the Liver.

Sandhill University In addition to product development, manufacturing and worldwide marketing, Sandhill places significant emphasis on clinician education. Under the banner of the industry-leading Sandhill University, comprehensive training and education programs are offered, covering the complete spectrum of the clinician’s needs. Hands-on clinical training courses are offered monthly at Sandhill’s headquarters in Colorado, where physicians and nurses are provided training in clinical applications and product operations.

A three-day, comprehensive esophageal course covers the areas of reflux monitoring and swallowing function testing. Two-day comprehensive anorectal manometry courses also are available.

The “Denver Course” is supplemented with a series of workshops held in major cities across the United States, Canada, Latin America, Europe and the Middle East. Sandhill University also provides web-based cybercoaching, allowing clinicians from around the world to review studies with a Sandhill clinical application expert.

Focus on the Future Perpetually focused on creating “what’s next,” Sandhill conducts product development research with clinical thought leaders around the world. As validated by more than 30 years of product innovation and 250 peer-reviewed publications, the Sandhill development team plays a key role in the evolution and utilization of endoscopic GI diagnostics.

Address Sandhill Scientific Inc 9150 Commerce Center Circle, No. 500 Highlands Ranch, CO 80129 Phone (800) 468-4556 (303) 470-7020 Fax (303) 470-2975 Web www.sandhillsci.com

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Parameters That Define a Successful Colonoscopy Professor of Medicine Chief of Gastroenterology Eastern Virginia Medical School Norfolk, Virginia

Introduction When used properly, colonoscopy is the most powerful strategy for the primary and secondary prevention of colorectal cancer (CRC).1 However, the efficacy and safety of this procedure is dependent on a variety of factors, including operator skill and experience, quality of examination, achievement of goal-directed end points, compliance with guideline recommendations, and multiple technical aspects regarding patient preparation for the procedure and the procedure itself.1-3 As with other areas of clinical medicine, currently there is a concerted shift to define the critical aspects of quality delivery of colonoscopy in an effort to increase the related utility and optimize the effect, while simultaneously limiting unnecessary health care expenditures and patient risk. Future colonoscopy quality regulations may cause confusion among endoscopists, particularly long-practicing clinicians or those practicing individually outside of a hospital system.

Thus, standardizing the process for illustrating how value-based care is delivered and core capabilities are demonstrated may be beneficial for these practitioners.

Current Problems With Colonoscopy Quality Although removal of premalignant lesions via colonoscopy is the single most

effective strategy to prevent the development of CRC,1 a reported and notable percentage of patients who undergo screening colonoscopy still develop interval CRCs3—a concept known as “incomplete protection.”

This deficiency is likely related to several different factors. Indeed, there is considerable evidence of variability among the type or defined quality of the endoscopists in terms of the technical performance of colonoscopy, thereby resulting in a suboptimal adenoma detection rate (ADR).4 This may be due to failure to achieve cecal intubation3 or rapid withdrawal, both of which may result in missed lesions or incomplete polypectomy.5 Proximal serrated lesions are responsible for a significant proportion of CRCs after the use of colonoscopy,6 but inadequate education and training in the recognition and pathophysiologic significance of such lesions also plays a likely role in suboptimal outcomes.6-8 The quality of bowel preparation has a major effect on the ability to perform a complete examination and on the duration of the procedure. Inadequate bowel preparation quality (defined as ability to exclude polyps smaller than 6 mm) occurs in approximately 20% of cases.9 Because inadequate bowel preparation quality can result in the need to cancel/reschedule procedures or change screening/surveillance recommendations for repeat examination, this is a major contributor to impairment of qualityrelated outcomes as well as to consequent related increased health care costs.10 Finally, despite strong evidence suggesting that using appropriate screening and surveillance intervals results in improved patient outcomes and reduced costs, more than 50% of all colonoscopies performed are in noncompliance with these recommended intervals.11,12 Clearly, this percentage should

Table 1. Quality Indicators for Colonoscopy Current

Future

ADR

Adequacy of bowel preparation

Appropriate use of surveillance/screening intervals

Adequacy of polypectomy

Cecal intubation rates

Periprocedural management of antiplatelet and anticoagulant drugs

Current and Future Quality Measures The potential variability in endoscopists’ performance suggests that objective measures are needed to improve the quality of this procedure. Currently, widely accepted and often used quality measures include ADR, cecal intubation rates, and compliance with recommended screening and surveillance intervals (Table 1). Of these, ADR is probably the most widely used and studied, with clinical practice guidelines defining quality endoscopy as an ADR in a screening population cohort of at least 25% in men and at least 15% in women.13 These measures already are being used within voluntary central registries that are designed to

2

Rate of lost specimens Rate of surgical referrals Recognition of sessile serrated lesions ADR, adenoma detection rate

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

track colonoscopy quality to identify providers and programs that would benefit from specific quality improvement training.

However, medical societies already are looking beyond these established measures toward the next iteration of quality end points. For example, experts have noted that multiple (rather than solitary) adenomas usually are present in the colon and that an endoscopist who finds one adenoma per colonoscopy receives the same ADR quality assessment as another endoscopist who finds multiple adenomas.14 Because every adenoma carries some risk for malignancy, it is likely that these 2 endoscopists provide different levels of CRC protection, although they receive an equal quality assessment via the ADR metric.14 Therefore, investigators have advanced the concept of tracking the “ADR-plus” rate—defined as the detection of more than one adenoma per colonoscopy—as a measure of quality.

Wang and colleagues demonstrated how the use of the ADR-plus rate could further differentiate quality performance among endoscopists who had the same conventional ADR score (Figure).14 The recognition and management of sessile serrated lesions such as sessile serrated adenomas also is likely to emerge as an indicator of quality of colonoscopy. Such lesions tend to appear flat or depressed and covered

“All or None”

“Optimal”

“None and Done”

“One and Done”

16 1.6

12 1.2

08 0.8

04 0.4 Teaching Non-Teaching 0 0

10

ADR-plus (rate of detection of multiple adenomas within one colonoscopy)

Rate of interval cancers

14

be placed in context and on occasion, diverging from following guidelines should be individualized by the best recommendations of the clinician based on an individual patient. Nevertheless, guideline recommendations should be the overarching perspective and plan in general. Noncompliance with evidence-based guideline recommendations may result in overutilization, thereby increasing costs and needless risk for adverse events, or paradoxically to the underuse of colonoscopies, which results in the potential for missed cancers, which may be preventable lesions.

ADR-plus, mean beyond 1

David A. Johnson, MD

20

30

40

50

ADR, %

Figure. Use of the ADR-plus rate to further differentiate quality performance among endoscopists with the same ADR score.

There is a wide distribution of endoscopists within the optimal, one and done, none and done, and all or none categories. Endoscopists meeting the US Multi-Society CRC Task Force ADR Criterion (>25% for men) can still vary widely in terms of total adenomas detected, here measured with ADR-plus, a metric independent of the ADR. The size of the circle reflects the total number of procedures performed by the endoscopist.

ADR, adenoma detection rate Reprinted with permission from reference 14.

Supported by

Other quality measures that might be used in the near future include the rate of lost polyps and the rate of surgical referral.

Because of its global effect on the quality of colonoscopy, adequacy of bowel preparation also is likely to be used as a quality indicator for colonoscopy.

Embracing Change In addition to the universal goal of improving patient outcomes and delivering efficient and safe care, other entities are likely to apply pressure to recognize performance and improve quality. These entities include insurers/payors for the purposes of value-based purchasing and reimbursement, regulatory agencies, accrediting bodies, and even hospitals and group practices for the purposes of qualifying assurance and marketing to the general public. As such, the successful endoscopist should be motivated to participate in quality assurance programs in an effort to recognize any deficiencies and take advantage of programs designed to improve colonoscopy performance.

Fortunately, there is an increasing number of pathways to improve quality performance of colonoscopy. The first step is the recognition of suboptimal performance.

Many commercial electronic medical record systems already have the capabilities to

Table 2. Effect of a Quarterly Report Card (Without Any Other Defined Intervention) on Subsequent Colonoscopy Performance Indicators Variable Rate, % (95% CI, %)

Before Intervention

Intervention

P Value

Adenoma detection

44.7 (39.1-50.4)

53.9 (49.7-58.1)

0.013

Proximal adenoma detection

29.3 (24.4-34.8)

39.8 (35.7-44.0)

0.003

Distal adenoma detection

28.4 (23.6-33.7)

27.8 (24.2-31.7)

0.840

Advanced neoplasm detection

11.5 (8.4-15.5)

13.3 (10.8-16.4)

0.441

Serrated polyp detection

33.8 (28.5-39.5)

32.7 (28.7-36.9)

0.741

Cecal intubation

95.6 (92.5-97.5)

98.1 (96.7-99.0)

0.027

Number of adenomas per colonoscopy, mean (95% CI)

1.1 (0.7-1.4)

1.2 (0.9-1.5)

0.364

Adenoma size per colonoscopy, mean (95% CI), mm

5.6 (4.0-7.1)

5.5 (4.0-7.0)

0.956

record and sort the quality metrics for colonoscopy described above. Use of these systems allows easy searching of specific indices and subsequent generation of performance reports. Furthermore, these data can be submitted to central tracking registries, such as the GI Quality Improvement Consortium (GIQuIC, giquic.gi.org), on a voluntary basis to obtain benchmarking performance reports relative to other endoscopists and to identify areas for quality improvement.

Indeed, Kahi and colleagues assessed endoscopic quality measure over time and reported that providing the endoscopist with a quarterly report card of performance based on these metrics (and without further directed intervention) was associated with subsequent and progressive improvement in colonoscopy quality (Table 2).17 Data obtained from these programs can be used to focus training and education in terms of improved cecal intubation rates and longer withdrawal times, recognition of serrated lesions, effective polypectomy, and use of appropriate screening/surveillance intervals.

Furthermore, ongoing refinement in bowel preparation should be pursued.10 Both split-dose and same-day bowel preparations have been shown to result in a better quality examination with fewer adverse events,18,19 although administration time can affect performance. For afternoon procedures, both 2-day, split-dose regimens18 and morning, same-day preparations administered in 2 doses19 have demonstrated efficacy, whereas for morning procedures, a nighttime, single-dose regimen is often used.18 Understanding of the most successful dosing strategies could lead to improved colonoscopy quality.

Conclusion With the ongoing efforts by various organizations toward improved quality performance and optimal health care resource utilization, it is important for endoscopists to embrace the evolving regulatory landscape in order to ensure colonoscopy quality, positive patient outcomes, and reimbursement.

colonoscopy in the dietary Polyp Prevention Trial.

Gastrointest Endosc. 2005;61(3):385-391.

4.

Lee RH, Tang RS, Muthusamy VR, et al. Quality of colonoscopy withdrawal technique and variability in adenoma detection rates (with videos).

Gastrointest Endosc. 2011;74(1):128-134.

5.

Barclay RL, Vicari JJ, Doughty AS, et al. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med. 2006;355(24):2533-2541.

6.

Lu FI, van Niekerk de W, Owen D, et al. Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma. Am J Surg Pathol. 2010;34(7):927-934.

7.

Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 2012; 107(9):1315-1329; quiz 1314, 1330.

8.

Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011; 42(1):1-10.

9.

Ness RM, Manam R, Hoen H, et al. Predictors of inadequate bowel preparation for colonoscopy.

Am J Gastroenterol. 2001;96(6):1797-1802.

10.

Rex DK, Imperiale TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol. 2002;97(7): 1696-1700.

11.

Schreuders E, Sint Nicolaas J, de Jonge V, et al.

The appropriateness of surveillance colonoscopy intervals after polypectomy. Can J Gastroenterol.

2013;27(1):33-38.

12.

Shah TU, Voils CI, McNeil R, et al. Understanding gastroenterologist adherence to polyp surveillance guidelines. Am J Gastroenterol.

2012;107(9):1283-1287.

13.

Rex DK, Bond JH, Winawer S, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol. 2002;97(6):1296-1308.

14.

Wang HS, Pisegna J, Modi R, et al. Adenoma detection rate is necessary but insufficient for distinguishing high versus low endoscopist performance. Gastrointest Endosc. 2013;77(1):71-78.

15.

Pohl H, Srivastava A, Bensen SP, et al. Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study.

Gastroenterology. 2013;144(1):74-80.

16.

Veitch AM, Baglin TP, Gershlick AH, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut. 2008;57(9):1322-1329.

17.

Kahi CJ, Ballard D, Shah AS, et al. Impact of a quarterly report card on colonoscopy quality measures. Gastrointest Endosc. 2013;77(6):925-931.

18.

Gurudu SR, Ramirez FC, Harrison ME, et al.

Increased adenoma detection rate with systemwide implementation of a split-dose preparation for colonoscopy. Gastrointest Endosc. 2012;76(3): 603-608 e601.

19.

Longcroft-Wheaton G, Bhandari P. Same-day bowel cleansing regimen is superior to a splitdose regimen over 2 days for afternoon colonoscopy: results from a large prospective series.

J Clin Gastroenterol. 2012;46(1):57-61.

References 1.

Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.

Gastroenterology. 2008;134(5):1570-1595.

2.

Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology.

1997;112(1):24-28.

CI, confidence interval Reprinted with permission from reference 17.

3.

Pabby A, Schoen RE, Weissfeld JL, et al. Analysis of colorectal cancer occurrence during surveillance

Disclosures Dr. Johnson reported that he is a consultant for and has received honoraria from Abbott, AstraZeneca, Epigenomics, Given Imaging, Merck, Pfizer, Roche, and Takeda, and has received grant/research support from Epigenomics and Exact Sciences.

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ OCTOBER 2013

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BB1318

in mucus, allowing them to be missed easily without careful examination.7 Indeed, a significant proportion of cancers that occur between colonoscopies are the result of unrecognized sessile serrated adenoma lesions that progress to frank carcinomas.8 A natural companion to this quality measure, therefore, is the rate of cancers that occur in the interval between colonoscopies that are otherwise performed according to guidelines. In addition to missed serrated lesions, some of these interval cancers can result from inadequate polypectomy.15 This phenomenon is highlighted by a study of 346 neoplastic polyps removed by 11 gastroenterologists, in which 10.1% (range, 6.5%22.7%) were incompletely resected.15 The increasing prevalence of antiplatelet drugs and anticoagulants poses a challenge to the appropriate periprocedural management of patients undergoing endoscopy.16 Adverse outcomes in patients using these agents can include procedural and postprocedural bleeding if patients do not follow instructions regarding cessation of these agents as well as thrombotic complications for patients who are not restarted on these agents at an appropriate interval after colonoscopy. Therefore, the management of these agents represents another fertile area for quality indicators related to colonoscopy.

16

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Experts’ Picks:

Best of Hepatology: A Survey of Recently Published Studies COMPILED AND WRITTEN BY DAVID WILD

Keeping up with the literature is a difficult task, even when narrowing the focus to only one topic in gastroenterology. Gastroenterology & Endoscopy Newss asked two experts to comment on recently published studies in hepatology. Following are their insights.

Jacqueline O’Leary, MD, MPH Medical Director Inpatient Liver and Transplant Unit Baylor University Medical Center Dallas, Texas

O

nce-daily simeprevir (TMC435) with peginterferon and ribavirin in treatmentnaive genotype 1 hepatitis C: The randomized PILLAR study.

(Fried MW et al. Hepatology 2013 Aug 2 [Epub ahead of print]) This international, multicenter, double-blind Phase IIb study examined the safety and efficacy of combination treatment with simeprevir, an oral hepatitis C virus (HCV) NS3/4A protease inhibitor, pegylated interferon (PEG-IFN) alfa-2a and ribavirin (RBV) in patients with chronic HCV genotype 1 infection.

Researchers randomly assigned 77 patients to receive PEG-IFN 180 mcg per week and RBV 1,000 to 1,200 mg per day in combination with placebo with for 24 weeks, followed by an additional 24 weeks of treatment with PEG-IFN and RBV. Another 153 patients were randomly assigned to receive simeprevir 75 mg per day in combination with PEG-IFN and RBV for 12 or 24 weeks, followed by 24 weeks of treatment with PEGIFN and RBV. A third group of 156 patients followed the same treatment regimen but with simeprevir 150 mg per day. Between 38% and 49% of patients had HCV genotype 1a infection, and most had the interleukin-28 B (IL28B) CT T genotype.

The researchers reported that 68% to 76% of patients in the simeprevir treatment groups achieved a rapid virologic response (RVR) after four weeks of treatment compared with 5.2% of placebo recipients.

Additionally, between 75% and 86% of simeprevir recipients had a sustained virologic response (SVR) at week 24 of simeprevir treatment compared with 65% of placebo recipients (P<0.05 for all vs. placebo, except SVR at week 24 for simeprevir 75 mg).

A subanalysis that included only patients with HCV RNA levels less than 25 IU/mL after 24 weeks of simeprevir treatment revealed that 85% to 95.6%

of these patients achieved SVR att week 24. Also, between 71% and 85% of simeprevvir recip pients achieved SVR at week 72 compared d with 65% of placebo recipients.

Viral breakthrough occurred in n 6.4% to 7.8% of 12-week simeprevir reciipients and 2.5% to 2.7% of 24-week simeeprevir recipients compared with 5.2% off placebo recipients. Viral relapse occcurred in 11.1% and 19.4% of 12- and 24-week simeprevir 75 mg recipients, respectively, and in 8.7% and 8% of 12- and 24-weekk simeprevir 150 mg recipients, resp pectivelly; approximately 18% of placebo recip pients exxperienced viral relapse.

Rates of serious adverse eventss (AEs)) occurred in 3.8% to 11.5% of simeprevir recipients nts compared with 13% of placebo patients. Therre was no significant difference between groups in thee rates of treatment discontinuation.

Dr. O’Leary: We are nearing the launch of a new protease inhibitor for HCV. Simeprevir is dosed once daily, and fortunately, does not worsen the aneemia associated with PEG-IFN and RBV and has minim mal drug–drug interactions. Although at launch, simep previr will need to be combined with PEG-IFN and RBV, BV, we anticipate utilization of this direct-acting antiviral agent (DAA) in combination with other DAAs in multidrug, IFN-free

ofosbuvir for previously untreated chronic hepatitis c infection.

S

(Lawitz E et al. N Engl J Med 2013;368: 1878 1887) 1878-1887)

Lawitz et al reported findings from two Phase III trials of sofosbuvir: NEUTRINO and FISSION. NEUTRINO included 327 treat‘Although at launch, simeprevir will need to be ment-naive patients with chronic combined with PEG-IFN and RBV, we anticipate HCV infection: 292 patients with HCV genotype 1, 28 patients with utilization of this direct-acting antiviral agent HCV genotype 4, and seven patients (DAA) in combination with other DAAs in with HCV genotype 5/6. All patients multidrug, IFN-free cocktails in the future.’ received sofosbuvir, an HCV NS5B polymerase inhibitor, 400 mg per day, —Jacqueline O’Leary, MD, MPH in combination with RBV 1,000 to 1,200 mg per day and PEG-IFN 180 mcg weekly, for 12 weeks. Seventeen cocktails in the future. For example, interim results from percent of patients had compensated cirrhosis and cohort 2 of the COSMOS study demonstrated that 12 29% had IL28B CC genotype. At baseline, all patients weeks of treatment with simeprevir and sofosbuvir in had a platelet count of greater than 90,000 platelets patients with hard-to-cure HCV (prior null responders per mcL, none had neutropenia, and the mean HCV and treatment-naive patients with HCV genotype 1 and RNA viral load was 6.4 log10 IU/mL. advanced liver fibrosis or cirrhosis) led to SVR rates at At week 12, 90% of patients achieved SVR, which week 4 of 96% and 100% for treatment given with or is higher than the 60% rate demonstrated in historiwithout RBV, respectively. cal controls, the researchers reported. All patients

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER OCTOBER 2013 2013

S

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fosbuvir for hepatitis C genotype 2 or 3 who did not achieve SVR at week 12 experienced without or with cirrhosis, respectively, experienced SVR in patients without treatment options. viral relapse; no patients had HCV NS5B S282T at week 12. There were no viral breakthroughs. ( Jacobson IM et al. N Engl J Med resistance following relapse. Among patients with Two percent and 4% of patients in the sofosbuvir and 2013;368:1867-1877) cirrhosis, 80% achieved SVR at week 12. Additionplacebo groups, respectively, discontinued treatment and ally, 92% of patients without cirrhosis, 96% patients This paper reported data from the FUSION and POSI- 5% and 3%, respectively, had serious AE. Common AEs with HCV genotype 4 and 100% of patients with TRON studies—two randomized, Phase III trials of among patients in the sofosbuvir and placebo groups HCV genotype 5/6 achieved SVR at week 12. sofosbuvir in patients with HCV genotype 2 or 3 who included fatigue (44% vs. 24%, respectively), nausea (22% The FISSION trial included 499 treatment- were either not able to receive, or had not responded to vs. 18%, respectively), headache (21% and 20%, respecnaive patients with HCV previous treatment with, tively), insomnia (19% vs. 4%, respectively), pruritus (11% genotype 2 or 3 infection.

PEG-IFN. vs. 8%, respectively), anemia (13% vs. 0%, respectively) Patients were randomThe FUSION study and irritability (9% vs. 1%, respectively). Additionally, 7% ‘Although most HCV patients ized to receive 12 weeks included 201 patients with of sofosbuvir recipients had decreased hemoglobin levels of treatment with sofosbuHCV genotype 2/3 who compared with none of the placebo recipients. will have excellent therapeutic vir and RBV or 24 weeks had been treated previously options once sofosbuvir and of treatment with PEGwith PEG-IFN and not Dr. O’Leary: IFN alfa-2a and RBV, in responded, 75% of whom Although most HCV patients will have excellent therasimeprevir are launched, an open-label fashion. In had prior virologic break- peutic options once sofosbuvir and simeprevir are launched, therapy for patients with HCV the sofosbuvir treatment through. Patients were ran- therapy for patients with HCV genotype 3 is now emerggroup, dosing of sofosbudomized to receive 12 or ing as the Achilles’ heel of HCV therapy. Although longer genotype 3 is now emerging vir and RBV was the same 16 weeks of treatment with duration of therapy with sofosbuvir and RBV promises as the Achilles’ heel of HCV as in the NEUTRINO sofosbuvir 400 mg per day improved SVR rates, we still need to do better. Time will study; in the control group, and RBV 1,000 to 1,200 tell if it will be necessary to add IFN or a second HCV therapy.’ patients received RBV 800 mg per day. Thirty per- DAA, or simply if longer treatment duration will achieve —Jacqueline O’Leary, MD, MPH mg per day, in two divided cent of participants in each the SVR rates patients and practitioners are now demanddoses. Approximately 20% group had the IL28B CC ing—higher than 90%! of patients in both groups genotype, 34% had comhad cirrhosis. pensated cirrhosis, 63% had ew Consensus Definition of Acute Kidney Findings showed 67% of patients in both groups HCV genotype 3 and 25% were prior null responders.

Injury Accurately Predicts 30-day Mortality achieved SVR at week 12. One patient who received Among patients with HCV genotype 2, 100% of in Patients with Cirrhosis with Infection. sofosbuvir and 18 patients in the control group had patients without cirrhosis and 78% of patients with cir- (Wong F et al. Gastroenterologyy 2013 Aug 30 virologic breakthrough. Additionally, 29% of sofos- rhosis in the 16-week treatment group achieved SVR at [Epub ahead of print]) buvir recipients and 20% of PEG-IFN/RBV recipi- week 12 compared with 96% and 60% of patients without ents experienced virologic relapse after treatment. and with cirrhosis, respectively, in the 12-week treatment This study evaluated a newly-proposed definition for Subgroup analyses revealed that 97% of patients group. Among patients with HCV cirrhosis-associated with HCV genotype 2 and 56% of those with HCV genotype 3, 63% of patients without acute kidney injury genotype 3 who received sofosbuvir achieved SVR cirrhosis and 61% of patients with (AKI): an increase ‘Fortunately, the new at week 12 compared with 78% and 63% of patients cirrhosis in the 16-week treatment in serum creatinine consensus definition of AKI with HCV genotype 2 and 3, respectively, in the con- group achieved SVR at week 12, level of greater than trol group. Among patients with cirrhosis at baseline, whereas 37% and 19% of patients 50% relative to baseproposed by the International 47% and 38% achieved SVR at week 12 in the sofos- without and with cirrhosis, respecline over a six-month Ascites Club has been buvir and PEG-IFN/RBV groups, respectively. tively, in the 12-week treatment period, or a decrease In the FISSION trial, 1% of sofosbuvir recipients group achieved SVR at week 12. of 0.3 mg/dL or validated in a large, prospective discontinued treatment due to an AE, 3% experiSerious AEs occurred in 5% more over 48 hours. multicenter trial.’ enced a serious AE and 86% experienced any AE; and 3% of patients in the 12- and Researchers at 12 —Jacqueline O’Leary, MD, MPH corresponding rates in the PEG-IFN/RBV group 16-week treatment groups, respeccenters prospectively were 11%, 1% and 96%, respectively. tively. No participants required AEcollected data from Common sofosbuvir-related AEs reported by related treatment discontinuation.

337 patients with patients in both the FISSION and NEUTRINO Five percent and 10% of patients in cirrhosis who were studies included fatigue, headache, nausea and insom- the 12 and 16-week treatment groups, respectively, expe- hospitalized for infection or who developed infection while nia. In the FISSION trial, 9% and 14% of sofosbuvir rienced a drop in hemoglobin to less than 10 g/dL, and in the hospital. Slightly more than half of the participants and PEG-IFN/RBV recipients, respectively, expe- 2% of patients in the 12-week treatment group had levels were men; mean age was 56 years and mean Model for rienced a reduction in hemoglobin concentration. below 8.5 g/dL. Common AEs in both groups included End-Stage Liver Disease (MELD) score was 20.

No patients who received sofosbuvir experienced fatigue, headache, insomnia, nausea, irritability, cough and The investigators determined that 49% of patients met decreased lymphocyte, neutrophil, platelet or white diarrhea. the new criteria for AKI during hospitalization. Patients cell counts compared with 11%, 14%, 7% and 5%, In the POSITRON study, 278 patients with HCV with AKI defined by the new criteria had a higher mean respectively, of PEG-IFN/RBV recipients. genotype 2/3 for whom IFN treatment was not an option Child-Pugh score compared with those who did not have were randomized to receive 12 weeks of treatment with AKI (11 vs. 9.6, respectively; P<0.001), a higher mean Dr. O’Leary: either sofosbuvir 400 mg per day and RBV 1,000 to 1,200 MELD score (23 vs. 17, respectively; P<0.001) and a We are on the verge of FDA approval of the first mg per day, or RBV plus a placebo. lower mean arterial pressure (81 mm Hg vs. 85 mm Hg, HCV NS5B polymerase inhibitor. Sofosbuvir, a In the sofosbuvir treatment group, 78% of patients respectively; P<0.01). Additionally, 34% of those with AKI once-daily, active site nucleotide inhibitor, must be achieved SVR at weeks 12 and 24 compared with none of defined by the new criteria died within 30 days of hospitalcombined with PEG-IFN and RBV for 12 weeks the patients in the placebo group. Broken down according ization compared with 7% of those who did not meet the in treatment-naive patients with HCV genotype 1 to genotype, 93% of those with HCV genotype 2 who new criteria; 46% and 20%, respectively, required intensive patients, and holds the promise of 90% SVR rates, received sofosbuvir achieved SVR at week 12 compared care; 27% and 6%, respectively, required ventilation; and dropping only to 82% in patients with compensated with 61% of patients with HCV genotype 3. Assessed 31% and 8%, respectively, experienced shock. The mean cirrhosis. Patients with HCV genotype 2, regard- according to cirrhosis status, 92% of HCV genotype 2 length of hospital stay among patients with AKI was 18 less of fibrosis status, will now have an outstanding patients without cirrhosis who received sofosbuvir had days compared with 13 days for patients without AKI IFN-free treatment option, promising SVR rates that SVR at week 12 compared with 94% of patients with (P<0.001). continued on page 18 approach 100%. cirrhosis; 68% and 21% of HCV genotype 3 patients

N

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continued from page 17

The investigators also found that 56% of AKI episodes were transient, 28% were persistent and 16% necessitated dialysis. Eighty-percent of those who did not recover from AKI died compared with 40% of those who had a partial recovery, 15% of those who had complete recovery and 7% of those without AKI. Dr. O’Leary: Fortunately, the new consensus definition of AKI proposed by the International Ascites Club has been validated in a large, prospective multicenter trial by

Wong et al. This new definition: 1) facilitates early diagnosis, 2) encompasses all patients with AKI and 3) accurately predicts the risk for death. This user-friendly definition should facilitate earlier interventions to improve outcomes in patients with AKI and encourage drug development for this critical condition that has a dramatic effect on survival.

■ Dr. O’Leary has received fees for research, consulting or speaking from Genentech, Gilead Sciences and Vertex Pharmaceuticals.

Zobair Younossi, MD, MPH Vice President for Research Inova Health System Chairman, Department of Medicine Inova Fairfax Hospital Falls Church, Virginia

IRA M. JACOBSON, MD Vincent Astor Distinguished Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director, Center for the Study of Hepatitis C NewYork-Presbyterian Hospital/Weill Cornell Medical College New York, New York

S

erum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children.

(Feldstein AE et al. Am J Gastroenteroll 2013;108:1526-1531) The authors of this paper examined the diagnostic accuracy of serum cytokeratin-18 (CK-18) fragment levels—a noninvasive biomarker of increased hepatocyte apoptosis—in the diagnosis of nonalcoholic steatohepatitis (NASH) in children.

The study included 201 children (mean age, 10.7 years; 37% male) who had biopsy-proven nonalcoholic fatty liver disease (NAFLD). NAFLD activity was scored using an 8-point scale and fibrosis was staged on a 4-point scale. CK-18 levels were measured with the M30-Apoptosense enzyme-linked immunosorbent assay kit using blood samples collected during biopsy. NASH was diagnosed based on Brunt’s criteria and a scoring of histologic features, including steatosis, lobular inflammation, ballooning and portal inflammation.

‘Although this study shows that CK-18 has fairly good performance in pediatric patients, the findings suggest only that it is a promising— but not a proven— noninvasive biomarker. … At the moment, it is not ready for prime time.’

—Zobair Younossi, MD,

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ecent research has demonstrated the eagerly awaited proof of concept that hepatitis C virus (HCV) infection can be cured without interferon. Trials involving directacting antiviral agents of several classes, as well as drugs with other mechanisms of action, either with or without interferon and ribavirin are proceeding at a remarkable pace. These exciting developments mandate the education of all physicians who treat patients with HCV infection in the proper use of the new agents, including management of side effects. Individualization of treatment decisions, both in treatment-naive and treatment-experienced patients, remains of paramount importance. The latest data will be summarized in this comprehensive review, scheduled for publication in 2014.

MPH

The researchers found that children with NASH had a mean of 322.1±104.8 U/L of CK-18 compared with a mean of 164.2±62 U/L among children without NASH (P<0.001). The likelihood of having biopsy-proven NASH increased by 70% with each increase of 10 U/L in CK-18 levels, after adjusting for potentially confounding variables (P<0.001).

A cut-off of 233 U/L was 85% sensitive and 87% specific, and had a positive predictive value of 93.7% and a negative predictive value of 71%, the researchers found. They also found that CK-18 levels were significantly higher in patients with biopsy-proven fibrosis (F1-F3) compared with patients without fibrosis (304.6±124.8 U/L vs. 210.4±70.9 U/l; P<0.001).

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‘Findings like these confirm that although NAFLD is more common in obese and overweight individuals, it is also seen in nonobese people.’

—Zobair Younossi, MD, MPH

Dr. Younossi: Currently, the only reliable and accurate way to distinguish NASH from nonprogressive NAFLD is with liver biopsy, which is expensive, invasive and associated with complications. Because of this, researchers have been trying to develop noninvasive serum biomarkers, among which CK-18 is a candidate. CK-18 is a marker of apoptosis, which is one of the mechanisms postulated to lead to the development of NASH, as well as progressive cirrhosis.

There have been some good studies showing CK-18 has a reasonable diagnostic performance, but at this point it has not proven to stand the test of external validation. Although this study shows that CK-18 has fairly good performance in pediatric patients, the findings suggest only that it is a promising—but not a proven—noninvasive biomarker. Now, we have to validate this in other pediatric populations. At the moment, it is not ready for prime time.

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revalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai study.

(Xu C et al. Am J Gastroenterol 2013;108:1299-1304) This longitudinal, cross-sectional study examined the prevalence and risk factors for NAFLD in nonobese Chinese individuals over a five-year period. The study included 6,905 nonobese employees (body mass index [BMI] <25 kg/m2) at the Zhenhai Refining & Chemical Company in Ningbo, China. Of these individuals, 502 (7.27%) had NAFLD at baseline. Mean baseline BMI was 23.6 kg/m2 among those with NAFLD and 21.5 kg/m2 among those without NAFLD. Five years after study outset, 8.88% (494/5,562) of those who did not have NAFLD at baseline developed it. Multivariate analyses showed that older age, male gender, BMI, waist circumference, serum triglycerides, high-density lipoprotein cholesterol, serum uric acid, hemoglobin and higher platelet counts all were independent and significant predictors of NAFLD. Although all individuals had a BMI

less than 25 kg/m2 at baseline, when BMI values were grouped into quintiles, the researchers found the five-year

cumulative incidence of NAFLD was 1.53%, 3.15%, 8.27%, 11.51% and 19.96%, respectively, in the five groupings (P<0.001 for trend).

Dr. Younossi: Previous research our team has conducted examined the NHANES (National Health and Nutrition Examination Survey) III dataset and found that, even in nonobese individuals, NAFLD is present (Younossi ZM et al.

Medicine (Baltimore) 2012;91:319-327).

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This was an interesting study from China that suggests that NAFLD is becoming more common, not only in the United States but also in other countries. Findings like these confirm that although NAFLD is more common in obese and overweight individuals, it is also seen in nonobese people. Given the increasing rates of obesity from all corners of the world, NAFLD is becoming the most serious liver disease today. continued on page 20

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xternal V Validation of the Fatty Liver Index for Identifying Nonalcoholic Fatty Liver Disease in a Population-based Study.

‘The Fatty Liver Index [FLI] may be good for

(Koehler EM et al. Clin Gastroenterol Hepatol 2013;11:1201-1204)

hepatic fibrosis. The FLI, therefore, does not hone

In this study, Dutch researchers set out to validate the accuracy of the Fatty Liver Index (FLI), a 100-point scale used for diagnosing NAFLD. The score is based on measurements of waist

progressive disease. Therefore, I believe that the FLI

E

determining if a patient has NAFLD, but it does not tell you if the patient has NASH, nor does it estimate in on the group of patients with NAFLD who have has limited clinical utility.’

—Zobair Younossi, MD, MPH

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circumference, BMI scores, and levels of triglycerides and γ-glutamyltransferase. γ The investigators used cut-off values recommended by the FLI’s creators: a score less than 30 to rule out NAFLD, and a score of at least 60 to confirm NAFLD. The authors collected ultrasonography and FLI data from participants in the prospective, population-based Rotterdam Study from February 2009 to February 2012. They identified data from 2,652 patients (mean age, 76.3) that comprised information derived from interviews and clinical examination results, including abdominal ultrasound images, fasting blood samples and anthropometric assessments. NAFLD was defined as the presence of ultrasound-confirmed fatty liver in the absence of excessive alcohol consumption, hepatitis B surface antigen, HCV infection or use of medications known to be associated with fatty liver.

According to the investigators, 34.9% of individuals (925 of 2,652) had ultrasound-confirmed NAFLD, including 139 with mild disease and 786 with moderate-to-severe NAFLD. Univariate and multivariate statistical analyses confirmed that FLI scores strongly correlated with the likelihood of ultrasoundconfirmed NAFLD. In an area under the receiver operating characteristic curve analysis, they found that FLI scores predicted ultrasound-confirmed NAFLD in 81.3% of cases. An FLI score less than 30 was 91.5% sensitive and 49% specific in ruling out NAFLD, and an FLI score of 60 or higher was 60.4% sensitive and 82.3% specific in predicting the presence of the disease.

Dr. Younossi: This study is consistent with previous literature showing that FLI can accurately predict NAFLD. However, the study does not address the clinical dilemma, which is how to predict, detect and distinguish NASH from non-progressive NAFLD. The FLI may be good for determining if a patient has NAFLD, but it does not tell you if the patient has NASH, nor does it estimate hepatic fibrosis. The FLI, therefore, does not hone in on the group of patients with NAFLD who have progressive disease. Therefore, I believe that the FLI has limited clinical utility.

E

xtra-hepatic complications of nonalcoholic fatty liver disease.

(Armstrong MJ et al. Hepatology 2013 Sept 3 [Epub ahead of print]) This review includes the recent literature examining the correlation between NAFLD and cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease (CKD) and colorectal cancer (CRC).

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER OCTOBER 2013 2013

The authors identified six retrospective and nine prospective studies analyzing a link between NAFLD and CVD, with follow-up periods ranging from 7.6 to 18 years for the retrospective studies and from 4 to 14.5 years for the prospective studies. The retrospective studies showed that NASH, but not simple steatosis, was associated with significantly increased rates of CVD-related and overall mortality. The prospective studies yielded conflicting findings.

For example, one study showed an 87% increase in the risk for incident non-fatal and fatal CVD events associated with NAFLD over a 6.5-year period, whereas an analysis of the NHANES III database, which included over 11,000 Americans, revealed no association with risk for CVD events or death over 14 years.

Rather, the NHANES III data showed that only NAFLD with advanced fibrosis was associated with an increased risk for CVD-related mortality.

of NAFLD was examined in 12 retrospective studies and five prospective studies. The retrospective studies showed that between 21% and 54% of NAFLD patients had CKD compared with a prevalence of 3.7% to 24.2% among those without NAFLD. Of the five prospective studies, four showed an increased risk for CKD and/or microalbuminuria, ranging from 1.49 to 4.38 times that of individuals without NAFLD. Finally, five retrospective studies examined the risk for CRC in patients

with NAFLD. Most found an independent association with colorectal adenomas, with the increased risk ranging from 1.45 to 4.89. The reviewers noted that there were no welldesigned, prospective studies looking at this association.

Dr. Younossi: It has been known for a while that NAFLD is strongly associated with CVD and CVD-related mortality, as well as several other conditions. One of the more novel areas researchers are

21

focusing on, and one that this article reviewed, is the possible association between NAFLD and CKD. In my view—similar to CVD—CKD is just another manifestation of metabolic abnormalities, such as type 2 diabetes, all of which are tied together through a common mechanism.

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

‘One of the more novel areas researchers are focusing on … is the possible association between NAFLD and CKD. In

For overt HE* patients

my view—similar to CVD—CKD is just another manifestation of metabolic abnormalities, such as type 2 diabetes, all of

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS “After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indefinite period of time or until liver transplantation.”

which are tied together

—Clinics in Liver Disease, February 20121

through a common

73% of recurrences among lactulose patients result in hospitalization 2

mechanism.’

Xifaxan 550 mg reduces the risk of HE-related hospitalizations by 50%3†‡

—Zobair Younossi, MD, MPH

The most common adverse reactions (≥12% incidence) in clinical trials with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.

Prescribe. Protect. Repeat.

*HE=hepatic encephalopathy. † Over a 6-month period; P=0.0129 vs placebo.3 ‡ HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.3

Six retrospective studies with followup periods of 4 to 13.7 years and three prospective studies with follow-up periods ranging from 7 to 10 years examined the link between NAFLD and type 2 diabetes. Most studies found an independent and significant association between NAFLD and incident type 2 diabetes. Those that did reported that individuals with NAFLD had a two- to 5.5-fold increased risk for type 2 diabetes. This relationship held after adjusting for several lifestyle and metabolic variables.

The risk for CKD in the presence

Important Safety Information About XIFAXAN 550 mg XIFAXAN® (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFA X AN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother.

The most common adverse reactions occurring in ≥10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).

Xifaxan 550 mg is not available for sale outside the U.S. Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see Brief Summary on reverse.

References: 1. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis. 2012;16(1):73-89. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):10121017. 3. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2011.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74-1

www.Xifaxan550.com

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Sofosbuvir With Ribavirin Shows Promise in Traditionally Difficult-To-Treat Patients With Hepatitis C

BY GEORGE OCHOA The experimental drug sofosbuvir (Gilead Sciences), in combination with ribavirin, showed promising results in a single-center, randomized open-label Phase II trial of 60 patients with hepatitis C virus (HCV) genotype 1. The interferon-free, 24-week,

The following is a brief summary; see complete Prescribing Information at www.Xifaxan550.com.

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

oral regimen was safe and well tolerated, and resulted in a sustained virologic response (SVR) rate of 68% in patients who received a weightbased dose of ribavirin and 48% in patients who received low-dose ribavirin. The study was published in the Aug. 28 issue of the Journal of the American Medical Association (Osinusi A et al. 2013;310:804-811).

had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

Table 1: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo

Hepatic Encephalopathy XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.

In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed.

XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores > 25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

CONTRAINDICATIONS Hypersensitivity XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis [see Adverse Reactions (6.2)].

WARNINGS AND PRECAUTIONS Travelers’ Diarrhea Not Caused by Escherichia coli XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered.

XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug Resistant Bacteria Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Severe (Child-Pugh C) Hepatic Impairment There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The population studied

Number (%) of Patients

MedDRA Preferred Term Edema peripheral Nausea Dizziness Fatigue Ascites Muscle spasms Pruritus Abdominal pain Abdominal distension Anemia Cough Depression Insomnia Nasopharyngitis Abdominal pain upper Arthralgia Back pain Constipation Dyspnea Pyrexia Rash

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

21 (15%) 20 (14%) 18 (13%) 17 (12%) 16 (11%) 13 (9%) 13 (9%) 12 (9%) 11 (8%) 11 (8%) 10 (7%) 10 (7%) 10 (7%) 10 (7%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 7 (5%)

13 (8%) 21 (13%) 13 (8%) 18 (11%) 15 (9%) 11 (7%) 10 (6%) 13 (8%) 12 (8%) 6 (4%) 11 (7%) 8 (5%) 11 (7%) 10 (6%) 8 (5%) 4 (3%) 10 (6%) 10 (6%) 7 (4%) 5 (3%) 6 (4%)

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure.

Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension

Postmarketing Experience The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Infections and Infestations Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)].

General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

DRUG INTERACTIONS In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use.

“There is a pressing need for hepatitis C virus treatments that are less burdensome to the patient, have fewer side effects and take less time to complete. Building on previous work, this trial provides compelling evidence that interferon-free regimens can be safe and effective,” said study coauthor Anthony S. Fauci, MD, director of the National Institute

An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium.

The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients, based upon plasma AUC comparisons.

Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

Nursing Mothers It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

‘Building on previous work, this trial provides compelling evidence that interferon-free regimens can be safe and effective.’

—Anthony S. Fauci, MD

Pediatric Use The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age.

Geriatric Use Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC␶) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally.

Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)].

Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74

of Allergy and Infectious Diseases, Bethesda, Md., in a press statement.

The patients included in the trial were treatment-naïve and had chronic HCV infection. Notably, there was a high prevalence of unfavorable traditional predictors of treatment response in this study population (e.g., black race, HCV genotype 1a, advanced fibrosis, body mass index greater than 30 kg/ m2) compared with previous trials of other direct-acting antiviral agents.

Thus, the patients were demographically representative of the HCV epidemic in the United States, the authors wrote.

The primary end point of the study was undetectable HCV viral load at 24 weeks after treatment completion. The trial was conducted in two parts. The first part was a proof-ofconcept study in which 10 patients with early to moderate liver fibrosis

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER OCTOBER 2013 2013

There was a high prevalence of unfavorable traditional predictors of treatment response in this study population compared with previous trials of other directacting antiviral agents.

were treated for 24 weeks with 400 mg per day of sofosbuvir and weightbased ribavirin (if <75 kg, 400 mg in the morning, 600 mg in the evening; if >75 kg, 600 mg twice daily). In this part of the study, nine patients (90%) achieved SVR at week 24 (95% confidence interval [CI], 55%-100%).

In the second part of the study, 50 patients with all stages of liver fibrosis were randomized to receive 400 mg per day of sofosbuvir combined with either a weight-based dose of ribavirin or low-dose ribavirin (600 mg daily) for 24 weeks. By week 4, viral suppression was achieved by 24 of 25 patients (96%) in each of the dosage groups. However, some of these patients relapsed at treatment completion: Seven patients (28%) in the weight-based ribavirin group and 10 patients (40%) in the low-dose ribavirin group relapsed at week 24.

SVR rates at week 24 were 68% in the weight-based treatment group and 48% in the low-dose treatment group (95% CI, 46%-85% and 28%69%, respectively; P=0.20).

“Bivariable analysis of baseline factors showed that in all randomized patients who completed treatment, the odds of relapse were significantly higher in participants who were

H E PAT O L O G Y I N F O C U S

male (odds ratio [OR], 6.09; 95% CI, 1.17-31.6), had advanced fibrosis (OR, 4.27; 95% CI, 1.10-16.54) and had baseline HCV RNA greater than 800,000 IU/mL (OR, 5.74; 95% CI, 1.35-24.38),” the authors wrote.

Twenty patients were included in a pharmacokinetic–viral kinetic substudy, which showed that patients who relapsed had a slower loss rate of infectious HCV than those who achieved SVR (HCV rate clearance 3.57 vs. 5.60 per day, respectively; P=0.009).

23

None of the study participants discontinued treatment due to adverse events. The most common side effects of treatment, ranging from mild to moderate in severity, were headache, anemia, fatigue and nausea.

The authors acknowledged the small sample size as a limitation of the study.

“Due to the small size, associations described are preliminary in nature and require further evaluation in larger studies,” the authors wrote.

■

24

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Single-Port Liver Resection Safe, Feasible in Selected Patients

BY VICTORIA STERN Surgeons have been performing laparoscopic liver resections since the late 1980s, but the standard approach to managing liver malignancies is still open surgery.

“Liver resection has been one of the last areas where we’ve applied minimally invasive techniques,” said T. Peter Kingham, MD, Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York City. “It’s a challenge to safely perform the same liver resection laparoscopically, as open, in all segments of the liver.”

A new study, led by Mitsuhiro Asakuma, MD, Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki City, Japan, demonstrated the safety and feasibility of single-port laparoscopic liver resection using a surgical glove port in 19 patients, all of whom recovered quickly and experienced minimal postoperative pain. The new research, presented at the 21st International Congress of the European Association for Endoscopic Surgery (EAES) in June, won the Olympus EAES Award for best oral presentation on single-port surgery.

“I think this is a well-done study,” said Dr. Kingham, who was not involved in this research. “The surgeons’ surgical glove method, in particular, is novel and applicable in most hospitals because it does not require any extra equipment.”

Other recent efforts have shown promise for a single-port approach to liver resection in selected patients. In 2011, Dr. Kingham and his colleagues published information on a small series of single-port liver resections, in which they reported the safety and feasibility of left-liver wedge resection through a single port (Gaujoux S et al. Surg Endosc 2011;25:1489-1494). Research by surgeons in Japan showed the success of single-port laparoscopic hepatectomy in eight patients, none of whom experienced wound pain or liver dysfunction after a two-week follow-up (Aikawa M et al. Surg Endoscc 2012;26:1696-1701).

Another recent study from Korea found single-port laparoscopic liver resection to be feasible in “well-selected cases” (Shetty GS et al. Surg Endoscc 2012;26:16021608). In this study, of the 24 patients with hepatocellular carcinoma who underwent the single-port procedure, two were converted to multiport laparoscopic hepatectomy due to limitations of the instrument length and four were converted to open surgery.

In the current prospective study, Dr.

Surgical glove port for single-port laparoscopic liver surgery as used by a team of surgeons in Takatsuki City, Japan.

‘The estimated advantages of the [single-port approach] are less postoperative pain, better cosmetic results and greater patient satisfaction. Potential disadvantages are sacrifices to safety, which we aim to eliminate.’

—Mitsuhiro Asakuma, MD

Asakuma and his colleagues completed 339 single-port procedures from June 2009 to May 2013 at their hospital, 19 of which were single-port hepatectomies— eight partial resections, seven lateral sectionectomies, three fenestrations and one mast cell tumor. (The series also included 293 cholecystectomies, three cholecystectomies with common bile duct stones, 12 appendectomies, five colectomies and three additional operations.)

Dr. Asakuma’s team performed the procedures using a surgical glove port, which they previously found was an effective and low-cost tool to facilitate single-port surgery (Hayashi M et al.

World J Surgg 2010;34:2487-2489). During the surgery, the team created a 2-cm incision along the umbilicus to insert the port and extract the specimens. The resection surface was a flat plane in nine cases and a curved plane in six. All but three patients had malignancies on the left side of the liver.

Of the eight patients undergoing partial resection, operative time ranged

from 60 to 225 minutes and bleeding occurred in one patient (800 mL). For the seven patients undergoing lateral sectionectomy, operative time ranged from 50 to 155 minutes and bleeding was minimal, also occurring in only one patient (330 mL). No blood transfusions were needed and the resection margins remained clear. Patients resumed an oral diet and regained full mobility on postoperative day 1.

The authors concluded that the single-port liver resection is an achievable technique, especially for lateral segments, and comes with several benefits to patients.

“The estimated advantages of the [single-port approach] are less postoperative pain, better cosmetic results and greater patient satisfaction,” said Dr. Asakuma.

“Potential disadvantages are sacrifices to safety, which we aim to eliminate.”

According to Dr. Asakuma, the next step is to conduct a randomized controlled trial comparing the singleport approach to liver resection with

laparoscopic and open approaches. Dr. Asakuma believes that, although singleport surgery for liver resection was born just three years ago, it has the potential to replace laparoscopic or open techniques through patient demand.

However, Dr. Kingham is more skeptical of the benefits of single-port liver resection beyond cosmesis.

“The single-port technique is very limited to the superficial left sides of the liver,” Dr. Kingham noted.

“Our team, for instance, is focusing more on developing laparoscopic techniques that we can use anywhere in the liver, including the harder-to-reach right side.”

As instrumentation improves and allows for more maneuverability, singlesite liver resection may be applied to more parts of the liver, but is unlikely to become the standard of care, Dr. Kingham added.

“I believe, however, that it’s important to show that single-site is possible.

That is how the field of surgery truly advances.”

■

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

25

CRC Screening continued from page 1

based on an individual’s risk, and would optimize the balance between benefit and risk, Dr. Imperiale said. In this scenario, CRC screening would be more aggressive in high-risk groups of patients, and could be delayed or performed with noninvasive testing for individuals in whom risk for CRC is low.

David Lieberman, MD, of Oregon Health & Science University in Portland, presented data at the DDW meeting in support of a more individualized CRC screening methodology, based on an individual’s age, gender and race. However, he acknowledged, there is controversy surrounding limiting some forms of CRC screening.

“CRC screening is already confusing due to the availability of different screening options. Risk-based screening could paradoxically reduce screening rates by creating more confusion,” Dr. Lieberman said.

“But,” he added, “the more rational use of colonoscopy resources would avoid the risks and expense of colonoscopy in persons who would derive little benefit.”

Dr. Lieberman noted that the concept of risk-based stratification in CRC screening is not new.

“We already make risk-based decisions for CRC screening,” he said. “For example, it is not recommended for average-risk individuals before age 50, because the yield is low.”

Delayed Screening for Some Women As one way of more efficiently screening for CRC in the general population, Dr. Lieberman presented data

to the availability of different screening options. Risk-based screening could paradoxically reduce screening rates by creating more confusion.’

—David Lieberman, MD

in support of delaying CRC screening in some women.

He and his colleagues examined data from the largest ever survey of average-risk individuals undergoing colonoscopy screening for CRC: The Clinical Outcomes Research Initiative (CORI) database of 327,785 colonoscopies in average-risk individuals aged 50 to 74 years.

“Our study aimed to determine the age when women would have a similar risk for large polyps (>9 mm) as compared to the benchmark of white men aged 50 to 54, for whom screening is not controversial.”

Their analysis showed that among average-risk individuals, women have a lower age-adjusted risk for large polyps compared with men (Figure).

“The results are consistent with the biologic hypothesis that colon neoplasia is delayed in women,” Dr. Lieberman said. “Age-adjusted CRC risk is higher in men than in women, with a 10-year lag in cancer risk observed in women.”

10

‘But, the more rational use of colonoscopy resources would avoid the risks and expense of colonoscopy in persons who would derive little benefit.’

—David Lieberman, MD When Dr. Lieberman’s group analyzed the results according to race, black women aged 50 to 55 years had the same risk for CRC as white men of the same age.

However, white women did not reach the same risk level until age 65 years, and Hispanic women did not have a similar risk until age 70 years.

“The implications are that the initiation age for [CRC] screening should be risk-based—delayed for white and Hispanic women, but remaining at age 50 for black women,” Dr. Lieberman concluded.

Women Men

12

Age-adjusted Risk, %

‘CRC screening is already confusing due

White men, 50-54 y

8 6 4

Changing Recommendations for Some Blacks 2 0 40-49

50-54

55-59

60-64

65-69 Age, y

70-74

75-79

>79

Figure.

Figure. Women have a lower age-adjusted risk for large polyps (>9 mm) compared with men. p Table 1. Number of Individuals Needed To Screen To Detect One Patient With a Large Polyp, Based on Gender, Age and Race Age, y 40-49

50-54

55-59

60-64

65-69

70-74

75-79

White

18.6

16.2

13.5

11.5

10.4

10.2

9.4

Black

20.0

14

11.7

8.4

8.1

8.7

9.9

Hispanic

16.4

21

16

13.2

11.8

13

9.3

White

28.8

24

22.5

19.1

16.6

15.3

13.9

Black

17.7

19.4

15.2

14.5

15.5

17.9

13.5

Hispanic

45.9

39.1

25

21.9

23.8

16.3

15.8

Men

Women

Black individuals have a higher incidence of CRC and CRC-related mortality, possibly because of earlier onset of CRC precursors, more aggressive tumor biology or lower access or adherence to recommendations for CRC screening. Therefore, the American College of Gastroenterology recommends that CRC screening begin at age 45 years for black individuals.

“It’s not clear, however, what would be more effective—earlier screening, or more aggressive adherence to screening at age 50,” Dr. Lieberman said.

An analysis of the CORI data revealed that the risk for large polyps in black men and women aged 40 to 49 years is lower than the risk for large polyps in white men aged 50 to 54 (Table 1). After the age of 50 years, however, black men and women are more likely to have large polyps compared with white individuals.

“These data support the initiation of screening in black men and women at age 50 years, when risk is similar to the risk in white men aged 50 to 54. Since blacks have higher risk for large polyps after age 50, screening efforts should be intensified beginning at age 50,” Dr. Lieberman suggested.

“Improving screening adherence among blacks will see CRC Screening, page 26

26

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

CRC Screening continued from page 25

likely have a greater impact on outcomes than the early initiation of screening, before age 50 years,” he concluded.

The data also confirm that blacks are screened for CRC at lower rates than whites. Although blacks comprise 12% of the U.S. population, they accounted for less than 6% of the population screened for CRC.

‘The index effectively stratified the risk for

Using Risk Factors To Stratify CRC Screening

be preferred.’

Dr. Imperiale pointed out that although several different risk factors for CRC have been established, only age (50 years as the threshold) and family history (one or more first-degree relatives with adenoma of CRC) are used in clinical practice. Other factors known to increase the risk for CRC include male gender, cigarette smoking, alcohol use, being overweight or obese, having diabetes and a diet high in red meat. Factors associated with lower risk for CRC include exercise; a diet high in fruits and vegetables; previous negative CRC screening results; and the use of aspirin, nonsteroidal anti-inflammatory drugs or postmenopausal estrogen.

“We don’t use any factors except for age and family history [in CRC screening], maybe because we lack an integrated model,” Dr. Imperiale said.

To this end, Dr. Imperiale and his colleagues developed a risk assessment index—based on a scale of 0 to 13—for the presence of advanced CRC neoplasia using literature-derived risk factors. They validated the model in a cross-sectional study of individuals undergoing first-time screening colonoscopy. Participants included asymptomatic persons aged 50 to 80 years. Individuals with previous findings of adenomatous polyps or CRC, and those with confirmed inflammatory bowel disease were excluded from the analysis. The derivation set included 3,025 individuals, and the validation set included 1,475 individuals. Advanced neoplasia was diagnosed in approximately 9% of each cohort.

“The index effectively stratified the risk for advanced neoplasia,” Dr. Imperiale said. “It identified low-risk

advanced neoplasia. It identified low-risk subgroups that may be screened effectively with tests other than colonoscopy, and highrisk subgroups for which colonoscopy may —Thomas Imperiale, MD

subgroups that may be screened effectively with tests other than colonoscopy, and high-risk subgroups for which colonoscopy may be preferred. If independently validated, this index could increase the uptake and efficiency of CRC screening,” he said.

Subgroups of individuals with very low risk and low risk comprised 53% of the cohort in Dr. Imperiale’s study (N=2,377); these groups combined accounted for five CRCs (all distal) and 94 advanced adenomas, detectable with sigmoidoscopy (Table 2).

Using FIT To Complement CRC Risk Assessment Joseph Sung, MD, of the Chinese University of Hong Kong, also presented data at the DDW meeting on a risk assessment model. Dr. Sung and his colleagues developed the Asia-Pacific CRC Screening (APCS) score, an index based on a score of 0 to 8, which aims to identify asymptomatic individuals at high risk for CRC using four parameters: age (score, 0-3), gender (score, 0-1), family history (score, 0-2) and smoking status (score, 0-1).

Dr. Sung’s group performed a prospective validation study of the APCS score in a cohort of 3,915 individuals aged 18 years and older from 10 countries and regions throughout Asia. Using the APCS index, individuals were classified as high-risk (score, 4-7), moderate-risk (score,

Table 2. Validation of Risk Assessment Index for Presence of Advanced CRC Neoplasia Risk Subgroup

Risk Assessment Index (score, 0-13)

% of Cohort

CRC Risk, %

Very low

0

8.2

1.65

Low

1-3

45.3

3.31

Intermediate

4-6

31.7

10.9

High

7-12

14.7

21.9

Table 3. Prospective Validation Study of Asia-Pacific CRC Screening Score for Detection of Advanced Neoplasia and CRC Low-Risk Group

Moderate-Risk Group

High-Risk Group

Advanced neoplasia

3

72

67

CRC

0

2

10

CRC, colorectal cancer

‘The APCS score selected the majority of subjects who required early colonoscopy for CRC screening.’

—Joseph Sung, MD

2-3) or low-risk (score, 0-1) for CRC. Risk was low in 20% of the cohort, moderate in 56% and high in 24%.

Individuals at high risk for CRC were offered the option of early colonoscopy (within four weeks), whereas moderate- and low-risk individuals were offered fecal immunochemical testing (FIT). Patients with positive FIT results were offered early colonoscopy, whereas FITnegative individuals underwent routine colonoscopy.

Compared with the low-risk group, Dr. Sung’s team found that CRC risk was fourfold higher among highrisk individuals and 2.4-fold higher in the moderate-risk group for patients in the derivation set. In the validation set, there was a three- to fourfold increased risk in the moderate-risk group, and a 10-fold increased risk in the high-risk group.

“The APCS score selected the majority of subjects who required early colonoscopy for CRC screening,” Dr. Sung reported.

Compared with the low- and moderate-risk groups combined, the high-risk group had roughly a fourfold increased risk for CRC, regardless of the FIT result.

There was an even greater difference in risk between low- and moderate-risk individuals with a negative FIT result compared with moderate- and high-risk individuals with a positive FIT result, Dr. Sung noted.

The prevalence of advanced neoplasia or CRC was 1.8% among individuals in the low- and moderate-risk groups who had a negative FIT result compared with approximately 9% among low- and moderate-risk individuals with a positive FIT result and those determined see CRC Screening, page 28

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28

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ OCTOBER 2013

CRC Screening continued from page 26

high-risk by risk stratification. FIT results, therefore, complemented risk scores in the selection of patients who would benefit from early colonoscopy, Dr. Sung said.

â&#x20AC;&#x2DC;Dr. Lieberman and colleaguesâ&#x20AC;&#x2122; findings support the results of our modeling study and

24,961 black adults and found that initiation of screening at age 50 years or older detected 48% of individuals with CRC compared with screening at age 45 years or older, which detected CRC in 53% of individuals (Gupta S et al. Arch Intern Medd 2012;172:182-184). They predicted that a 5% increase in screening rates would increase CRC detection rates in these groups to 53% and 57%, respectively. Based on this, they

concluded that a 5% increase in screening initiated at age 50 would be as effective as earlier initiation of screening, and a 10% increase in screening would result in higher detection rates. â&#x20AC;&#x153;Dr. Lieberman and colleaguesâ&#x20AC;&#x2122; findings support the results of our modeling study and challenge the traditional approach to managing populations at increased risk for CRC,â&#x20AC;? Dr. Gupta said. â&#x20AC;&#x153;Previously, our approach has been

to initiate screening earlierâ&#x20AC;&#x201D;e.g., start screening at age 40 for individuals with a family history of CRC, or at age 45 for African Americans. However, our modeling study, as well as Dr. Liebermanâ&#x20AC;&#x2122;s work, suggests that alternative approaches to managing risk, such as focusing on maximizing the screening rates for high-risk individuals above age 50 (in this case, for African Americans) might be more effective than lowering

challenge the traditional approach to managing populations at increased risk for CRC.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Samir Gupta, MD

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

â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s important for us to note how many cases of cancer we missed. Fortunately, 10 of the 12 cancers were in the high-risk group; two were in the moderate-risk group, but FIT picked them up; none were in the low-risk group,â&#x20AC;? he said (Table 3, page 26).

Earlier Screening Not Necessarily Better In another modeling study of CRC risk, Samir Gupta, MD, of the San Diego Veterans Affairs Healthcare System and associate professor of clinical medicine at the University of California, San Diego, and his colleagues analyzed CRC screening data from a cohort of

INDICATIONS AND USAGE UCERISâ&#x201E;˘ 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 t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B glucocorticosteroid, general warnings concerning glucocorticoids should be followed. t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH 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. t *ODSFBTFE TZTUFNJD HMVDPDPSUJDPJE TVTDFQUJCJMJUZ 3FEVDFE MJWFS function affects the elimination of glucocorticosteroids. t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT 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.

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USE IN SPECIFIC POPULATIONS )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT of hypercorticism.

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DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

the screening age,” he said.

“The public health implications are potentially very substantial,” Dr. Gupta added. “Instead of promoting a guideline lowering the screening age, we need to work to implement strategies proven to increase screening rates among African Americans, something that requires gastroenterologists to work much more closely with partners in primary care and public health.”

■

‘Our modeling study … suggests that alternative approaches to managing risk, such as focusing on maximizing the screening rates for high-risk individuals above age 50 (in this case, for African Americans) might be more effective than lowering the screening age.’

UCERIS™:

A POWERFUL, LOCALLY ACTING STEROID1-3 t

MMX® technology targets delivery of budesonide throughout the full length of the colon1,2

t

3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

A SAFETY PROFILE THAT OFFERS CONFIDENCE1 t The rates of overall expected glucocorticoid-related side effects were similar for UCERIS

and placebo at 8 weeks—10.2% vs 10.5%, respectively1*

www.UCERIS.com 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 *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. 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. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

© 2013 Santarus, Inc. 1-UCE13229 June 2013 Printed in the USA.

—Samir Gupta, MD

29

Dr. Lieberman has served on an advisory committee/review panel for Exact Sciences, and has consulted for Given Imaging Ltd., and Pfizer Consumer Healthcare. Dr. Gupta has consulted for Exact Sciences and has received grant/research support from Polymedco.

Drs. Imperiale and Sung reported no conflicts of interest.

30

DDW 2013

Choosing Wisely continued from page 1

to reduce the overuse of tests and procedures. The specialty societies that support the initiative have identified tests or procedures commonly used in their field, whose necessity should be questioned and discussed. â&#x20AC;&#x153;We recognize that patients often ask for tests and treatments that are not necessarily in their best interest, and physicians often struggle with decisions about prescribing tests and procedures as a way 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;˘ OCTOBER 2013

of covering all possible bases,â&#x20AC;? said Lawrence Kosinski, MD, chair of the AGA Practice Management and Economics Committee. â&#x20AC;&#x153;In many cases, more care is not always higher-quality care.â&#x20AC;?

To this end, the AGA published a list of â&#x20AC;&#x153;Five Things Physicians and Patients Should Question.â&#x20AC;? The list is available online at www.choosingwisely.org/ doctor-patient-lists/american-gastroenterological-association, and includes the following five directives: 1. For pharmacologic treatment of patients with gastroesophageal reflux 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

â&#x20AC;&#x2DC;We recognize that patients often ask for tests and treatments that are not necessarily in their best interest, and physicians often struggle with decisions about prescribing tests and procedures as a way of covering all possible bases.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Lawrence Kosinski, MD

disease, long-term acid suppression therapy (proton pump inhibitors or histamine-2 receptor antagonists) should be titrated to the lowest effective dose 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).

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

1-UCE13033 V1

needed to achieve therapeutic goals.

2. Do not repeat colorectal cancer screening (by any method) for 10 years after a high-quality colonoscopy is negative in average-risk individuals.

3. Do not repeat colonoscopy for at least five years for patients who have one or two small (<1 cm) adenomatous polyps, without high-grade dysplasia, completely removed via a high-quality colonoscopy.

4. For a patient who is diagnosed with Barrettâ&#x20AC;&#x2122;s esophagus, who has undergone a second endoscopy that confirms the absence of dysplasia on biopsy, a followup surveillance examination should not be performed in less than three years as per published guidelines.

5. For a patient with functional abdominal pain syndrome (as per ROME III criteria), computed tomography (CT) scans should not be repeated unless there is a major change in clinical findings or symptoms.

At a Choosing WiselyÂŽ symposium held at the 2013 Digestive Disease Week (DDW) meeting, David Lieberman, MD, chief of the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland, instructed attendees on proper intervals for colonoscopy screening and surveillance, while Dr. Kosinski, managing partner of the Illinois Gastroenterology Group in Elgin, discussed the overutilization of repeat CT scans for abdominal pain.

Is Colonoscopy Overutilized?

Adherence to evidence-based guidelines for colonoscopy screening and surveillance will be an important element of our future health care system, Dr. Lieberman told DDW attendees. â&#x20AC;&#x153;Under the current fee-for-service world, more colonoscopies are better, especially if we can get paid for it,â&#x20AC;? he said. â&#x20AC;&#x153;But with the dawn of the new world of coordinated care organizations, which discourage unneeded tests, we have to ask whether we are doing too much unnecessary surveillance.â&#x20AC;?

Dr. Lieberman predicted that in the near future, payors will be expecting highquality examinations, as well as screening and surveillance intervals consistent with evidence-based guidelines (Table, page 32). Physicians who do not adhere to recommendations will be pressed to provide reasons for deviating from the

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

recommended standards. For those who exercise poor judgment, there may be no reimbursement, Dr. Lieberman said.

For example, Dr. Lieberman noted, the U.S. Preventive Services Task Force recommends capping the age for routine screening colonoscopy at 75 years. However, an analysis of 327,000 average-risk individuals in the Clinical Outcomes Research Initiative database revealed that 5% of those who underwent screening colonoscopy were older than 75 years, and 2% were older than 79 years.

“One might argue that, in some cases, this may represent overutilization of screening,” Dr. Lieberman said.

Another concern is the length of screening intervals. The current recommendation, which is for a 10-year interval after a negative screening colonoscopy, is based only on indirect evidence. However, the risk for an interval advanced neoplasia after five years is well established, at somewhere between 1.3% and 2.4% (Lieberman DA et al. Gastroenterologyy 2012;143:844-857).

‘Repeat procedures for poor preps will be monitored as a quality indicator, and I don’t think we will be given a green light for them because the prep was so-so. Coordinated care will demand that we adhere to evidence-based screening guidelines.’

—David Lieberman, MD

Lieberman warned. “Coordinated care will demand that we adhere to evidencebased screening guidelines.”

There also are indications that

surveillance colonoscopies occur too frequently, Dr. Lieberman noted.

“We do this out of fear over missed lesions and interval cancers. Up to 17% of

polyps less than 1 cm are missed,” he said.

Endoscopists should keep in mind that different patients have varying degrees of risk for colorectal cancer and honor the established surveillance intervals based on risk stratification. This means doing colonoscopies in less than five to 10 years only in only certain subsets of patients, Dr. Lieberman said.

The evidence is less clear for surveillance in patients with serrated polyps.

Guidelines suggest that when serrated polyps contain dysplasia or are larger see Choosing Wisely, page 32

Visit us at ACG in booth #1411.

Ingenuity Delivered!

‘In many cases, more care is not always higher-quality care.’

—Lawrence Kosinski, MD

In this case, “our concerns are that the baseline prep was not pristine,” Dr. Lieberman said. Indeed, studies have shown that repeat examinations after suboptimal bowel preparation can have high yields. “What we need to do instead is to make fair preps into good preps with meticulous cleaning.”

The occurrence of interval cancers is another fear that leads some endoscopists to perform too-frequent screening. This fear is based on the fact that 2% to 9% of patients with colorectal cancer who are enrolled in cancer registries report having had a colonoscopy within the prior three years.

“The recommended interval is 10 years, but in real life, the interval is often less,” Dr. Lieberman noted.

This is supported by a study in which 30% of Medicare patients underwent colonoscopy five years after a negative examination (Goodwin JS et al. Arch Intern Medd 2011;171:1335-1343).

“Maybe there were good reasons, but this is potentially overutilization,” Dr. Lieberman said.

In the future, endoscopists may be held accountable for straying from guidelines for colonoscopy screening.

“Repeat procedures for poor preps will be monitored as a quality indicator, and I don’t think we will be given a green light for them because the prep was so-so,” Dr.

31

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DDW 2013

Choosing Wisely continued from page 31

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Physicians doing workups for abdominal pain in the emergency room should follow protocols and guidelines: Apply the Alvarado score (<5 means the patient can be safely discharged); employ clinical decision support tools when available; and use limited radiation scanning, Dr. Kosinski said.

similar circumstances have little cause to worry.

“My conclusion is that it comes down to clinical judgment,” Dr. Kosinski said. “We must make sure the original CT [scan] was of good quality. If the symptoms change, you may need to repeat the CT scan, but if there is no change, there is no reason to repeat it. Finally, when in doubt, just reevaluate the patient.”

than 10 mm in diameter, they should be treated the same as a high-risk adenoma (i.e., surveillance at threeyear intervals). For serrated polyps without dysplasia or less than 10 mm in diameter, a low-risk protocol applies (i.e., surveillance at five-year intervals).

The fact that risk-based surveillance guidelines ‘The idea is that some think colonoscopies and often are ignored is illustrated in the multicenter Prostate, Lung, Colorectal and Ovarian Cancer other commonly performed procedures are Screening Trial sponsored by the National Canassigned too many RVUs [relative value units], cer Institute (Schoen RE et al. Gastroenterology and this spurs excess utilization.’

2010;138:73-81). Patients in this study underwent screening sigmoidoscopy and were referred —Spencer Dorn, MD, MPH for colonoscopy if polyps were found during the examination. Researchers found that many of the polyps identified by sigmoidoscopy were not adenomas; however, 26% of patients without Table. Recommended Surveillance Intervals adenomas were examined again at five years, and After Colonoscopy With Adequate Bowel 10% underwent two or more surveillance examiPreparation nations within seven years. Among patients in whom one or two nonadvanced adenomas were Baseline Findinga Recommended found, 47% underwent colonoscopy within five Surveillance Interval, y years and 18% underwent two or more examinations within seven years.

Low risk “This is real-life evidence that there is overutilization in the community,” Dr. Lieberman said.

Repercussions of Payment Reform

Spencer Dorn, MD, MPH, assistant professor of medicine at the University of North Carolina at Chapel Hill School of Medicine, who has authored numerous articles on health care reform, predicted new payment models will result in a reduction in overutilization of several gastroenterology services, including colonoscopy.

“With the rapid rise in medical knowledge, we have seen increasing practice variation, and this has had significant ramifications in terms of quality and cost of care,” Dr. Dorn told DDW attendees.

“Payment reform is one strategy we are seeing in an attempt to increase the practice of evidence-based medicine.”

Under the current fee-for-service model, physicians are paid, “no matter what they do,” creating incentives to possibly overtreat, Dr. Dorn No polyp 10 noted. Payors are taking three broad approaches Is CT Scanning Overutilized? to change this.

Hyperplastic polyp, left-sided 10 Abdominal pain is the single most comFirst, payors are recalibrating fee-for-service mon reason for visits to the emergency room, by revaluing certain expensive procedures, such 1-2 tubular adenomas, <10 mm 5-10 and approximately 14% of these visits involve a as colonoscopy, in order to reduce the financial CT scan. The diagnosis most likely to be made incentive for potential overuse.

High risk with a CT scan—for one-third of patients—is “The idea is that some think colonoscopies “abdominal pain”—that is, a “normal finding,” and other commonly performed procedures are 3 or more tubular adenomas 3 Dr. Kosinski pointed out. assigned too many RVUs [relative value units], Tubular adenoma, >10 mm 3 The Choosing Wisely® statement suggests and this spurs excess utilization,” Dr. Dorn that for a patient with functional abdominal pain, explained. “The government hopes that if it Villous adenoma (>25% villous) 3 CT scans should not be repeated unless there is pulls back the RVUs assigned to colonoscopy, a major change in clinical findings or symptoms then providers won’t do as many.”

Adenoma with high-grade dysplasia 3 from the initial scan, Dr. Kosinski said.

Dr. Dorn told gastroenterologists to expect Although CT scans account for 10% of all “significant cuts.” Currently, a colonoscopy >10 adenomas <3 radiology imaging, these scans are responsible for with biopsy is valued at 45 minutes of pre50% of imaging radiation and have been assoservice time, 51 minutes of intraservice time Piecemeal resection 2-6 mo ciated with a small, but measurable, increase in and 22 minutes of postservice time. When the risk for cancer from x-ray exposure. For example, Centers for Medicaid & Medicare Services Cancer 1 radiation associated with an abdominal CT scan reevaluates the procedure, as it is doing now (at is equivalent to three years’ worth of natural press time), the RVU numbers will be dramatia Most advanced finding during colonoscopy background radiation, or 100 to 250 chest x-rays. cally lower, Dr. Dorn predicted.

“Over a lifetime, patients who receive two or Second, payors are pinning “carrots and sticks” three abdominal CT scans are exposed to more on top of fee-for-service schedules to reward radiation than many Hiroshima survivors,” Dr. physicians for quality and to penalize those who ‘The government hopes that if it pulls back the Kosinski noted. fall short. Examples of this strategy include the RVUs assigned to colonoscopy, then providers Despite this risk, the use of abdominal CT Physician Quality Reporting System, the Meanscanning is actually increasing and rising faster ingful Use Incentive Program and the upcoming won’t do as many.’ than the rate of emergency department visits.

Value-Based Payment Modifier system.

—Spencer Dorn, MD, MPH And many of these scans are repeat scans that Lastly, in the long term, payors are moving are probably unnecessary, Dr. Kosinski said. away from fee-for-service schedules toward A study from Brigham and Women’s Hospicompletely new models of payment, such as tal in Boston, found that 33% of patients had underMedicolegal issues surround much of the overuti- bundled payments and shared savings models. gone at least five lifetime CT scans, with 5% having had lization of CT scans, Dr. Kosinski added. He quoted “These new models will increase provider risk—movbetween 22 and 132 scans (Sodickson A et al. Radiology attorneys who have advised him to “look to published ing from fee-for-service, where risk is low because no 2009;251:175-184). The value of these repeat scans has criteria, such as the Alvarado score,” understand that matter the utilization providers will get paid for their been debated, with some studies showing that only 10% “unnecessary is defendable” and “use judgment, but work, toward higher provider risk,” Dr. Dorn said. of repeat scans reveal a positive finding, whereas a rate as don’t order scans because you are afraid of being sued.”

“Payment reform is one way payors are attempting high as 23% has been reported in other studies.

Usually, clinicians who follow the standard of care, prac- to ensure that we ‘choose wisely.’ It makes improving, “There seem to be two sides to the issue of value,” Dr. tice within the acceptable range and behave the way any measuring and reporting quality increasingly imporKosinski noted. reasonably careful physician would under the same or tant,” he concluded.

■

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

33

Optimal Bowel Prep Becoming Incumbent on Physicians Performing Endoscopy

BY CAROLINE HELWICK ORLANDO, FLA.—Optimal bowel preparation is key for the success of colonoscopy, obviating the need for repeat procedures, reducing the risk for interval cancers and becoming essential for endoscopists to meet quality indicators,

said experts in a presentation at the 2013 Digestive Disease Week (DDW) meeting entitled, “Hot Topics in Colonoscopy Quality.”

Brian C. Jacobson, MD, MPH, associate professor of medicine, Boston University School of Medicine, provided the following recommendations to ensure the best performance in bowel preparation.

Split-Dose Is Preferable As purgatives have improved, so has bowel preparation. Reviewing the recent literature, Dr. Jacobson said split-dose polyethylene glycol (PEG) is superior to full-dose PEG with respect to satisfactory colon cleansing. Additionally, the evidence is strong, but not definitive, for other outcomes, including better

Read the No. 1 publication in the

‘Split-dose prep is more

gastroenterology market,

effective and better tolerated than full-dose evening prep,

anywhere, anytime!

with demonstrated superiority.’

—Brian C. Jacobson, MD, MPH

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compliance with the regimen, greater willingness to repeat the same preparation and less prep-related nausea for patients.

“Split-dose prep is more effective and better tolerated than full-dose evening prep, with demonstrated superiority,” Dr. Jacobson said.

However, he acknowledged that some factors may tip the balance in favor of a full-dose PEG prep for some patients, including transit time to the endoscopy facility (e.g., some patients driving long distances to their procedure may prefer day-prior prep), and patients’ resistance to taking the second dose after midnight (e.g., about 25% of well-intentioned patients do not follow through).

Dr. Jacobson conducted a survey of 165 endoscopists that showed that 43% were using split-dose preps exclusively, 39% were using both single-dose and split-dose preps, and 18% were using single-dose preps.

“This shows that while there is still variability, split-dose preps are catching on,” Dr. Jacobson said.

A recent study of about 5,000 patients showed that when an endoscopy practice incorporates split-dose bowel preparation, multiple outcomes improve (Gurudu SR et al. Gastrointest Endosc 2012;76:603-608), including polyp and see Bowel Prep, page 36

Superior GPIERWMRK IJ½ GEG]*

*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. P<0.002 [Prepopik: n=256/304; comparator: n=221/297].1-3

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.

…with the lowest volume of active prep solution

Prepopik helps patients arrive ready with: SUPERIOR CLEANSING with ACG-recommended split-dose regimen*†1 84% of Prepopik bowel preparations were graded as “excellent” or “good” vs 74% with the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets), assessed using the validated Aronchick scale*1,2

90% of Prepopik patients had successful cleansing in the ascending colon vs 79% with the comparator, assessed using the validated Ottawa scale†1

EXCELLENT TOLERABILITY reported by patients in pivotal trials1,3 89% of patients found Prepopik easy to take vs 29% of those taking the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets); P<0.00011

99% of patients taking Prepopik completed their regimen vs 91% of those taking the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets)1

FLEXIBLE DOSING using either a split-dose or day-before regimen 4 A DUAL MECHANISM that stimulates peristalsis and produces osmotic water retention 4 †

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 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. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

Visit prepopik.com/tools to access a variety of helpful patient tools!

PREPOPIK® is a registered trademark of Ferring B.V. © 2013 Ferring B.V. All rights reserved.

PK/738/2013/US

36

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ OCTOBER 2013

Bowel Prep continued from page 33

adenoma detection rates, colonoscopy completion rates and quality of bowel preparation.

A valid option, especially for afternoon procedures, is a same-day split-dose prep, taken at about 6 a.m., Dr. Jacobson said.

A 4-L split-dose prep is preferable, but 2-L preps can suffice, he said. â&#x20AC;&#x153;Full-dose morning prep is actually superior to day-prior prep,â&#x20AC;? Dr. Jacobson said. â&#x20AC;&#x153;Low-volume morning prep is

comparable to low-volume split dosing (p.m./a.m.), and patients are less likely to lose sleep or have bloating, compared with evening or split-dose preps.â&#x20AC;?

Suboptimal Preps Should Be Abandoned Proceeding with colonoscopy in patients who have inadequate bowel preparation is usually unwise. â&#x20AC;&#x153;The procedure may not be as effective

Aspiration Patients with impaired gag reĂ&#x20AC;ex and patients prone to regurgitation or aspiration should Ee oEserYed during the administration of PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion Each packet must Ee dissolYed in ounces of cold water and administered at separate times according to the dosing regimen.

The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolYed powder may increase the risk of nausea, Yomiting, dehydration, and electrolyte disturEances.

INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults.

Clinical Trials Experience %ecause clinical trials are conducted under widely Yarying conditions, CONTRAINDICATIONS adYerse reaction rates oEserYed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: Ee directly compared to rates in clinical trials of another drug and may Â&#x2021; Patients with seYerely reduced renal function (creatinine clearance not reĂ&#x20AC;ect the rates oEserYed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and Yomiting were the most common adYerse reactions (! ) Â&#x2021; *astrointestinal oEstruction or ileus following PREPOPIK administration. 7he patients were not Elinded to Â&#x2021; %owel perforation the study drug. 6ince aEdominal Eloating, distension, pain/cramping, Â&#x2021;7 7oxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing Â&#x2021; *astric retention preparations, these effects were documented as adYerse eYents in Â&#x2021; $n allergy to any of the ingredients in PREPOPIK the clinical trials only if they reTuired medical interYention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adYerse eYent), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signiÂżcant worsening during the study that was $dYise patients to hydrate adeTuately Eefore, during, and after the not in the frame of the usual clinical course, as determined Ey the use of PREPOPIK. 8se caution in patients with congestiYe heart inYestigator. failure when replacing Ă&#x20AC;uids. If a patient deYelops signiÂżcant Yomiting PREPOPIK was compared for colon cleansing effectiYeness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters ( L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PE* E) and two -mg Eisacodyl taElets, all laE tests (electrolytes, creatinine, and %81) and treat accordingly. administered the day Eefore the procedure. 7a 7 Ele displays the most $pproximately 0 of patients in Eoth arms (PREPOPIK, L of PE* common adYerse reactions in 6tudy and 6tudy for the PREPOPIK E plus two x -mg Eisacodyl taElets) of clinical trials of PREPOPIK 6plit-Dose and Day-%efore dosing regimens, respectiYely, each as had orthostatic changes (changes in Elood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seYen days post colonoscopy.

Table 1: Treatment-Emergent Adverse Reactions observed in at )luid and electrolyte disturEances can lead to serious adYerse eYents Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte aEnormalities should Ee corrected Eefore treatment with PREPOPIK. In addition, use caution when prescriEing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who haYe conditions or who are using medications that Reaction increase the risk for Ă&#x20AC;uid and electrolyte disturEances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adYerse eYents of seizure, arrhythmia, and renal (N=296) with 2 x (N=305) with 2 x 5-mg impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl Seizures 7here haYe Eeen reports of generalized tonic-clonic seizures with the use of Eowel preparation products in patients with no prior history of seizures. 7he seizure cases were associated with electrolyte aEnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. 7he neurologic aEnormalities resolYed with correction of Ă&#x20AC;uid and electrolyte aEnormalities.

8se caution when prescriEing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or Eenzodiazepines, patients with known or suspected hyponatremia.

Use in Patients with Renal Impairment $s in other magnesium containing Eowel preparations, use caution when prescriEing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin conYerting enzyme inhiEitors, angiotensin receptor Elockers, or non-steroidal anti-inĂ&#x20AC;ammatory drugs). 7hese patients may Ee at increased risk for renal inMury. $dYise these patients of the importance of adeTuate hydration Eefore during and after the use of PREPOPIK. &onsider performing Easeline and post-colonoscopy laEoratory tests (electrolytes, creatinine, and %81) in these patients. In patients with seYerely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

bisacodyl tablets (N=302) n (% = n/N) 1ausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) L PE* E two liters polyethylene glycol plus electrolytes solution. aEdominal Eloating, distension, pain/cramping, and watery diarrhea not reTuiring an interYention were not collected tablets (N=298) n (% = n/N)

arrhythmias, and prolonged 47 in the setting of Ă&#x20AC;uid and electrolyte aEnormalities. 7his includes patients receiYing drugs which may Ee associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inĂ&#x20AC;ammatory drugs (16$ID6) or drugs known to induce $ntidiuretic Hormone 6ecretion (6I$DH), such as tricyclic antidepressants, selectiYe serotonin re-uptake inhiEitors, antipsychotic drugs and carEamazepine, as these drugs may increase the risk of water retention and/or electrolyte imEalance. &onsider additional patient eYaluations as appropriate.

Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may Ee Ă&#x20AC;ushed from the *I tract and the medication may not Ee aEsorEed. 7etracycline and Ă&#x20AC;uoroTuinolone antiEiotics, iron, digoxin, 7 chlorpromazine and penicillamine, should Ee taken at least hours Eefore and not less than hours after administration of PREPOPIK to aYoid chelation with magnesium.

Antibiotics Prior or concomitant use of antiEiotics with PREPOPIK may reduce efÂż f cacy of PREPOPIK as conYersion of sodium picosulfate to its actiYe metaEolite %HP0 is mediated Ey colonic Eacteria.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy &ategory % Reproduction studies with PREPOPIK haYe Eeen performed in pregnant rats at oral doses up to 000 mg/kg/day (aEout . times the recommended human dose Eased on the Eody surface area), and did not reYeal any eYidence of impaired fertility or harm to the fetus due to PREPOPIK. 7he reproduction study in raEEits was not adeTuate, as treatment-related mortalities were oEserYed at all doses. $ pre and postnatal deYelopment study in rats showed no eYidence of any adYerse effect on pre and postnatal deYelopment at oral doses up to 000 mg/kg twice daily (aEout . times the recommended human dose Eased on the Eody surface area). 7here are, howeYer, no adeTuate and well-controlled studies in pregnant women. %ecause animal reproduction studies are not always predictiYe of human response, PREPOPIK should Ee used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether this drug is excreted in human milk. %ecause many drugs are excreted in human milk, caution should Ee exercised when PREPOPIK is administered to a nursing woman.

Pediatric Use 7he safety and effectiYeness of PREPOPIK in pediatric patients has not Eeen estaElished.

Geriatric Use In controlled clinical trials of PREPOPIK, of 0 ( ) patients were years of age or older. 7he oYerall incidence of treatmentemergent adYerse eYents was similar among patients Â&#x2022; years of age ( 3 ) and patients < years of age ( ). $mong all patients Â&#x2022; years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group ( . ) than in the comparator In general, PREPOPIK was associated with numerically higher rates group ( 0. ). of aEnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing L of PE* E plus two x -mg Eisacodyl Renal InsufĂ&#x20AC; f ciency taElets. 7hese shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant Eetween treatment arms at the Day 30 Yisit. medications that may affect renal function (such as diuretics, angiotensin conYerting enzyme inhiEitors, angiotensin receptor Postmarketing Experience Elockers, or non-steroidal anti-inĂ&#x20AC;ammatory drugs) may Ee at 7he following foreign spontaneous reports haYe Eeen identiÂżed during increased risk for further renal inMury. $dYise these patients of the use of formulations similar to PREPOPIK. %ecause these eYents are importance of adeTuate hydration Eefore during and after the use reported Yoluntarily from a population of uncertain size, it is not always of PREPOPIK. &onsider performing Easeline and post-colonoscopy possiEle to reliaEly estimate their freTuency or estaElish a causal laEoratory tests (electrolytes, creatinine, and %U1) in these patients. relationship to drug exposure.

In patients with seYerely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. 7he Allergic reactions signs and symptoms of hypermagnesemia may include, Eut are not &ases of hypersensitiYity reactions including rash, urticaria, and limited to, diminished or aEsent deep tendon reĂ&#x20AC;exes, somnolence, purpura haYe Eeen reported. hypocalcemia, hypotension, Eradycardia, muscle, respiratory paralysis, complete heart Elock, and cardiac arrest.

Electrolyte abnormalities 7here haYe Eeen reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation 7he patient who has taken an oYerdose should Ee monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias 7here haYe Eeen rare reports of serious arrhythmias associated with the use of ionic osmotic laxatiYe products for Eowel preparation. 8se caution when prescriEing PREPOPIK for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged 47, 7 uncontrolled arrhythmias, recent myocardial infarction, unstaEle angina, congestiYe heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal E&*s should Ee considered in patients at increased risk of serious $Edominal pain, diarrhea, fecal incontinence, and proctalgia haYe Eeen reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. 7here haYe Eeen isolated reports of reYersiEle Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has Eeen reported with the use Osmotic laxatiYes may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. HoweYer, a and there haYe Eeen reports of more serious cases of ischemic colitis causal relationship Eetween these ischemic colitis cases and the use reTuiring hospitalization. &oncurrent use of additional stimulant of PREPOPIK has not Eeen estaElished. laxatiYes with PREPOPIK may increase this risk. 7he potential for mucosal ulcerations should Ee considered when interpreting Neurologic colonoscopy Âżndings in patients with known or suspected inĂ&#x20AC;ammatory 7here haYe Eeen reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients.

Eowel disease.

Use in Patients with SigniĂ&#x20AC;cant Gastrointestinal Disease If gastrointestinal oEstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions Eefore administering PREPOPIK. 8se with caution in patients with seYere actiYe ulceratiYe colitis.

in the setting of a poor prep, and you will need to bring the patient back,â&#x20AC;? Dr. Jacobson said.

He suggested that staff inquire about bowel preparation quality when the patient checks in. Patients who have inadequate bowel cleansing should be immediately rescheduled. Alternatively, patients can continue the prep while in the office, although scheduling often does not permit this.

DRUG INTERACTIONS

0anufactured Ey: Ferring Pharmaceuticals (China) Co., Ltd. 1o. HuiLing Lu (Ferring Road) 1ational Health 7 7echnology Park =hongshan City, *uangdong ProYince, CHI1$ 0anufactured for: Ferring Pharmaceuticals Inc. Parsippany, 1.-. 0 0

www.ferringusa.com - -FERRI1* Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Â&#x2039; 0 Ferring Pharmaceuticals Inc. Use caution when prescriEing PREPOPIK for patients with conditions $ll rights reserYed. Printed in U6$. or who are using medications that increase the risk for Ă&#x20AC;uid and PREPB%R60B00 B0 electrolyte disturEances or may increase the risk of seizure,

Dietary Restrictions Are Debatable With the superior bowel cleansing that occurs with split-dose preparations, it is possible that dietary restrictions can be liberalized, Dr. Jacobson said.

In a meta-analysis of split-dose PEG versus full-dose PEG, splitdosing remained superior, even when a regular diet was allowed until 6:30 p.m. the evening before colonoscopy (Kilgore TW et al. Gastrointest Endosc 2011;73:1240-1245). â&#x20AC;&#x153;This begs the question, â&#x20AC;&#x2DC;are we being too rigid in terms of diet modification with split-dosing?â&#x20AC;&#x2122; â&#x20AC;? Dr. Jacobson asked.

The 165 endoscopists who participated in Dr. Jacobsonâ&#x20AC;&#x2122;s survey gave various dietary instructions to their patients undergoing bowel preparation: 75% ordered clear liquids only for the day before the examination; 82% prohibited milk products; 32% prohibited seeds, nuts and pulp; and 33% forbade alcohol.

â&#x20AC;&#x2DC;Diet instructions are a black box. None of these restrictions are evidence-based. The jury is still out, but it may be fine to liberalize diets when using split-dose preps.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Brian C. Jacobson, MD, MPH

â&#x20AC;&#x153;Diet instructions are a black box.

None of these restrictions are evidencebased,â&#x20AC;? Dr. Jacobson said. â&#x20AC;&#x153;The jury is still out, but it may be fine to liberalize diets when using split-dose preps.â&#x20AC;?

It is recommended to discontinue iron supplementation and adjust diabetes medications prior to bowel preparation, but aspirin and/or nonsteroidal antiinflammatory drugs (NSAIDs) may be continued or discontinued, depending on the underlying indication. â&#x20AC;&#x153;In our survey, 34% [of endoscopists] tell patients to continue aspirin/NSAIDs; 21% say to stop; 11% say to consult their primary physician; and 34% donâ&#x20AC;&#x2122;t mention these drugs at all. This is an area where we need improvement,â&#x20AC;? Dr. Jacobson said.

Documentation Provides Justification Dr. Jacobson emphasized the need to document the quality of bowel preparation, which, if poor, will justify any altered colonoscopy surveillance intervals. see Bowel Prep, page 38

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

37

Low-Residue Diet Comparable to Clear Liquid Diet For Bowel Prep in Colonoscopy Study ORLANDO, FLA.—A — low-residue diet provides results equivalent to a clear liquid diet for bowel cleansing for colonoscopy, according to a randomized controlled trial reported at the 2013 Digestive Disease Week meeting.

“Interestingly, patient tolerance [for the diets] was equivalent, but we found a nonsignificant trend toward higher acceptance in the low-residue diet group,” reported study author David R. Stolpman, MD, of Park Nicollet Clinic, St. Louis Park, Minn.

diet compared with 68% of patients on the low-residue diet, including right-sided polyps in 55% and 50% of patients, respectively. Overall procedure and withdrawal times did not differ between the two groups.

More patients in the low-residue diet group said they would “definitely” use the same preparation again, including patients who had

never undergone a colonoscopy as well as those with prior examinations.

Additionally, more patients in the lowresidue diet group rated their bowel preparation “acceptable.”

More patients who followed the clear liquid diet reported hunger as their worst symptom, whereas patients on the low-residue diet reported more bloating.

The low-residue diet in this study restricts patients from eating whole grains and nuts; it allows cooked vegetables and fruits without skins or seeds, as well as white bread, white pasta, white rice and other foods low in fiber.

■ Dr. Stolpman has received a research grant from Braintree Laboratories, Inc., which funded a grant for this study.

All trademarks are owned by Société des Produits Nestlé S.A., Vevey, Switzerland or used with permission. © 2013 Nestlé. All rights reserved. Florham Park, NJ 07932-1521 U.S.A. NEST-12491-0313

BY CAROLINE HELWICK

‘The low-residue diet proved equivalent to the clear liquid diet in bowel prep quality: Polyp detection rates, including adenomas, flat polyps and right-sided lesions, were equivalent.’

—David R. Stolpman, MD

The study was a prospective, single-blind, randomized controlled trial comparing the two diets in 201 patients who used a split-dose, reduced-volume oral sulfate solution for bowel preparation (Suprep, Braintree) prior to screening or surveillance colonoscopy. Patients were instructed to consume a clear liquid diet the day before colonoscopy, until midnight, or a low-residue breakfast and lunch the day before the procedure followed by clear liquids until midnight.

On the Boston Bowel Preparation Scale (BBPS), a score of 9 was achieved by 58% of patients in the clear liquids group and 50% of those in the low-residue group; 98% and 94% of patients in the two groups, respectively, achieved scores between 6 and 9. Mean BBPS scores for patients in the clear liquids and low-residue groups were 5.7 and 5.6, respectively, before cleansing, and 8.1 and 7.8, respectively, after cleansing, which did not differ significantly.

“The low-residue diet proved equivalent to the clear liquid diet in bowel prep quality: Polyp detection rates, including adenomas, flat polyps and right-sided lesions, were equivalent,” Dr. Stolpman reported.

Polyps were detected in 65% of patients who followed the clear liquid

LAST WEEK HE COULDN’T TOLERATE A FEEDING, LET ALONE A WALK DOWN THE HALL. Nutrition can be a powerful ally. When combined with your expertise, nutrition has the power to support better outcomes. Our evidence-based solutions promote tolerance and absorption to help patients with GI dysfunction avoid complications.1-6 USE UNDER MEDICAL SUPERVISION References: 1. Sucher KP. Nutr Clin Pract. 1986;1:146-150.

2. Flack S et al. J Hum Nutr Diet. 2003;16:366. 3. Fried MD et al.

J Pediatr. 1992;120:569-572. 4. Shea JC et al. Pancreatology.

2003;3:36-40. 5. Borlase BC et al. Surg Gynecol Obstet.

1992;174:181-188. 6. Dylewski ML et al. Nutrition Poster 72; A.S.P.E.N. Clinical Nutrition Week; February 11-15, 2006: Dallas, TX.

www.NestleHealthScience.us

utrition. The factor that can make a difference.

TM

38

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Smartphone App Boosts Bowel Prep Quality ‘Ingenious Approach’ Could Increase Polyp Detection Rates

BY AUDREY ANDREWS ORLANDO, FLA.—A — new smartphone application can help to improve the quality of bowel preparation prior to colonoscopy, according to a group of clinicians who developed the application and presented the findings at the 2013 Digestive Disease Week (DDW) meeting. The first-of-its-kind application provides instructions and timed alerts to help patients follow their bowel preparation protocol.

“The smartphone app is harnessing technology for a better health care outcome,” said study author Paul J. Berggreen, MD, president of Arizona Digestive Health, Phoenix.

To use the application, patients enter the date and time of their colonoscopy and the purgative chosen by their physician. The phone synchronizes this information with timed alerts (e.g., when to take a dose), instructions, tips and pictures of optimal bowel preparation.

Dr. Berggreen and his colleagues evaluated the usefulness of the application in two phases. The first phase of the study took place before the launch of the app: Patients were asked if they owned a smartphone and about their likelihood of using the app, and then underwent bowel preparation without using the app. The colonoscopist was blinded to the patients’ answers and used the Boston Bowel Preparation Scale (BBPS) to measure the quality of bowel preparation. In the second phase of the study, patients were told about the app and given instructions on how to download it. At the time of colonoscopy, patients were asked if they had used

the application, and those that used the app were asked to rate their level of satisfaction with it. Again, the colonoscopist was blinded to patients’ answers and scored the bowel preparation using the BBPS. Of the 215 patients in the study, 119 owned smartphones, and of these, 52 used the app.

Patients who used the app had an average bowel preparation score of 8.1 on a 9-point

scale compared with a score of 6.5 for nonusers (P<0.001). A good bowel preparation (BBPS ≥7) was achieved by 84% of app users compared with 62% of nonusers (P<0.001).

“This score is significantly improved from the Boston Bowel Preparation Scale score of 6.9 we saw before the app was released,” Dr. Berggreen said.

“We concluded that the app did make a significant difference in bowel preparation quality, and that difference could not be explained by people who were technologically comfortable or could follow directions better,” Dr. Berggreen noted.

“This has fairly large implications. Here, we are using the app to improve bowel preparations and polyp detection rates, in turn. But encouraged by these results, we are working on an upgrade to give the app even more functionality.”

Lawrence S. Friedman, MD, chairman of medicine at Newton-Wellesley Hospital in Newton, Mass., praised the new technology in a DDW press briefing.

“Anything that encourages patients to complete the preparation—the worst part of colonoscopy—and perhaps enjoy doing it more than they generally do, is welcome. The use of a smartphone app is an ingenious approach, and I believe it will improve the quality of screening,” Dr. Friedman said.

The application is available as a free download from the iTunes app store at https://itunes.apple.com/us/app/adh/ id568880917?mt=8&ls=1.

Drs. Berggreen and Friedman reported no relevant conflicts of interest.

Bowel Prep continued from page 36

“It also lets you compare yourself with benchmarks and enables quality improvement projects,” Dr. Jacobson added.

He recommended using the Boston Bowel Prep Scale to measure the quality of bowel preparation. Patients with a score of “1” on any segment of the rating scale should undergo another examination.

Quality Incumbent on Physicians Philip Schoenfeld, MD, professor of medicine at University of Michigan Medical School in Ann Arbor, who moderated the DDW session, said patients with suboptimal bowel

‘You can’t just say, “I have bad patients.” It’s going to be incumbent on us to improve the quality of this process.’

—Philip Schoenfeld, MD preparations should be brought back in one year, not five years, for a repeat colonoscopy.

“The best data show that interval cancers usually occur in less than five years. We are fooling ourselves if we [say] it’s OK to bring this patient back in five years.

“We have to change our system, and this includes better educating patients about bowel preps so we get good quality preps most of the time,” emphasized Dr. Schoenfeld, who is coauthoring the newest “Quality Indicators for Colonoscopy” statement by the American College of Gastroenterology.

“Soon, we are going to have to show that we follow guidelines 80% to 90% of the time, based on the colonoscopy findings,” Dr. Schoenfeld added, referencing the emerging need to meet quality indicators. “You should strive to help your patients achieve good to excellent preps 80% to 90% of the time. If 60% of the time your preps are suboptimal and you tell these patients to come back in five years, then that won’t be consistent with quality indicators,” Dr. Schoenfeld said.

“You can’t just say, ‘I have bad patients.’

It’s going to be incumbent on us to improve the quality of this process.” ■

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Edi[j _i hWf_Z Wffhen_cWj[bo )& i[YedZi WdZ j^[ ZkhWj_ed e\ Wd[ij^[i_W _i jof_YWbbo )&#,& c_dkj[i" when used as directed ?dZ_YWj[Z je Yedjheb fW_d WdZ \eh ki[ \eh ikh]_YWb eh [dZeiYef_Y fheY[Zkh[i _d j^[ f^Whodn" bWhodn" jhWY^[W and esophagus ?dZ_YWj[Z \eh ki[ je Yedjheb ]W]]_d] Important Safety Information Hypersensitivity Reactions: Unpredictable adverse reactions (i.e. hypersensitivity, including anaphylaxis) are extremely rare. Localized allergic reactions may occur after prolonged or repeated use of any aminobenzoate anesthetic. The most common adverse reaction caused by local anesthetics is contact dermatitis characterized by erythema and pruritus that may progress to vesiculation and oozing.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

The Physician as CEO, Once Again More Doctors Fusing Clinical and Business Sides of Medicine In Leadership Roles; Will This Lead to Better Health Care?

BY VICTORIA STERN The number of physicians in leadership roles has been diminishing for more than a century. In the early 1900s, physicians ran more than one-third of hospitals in

the United States, but this number has steadily dwindled over the years. Today, the majority of hospital administrators are nonphysicians, with one study estimating that of 6,500 hospitals in the United States, only 235 or 3.6% are physician-led (Gunderman R, Kanter

SL. Acad Medd 2009;84:1348-1351).

“In the early days, physicians often ran the business side of hospitals and medical organizations because it was simpler,” said Chalmers Nunn Jr., MD, a practicing gastroenterologist and CEO at Gastroenterology Associates

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TOPICAL ANESTHETIC SPRAY Brief Summary of the Prescribing Information Active Ingredients Benzocaine .............................................................................. 14.0% Butamben.................................................................................. 2.0% Tetracaine Hydrochloride .......................................................... 2.0% Contains Benzalkonium Chloride ............................................................. 0.5% Cetyl Dimethyl Ethyl Ammonium Bromide ............................................................. 0.005% In a bland water-soluble base.

Action The onset of Cetacaine-produced anesthesia is rapid (approximately 30 seconds) and the duration of anesthesia is typically 30-60 minutes, when used as directed.

Indications Cetacaine is a topical anesthetic indicated for the production of anesthesia of all accessible mucous membrane except the eyes. Cetacaine is indicated to control pain and for use for surgical or endoscopic or other procedures in the ear, nose, mouth, pharynx, larynx, trachea, bronchi, and esophagus.

Dosage and Administration Cetacaine Spray should be applied for approximately one second or less for normal anesthesia. Only a limited quantity of Cetacaine is required for anesthesia. Spray in excess of two seconds is contraindicted. Average expulsion rate of residue from spray, at normal temperatures, is 200 mg per second.

An appropriate pediatric dosage has not been established for Cetacaine Spray.

Dosages should be reduced in the debilitated elderly, acutely ill, and very young patients.

Adverse Reactions Hypersensitivity Reactions: Unpredictable adverse reactions (i.e. hypersensitivity, including anaphylaxis) are extremely rare. Localized allergic reactions may occur after prolonged or repeated use of any aminobenzoate anesthetic. The most common adverse reaction caused by local anesthetics is contact dermatitis characterized by erythema and pruritus that may progress to vesiculation and oozing. This occurs most commonly in patients following prolonged self-medication, which is contraindicated. If rash, urticaria, edema, or other manifestations of allergy develop during use, the drug should be discontinued. To minimize the possibility of a serious allergic reaction, Cetacaine preparations should not be applied for prolonged periods except under continual supervision. Dehydration of the epithelium or an escharotic effect may also result from prolonged contact.

Precaution: On rare occasions, methemoglobinemia has been reported in connection with the use of benzocaine-containing products. Care should be used not to exceed the maximum recommended dosage (see Dosage and Administration). If a patient becomes cyanotic, treat appropriately to counteract (such as with methylene blue, if medically indicated).

Use in Pregnancy: Safe use of Cetacaine has not been established with respect to possible adverse effects upon fetal development. Therefore, Cetacaine should not be used during early pregnancy, unless in the judgement of a physician, the potential benefits outweigh the unknown hazards. Routine precaution for the use of any topical anesthetic should be observed when Cetacaine is used.

Contraindications Cetacaine is not suitable and should never be used for injection. Do not use on the eyes. To avoid excessive systemic absorption, Cetacaine should not be applied to large areas of denuded or inflamed tissue. Cetacaine should not be administered to patients who are hypersensitive to any of its ingredients or to patients known to have cholinesterase deficiencies. Tolerance may vary with the status of the patient. Cetacaine should not be used under dentures or cotton rolls, as retention of the active ingredients under a denture or cotton roll could possibly cause an escharotic effect. Routine precaution for the use of any topical anesthetic should be observed when using Cetacaine.

Rx Only. Made in U.S.A. © 2013 Cetylite Industries, Inc. All rights reserved. Information is summary in nature and subject to change. Cetacaine and Cetylite are registered trademarks of Cetylite Industries, Inc. All other copyrights are the property of their respective owners.

Tissue need not be dried prior to application of Cetacaine. Cetacaine should be applied directly to the site where pain control is required. Anesthesia is produced within one minute with an approximate duration of thirty minutes.

Each 200 mg dose of Cetacaine Spray residue contains 28 mg of benzocaine, 4 mg of butamben and 4 mg of tetracaine HCl.

Preference for Physician Managers

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of Central Virginia, Lynchburg. “As our society evolved and more money infused into the medical system, physicians began to hire cheaper nonphysician administrators to run the business.”

But in the past few years, the pendulum appears to be swinging back in the direction of the clinician leader. As the business and clinical sides of medicine have become more multifaceted, “we have started to need physician leadership to run both fronts again,” Dr. Nunn said.

Dhruv Khullar, a medical student and class president at Yale School of Medicine who is seeking his master’s in public policy at Harvard University’s Kennedy School, also has observed this shift among his classmates and colleagues.

“The number of students taking time to pursue research or another degree is growing so quickly that [my colleagues] joke that medical school is now five years with an option for four,” Mr. Khullar said. “I think this [cross-disciplinary focus] comes from a strong recognition of the broader societal influences on and impacts of health care in this country.”

James Mandell, MD, CEO of Boston Children’s Hospital and a practicing surgeon agrees that “more clinicians are becoming interested in leadership positions and are getting advanced degrees in administration or business, but whether that will translate into a large-scale leadership change remains to be seen.”

The key to effectively managing a medical organization is being “intimately familiar with the health care delivery challenges that doctors and other providers encounter on a dayto-day basis,” Mr. Khullar said. Thus, although hospitals can be run equally well by physicians and nonphysicians, physicians may have a distinct advantage

41

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

World Report’s Best Hospitals ranking system, lead author Amanda Goodall, PhD, senior lecturer at Cass Business School in London and research fellow at IZA Institute for the Study of Labor, Germany, identified the top 100 U.S. hospitals in three specialties—cancer, heart and heart surgery, and digestive disorders—and classified the 300 CEOs as physician or nonphysician managers.

In all three fields, the results showed that hospitals with higher rankings were led disproportionately by physicians (P<0.001): For cancer, 51 of the 100

Among the 300 CEOs at the top 100 U.S. hospitals in three specialties— cancer, digestive disorders, and heart and heart surgery—hospitals with higher rankings were led disproportionately by physicians rather than nonphysician managers.

because they are naturally more in tune with the medical landscape.

Dr. Mandell believes that “having physician leadership in the top echelons of medical institutions is very important, but whether that role is at the CEO level or another level is relatively unimportant as long as physicians have the ability to influence decision making in the organization.”

In an editorial, Lord Ara Darzi, MD, Paul Hamlyn Chair of Surgery at Imperial College, London, observed that clinicians in the United States can provide unique insights about where health care resources should be allocated and should become more active in implementing these changes (Darzi A. N Engl J Med 2009;361:e8). To this end, Dr. Darzi called for more clinicians in the country to take on leadership roles in the health care system, instead of allowing bureaucrats and insurance companies such extensive control.

Robert J. Fitzgibbons, MD, Harry E. Stuckenhoff Professor of Surgery, Creighton University School of Medicine, Omaha, Neb., agreed that physician leaders are well equipped to bring together the clinical and administrative sides of a health care organization because they “have perspective on what is going on in the trenches.”

Now empirical evidence is emerging that supports this move toward trained physician managers. One 2010 study, which surveyed 1,200 hospitals across seven countries, including the United Kingdom, Germany and Canada, found that hospitals with clinician managers had the most effective management practices (“Management in Healthcare: Why Good Practice Really Matters,” www.worldmanagementsurvey.org).

Another recent study that explored whether hospitals perform better when led by doctors (Goodall AH. Soc Sci Med 2011;73:535-539), found a similar relationship. Using the 2009 U.S. News &

1978

—

top-ranked hospitals were physician-led; for heart and heart surgery and digestive disorders, 37 of 100 and 34 of 100 topranked hospitals, respectively, were run by physicians. Dr. Goodall makes it clear, however, that “the findings do not prove that doctors make more effective leaders than professional managers,” and hopes her study will fuel further investigation.

Physician CEOs Over the past 10 years, Dr. Mandell has observed complex changes to the models see Physician CEO, page 42

35th Anniversary — 2 0 1 3

The Independ Independent Monthly Newspaper for Gastroenterologists

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 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 1 • January 2013

ACG 2012

IBS No Longer Only Functional Disorder

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

BY DAVID WILD

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

Mesalamine Elicits Response in IBS

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

If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search.

The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training.

With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy Newss summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

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, STEPHEN SCHENTHAL, MD ..................... page 29 AND

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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42

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Physician CEO continued from page 41

of care and payment systems in the United States, and has had to deal with the internal challenges of information technology (IT) and ongoing patient safety and quality initiatives, as well as the external forces of the private payor and government.

“These are complex issues that require talent and a clinician’s voice,” Dr. Mandell said. As a CEO and practicing surgeon, “I get a good bird’s-eye view of the problems

“

practicing in a large institution and the difficulties involved in supporting nurses and doctors in their roles.”

In his roles as CEO and practicing gastroenterologist, Dr. Nunn has worked extensively to improve the quality and efficiency of Gastroenterology Associates and to foster strong relationships between colleagues, nonphysicians, IT and the local health system. One of the first things Dr. Nunn did as CEO was improve electronic medical records (EMR), which he characterizes as one of the biggest challenges any manager faces.

“The biggest mistake health systems make is under-resourcing this,” Dr. Nunn said. “You have to invest in implementing and customizing an EMR system; it can’t just be an add-on project. Doctors have to get involved and engaged, and organizations have to understand it’s never-ending work to update this system.”

Dr. Nunn worked with his IT staff to develop order sets and templates to help standardize the practice’s approach to electronic records, and built in specific treatment protocols to help manage specific illnesses better. “Only a physician has

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the knowledge to make those kinds of changes,” Dr. Nunn said.

To help strengthen relationships among his staff, Dr. Nunn also organized a retreat with the practice’s eight physicians to develop a strategy for the coming year, which included how to expand the practice, improve patient satisfaction and negotiate better with payors.

“It’s important to educate and incorporate physicians in the goals and decision making of a practice,” he said.

Need for Training Despite the growing clamor for more clinician managers, most physicians cannot take on a managerial role without extensive training.

“If a practicing physician who’s never had any business training or experience is just thrust into a managerial role, that physician will not be as good as a nonphysician who has the commitment, training and experience in business,” Dr. Nunn said.

“Most physicians are [sub]consciously incompetent when it comes to business.

In other words, doctors are very smart and have outstanding training, but many don’t realize that today the business side of medicine is as complex as neurosurgery or general surgery and you need years of training and experience to be able to perform well.”

This is why many medical organizations are establishing programs for physicians to gain leadership and business experience.

Institutions, such as the Cleveland Clinic, Mayo Clinic and Hartford HealthCare, as well as specialty associations, including the American College of Physician Executives (ACPE) and the American College of Healthcare Executives, have implemented such programs.

Two years ago, Hartford HealthCare introduced a 10-month program to provide its physicians formal leadership training.

“Hartford HealthCare’s mission to drive quality and safety is completely dependent on the quality and depth of physician leadership,” said Rocco Orlando III, MD, general surgeon and chief medical officer for Hartford HealthCare, in Connecticut. “We are bringing a class of physician leaders through this process together in the hopes that they will build relationships that will help them in their careers at Hartford HealthCare, and because the traditional model of doctors providing clinical care only is insufficient to be successful in this increasingly complex world.”

The curriculum, which borrows components from the ACPE program, is centered on enhancing leadership behaviors and technical skills, such as quality and safety, marketing and strategic planning for doctors and basic health care finance. The curriculum also requires participants to work on realworld problems, including the gap in

43

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

interprovider communication.

Physicians who have practiced for years are also pursuing master’s degrees. Sumeet Mittal, MD, associate professor of surgery in the Department of Surgery at Creighton University School of Medicine, Omaha, Neb., is receiving MBA training at Creighton University so he can become more engaged in all aspects of medicine and eventually take on administrative roles at the hospital and university.

“The MBA will allow me to change the conversation,” Dr. Mittal said. “I most likely won’t transition into full-time administrative work for many years to come because I love surgery too much to leave. A business degree will allow me to take on a more active role, ask the right questions, advocate for the patients, and generally be on a level playing field with the administrators in program development and cost analysis, rather than simply listen to their decisions. Ultimately, only physicians can put the profit–loss ratio in the correct perspective of patient care.”

Mr. Khullar plans to work at the interface of medicine and government when he completes his degrees in medicine and public policy.

“I think it’s important to infuse the clinical perspective into policy debates, and likewise bring larger cost and access concerns to everyday clinical practice,” he said. “The problems we face in the health system, and more broadly in society, are becoming increasingly complex and will require interdisciplinary solutions to address them. I think being able to understand the various medical, policy and economic players—and speak the language of each—will be vital in the future.”

‘For me, being an administrator has made me a better physician. I now understand patient satisfaction, quality improvement, standardizing care [and] what makes things work, whereas before I didn’t.’

—Chalmers Nunn Jr., MD administration, but without a better balance of duties and time, they’re going to get doubly burned out.”

Seeking a second degree while practicing medicine is indeed demanding: Dr. Mandell balances his dual career by performing clinic duties and operations

NEW

on two half-days a week, and Dr. Mittal tends to clinical duties during the day while only taking one evening or online class at a time.

“Burnout is a concern,” Dr. Mandell said. “The work is increasingly hard and the challenges are not going away. I think

In bowel preparation

The NEW Combination Makes the Difference Introducing Suclear Provides the flexibility and convenience of two dosing regimens (same-day, split-dose), with success* achieved in 90% of patients1,2 Significantly more “excellent” preps* with Suclear vs HalfLytely (47.7% vs 35.6%, respectively; P=0.01†) in same-day dosing comparison1 – Prep time was 33% less with Suclear compared to HalfLytely (3.7 hours vs 5.5 hours, respectively; P<0.001†)1 Equivalent rates of excellent cleansing* between Suclear and MoviPrep®‡ (51.9% vs 51.4%, respectively) in split-dose comparison1

The Future Despite the push for more physicians in leadership roles, taking on two demanding careers can have its downsides. One study, in which investigators interviewed 30 clinicians in management positions in Norwegian hospitals, found that many participants found themselves “thrown” into the position, without being sufficiently trained, and had to learn management “on the fly,” while some expressed frustration because of increasing administrative workloads and minimal opportunities to delegate responsibilities (Spehar I et al. BMC Health Serv Ress 2012;12:421).

“Although doctors can get burned out clinically, I’m starting to see physicians become burned out administratively as well,” Dr. Nunn said.

Now that more doctors are becoming involved in running health systems, there are physicians practicing all day and then going to meetings all night.

“That’s what’s concerned me most about this integration,” Dr. Nunn added. “Yes, we want to get doctors more involved in

it’s important to get clinician input at the administrative level, but I’m realistic enough to know that it’s not an easy job.”

Finding the right balance between clinical and administrative duties will be key for the growing ranks of physician leaders, although the benefit of having both skill sets is undeniable.

“For me, being an administrator has made me a better physician,” Dr. Nunn said. “I now understand patient satisfaction, quality improvement, standardizing care [and] what makes things work, whereas before I didn’t.”

■

Cecum reached in almost all patients using Suclear (split-dosing: 100%; same-day dosing: 99%)1 * *Based on investigator grading. † Statistically significant difference. ‡ MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies.

IMPORTANT SAFETY INFORMATION Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution) is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended (sodium sulfate, potassium sulfate, and magnesium sulfate final volume.

NEW

Please see brief summary of Full Prescribing Information on adjacent page.

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

44

OPINION

GASTROENTEROLOGY ENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

The ICD-10 and the Importance of Specificity of Diagnosis Lucian Newman III, MD General Surgeon Gadsden, Alabama From our first days in medical school, we are taught to respect the human form and learn to understand the diseases that lead to its

ultimate demise. When needed, physicians intervene to impede these conditions, whether they be infectious, traumatic, idiopathic, genetic or the inevitable result of aging. “Comorbidity” can be defined as the effect of all other diseases an individual patient might have other than the primary disease of interest. We quickly realize that no single condition stands alone. Instead, each patient possesses an array of risk

factors that affects the other conditions.

Consider the myriad effect of diabetes or immunosuppressive disorders. We are challenged with treating the whole patient precisely because each disorder may affect another. The research done to study the effects of medical and surgical treatments often shows results that are unintended and unanticipated. Even with the level of sophistication seen in the modern practice of medicine,

NEW (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

Introducing Suclear The NEW combination for dosing flexibility High success rates in same-day and split-dose regimens1,2 Cecum reached in nearly 100% of patients1 Significantly less prep time compared to HalfLytely1 References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Suclear [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2013.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution). INDICATIONS AND USAGE: A combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: Suclear is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended final volume. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 362 patients who took Suclear in clinical trials, 90 (25%) were 65 years of age or older, while 29 (8%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger subjects.

DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of each Suclear dose may not be absorbed completely.y Concurrent use of stimulant laxatives and Suclear may increase the risk of mucosal ulcerations or ischemic colitis. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Consume only clear liquids (no solid food or milk) and avoid alcohol on the day before colonoscopy until after completion of the colonoscopy. Split-Dose (2-Day) Regimen (Preferred Method): Dose 1 – Evening before the colonoscopy (10 to 12 hours prior to Dose 2): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Refill the container and drink another 16 oz. of water over the next 2 hours, and another before going to bed. Dose 2 – Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Complete drinking the solution at least 2 hours before the colonoscopy. Consume only clear liquids until 2 hours prior to colonoscopy. Day-Before (1-Day) Regimen (Alternative Method): On the evening before the colonoscopy: Dose 1 (begin at least 3 ½ hours prior to bedtime): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Drink another 16 oz. of water over the next 2 hours. Dose 2 (approximately 2 hours after starting Dose 1): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Refill the container and drink another 16 oz. of water before going to bed. Consume only clear liquids until 2 hours prior to colonoscopy.

STORAGE: Store at 20-25°C (68-77°F). Excursions permitted between 15-30°C (59-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.braintreelabs.com ©2013 Braintree Laboratories, Inc.

SU-14168

March, 2013

perfection of care is not possible, in part due to a lack of understanding of differences attributable to each individual patient and his or her comorbidities, both known and unknown.

As our society searches for the optimum way to care and pay for our population, a more intense focus on costs is natural.

Generally, there are wide variations in expenditures based on the age, lifestyle, comorbidities and even geographical location of the patient. Although controlling the variables is difficult, simply knowing the variables is possible by aggregating all descriptions and treatments attributable to individuals. Accuracy in this endeavor is paramount, and this is the cornerstone of documentation and coding-improvement projects that are so important today.

Payment mechanisms based on diagnosisrelated groups (DRGs) reward facilities and physicians for describing the care of sicker patients generally limited to three levels of care. Newer initiatives will likely create more levels, and also will consider quality metrics and satisfaction scores to arrive at reimbursement totals. The physician’s role is paramount and increasing in these models.

Medicine is becoming increasingly complex. As physicians treat a narrower spectrum of disease, their comfort level in describing the wholee patient decreases.

Nevertheless, we are responsible for taking into account many variables before recommending both medical and surgical treatments. No physician is capable

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOB OCTOBER 2013

There are many ways to criticize the move to ICD-10, but understanding that the ICD system was created to foster a better understanding of disease and death should be recognizable by all health care providers.

“value-based purchasing.” Comparing hospitals against their clinical performance guidelines (70%) and on patients’ perception of the quality of care (30%) will generate a basis for bonus or penalty.

The Hospital Consumer Assessment of Healthcare Providers and Systems (or HCAHPS) form is the vehicle used to generate information by communicating with patients. The survey, which has 27 questions and is not limited to the discharge of Medicare patients, is conducted between two days and six weeks after discharge.

Many physicians are frustrated by the intrusion into their relationships with their patients and the time spent with them. Each new directive, requirement or protocol requires a level of understanding and commitment, and often changes the status quo. Even the “meaningful use” set of standards has been shunned by some physicians who object to it on many levels. Clearly, the near future of medicine requires some adjustments to most health care practices.

Attention to details previously ignored will be suggested, if not absolutely

45

required. As responsibility for management shifts, the physician’s autonomy may disappear.

The ICD-10 codes will be introduced on Oct. 1, 2014. For further information, visit the Centers for Medicare & Medicaid Services at www.cms.gov/Medicare/ Coding/ICD10/index.html?redirect=/ icd10.

■ Dr. Newman is founder and CMO of ComplyMD (complymd.com), a company that provides procedural documentation solutions.

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of knowing everything, but he or she should be capable of assembling information that is known and searching for unknowns, particularly in their respective disciplines. The language of medicine does not always translate into the appropriate classification code assigned to describe the condition, or the language is not specific enough to distinguish between code options. The revision in the International Classification of Diseases [ICD]-10 codes requires greater specificity, but it is needed because our advances have outstripped our ability to describe the disorders specifically. There are many ways to criticize the move to ICD-10, but understanding that the ICD system was created to foster a better understanding of disease and death should be recognizable by all health care providers (although I’m not convinced that knowing whether an injury was caused by a raccoon or the pilot of a spacecraft is germane).

A sound argument can be made for higher reimbursement to those facilities and physicians who are responsible for higher-acuity patients. Determining what constitutes meaningful differences in acuity, and thereby justifying a higher or lower payment, would seem to be more difficult. Payment variables also now involve the level of patient satisfaction including 1% at risk for Medicare services. Satisfaction ratings are a part of Medicare plans by linking a small percentage of reimbursements to

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46

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Risk Management Education Helps Physicians Reduce Medical Malpractice Claims, Lower Premiums gaffes, communication errors and the like,” said Ms. Lagnese. “These are all avoidable via practical risk mitigation A review of malpractice cases involvpractices.” ing gastroenterologists over the past two Even though roughly four-fifths of all decades found that, in those cases where cases are resolved in favor of the physimedical malpractice was alleged, the most cian, billions of dollars are paid out in common problems cited were: settlements that, according to Mr. Dana• errors in diagnosis; her, “should never have seen the light of • failure to supervise or monitor a day” (Table 1). The estimated medical Proactive Approach to Risk patient; malpractice payments in 2011 totaled Management • failure to recognize a complication $4.65 billion. of treatment; In 2003, attorneys Neil Danaher, Joyce In 2003, with the crisis in medical mal• leaving a foreign body in the patient Lagnese and Kenneth Neal, all of whom practice liability becoming dire, MRM after a surgical procedure; are associated with DanaherLagnese, a sought to generate strategies that would • procedure performed when either Connecticut legal practice with extensive help reduce malpractice exposures and not indicated or contraindicated; experience in medical malpractice defense improve patient safety. The company’s • a delay in performing a procedure; litigation, partnered with Mr. Kelly to goal is to create a proactive attitude toward and launch Medical Risk Management, LLC risk management, and ultimately patient • medication errors.

(MRM), based in Hartford, Conn. safety, and discard what has been a reacA careful review of claims records “As seasoned defense attorneys, we tive, ineffective approach. MRM focuses shows there is no shortage of possible understand that most malpractice cases on areas of high malpractice exposure and ways to end up in court. Specific examstem not from bad doctors practicing bad areas of emerging risk, and then teaches its ples of malpractice pitfalls are not hard medicine but rather by administrative clients what the company has found. to come by, and sometimes come “The key to why we’ve been from surprising sources. successful is that 70% of claims ‘As seasoned defense attorneys, we understand that most malpractice Take, for example, the rise of are not due to bad doctors, which hospitalists, who theoretically means they are preventable,” cases stem not from bad doctors practicing bad medicine but rather keep primary care physicians Mr. Danaher said. “They are by administrative gaffs, communication errors, and the like.

(PCPs) fully apprised of their from things like communication These are all avoidable via practical risk mitigation practices.’ patients’ status during hospilapses, follow-up lapses, system talization. Practically speaking, deficiencies, inadequate informed —Joyce Lagnese, Chief Legal Officer, Medical Risk Management LLC however, complete communicaconsent and poor patient relation is rare. As it turns out, intertions—all things that we can provider communication between work on, and provide education the hospitalist and PCP is an and implement practical interincreasingly frequent issue in malventions in order to reduce or practice claims. A patient arrives eliminate them altogether.” in the emergency room with left “We identify the 20% of types quadrant belly pain, and appendiof claims that represent 80% of citis is diagnosed. The patient has the malpractice losses, and we chest x-rays that the radiologist determine these high-exposure reads, and the patient is cleared areas by specialty,” Mr. Kelly for emergency surgery. Incidental added. “We do a frequencyto the appendectomy is the findseverity distribution analysis, ing of a lung nodule, the fact of and then focus our educational which the PCP does not notice as curriculum on those areas where it is buried on page 23 of the elec- Table 1. Total Amount Paid in Medical Claims by State in 2011: Top 10 the highest yield will be.” tronic health record (EHR). The MRM collects cartons of Rank State Number of Total Amount Average Amount appendectomy is successful, but medical malpractice files and Claims Paid, $ Per Claim, $ the lung nodule is not biopsied mines them for data, separating 1 New York 1,379 627,067,500 454,726 and the patient succumbs to lung information out by specialty and 2 Pennsylvania 767 299,671,500 390,706 cancer two years later. Among the sorting them by risk issue. The 3 Florida 758 188,324,250 248,449 problems evident in this example files are redacted for HIPAA is the education of hospitalists, purposes and then a case-based, 4 California 758 186,235,900 209,489 many of whom are graduates specialty-specific educational 5 Illinois 315 183,968,050 584,026 of internal medicine residency program is created. The firm is 6 New Jersey 429 164,494,500 383,437 programs but are relatively inexdedicated to multimodal risk 7 Massachusetts 212 130,749,750 616,744 perienced in managing complex education—much of it comprissurgical patients and ensuring ing continuing medical and/or 8 Missouri 159 100,348,250 631,121 comprehensive follow-up. nursing education (CME and 9 Maryland 249 84,688,000 340,112 Another generator of malpracCNE)—that is delivered via a 10 Texas 445 76,144,750 171,112 tice claims stems from the advent variety of media, including: of EHR systems. see Risk Management, page 48 Source: Data from The Kaiser Family Foundation, State Health Facts, available at http://kff.org/statedata.

BY JAMES PRUDDEN

“The Obama administration has provided significant financial incentives through stimulus funds for physicians to quickly adopt EHRs,” said Kevin W. Kelly, president and CEO of Medical Risk Management LLC. “The problem has been that, during the adoption period of EHRs, there are many unintended consequences that may increase malpractice exposures. The vast majority of smaller physician groups are ill-prepared—they don’t have an information technology department, they don’t have the infrastructure.”

Mr. Kelly offered two examples. First is the “all-normal” button, which a physician can click to document that the assessment was normal for all physical systems. “However, if the exam was not complete but the results were posted as ‘all normal,’ there could be significant consequences if an adverse event occurred,” Mr. Kelly said. “This could be portrayed very negatively to a jury.”

He added, “A second example is to copy and paste, or the ‘carry forward’ function. In this situation a physician can copy and reuse the exact text, but if there are multiple notations in the EHR that are all exactly the same, then the EHR record can lose credibility in the eyes of a jury. Again, that is portrayed very negatively in court.”

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48

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Risk Management continued from page 46

•

annual specialty-specific risk management lectures; • web-based learning modules and movies, featuring a defense attorney, a physician and a content expert; • risk alerts sent via email, offering short vignettes; • tutorials; and • an Automated Risk Knowledge System, a web-based learning management platform developed by MRM that allows users to access customized educational materials at any time over the Internet.

MRM sets itself apart from other medical risk management companies, such as ELM Exchange, Inc. (www.elmexchange.com) and Medical Risk Management Inc. (www.medrisk.com), by offering a greater emphasis on live, specialty-specific presentations using expert defense lawyers and practicing physicians who discuss real-life cases.

Table 2. Decline in Premiums Following Implementation of Risk Management Program at ProHealth Physicians

Year

Internal Medicine/ Family Practice Premiums, $

Pediatrics Premiums, $

2004-2005

19,424

17,851

2005-2006

17,453

16,122

2006-2007

15,069

13,849

2007-2008

13,799

12,681

2008-2009

12,749

11,717

2009-2010

10,904

10,021

2010-2011

9,476

8,708

2011-2012

7,827

7,193

Source: Jacobs L et al. Conn Med. 2012;76:291-297

Fewer Claims, Lower Costs MRM can point to significant successes in its decade of existence. Key performance metrics are regularly assessed by MRM, and include basic knowledge, attitudinal measures, behavior change, and claims and premium reductions.

The firm’s first client was ProHealth Physicians, one of the largest primary care group practices in Connecticut. In an interview, Jack Reed, president and CEO, and James Cox-Chapman, MD, chief medical officer and senior vice president, recounted the effect the implementation of the risk management program had on their group, a story they summarized in Connecticut Medicinee ( Jacobs L et al.

2012;76:291-297). Participation rates for the CME modules and risk management grand rounds were 98.7% or higher since their inception in 2004, and participation in focused educational efforts in highexposure areas, such as failure to diagnose colon cancer, was 100%. More than 90% of physicians agreed that the educational efforts were worth their time or relevant to their practice, and between 93.3% and 99.5% of respondents indicated they would “somewhat” or “completely” change their practice as a result of what they had learned.

Thus, the clinicians at ProHealth Physicians were enthusiastic and successful students of the programs offered by MRM, and the resultant claims data from the years following its implementation bear this out.

For instance, a comparison of the number of claims from the six years before the program was initiated (10±3.46) to the eight years after (3.62±2.13) shows an impressive 63.8% reduction in the average number of claims. The claims for failure to diagnose or treat, an area that was a focus of study for the group, were reduced by 67.9%. Meanwhile, the severity of claims, measured in dollars per physician, was reduced by 73%. Eventually, premiums fell as a result of the reduced claims. Since 2005, the gross premiums for ProHealth Physicians are down 59.7% for the specialties of internal medicine/family practice and pediatrics (Table 2). Reduced premiums resulted in an aggregate savings of about $14 million from their malpractice insurance underwriting.

“Medical Risk Management LLC has been a winner for our patients and doctors,” Mr. Reed said.

“We have about 200 physicians in our group, but we also have several hundred other providers, such as nurse practitioners and physician assistants,” added Dr. Cox-Chapman. “It is not just the physicians who are taking these courses—anyone who interacts with patients needs to take them.”

Indeed, MRM provides educational instruction for office managers and others involved in administration.

Peace of Mind It comes as an unpleasant shock to many physicians to hear that the allegations against them will not be heard in court for two or more years as the case wends its way through the legal system, during which time they must live with a professional cloud hanging over their heads.

“Medical Risk Management LLC is constantly evaluating its educational endeavors, but the unmeasured benefit of all this is the increased confidence that comes with preparation and use of one’s resources to deal with the problem of risk management,” Dr. Cox-Chapman said. “Don’t underestimate the emotional distraction that comes with a lawsuit—there is a much higher level of confidence that exists when you are prepared.”

The savings achieved by ProHealth Physicians are extraordinary, but overall savings are a frequent byproduct of the risk management programs. MRM’s client base is diverse, including large health care systems, like Hartford HealthCare; specialty-specific hospitals, like the Hospital for Special Surgery in New York City and Connecticut Children’s Medical Center; university teaching centers, like the University of Connecticut; and smaller hospitals and group practices (see sidebar). MRM has been able to customize its programs based on practice size and need.

Ultimately, everybody wins—the culture of safety that develops from managing medical risk helps lower premiums for physicians and heightens safety for patients.

■ Mr. Kelly is president and CEO, Ms. Lagnese is chief legal officer and Mr. Danaher is chairman of MRM. MRM was founded in 2003 by a team of health care and legal professionals dedicated to developing practical risk management solutions for health care providers. For more information about MRM, visit www.1mrm.com.

Case Studies in Risk Management Case 1. University of Connecticut School of Medicine Kiki Nissen, MD, associate dean for graduate medical education and professor of medicine at University of Connecticut School of Medicine (UCSM), oversaw the implementation of a risk management curriculum, developed by Medical Risk Management, LLC (MRM), together with UCSM, for UCSM residents (there are approximately 630 residents at UCSM). A review of the experience was published in the Journal of Graduate Medical Education (Nissen K et al. 2010;2:589-594).

The multimodality program relied on live lectures, web-based video modules, and emailed publications designed to educate residents about medical risk management. Pre-tests and post-tests were administered, and participant satisfaction was measured. The entire curriculum spanned two years.

Of survey respondents, 97% found the content to be relevant to their specialty, and 95% agreed that the live sessions should be held annually. When asked if they would change their practice based on what they had learned in the program, only 2.5% said not at all—nearly 70% said mostly or completely.

“The program was extended to include fellows in 2011,” Dr. Nissen said. “The medical risk program is called the Patient Safety Curriculum.”

The improvements in reduced malpractice claims are being tracked.

Case 2. Connecticut Children’s Medical Center Martin J. Gavin, president and CEO, and Trisha Farmer, director of risk management, Connecticut Children’s Medical Center, described the medical risk educational program initiated for the medical center, which has 187 beds and employs 160 physicians in 26 subspecialties.

“We were looking at providing much more standardization in our approach to medical education,” Mr. Gavin explained, which was one impetus for starting the MRM program five years ago.

The program entailed attending a live presentation once a year, and viewing two online web modules each year.

“We have seen a dramatic reduction in claims, due in large measure to the work done by this program,” he said.

The attitude of the physicians toward the process also was very positive.

“Physicians are very data-driven people, so when they are shown data that can help them improve their exposure, and also improve patient safety, they quickly accepted the program and got on board with it,” Mr. Gavin said.

“The program really changed our culture,” Ms. Farmer added. “We are a culture of safety and a culture of risk awareness, and all of the educational efforts have made us more aware. And this is a program that goes well beyond the physicians—we have had 850 people go through the program, including allied health professionals and administrators.”

“This program protects the physicians,” Mr. Gavin noted. “It protects them and helps them not end up in court, but it also is in the best interests of their patients and families. It puts the physicians back firmly where they should be, which is working as a caregiver and not a risk manager.”

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Conversely, when the patient received a colonoscopy with Fuse first, followed by TFV, the

Traditional Endoscope

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TFV Gralnek et al.

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Limited 170° Field of View

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50

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Are You Confident About Your Hospital’s Compounding Plan?

Cedars-Sinai Takes Issue to Heart

BY BRUCE AND JOAN BUCKLEY MINNEAPOLIS— —With public confidence in compounding pharmacies badly shaken by last fall’s deadly fungal meningitis outbreak, some hospital pharmacies have reexamined the oversight of their sterile preparation facilities to ensure greater compliance with U.S. Pharmacopeia

(USP) Chapter <797> standards.

Unfortunately, the number of hospitals that have done so is meager, said Eric Kastango, RPh, MBA, a compounding quality expert who is the president and CEO of Clinical IQ. In the harsh light of the fungal meningitis crisis, he said, he would have anticipated that hospital pharmacies “would be more concerned about their state of compliance relative

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to USP <797>.””

But Mr. Kas-tango said the he general attiitude had been n, “ ‘I really don on’t have to worry because this is just st about compounding pharmacies and not hospital pharmacies.’ There’s not an overarching sense of urgency in the hospital segment.”

That has to change, Mr. Kastango said.

“Based on the consulting that I do,” he said, “even people who are doing a good job have significant gaps in compliance that can have a [major] impact on the quality of medications they’re making for their patients.”

A survey by the Institute for Safe Medication Practices earlier this year supports Mr. Kastango’s contention that hospital pharmacies are lagging. The survey showed that three of four respondents (74%) felt contamination could be a risk for their facilities, and 13% said contamination actually had occurred during the past year.

Cedars-Sinai Initiative Cedars-Sinai Medical Center, in Los Angeles, took these compounding risks to heart. The hospital carried out a major reevaluation and revision of its sterile compounding quality plan, according to Rita Shane, PharmD, director of pharmacy services at the center. Dr. Shane said the review was prompted not only by the desire to update and improve the pharmacy’s long-serving compounding quality assurance plan but also by new California compounding safety rules, considered to be among the nation’s strictest.

The initiative was launched several months before the meningitis crisis erupted last September, said Katherine Palmer, PharmD, sterile products area supervisor at Cedars-Sinai, but its timing seemed to grow in importance as more and more infections and deaths from injections of contaminated methylprednisolone distributed by the New

51

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Who Is Taking the Compounding Crisis Seriously?

BY DAVID BRONSTEIN Tom Van Hassel, RPh, pharmacy director at Yuma Regional Medical Center, in Yuma, Ariz., is no stranger to the crisis of confidence in compounding triggered by the New England Compounding Center (NECC) debacle. For the past several months, he has been working in his capacity as the president of the Arizona State Board of Pharmacy to draft new guidelines intended to make the practice safer for patients and hospitals.

Given the intensive level of activity those efforts require, does Mr. Van Hassel take issue with the claim by Eric Kastango, RPh, MBA, that there is a lack of urgency among some elements in pharmacy to fix what’s broken in the admixture arena?

“I actually agree with Eric on this—there does need to be a lot more effort than I am seeing, at least in health systems,” he said. “And remember, there’s no one right solution: Some facilities will decide to bring compounding in-house to boost safety, which is fine—if — f they do it right and can guarantee USP [Chapter] <797> compliance. Other facilities will decide to continue to outsource, which is also OK—but again, only if they do it correctly, by thoroughly vetting vendors to ensure the companies take good manufacturing practices and patient safety seriously.

“The problem is I don’t see a groundswell of hospitals stepping up and implementing these important quality improvement strategies.”

Help may be at hand from recent actions taken by the National Association of Boards of Pharmacy (NABP), which recently decided that USP Chapter <797> has to be the common nationwide source for guidance on compounding policies and procedures. Mr. Van Hassel said he has been working with his own state chapter to make that happen, even though it’s something of a departure from previous policy.

“We used to pick and choose the parts of <797> that we thought would work for hospitals in our state,” he said. “Frankly, we did that because we felt <797> and the related USP materials on beyond-use dating and other safety issues were way too complicated to follow. But after the NABP meeting, we saw that kind of cherry-picking may have led to some confusion and an uneven playing field among the states in terms of safe compounding expertise and compliance. So we are working hard to redraft our guidelines and get everyone on the same page.”

Mr. Van Hassel said he hopes the current pharmacy compounding bill doesn’t antagonize the proactive steps that boards of pharmacy are taking to boost compounding safety. If the Senate version of the bill gets passed, he noted, the section that excludes health systems from some of its provisions could impede action.

“Some hospitals may be looking at that exclusion and feeling as though they will get a pass,” he said. “Well, even if the Senate version does get signed into law, nobody gets a pass from USP Chapter <797> when it comes to in-house compounding. And we all need to handle outsourcing of compounding in a responsible fashion. That’s an important safety message that can’t be lost.”

England Compounding Center (NECC) were reported.

“Compounding is on everyone’s radar right now,” said Dr. Shane, who with Dr. Palmer and pharmacy manager Bruce Vinson, PharmD, reported on CedarsSinai’s revised quality assurance plan at the June 2013 Medication Safety Collaborative meeting, held in conjunction with the American Society of Health-System Pharmacists Summer Meeting.

One new innovation in the medical center’s plan is an online dashboard, an

easy-to-grasp Excel tool that helps the pharmacy monitor and report progress in meeting USP Chapter <797> goals as well as state requirements for environmental control, personnel performance, medication storage and other factors.

The dashboard, Dr. Shane said, “serves as a kind of tickler or prompt to make sure that everything is being evaluated on a timely basis.”

Before the dashboard was introduced, compounding activities were monitored see Compounding Plan, page 54

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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

20

†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.

©2013 Braintree Laboratories, Inc.

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May, 2013

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Compounding Recalls Continue, but FDA Slow To Respond

BY BRUCE AND JOAN BUCKLEY A compounding pharmacy in Texas recalled all of its sterile products in August after 15 patients in two hospitals developed bacterial bloodstream infections linked to calcium gluconate infusions made and distributed by the compounder.

The voluntary action by Specialty Compounding, based in Cedar Park, Texas, was the latest of at least four recent national recalls involving pharmacy compounders or distributors of compounding products. Although relatively minor in comparison to last fall’s fungal meningitis crisis that left more than 60 people dead and in excess of 700 sickened in 15 states, the newest incidents have increased pressure on Congress to pass legislation giving the FDA the authority to oversee pharmacies that make and distribute bulk-quantity sterile products without specific patient prescriptions, and often across state lines.

As compounding legislation awaits Health Research Group, stated in the Compounding recall, there have been at further developments, Public Citizen, press release. That delay, he said, “exposed least three other recent recalls involving the Washington, D.C.-based public patients to unnecessary risk and might sterile compounded products: health advocacy group, sought to keep have contributed to 15 people being • Earlier in August, Nexus Pharmasafety and regulatory oversight top-of- infected.” ceuticals of Vernon Hills, Ill., volmind by issuing a critique untarily recalled two of how the FDA handled lots of benztropine the Specialty Commesylate, after vispounding recall. At press ible particles were ‘The FDA knew there was a serious problem here, but time, the group charged discovered in proddidn’t use its existing legal authority to take prompt, that the FDA knew of uct vials. Accordpotentially unsafe drug ing to the company, aggressive action against the company.’ production practices at the product was —Michael Carome, director, Public Citizen’s the Texas compounder manufactured by Health Research Group as early as March 2013, Allergy Laboratories when the agency found and distributed by manufacturing issues Nexus. during an inspection of the facility. And He asked: “What’s the purpose of • In July, Beacon Hill Medical Pharyet Specialty Compounding didn’t issue inspecting a facility if you’re not going macy of Michigan recalled 46 prodits voluntary product recall until Aug. 9, to take appropriate action when you ucts after the FDA raised questions Public Citizen pointed out. find conditions that pose a safety threat about their sterility.

“The FDA knew there was a serious to patients?”

• Also in July, Fresenius Kabi USA problem here, but didn’t use its existing The FDA was not immediately availrecalled four lots of benztropine legal authority to take prompt, aggres- able to comment on the Public Citizen mesylate injection, also due to the sive action against the company,” Michael charges. potential presence of glass particles Carome, director of Public Citizen’s In addition to August’s Specialty in the vials.

■

Compounding Plan continued from page 51

and documented in an assortment of notebooks, Dr. Shane said. Now, with the template in place, the new system “has enabled us to organize our quality assurance activities and include the frequency for each component to facilitate tracking of our monitoring [efforts].”

All of the components of the dashboard are essentially in compliance with USP Chapter <797> standards, Dr. Shane said, but a few specifically address California rules, such as the need to validate the time spent observing staff who prepare sterile medications, for example.

“This is USP <797> plus,” she said.

Are Hospitals Ready For Random Inspections?

California hospital pharmacies now are required to file self-assessment reports on compounding quality only every two years. But Dr. Shane said she expected the California board to add hospital pharmacies to the list of random inspection sites. She said a state inspector who was evaluating a new Cedars-Sinai outpatient cancer center last fall took a look at the pharmacy’s revised compounding quality plan and “felt that it did support what they expected organizations to be doing.”

The Cedars-Sinai pharmacy staff is not standing still when it comes to improving compounding quality. They are anticipating the imminent arrival of a new microbial air sampler, a much more efficient and accurate tool than the agar paddles now in use. The new device will allow the pharmacy to measure the biological burden around hoods and clean rooms more frequently than the twiceyearly intervals recommended by USP Chapter <797>.

“The machine will enable us to simulate what the certifiers are able to test when they’re here,” Dr. Palmer said.

What lessons can other hospital pharmacies take from the fungal meningitis crisis?

‘[Hospitals] need to understand that the events that happened at [the New England Compounding Center] can happen in their pharmacies, and they need to be vigilant.’

—Eric Kastango, RPh, MBA

Mr. Kastango said, “They need to understand that the events that happened at NECC can happen in their pharmacies, and they need to be vigilant,” even if they are not required to be inspected under federal or state rules.

“From a strategic and tactical position,” he added, “people need to get their house in order and understand where they are relative to compliance with <797>. The chapter has been out for nine years now, and this stuff matters.”

■

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

FDA Reasserts Concerns About NuVision Sterile Products

BY GEORGE OCHOA The FDA continued to advise health care providers not to use sterile products from NuVision Pharmacy of Dallas, because the sterility of the products is not assured, according to an Aug. 16 FDA news release. This alert followed an April recall by NuVision of methylcobalamin injection and lyophilized injection products due to a lack of sterility assurance, and a May 18 FDA announcement of expanded concerns about a lack of sterility assurance of all NuVision’s sterile drug products.

“The FDA received adverse event reports of fever, flu-like symptoms, and soreness at the injection site associated with the methylcobalamin injection product” that was recalled, said the Aug. 16 news release.

NuVision has repeatedly declined FDA requests for a more widespread recall of the company’s sterile products, according to the agency; the FDA said it lacks the authority to require such a recall. Most recently, on July 26, the FDA issued a letter to NuVision outlining poor sterile production practices observed during an

FDA inspection of NuVision’s Dallas facility.

Among the agency’s findings: • The firm’s facility design “was inadequate for the processing of aseptically filled, injectable products.”

HEPA filters, for example, “covered less than one-half of the area in which sterile drugs are aseptically manipulated.”

• The ISO area where the HEPA filters were located “consisted of a table with inadequate protection to safeguard the sterile product from influx of lower-quality air from the immediately adjacent ISO 7 clean room.”

Without an adequate physical barrier, the FDA’s letter noted, the compounding area was vulnerable to microbial contamination from the activities of personnel in or near the work area.

• The company lacked any proof the aseptic work area “was supplied with a clean unidirectional air of sufficient velocity to protect sterile components from microbial contamination during aseptic processing.”

The letter, from Melinda K. Plaisier, acting associate commissioner for regulatory affairs at the FDA, requested an immediate “recall of all

The FDA advises health care professionals to check their medical supplies for NuVision sterile products, quarantine any such products, and not administer them to patients. lots of all sterile products produced at NuVision that are within expiry,” and warned, “if a drug product marketed as sterile contains microbial contamination, patients could be at risk for serious infections, which may be lifethreatening.” NuVision responded by refusing the requested recall, according to the Aug. 16 news release.

On NuVision’s website, the company stated it is not recalling all sterile injectables, and all its sterile injectables are tested for sterility by a thirdparty laboratory before dispensing.

The website also reports NuVision is a compounding pharmacy, not a manufacturer.

“We are in compliance with USP [Chapter] <795> and [Chapter] <797> which are the standards of law for compounding pharmacy. The FDA has been inspecting compounding pharmacies based on a different set of standards for manufacturers called FDA 210 and 211. … The current state laws do not require compounding pharmacies to follow the standards for manufacturing.”

The FDA advises health care professionals to check their medical supplies for NuVision sterile products, quarantine any such products, and not administer them to patients.

■

Acetaminophen Linked to Serious Skin Reactions

BY GEORGE OCHOA, WITH ADDITIONAL REPORTING BY

DAVID BRONSTEIN

choose other medications,” Sharon Hertz, MD, deputy director of the FDA’s Division of Anesthesia, Analgesia, and Addiction, said in a statement. “However, it is extremely important that people recognize and react quickly to the initial symptoms of these rare but serious side effects, which are potentially fatal.”

Other drugs used to treat pain and reduce fever, including nonsteroidal anti-inflammatory drugs (NSAIDs), also carry the risk for serious skin reactions, the FDA noted. These drugs include aspirin, ibuprofen, naproxen and ketoprofen. A serious skin reaction can occur in people who have previously taken acetaminophen without incident.

The FDA said it is requiring the addition of a warning about serious skin reactions to the labels of prescription medications containing acetaminophen,

and will work with the manufacturers of OTC products that contain acetaminophen to add a warning to their labels.

According to the FDA, evidence of the reported risk comes primarily from three published case reports in which patients were rechallenged with acetaminophen and had the serious skin reaction recur. Two of the papers were published more than a decade ago (Halevi A et al. Ann Pharmacotherr 2000;34:32-34; Leger F et al. Acta Derm Venereoll 1998;78:222-223).

The most recent was published in 2010 (Trujillo C et al. Allergol Immunopathol [Madr] 2010;38:99-100).

Additional supporting data come from other case reports that did not involve positive rechallenge, as well as the FDA Adverse Event Reporting System database, the agency noted.

Acetaminophen carries the risk for rare but serious and potentially fatal skin reactions, the FDA warned on Aug. 1. The risk is present both in prescription and over-the-counter (OTC) products containing the pain reliever and fever reducer, whether it is the single active ingredient or is combined with other medications.

The skin reactions include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), both life-threatening, as well as acute generalized exanthematous pustulosis (AGEP), which is usually not life-threatening, the FDA said in documents that included warnings for consumers and health care professionals. In AGEP, the skin reddens and gives rise to up to hundreds of pustules. SJS and TEN begin with flulike symptoms, followed by rash, blisters and detachment of the skin’s upper surface.

Health care professionals should advise patients using an acetaminophen-containing product to stop using it at the first sign of a skin rash or reaction and seek immediate medical attention.

“This new information is not intended to Stevens-Johnson syndrome (left) and toxic epidermal necrolysis (right) are rare but worry consumers or health care profession- potentially lethal side effects of over-the-counter acetaminophen. als, nor is it meant to encourage them to

A History of Regulation This is not the first action the FDA has taken to address safety issues associated with acetaminophencontaining products. In April 2009, the agency issued a ruling requiring manufacturers of OTC acetaminophen and NSAID products to revise their labeling to include warnings about potential safety risks, including internal bleeding and liver damage, in see Acetaminophen, page 58

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

Acetaminophen continued from page 56

patients taking the drugs. Additionally, the FDA mandated that acetaminophen labeling include a warning that patients talk to their doctor about the risks posed by taking the painkiller in conjunction with warfarin, which can increase the risk for bleeding.

Two months after the OTC labeling rule was issued, the FDA convened an advisory committee meeting to discuss further steps the agency could take to

promote the safer use of acetaminophen, with many of the proposals targeted at prescription formulations. For example, the advisory panel voted overwhelmingly (36 to 1) to recommend that a black box warning regarding liver injury be added to labeling for prescription medications containing acetaminophen and other painkillers, including hydrocodone (Vicodin, Abbott Laboratories), oxycodone (Percocet, Endo Pharmaceuticals) and codeine (Tylenol, McNeil). During the deliberations, one of the panel members cited data showing that

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

approximately 10% of all fatal acetaminophen overdoses occur in patients taking such combination products. The overdoses typically occur because patients often do not realize they are taking multiple products (in many cases, an OTC and a prescription product) that contain acetaminophen, the panelist noted.

The advisory panel recommended several additional safety steps, including lowering the maximum single adult dose from 1,000 mg to 650 mg, and making 500-mg acetaminophen pills obtainable by prescription only—an effort by

‘[The FDA is] looking at all aspects of acetaminophen safety.’

—Lisa Kubaska, PharmD, FDA spokesperson

the panel to effectively put dose limits on OTC formulations. And in its most controversial decision, the panel voted by a very slim margin (20 to 17) to ban all prescription combination products containing acetaminophen.

In 2011, the FDA responded to the advisory panel recommendations, but adopted only some of the panel’s suggestions. The agency said, for example, it would now require a black box warning highlighting the painkiller’s potential for causing severe liver failure and allergic reactions. It also announced it would place a 325-mg dosage limit on prescription products containing acetaminophen—a ruling that primarily affected combination opioid/acetaminophen formulations. But the FDA chose not to place any dosage restrictions on OTC acetaminophen, and it passed on the polarizing panel recommendation to ban all acetaminophen combination products.

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Public Citizen’s Stance Public Citizen, a national nonprofit health advocacy group, has long championed that the FDA be more aggressive in its oversight of acetaminophen.

In a Jan. 13, 2011 statement posted on its website, the group’s director, Sidney Wolfe, MD, criticized the FDA’s decision to place dosage limits only on prescription acetaminophen.

“It is inexcusably poor judgment” for the agency not to have lowered acetaminophen doses in OTC formulations, which are “a major source of acetaminophen consumption and, consequently, acetaminophen toxicity,” Dr. Wolfe said.

Indeed, in 2008, more than 370 million bottles and packets of acetaminophen— nearly 24.6 billion doses—were sold in the United States, Dr. Wolfe noted, citing FDA data. “Nearly 80% of this entire market is [represented by] OTC consumption,” he said.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

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Public Citizen’s response to the most recent acetaminophen FDA action was considerably less combative. In a statement provided on Aug. 7, the group chose to focus on how patients should react to the new labeling changes in a safe manner. The group said it “does not advise consumers taking acetaminophen to switch to another pain reliever unless they experience an adverse reaction. This is because other drugs used to treat fever and pain/body aches [e.g., NSAIDs, ibuprofen, naproxen, etc.] also carry the risk of causing serious skin reactions, as described in the warning sections of their labeling.”

The statement also sought to ease any fears that the severe skin reactions cited in the new labeling are a common occurrence.

“The [FDA] has not been able to determine how frequently serious skin reactions occur with acetaminophen, but it estimates that these events are very rare.”

Public Citizen did not comment on whether it had any plans for reiterating its earlier calls for more aggressive oversight of OTC acetaminophen.

FDA Response As for the FDA, when asked whether the skin reactions cited in the new acetaminophen labeling will result in the agency taking another look at dosing limits on OTC formulations, agency spokesperson Lisa Kubaska, PharmD, responded that its Division of Nonprescription Regulation Development “is aware of this safety issue; we are assessing the data and working on a new proposal to improve the safe use of acetaminophen drug products.”

Asked to provide further details of the proposal, Dr. Kubaska said that no such details are available. “However, we are looking at all aspects of acetaminophen safety.”

■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

NaviPro Hydrophilic Guidewire Available for ERCP Boston Scientific has announced the availability of the NaviPro Guidewire, a 100% hydrophilic guidewire for the treatment of pancreaticobiliary diseases.

According to the company’s product brochure, the device is “designed for cannulation and smooth passage through tortuous anatomy … and for physicians who prefer using over-the-wire access and therapeutic devices for endoscopic retrograde cholangiopancreatography (ERCP).”

The NaviPro Guidewire is available in two tip configurations—angled and straight—to allow cannulation of the biliary ducts in a variety of

cases. The guide wire is 260 cm long, and is available in three diameter sizes: 0.018 in/0.46 mm, 0.025 in/0.64 mm and 0.035 in/0.89 mm.

The company brochure also states that the NaviPro Guidewire “offers a one-to-one torque response for selective cannulation. The highly radiopaque guidewire provides excellent visibility to facilitate ductal location and accurate positioning during ERCP.”

The NaviPro Guidewire is available in two tip configurations—angled and straight—to allow cannulation of the biliary ducts in a variety of cases.

Photo courtesy of Boston Scientific

—Based on a brochure from Boston Scientific

New IBD Drug, Vedolizumab, Receives Priority Review Status for Ulcerative Colitis On Sept. 4, Takeda Pharmaceutical Company Ltd., announced it received priority review status from the FDA for its drug vedolizumab, an investigational antibody for the treatment of adults with moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC). Takeda submitted a biologics license application (BLA) to the FDA in June for the treatment of CD and UC; the UC application will receive priority review, and the application for CD will be reviewed under the standard timeline.

The FDA grants priority review status for drugs that are designed to treat a serious condition, and that if approved, would provide a significant improvement in safety or effectiveness. Priority review designation allows for an eight-month review period compared with the standard 12-month review.

“The need to seek new treatment options is well recognized,” said William J. Sandborn, MD, chief, Division of Gastroenterology, and professor of medicine, University of California, San Diego School of Medicine, in a press statement. “Vedolizumab has demonstrated the potential to be another possible treatment option for people with moderately to severely active CD and UC.” Vedolizumab is a humanized monoclonal antibody that specifically antagonizes α4β7 integrin and inhibits it from binding to its target receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1).

MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. It interacts with α4β7 integrin, which is expressed on a subset of circulating white blood cells, to mediate the inflammatory process in patients with CD and UC. Takeda’s BLA submission is supported by four Phase III clinical studies—GEMINI I, II and III, and GEMINI LTS (Long-Term Safety)— which comprise the GEMINI StudiesTM, a clinical program designed to investigate the efficacy and safety of vedolizumab in clinical response and remission in patients with moderate to severe CD and UC. Patients enrolled in the studies failed at least one conventional therapy for inflammatory bowel disease, including corticosteroids, immunomodulators and/or a tumor necrosis factor–alpha antagonist.

The results of the Phase III studies of vedolizumab in patients with CD and UC were published recently in the New England Journal of Medicine (Sandborn WJ et al. 2013;369:711-721 and Feagan BG et al. 2013;369:699-710, respectively).

According to Takeda, vedolizumab has been studied in 2,700 patients in nearly 40 countries, making it the largest Phase III clinical trial program to date to simultaneously evaluate CD and UC. GEMINI LTS is an ongoing, open-label, long-term safety study of vedolizumab and is designed to collect data on the occurrence of important clinical safety events resulting from the administration of vedolizumab.

—Based on a press release from Takeda Pharmaceutical Company Ltd.

Steris Corporation Joins Practice Greenhealth Steris Corporation, a global provider of infection prevention and surgical products and services for critical care, pharmaceutical and research markets, recentlyy announced it has joined Practice Greenhealth, a national health organization whose members support environmental best practices.

“Steris has a long history of product development that incorporates lean manufacturing and environmentally sound principles and features to help our customers reduce their environmental footprint and waste,” said Cary Majors, vice president of sales and marketing strategy for the Steris Healthcare Group. “For example, we continue to develop systems and consumables that help reduce utility and water use, and we offer paperless workflow management and documentation options, among many other initiatives.

“We look forward to joining other health care colleagues to advance our collective sustainability efforts, and to making use of Practice Greenhealth’s resources to expand our own environmental contributions.”

In addition, Steris has agreed to sponsor CleanMed 2014, a conference on environmental sustainability for the health care sector.

CleanMed is presented annually by Practice Greenhealth and Health Care Without Harm. The mission of the CleanMed conference, which will take place in Cleveland next year, June 2-5, is to accelerate the health care sector’s commitment to environmental sustainability and regenerative health to improve the health of people and the environment.

Practice Greenhealth provides practical guidance, training, consultation and business solutions to help its members implement environmentally responsible practices. More than 1,000 health care providers have joined the organization since 2008.

—Based on a press release from Steris Corporation

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

Expiration date: December 1, 2013

Goal Provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

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.

Intended Audience General surgeons, vascular surgeons, colon and rectal surgeons, critical care surgeons, surgical oncologists, trauma surgeons, and thoracic surgeons.

Faculty

Course Format: Monograph

Michael J. Rosen, MD

Estimated Time for Completion: 60 minutes

Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation.

2 Summarize current strategies used to prevent postoperative adhesion formation.

Sponsored by

Supported by an Educational Grant from

Designation of Credit Statement The Medical College of Wisconsin designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should only claim credit commensurate with the extent of their participation in the activity.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

Aptalis Pharma Launches PYLERA 10-Day Therapy PAK for Treatment of H. pylori In September, Aptalis Pharma US Inc., announced the launch of PYLERA 10-day Therapy PAK in the United States. PYLERA (bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride), in combination with omeprazole, is indicated for the treatment of patients with

Helicobacter pylori infection and duodenal ulcer disease (for active disease or a history of disease within the past five years).

According to a press statement from Aptalis, PYLERA is the only branded treatment option on the market that does not contain clarithromycin, a macrolide

antibiotic, which is believed to contribute to the growing rate of clarithromycin-resistant H. pylori.

The 10-day Therapy PAK leverages three-in-one capsule technology in blister packaging for convenient administration.

“Almost 20 years after the establishment of clarithromycin-based

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere.

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The Independent Monthly Newspaper for Gastroenterologists

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 19-2 us W bo 1, 20 oth 13 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 Co olitis:

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

T

he e greatest ch hallenge for clinicians who cl

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

b

c

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

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

1

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

PYLERA 10-day Therapy PAK from Aptalis Pharma US Inc. Photo courtesy of Aptalis Pharma US Inc.

triple therapy for the eradication of Helicobacter pylori, eradication rates are declining with this therapy due to increasing rates of clarithromycin-resistant H. pylori,” said Frank Verwiel, MD, president and CEO of Aptalis Pharma. “Given this, it is important for physicians and patients to have a convenient non-macrolide treatment option like PYLERA for H. pylorii in the 10-day Therapy PAK,” he said in a statement.

Guidelines from the American College of Gastroenterology recommend that physicians ask their patients, before treating them for H. pylori, if they have previously used a macrolide for any reason, such as for the treatment of upper respiratory infection, as the likelihood of clarithromycin-resistant H. pylorii infection increases with multiple macrolide antibiotic courses prescribed before diagnosis of H. pylori. According to Aptalis, in one study, 92% of patients who had a clarithromycinresistant H. pylorii strain had been treated with a macrolide antibiotic in the past 10 years.

PYLERA is contraindicated in patients with renal impairment and with known hypersensitivity to the drug’s components. The most frequently reported adverse reactions in clinical trials were abnormal feces, diarrhea, nausea and headache.

—Based on a press release from Aptalis Pharma US Inc.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2013

63

Given Imaging Announces FDA Clearance for PillCam SB 3 On Aug. 13, Given Imaging announced it received 510(k) clearance from the FDA for its next-generation PillCam SB 3, a device used to detect and monitor small bowel abnormalities associated with Crohn’s disease, obscure gastrointestinal bleeding and irondeficiency anemia.

Medical Center, in a press release.

The PillCam SB 3 capsule measures 11 mm x 26 mm and weighs less than 4 g. Now in its third generation, PillCam SB 3 contains an imaging device and a light source, and transmits images at a rate between two and six images per

second. Initially cleared by the FDA in 2001, PillCam SB may be used in patients aged 2 years and older.

The risks of PillCam capsule endoscopy include capsule retention, aspiration and skin irritation.

Medical, endoscopic or surgical intervention may be necessary to

BRIEF SUMMARY Please consult package insert for full prescribing information.

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

PillCam SB 3 is the latest-generation capsule for endoscopy of the small bowel from Given Imaging.

Photo courtesy of Given Imaging

The PillCam SB 3 system is a minimally invasive, capsule endoscopy procedure.

The new capsule combines a 30% improvement in image resolution with adaptive frame rate technology to deliver more detailed small bowel images and coverage.

Additionally, the capsule’s video processing engine has been significantly improved, and proprietary algorithms in the system’s new software enable even smarter video compilation that is 40% more efficient than PillCam SB 2, according to a press release from Given Imaging.

“The improved image resolution and overall efficiency of the PillCam SB 3 system in capturing and analyzing images of the small bowel has potential to have a meaningful impact on patient care,” said Felice H. SchnollSussman, MD, director, Jay Monahan Center for Gastrointestinal Health, NewYorkPresbyterian Weill Cornell

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

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

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

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

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

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

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

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

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

address any of these complications, should they occur.

According to the manufacturer, PillCam SB 3 will be available in the United States at the beginning of the fourth quarter of 2013.

—Based on a press release from Given Imaging

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

Mesalamine is known to cross the placental barrier.

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

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

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

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

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

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

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

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

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

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

Bottles of 120 capsules Bottles of 4 capsules

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

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

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GM 08/22-1

MANUFACTURED FOR:

Maintain UC remission with a low average co-pay

APRISO SAVINGS PROGRAM HER MISSION:

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APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials.

The most common adverse reactions (incidence ≥3% and >placebo) with APRISO in clinical trials were headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, influenza and influenza-like illness, and sinusitis1 *Average co-pay (all payers), Wolters Kluwer Health, August 2012. †Fingertip Formulary®, November 2012. ‡VA Healthcare System, October 2012.

Please see Brief Summary of complete Prescribing Information.

Please see complete Prescribing Information available at AprisoRx.com.

APRISO® and INTELLICOR® are registered trademarks of Salix Pharmaceuticals, Inc. ©2013 Salix Pharmaceuticals, Inc. All rights reserved. GM 12/95

See reverse side of APRISO Card for eligibility criteria. For help processing this card, call 1-855-740-3034.

Transition to APRISO, an affordable, once-daily ulcerative colitis (UC) therapy for your adult patients Average co-pay of less than $35 (all tiers)* Extensive formulary coverage with ~90% covered lives† #1-prescribed 5-ASA in the VA Health Care System‡

For more information, visit AprisoRx.com.

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OCTOBER 2013

REPORT Management of Global Enteric Infections individuals, or those with preexisting nteric pathogens present a huge Faculty chronic diseases are particularly vulnerclinical challenge on both a local able to life-threatening complications.3 and global scale. Most serious cases Bruce Yacyshyn, MD of enteric infections are concentrated in The Centers for Disease Control and Professor of Digestive areas with poor hygiene or unsanitary Prevention (CDC) estimates that 48 milDiseases water supplies, and can be exacerbated lion cases of foodborne illness occur in by limited access to health care or antithe United States each year, leading to University of Cincinnati biotics. However, affordable airfare and approximately 130,000 hospitalizations College of Medicine the cruise ship industry have resulted and 3,000 deaths.1 Cincinnati, Ohio in a larger number of individuals travIndividuals may attempt to avoid coneling to and from areas of high enteric taminated food or water to prevent enteric pathogen endemicity. The front line of health care contact infections, but this can be particularly difficult for those between the industrialized and less-developed world abroad with limited options.4 Antibiotic chemoprophylaxis occurs in hotels or on cruise ships, which bring together is another preventative strategy, but it is not recommended individuals from a variety of socioeconomic areas. due to the high prevalence of infections caused by viral “Even for those who travel to areas where enteric or unknown etiologies, thus increasing the global risk for infection rates are not particularly high, there is a development of antimicrobial resistance.4,5 This review dissubstantial risk for diarrhea just from a change in diet and cusses the epidemiology of enteric infections and current exposure to the local food and water flora that disrupts strategies for their treatment and prevention. the gut flora. However, as any gastroenterologist knows, you do not need to travel abroad to acquire an enteric Epidemiology of Enteric Infections infection, these bugs can come to you quite well,” said Norovirus Bruce Yacyshyn, MD, professor of digestive diseases, University of Cincinnati College of Medicine in Ohio.

Norovirus is the most common cause of foodborne A variety of microorganisms cause enteric infections. illness in the United States, with an estimated 19 to 21 Frequent etiologies of foodborne illness include Salmonella, million infections annually, resulting in 56,000 to 71,000 Campylobacter species, noroviruses, and Escherichia hospitalizations and 570 to 800 deaths.6 The CDC esticoli—the most common of which is travelers’ diarrhea mates that more than 50% of foodborne illnesses can be (TD).1 Infections caused by Helicobacter pylori can lead attributed directly to norovirus infections.1 Recent media 2 to chronic conditions such as gastritis and peptic ulcers. attention has focused on norovirus outbreaks on cruise ships; however, they can occur in a variety of institutional The symptoms of enteric infections include diarrhea, settings that feature dense populations and communal abdominal cramps, fever, nausea, and dehydration.3 eating areas such as military encampments and longAlthough serious complications are relatively uncommon term care facilities, with elderly individuals representing a in otherwise healthy individuals and symptoms are genparticularly at-risk population in these settings.7 Despite erally self-limiting, populations such as children, elderly

E

Supported by

REPORT Table 1. Studies on the Use of BSS for TD and Acute Diarhea Researchers

Purpose

Treatment Regimen

Study Population

Outcomes

Steffan et al, 1986

To determine the minimal dose needed for TD prophylaxis in travelers; treatment administered 1 d before and 2 d after travel

· 2 x 525 mg BSS bid (2.1 g/d) · 2 x 262.5 mg BSS bid (1.05 g/d) · Placebo bid

310 teens and adults (16-70 y): · 112 (2.1 mg/d) · 98 (1.05 mg/d) · 100 (placebo)

· 41% protection (2.1 g/d) · 35% protection (1.05 g/d)

Efficacy of BSS prophylaxis for 21 d in US students studying in Mexico

· 1 x 262 mg qid (1.05 mg/d) · 2 x 262 mg qid (2.1 mg/d) · Placebo qid

182 adults (>19 y): · 55 (2.1 mg/d) · 66 (1.05 mg/d) · 61 (placebo)

· 65% protection (2.1 mg/d) · 40% protection (1.05 mg/d)

Soriano-Bucher et al, 1991

Use of BSS as adjunctive therapy to rehydration for 5 d in hospitalized children with acute diarrhea

· 100 mg/kg/d BSS · Placebo

142 children (4-26 mo): · 72 (BSS) · 70 (placebo)

Time to last loose stool (E. coli): · 72 h (BSS) · 139 h (placebo) Time to last loose stool (rotavirus): · 57.5 h (BSS) · 105.5 h (placebo)

FigueroaQuintanilla et al, 1993

BSS for 5 d as an adjunct to oral rehydration in hospitalized infants with acute watery diarrhea

· 100 mg/kg/d BSS · 150 mg/kg/d BSS · Placebo

252 children (3-59 mo): · 83 (150 mg/kg/d) · 85 (100 mg/kg/d) · 84 (placebo)

Hospital LOS: · 3.4 d (150 mg/kg/d) · 3.3 d (100 mg/kg/d) · 4.1 d (placebo) Total stool output: · 174 mL/kg (150 mg/kg/d) · 182 mL/kg (100 mg/kg/d) · 260 (placebo)

Chowdhury et al, 2001

BSS for 5 d for the treatment of acute diarrhea and prevention of persistent diarrhea in hospitalized children

· 100 mg/kg/d BSS · Placebo

451 children (4-36 mo): · 226 (BSS) · 225 (placebo)

Acute diarrhea duration: · 36 h (BSS) · 42 h (placebo) Total stool and urine output: · 386 g/kg (BSS) · 438 g/kg (placebo)

DuPont et al, 1987

Positive for E. coli: placebo group only

Positive for E. coli: · 6% (both BSS groups) · 33% (placebo)

bid, twice daily; BSS, bismuth subsalicylate; LOS, length of stay; qid, 4 times daily; TD, travelers’ diarrhea Based on references 20, 23, and 26-28.

its prevalence, there are no specific pharmacotherapy options for the treatment of norovirus.

Travelers’ Diarrhea The CDC estimates that 30% to 70% of people will develop TD,4 with a large percentage of individuals traveling from an industrialized country to a less-developed region experiencing TD at some point during their trip.8 A constellation of pathogens is implicated in the etiology of TD, including Salmonella, noroviruses, and Campylobacter species, with E. coli accounting for more than 50% of all cases.4,5 The specific risk for developing TD is based on a variety of factors, including regional endemicity, age, and duration of stay.4,9

2

“The fact that most enteric infections in otherwise healthy travelers are self-limiting without serious sequelae does not diminish the value of avoiding 2 to 4 days of acute and sometimes severe symptoms. All patients traveling to areas associated with travelers’ diarrhea should be encouraged to take precautions that not only include exercising common sense with regard to the origin of foods and beverages consumed, but, in many cases, also may include some form of chemopreventive treatment,” Dr. Yacyshyn suggested.

Helicobacter pylori H. pylori is a common enteric pathogen, and at one time it was estimated that more than one-third of the US population

REPORT Table 2. Studies of Helicobacter pylori Eradication With Bismuth Therapy in Adolescents Researchers

Population

Treatment Regimen

Outcome

Walsh et al, 1997

Infants, children, 22 and teens (14 mo-16 y)

Study Size

· Bismuth subcitrate (480 mg/1.73 m3 BSA) qid · Clarithromycin (15 mg/kg) bid · Metronidazole (20 mg/kg) tid

95.45% eradication rate after treatment for 1 wk

Nijevitch et al, 2000

Adolescents and teens (10-15 y)

50

· Rantidine bismuth citrate 400 mg bid (4 wk) · Tinidazole 20 mg/kg (2 wk) · Amoxicillin 50 mg/kg (2 wk)

80% eradication rate

Choi et al, 2006

Children and teens (2-15 y)

92

· BSS (8 mg/kg/d) · Amoxicillin (50 mg/kg/d) · Metronidazole (20 mg/kg/d)

85% eradication rate when used as a first-line regimen; 81% eradication rate when used as a second-line regimen

bid, twice daily; BSA, body surface area; BSS, bismuth subsalicylate; tid, 3 times daily; qid, 4 times daily Based on references 33-35.

was infected with this organism.10 H. pylori is thought to be acquired during childhood due to overcrowded living conditions and poor hygiene and sanitation.11 Most individuals remain asymptomatic, but H. pylori has been identified as a major cause of gastritis and peptic ulcers.2 The eradication of H. pylori also has been associated with a reduced incidence of gastric cancer12 and gastric mucosa-associated lymphoid tissue lymphoma.13

Management of Enteric Infections The American College of Gastroenterology (ACG) recommends rehydration with an electrolyte glucose solution, also known as oral rehydration therapy, as initial treatment for cases of diarrhea or vomiting caused by infectious organisms.14 Symptom management with agents such as loperamide hydrochloride also is recommended to attenuate diarrhea and cramping.14 Bismuth subsalicylate (BSS), commercially available in the form of Pepto-Bismol, increasingly has been recognized as an important option for the treatment and chemoprophylaxis of various enteric infections. Its benefits are 2-fold: BSS modulates nonspecific gastrointestinal symptoms such as heartburn, nausea, and diarrhea15 while providing bactericidal activity to decrease recovery time.16 The latter attribute is of particular importance. Increasing concerns about antibiotic resistance rates have limited the recommendation to use antibiotics for chemoprophylaxis or the treatment of diarrhea from an unknown etiology.4,17

BSS for Acute Gastroenteritis and Norovirus BSS has the added benefit of attenuating the symptoms of gastroenteritis such as diarrhea, nausea, and vomiting from infections of viral or unknown pathogen sources.15 In such cases, antibiotics are not beneficial and symptomatic treatment is favored. The ACG recommends the use of BSS for the treatment of acute infectious diarrhea accompanied by vomiting, which are trademark symptoms of norovirus infections.14 Additionally, BSS has previously been found to be effective in attenuating the symptoms of norovirus-induced gastroenteritis.18 In a controlled clinical trial, the use of BSS

for norovirus-induced gastroenteritis reduced the severity and duration of abdominal cramps and reduced the median duration of illness from 27 to 20 hours.18 “In patients with diarrhea with an undiagnosed etiology, bismuth is effective in a surprisingly high percentage of patients,” said Dr. Yacyshyn. He cited unpublished data that associated bismuth with a more than 6-fold increase in accelerated resolution of diarrhea compared with placebo.

“Relative to antibiotics, bismuth works against both bacterial and viral pathogens, including noroviruses, it poses a low risk for contributing to pathogenic changes in gut flora, and it avoids the issues of antibiotic overuse. It does cause transient blackening of the tongue and dark stools, which is related to the bismuth metabolite, but overall, it is generally well tolerated.”

BSS for Various Etiologies of Travelers’ Diarrhea For most healthy individuals, 2 non-antibiotic options are available to prevent TD: probiotics and BSS. Dr. Yacyshyn often recommends that patients use nutritional supplementation with yogurt that includes probiotic bacteria. However, probiotics currently are not recommended by the CDC due to inconclusive efficacy data; thus, BSS represents the only non-antibiotic option recommended for TD.4 BSS is particularly attractive for chemoprophylaxis because of its low risk for adverse events; the majority of side effects involve harmless darkening of the tongue or stools, transient tinnitus, and constipation.19,20 Several studies have shown that BSS has bactericidal activity across a wide variety of pathogens21,22; when taken 4 times a day, it may provide up to a 65% protective effect against TD.19,23 BSS is particularly effective against TD caused by enterotoxigenic E. coli, with several studies reporting undetectable rates in the fecal samples of travelers following its use prophylactically.19,20,23,24 Evidence also suggests that BSS is effective at treating TD by decreasing the amount of unformed stools and shortening the time to recovery.24,25 BSS also has proven effective in attenuating acute diarrhea from a range of bacterial and viral pathogens in children as young as 3 months (Table 1). 20,23,26-28 Similar to its effect against TD in adults, BSS reduces the duration of diarrhea

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REPORT and hospital length of stay while also decreasing the severity of diarrhea by improving stool consistency.26-29 It should be noted that the risk for constipation is less with the use of BSS than with loperamide.30 In addition to being extremely effective, patient preference is another advantage with BSS. “Antibiotics are not the best option for the average traveler because of several drawbacks, including the risk for side effects. When the options are discussed, most individuals will prefer bismuth, which does not require a prescription and is easy to obtain,” said Dr. Yacyshyn.

BSS for H. pylori There are 2 combination regimens recommended by the ACG for the eradication of H. pylori.31 The first is a 3-agent regimen that combines a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole for 14 days (ie, clarithromycin-based triple therapy); the second option combines a PPI or H2-receptor agonist with metronidazole, tetracycline, and BSS (ie, bismuth-based quadruple therapy) for 14 days.31 Bismuth-based quadruple therapy eradicates between 75% and 90% of H. pylori infections,31 and a 7-day course of bismuth-based quadruple therapy may be prescribed for persistent H. pylori infections that fail to respond to clarithromycin-based triple therapy.31 “All of these regimens are effective, although local rates of antibiotic resistance may make one a better choice than another in a specific area,” Dr. Yacyshyn said. He recommended verifying eradication 6 weeks after treatment. “In my practice, I prefer the fecal antigen test, which has a relative low rate of false-positive results, or the C13 urea breath test.”

Bismuth-based therapy as an effective early intervention is of particular interest for adolescent populations. Studies have found that bismuth-based treatment regimens have an efficacy rate of 80% to 95%,32 with some evidence that the treatment may be more efficacious for children than other treatment options (Table 2).33-35 As antibiotics become more frequently prescribed to children, bismuth-based therapy may be an increasingly attractive option due to the high prevalence of clarithromycin- and metronidazole-resistant H. pylori strains found in adolescents.36

References 1. Centers for Disease Control and Prevention. http://www.cdc.gov/ foodborneburden/2011-foodborne-estimates.html. Accessed July 29, 2013.

2. Helicobacter pylori in peptic ulcer disease. NIH Consens Statement.

1994;12(1):1-23.

3. National Digestive Diseases Information Clearinghouse. http://digestive. niddk.nih.gov/ddiseases/pubs/bacteria/. Accessed July 29, 2013.

4. Centers for Disease Control and Prevention. CDC Health Information for International Travel 2012. New York: Oxford University Press; 2012.

5. Shah N, et al. Am J Trop Med Hyg. 2009;80(4):609-614.

6. Hall AJ, et al. Emerg Infect Dis. 2013;19(8):1198-1205.

7. MMWR Recomm Rep. 2011;60(RR-3):1-18.

8. Steffen R, et al. J Travel Med. 2004;11(4):231-237.

9. Hill DR. J Travel Med. 2000;7(5):259-266.

10. Everhart JE, et al. J Infect Dis. 2000;181(4):1359-1363.

11. Brown LM. Epidemiol Rev. 2000;22(2):283-297.

12. Uemura N, et al. N Engl J Med. 2001;345(11):784-789.

13. Nakamura S, et al. Gut. 2012;61(4):507-513.

14. DuPont HL. Am J Gastroenterol. 1997;92(11):1962-1975.

15. Hailey FJ, et al. Arch Intern Med. 1984;144(2):269-272.

16. Sox TE, et al. Antimicrob Agents Chemother. 1989;33(12):2075-2082.

17. Diemert DJ. Clin Microbiol Rev. 2006;19(3):583-594.

18. Steinhoff MC, et al. Gastroenterology. 1980;78(6):1495-1499.

19. DuPont HL, et al. Rev Infect Dis. 1990;12(suppl 1):S64-S67.

20. Steffen R, et al. Antimicrob Agents Chemother. 1986;29(4):625-627.

21. Cornick NA, et al. Rev Infect Dis. 1990;12(suppl 1):S9-S10.

22. Manhart MD. Rev Infect Dis. 1990;12(suppl 1):S11-S15.

23. DuPont HL, et al. JAMA. 1987;257(10):1347-1350.

24. Graham DY, et al. Rev Infect Dis. 1990;12(suppl 1):S68-S72.

Conclusion Enteric pathogens represent a major source of morbidity in parts of the world where sources of clean water remain limited and low standards of hygiene persist. However, even in areas without these challenges, the risk for morbidity from enteric pathogens remains considerable and it represents a significant challenge to public health. Preventing enteric infections altogether or rapidly intervening with prudent supportive therapy when they occur provides an opportunity to limit the burden these infections impose. Agents such as BSS, an inexpensive, over-the-counter option in the form of Pepto-Bismol, offer an effective strategy to manage the risk for and fallout from enteric infections encountered throughout the world while preserving the efficacy of antimicrobial agents.

25. Steffen R. Rev Infect Dis. 1990;12(suppl 1):S80-S86.

26. Chowdhury HR, et al. Acta Paediatr. 2001;90(6):605-610.

27. Figueroa-Quintanilla D, et al. N Engl J Med. 1993;328(23):1653-1658.

28. Soriano-Brucher H, et al. Pediatrics. 1991;87(1):18-27.

29. Soriano-Brucher HE, et al. Rev Infect Dis. 1990;12(suppl 1):S51-S56.

30. Johnson PC, et al. JAMA. 1986;255(6):757-760.

31. Chey WD, et al. Am J Gastroenterol. 2007;102(8):1808-1825.

32. Pacifico L, et al. Aliment Pharmacol Ther. 2012;35(9):1010-1026.

33. Choi J, et al. J Korean Med Sci. 2006;21(6):1037-1040.

34. Walsh D, et al. Arch Dis Child. 1997;76(4):352-355.

35. Nijevitch AA, et al. J Gastroenterol Hepatol. 2000;15(11):1243-1250.

36. Koletzko S, et al. Gut. 2006;55(12):1711-1716.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Procter & Gamble, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

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Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Financial Disclosure: Dr. Yacyshyn reported that he has received research support from Furiex Pharmaceuticals, GlaxoSmithKline, Merck, and Santarus.

He has served as a consultant for N8 Medical and Regeneron. He has also served on the speakers’ bureaus of and received honoraria from Optimer Pharmaceuticals and Santarus.