December 2013 by McMahon Group

1978 —

Ple as A NY IBD e Vi SG bo sit E b ot Us oo h # ! th 9 #1 02

35th Anniversary — 2013

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The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 12 • December 2013

ACG 2013

Vedolizumab Yields Steroid-Free Remission

The U.S. Trillion-Dollar Medical Bill 99.6% Is Nott Related to Colonoscopy

BY DAVID WILD

BY VICTORIA STERN

SAN DIEGO—Pooled analyses of the placebo-controlled GEMINI 1 and 2 trials of vedolizumab revealed that nearly 60% of patients with inflammatory bowel disease (IBD) who initially exhibited a clinical response to the drug achieved steroid-free clinical remission at one year.

On June 1, Elisab beth Rosenthal’s exposé “Th he $2.7 Trillion Medical Billl” published in The New Yorkk Times singled out colonooscopy as a primary driver off the national health care crisis. Ms. Rosenthal reported that costs for health care in the United States trump th hose of any other developed country, and furthermore, thaat colonoscopy is “the mosst expensive screening test that healthy Americans routin nely undergo,” amounting to more than $10 billion in annual health care costs. Ms. Rosenth hal described the many tribulation ns of patients throughout the country who have received enormous bills for routine colonoscopiees. One patient’s bill reached nearly $20,000 because it included the removal and biopsy of a polyp. So, what’s behind the excessive medical billing in

see Vedolizumab, page 16

UEGW 2013

Treat-to-Target Dosing Of Infliximab: Induction Versus Maintenance BY TED BOSWORTH BERLIN—In patients with inflammatory bowel disease (IBD), monitoring infliximab levels during maintenance therapy, unlike induction, did not provide an advantage over clinically directed dose adjustments in a randomized trial. The maintenance therapy data were presented as see Infliximab Dosing, page 18

Overu and Abuse in U.S. Health Overuse Care e: Is Colonoscopy To Blame?

the United States, and is colonoscopy the culprit? “A major factor behind the high costs is that the United States, unique among industrialized nations, does not generally regulate or intervene in medical see Trillion-Dollar Bill, page 6

I N S I D E EXPERTS’ PICKS Best of the ACG Annual Scientific Meeting: Focus on IBD ............................................................... page 18

BY VICTORIA STERN This year, two major news outlets identified colonoscopy as a prime example of what’s wrong with the American health care system: The New York Timess published “The $2.7 Trillion Medical Bill: Colonoscopies Explain Why U.S. Leads the World in Health Expenditures,” see Colonoscopy Costs, page 26

Ashish Atreja, MD, MPH

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35th Anniversary — 2013

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

Guidance Equivocal On HCV Screening Of Baby Boomers

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

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

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

see NAFLD, page 14

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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

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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

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

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

In Memoriam The New York Society for Gastrointestinal Endoscopy (NYSGE) mourns the passing and celebrates the life of our dear friend, first executive director and society matriarch Florence Lefcourt. For 40 years, Florence provided continuity and administrative leadership to the Society as it grew from eight pioneers to the largest regional gastroPhoto courtesy of NYSGE intestinal endoscopy society in the nation. She was tireless in directing her exceptional energies toward the education of young endoscopy trainees. More than any other non-physician, she influenced the quality of endoscopy education and impacted the lives and practices of gastroenterologists in the greater New York area and around the country. With an everpresent smile and caring concern for all, Florence was truly the heart and soul of the Society. She is much loved and will be long remembered. At the suggestion of Florence’s family, contributions in her memory can be made to the NYSGE Fund for GI Endoscopic Research and Public Education to support grants through the Florence Lefcourt Award.

To donate to the NYSGE Fund for GI Endoscopic Research and Public Education, please visit www.asge.org/foundation/foundation.aspx?id=4130. The NYSGE Fund for GI Endoscopic Research and Public Education is a donor-advised endowment fund, established in 2004 between NYSGE and the American Society for Gastrointestinal Endoscopy (ASGE). Grants provided by the fund support collaborative projects in the areas of endoscopic research and educational outreach in the greater New York area. The fund, which is administered by the ASGE Foundation, provides grants via the Florence Lefcourt Award to physicians who are members of both NYSGE and ASGE and who are in practice or on full-time staff at an NYSGEaffiliated institution. This article was provided by NYSGE. © NYSGE. All Rights Reserved. www.nysge.org

The New York Society for Gastrointestinal Endoscopy (NYSGE) will hold its annual meeting in New York City in December.

37th Annual New York Course Challenges and Controversies in Endoscopy December 19-20, 2013 New York Marriott Marquis Hotel 1535 Broadway New York, New York

GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,500 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2013). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2013 by McMahon Publishing.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Happy Holidays

Prep in a Pill? Re: “Bowel Preparation for Colonoscopy: Maximizing Efficacy, Minimizing Risk,” by Lawrence B. Cohen, MD. Gastroenterology & Endoscopy News Special Edition October 2013;64(suppl):9-17.

from the Gastroenterology & Endoscopy News team

As a patient, I believe that patient compliance would be improved if the bowel preparations did not taste so awful. If a safe pill or capsule to be taken with water could be developed, compliance would be increased. Many patients do not have needed colonoscopies because the prep is so distasteful. —“lubin” Oct. 22, 2013

Web Comment

Living FODMAP-Free Re: “FODMAPS for IBS: Who Will Benefit?” by Caroline Helwick. Gastroenterology & Endoscopy News November 2013;1,18-21.

Great article! Thank you for sharing this information with the doctors who need it the most and can have the greatest impact! We are collecting scientific studies on the topic and creating FODMAP-free and low-FODMAP recipes to help people. Our site is http://fodmapliving.com. —“fodma” d Nov. 6, 2013

Dan, Jeanette, Brian, Cindy & Matt

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EXPERT ROUNDTABLE

GAS GAST A TR ROEN OEN E TERO R LOGY LO OGY & E ND NDOS N NDO DOS COPY NEW N S•D DECE ECE MBER M 2013

John Allen, MD, MBA

Chalmers Nunn, MD

Douglas Rex, MD

President Elect, American Gastroenterological Association Professor of Medicine Section of Digestive Disease Yale University School of Medicine New Haven, Connecticut

CEO Gastroenterology Associates of Central Virginia Lynchburg, Virginia

Distinguished Professor of Medicine Indiana University School of Medicine Director of Endoscopy Indiana University Hospital Indianapolis, Indiana

David Robbins, MD

Jerome Siegel, MD

Medical Director Manhattan Endoscopy Center New York, New York

Clinical Professor of Medicine Albert Einstein College of Medicine New York, New York

Trillion-Dollar Bill continued from page 1

pricing, aside from setting payment rates for Medicare and Medicaid,” Ms. Rosenthal wrote. As a result, Americans confront a system in which doctors, hospitals, pharmacies and insurers negotiate prices for individual services. This means every interaction with a health care professional represents an occasion to bill, and there is little to no consistency or transparency in pricing for a given service, procedure or test. This lack of standardization contributes to the problem of health care costs. In the United States, insurance companies contract with individual hospitals, pharmacies and facilities, including doctors’ offices and ambulatory surgery centers (ASCs), and negotiate different prices and levels of reimbursement for the same services. The prices and reimbursement scales often are based on the negotiating power of the individual hospitals, pharmacies and physicians. Each insurance company provides a range of plans to patients—full coverage that comes with a copay and no deductible, full coverage that includes a deductible and partial coverage, such as emergency insurance. Some patients have Medicare or Medicaid, and some still have no insurance coverage at all. In what turned out to be a seminal article (“The Bitter Pill: Why Medical Bills Are Killing Us,” Time, Feb. 20, 2013), Steven Brill revealed that Medicare routinely reimburses hospitals for less than one-tenth of what they charge patients for the same service. Hospital charges, Mr. Brill reported, are based on the chargemaster list—a hospital’s internal price list, for which there “seems to be no process, no rationale, behind the core document that is the basis for hundreds of billions of dollars in health care bills.” The prices for services are so opaque that doctors often

cannot tell patients what a routine procedure, like colonoscopy, will cost them. Additionally, there are other layers in the case of colonoscopy costs. Each component of a colonoscopy can quickly add up to a huge sum, according to Ms. Rosenthal. The endoscopist’s professional fee is just one component of the total bill, which also may include charges for an anesthesiologist, a pathologist and a facility fee. The facility fee varies widely depending on whether the procedure is performed in a hospital, doctor’s office or ASC. Although hospitals charge the highest facility fees,

‘At around $10 billion, these costs represent less than 0.4% of the total $2.7 trillion bill.’ —Ellen J. Scherl, MD

Ms. Rosenthal pointed out that ASCs, where procedures are often billed as “a quasi-operation,” also contribute to skyrocketing costs. The presence of an anesthesiologist during the procedure also contributes to high costs. One study, published by the RAND Corporation in 2012, found that “ending the practice for healthy patients could save $1.1 billion a year” (Liu et al. JAMA 2012;307:1178-1184). Some physicians argue that anesthesiologists are not needed during a colonoscopy. For example, in many other countries, non-anesthesiologists provide sedation for patients, and in the United States,

the Department of Veterans Affairs does not routinely use an anesthesiologist for screening colonoscopies. Although in her article, Ms. Rosenthal does not deny “screening for colon cancer is crucial,” she did question whether colonoscopy prevents colorectal cancer (CRC) or CRC-related mortality better than other cheaper and less-invasive screening methods.

Reaction From Gastroenterologists The publication of Ms. Rosenthal’s piece generated a flood of comments on The New York Times website. Patients voiced agreement and alarm over the mounting price tag of medical care, sharing personal struggles and fears associated with maintaining health. Others, including patients and physicians, proposed possible solutions. Letters to the editor from leaders in the gastroenterology community expressed concern that Ms. Rosenthal chose to focus on colonoscopy, the best test for prevention and detection of early signs of CRC. “The fact that the writer chose to focus her attention on the one and only preventive cancer test that has been demonstrated to significantly reduce the incidence of colon cancer and death from the disease is disappointing,” wrote Ronald J. Vender, MD, then president of the American College of Gastroenterology (ACG), in a statement. Ellen J. Scherl, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medical College, New York City, said Ms. Rosenthal’s article was misleading and did not adequately put colonoscopy costs into perspective. “At around $10 billion, these costs represent less than see Trillion-Dollar Bill, page 8

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Trillion-Dollar Bill continued from page 6

0.4% of the total $2.7 trillion bill,” Dr. Scherl said in an interview. H. Gilbert Welch, MD, professor of medicine, Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, N.H., asked, “At what point does it become a crime” to charge such outrageous prices for medical services (“Diagnosis: Insufficient Outrage,” The New York Times July 4, 2013). After postulating that medical costs continue to grow, Dr. Welch proposed strategies to improve the health care system, including ensuring that every patient has access to a standardized set of prices, like the Medicare fee schedule, or mandating a flat-fee system in lieu of a fee-for-service one. However, he noted, “Too many of us have passively accepted the situation as being beyond our control.”

The authors reported that the RVUs assigned to medical services are greatly inflated, using colonoscopy as the prime example.

With colonoscopy still fresh on the public’s collective mind, The Washington Post published a provocatively titled piece, “How a Secretive Panel Uses Data that Distort Doctors’ Pay” by Peter Whoriskey and Dan Keating ( July 20, 2013). The authors reported that the relative value units (RVUs) assigned to medical services are greatly inflated, using colonoscopy as the prime example. In a commentary on the article, Dr. Vender along with Anil K. Rustgi, MD, president of the American Gastroenterological Association (AGA), and Kenneth K. Wang, MD, president of the American Society for Gastrointestinal Endoscopy, attempted to clarify inaccuracies in the article, stating, for example, that the author confused procedure time with the total time spent with a patient, and that Medicare’s reimbursement to physicians for colonoscopy has actually decreased over the past 20 years. To further explore the issue, Gastroenterology & Endoscopy News (GEN) asked five gastroenterologists to comment on Ms. Rosenthal’s piece and provide insights on the current complex medical landscape in the United States.

GEN: What is your reaction to Ms. Rosenthal’s article, “The $2.7 Trillion Medical Bill,” published in The New York Times? Dr. Nunn: I feel that Ms. Rosenthal’s article missed the point of the problem of high medical costs by focusing on colonoscopy as the sole piece of expensive medical care. What she didn’t explain is that most of the high costs she references for colonoscopy are hospital charges, based on the chargemaster list, which are overinflated figures, and insurance companies only pay a percentage of those amounts. What Ms. Rosenthal did right is to highlight that

prices for medical services are incredibly expensive in the United States—60% higher than anywhere else in the world—and that we need transparency in pricing. Dr. Robbins: Although I agree with Ms. Rosenthal that we, as a nation, face runaway health care spending and need greater transparency, her assertion that the cost of routine colonoscopy is the main reason America leads the world in health expenditures is distorted and jeopardizes the strides we have made in the war on cancer. I hope the article does not erode these recent hard-won gains.

1. Prices: Services are more expensive in the United States. 2. Provider income: It is higher in the United States than in other countries.

‘Doctors may feel encouraged to diagnose and treat problems using more expensive tests and procedures because they can make more money.’ —Chalmers Nunn, MD

Dr. Siegel: Ms. Rosenthal’s article was simply journalistic sensationalism. Most responses to her article showed that her data were flawed and slanted. Dr. Rex: Although I agree that prices for medical procedures are high and often lack transparency, overall I think that Ms. Rosenthal’s article is biased and inaccurate. One major problem is the implication that colonoscopy is not effective, or as effective, in preventing CRC compared with other tests. We know from case–control studies that colonoscopy does prevent CRC. There is no other test that has this level of evidence for prevention, and the United States is the only country in the world that has declining incidence rates for CRC, thanks in large part to screening colonoscopy. Another issue is Ms. Rosenthal’s assertion that we have moved endoscopic procedures from doctors’ offices into ASCs because it’s more profitable. This is incorrect. Outside of the New York–New Jersey–Philadelphia area, offices have always represented a small percentage of where colonoscopies are performed. The move from hospitals to ASCs is associated with a reduction in costs, with ASCs typically charging onethird to one-fifth of what hospitals do. Dr. Allen: The article by Ms. Rosenthal highlights an important topic—the range in prices for medical services—but fails to elucidate many of the reasons for price differences. Even within a single institution, the prices for colonoscopy can vary three to five times, depending on how contracts with payors are negotiated. Some payors negotiate a single reimbursement rate for all outpatient surgical procedures, so simpler procedures, like colonoscopy, are blended in with multilayer spinal surgeries, consequently driving up rates for colonoscopy. A simplified analysis looking only at patients’ bills will fail to identify true cost drivers and gives the incorrect assumption that physicians control and drive price differences. The implication that physicians’ primary motivation is financial calls into question the integrity of our profession.

GEN: What factors contribute to the high costs of medical care? Dr. Nunn: In my opinion, there are six main reasons for the high costs of medical care:

3. A fee-for-service system: Doctors may feel encouraged to diagnose and treat problems using more expensive tests and procedures because they can make more money. 4. Technology: We scan too much and perform too many tests, which drives up costs substantially. Period. 5. Administrative costs: These are higher in the United States because practices and hospitals have great administrative complexity. 6. Tort: Legal concerns may drive a doctor to overtest and overtreat. Many doctors may fear being sued if they fail to perform all necessary tests to rule out a serious underlying problem. Dr. Robbins: I don’t necessarily think the cost of colonoscopy is particularly high in this country, but there is a range in price and quality. At $1,200 on average in the United States, colonoscopy has been modeled in dozens of cost-effectiveness studies and its lifesaving potential has been shown to save health care dollars by abrogating the need for much more costly cancer care. The price of a colonoscopy needs to be compared with what it aims to prevent—CRC—and not just considered in the abstract.

‘Even within a single institution, the prices for colonoscopy can vary three to five times, depending on how contracts with payors are negotiated.’ —John Allen, MD, MBA

Dr. Siegel: I believe the high cost of medical care in the United States is largely due to duplications or redundant services and the high cost of administrators. Devising a system to eliminate both is preferred. In 10 years, redundant or repeated procedures and tests will amount to $1.6 trillion,

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

and administrative costs will approach $1.5 trillion. Some of these high costs are a result of “defensive medicine.” Dr. Rex: The biggest culprit driving health care costs is hospitals. Additionally, colonoscopy is just one of a long, almost endless string of medical procedures that are subject to high and variable charges, all of which contribute to the high costs of medical care. Colonoscopy is being

19 7 8

—

targeted in large part because of how frequently it’s performed, which in turn reflects its great value to patients and cancer prevention. Ultimately, colonoscopy is targeted because of its success as a medical procedure. However, there’s little point in singling out colonoscopy to make a point about health care costs in general. Dr. Allen: Some of the main contributors to high medical costs are:

• Obesity, smoking, traumatic accidents and alcohol use; • Overuse and misuse of medical procedures and tests; • Threat of litigation; • Lack of a single, coordinated billing language and system, estimated by health care economist Uwe E. Reinhardt, PhD, to cost about $70,000 per physician; • Excessive regulations that do not add benefit to patients’ health outcomes;

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• Duplication of high-margin services; • A lack of clinical integration and information transfer for patients who are chronically ill or have multiple medical comorbidities; • Administrative costs of institutions and payors; and • Lack of political will to overcome barriers to a patient-focused health care system.

GEN: Do you think reimbursement for colonoscopy is fairly priced? Dr. Nunn: Overall, I agree with the response from the ACG, which stated, “Medicare reimbursement rates for colonoscopy do not accurately reflect its value for CRC prevention,” in terms of savings in cost of cancer treatment, improvement in quality of life and reduction in deaths from CRC.

‘No, I don’t think the fee for a sophisticated, resource-intensive and

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 —

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

—David Robbins, MD

Dr. Robbins: The Medicare professional fee for colonoscopy is $220, or about what one would pay to have dents removed from a car’s rear quarter panel. So no, I don’t think the fee for a sophisticated, resourceintensive and potentially lifesaving test is fairly priced.

gastroendonews.com Volume 64, Number 1 • January 2013

IBS No Longer Only Functional Disorder

test is fairly priced.’

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potentially lifesaving

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

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

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

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

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

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

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

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Dr. Siegel: Reimbursement for colonoscopy from Medicare is totally insufficient, and if the payment remains this low or lower, doctors will opt out or perform more procedures than should be done. The customary fee should be $1,500 to $2,000. If physicians opt out of Medicare, they can charge what they feel is fair, if patients wish to pay it. If a doctor is out of network and the patient pays more for an out-of-network doctor, the doctor can receive his or her usual fee and the patient will pay the 20% balance. see Trillion-Dollar Bill, page 10

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Trillion-Dollar Bill continued from page 9

Dr. Rex: What gastroenterologists receive for their professional performance of a colonoscopy is only a small fraction of the total bill. If we reduce gastroenterologists’ reimbursement for performing colonoscopies, it may disincentivize doctors from performing the procedure, which will have negative consequences for the prevention of CRC.

‘Medicare’s reimbursement to physicians for colonoscopy has decreased by 16% since 1992 (49%, when adjusting for inflation).’ —John Allen, MD, MBA

Dr. Allen: Medicare pays gastroenterologists $220, on average, for their time, expertise and clinical care. This is certainly not excessive. In fact, Medicare’s reimbursement to physicians for colonoscopy has decreased by 16% since 1992 (49%, when adjusting for inflation). For every patient who does not develop CRC because a large precancerous polyp was removed during a colonoscopy, I imagine this price is acceptable. The AGA is developing a model to help gastroenterologists negotiate a fixed price with payors for care before, during and after a colonoscopy. With bundled payments, providers share risk and have financial incentives to be prudent.

GEN: What is your opinion of the Washington Post article, “How a Secretive Panel Uses Data that Distort Doctors’ Pay,” which explores inflated RVUs and medical costs? Dr. Nunn: The American Medical Association (AMA) Specialty Society Relative Value Scale Update Committee (RUC) process seems to be a good one, but the underlying system is open to debate, as is our flawed feefor-service system. I suspect if you looked at every procedure and the estimated procedure lengths, the values often would be inflated. But time is just one relative measure. You could make procedure times more accurate, but then change the rate of payment, for example. I don’t have an answer as to what would be better. We could debate that for a long time.

‘The idea

expect a layperson—or even a physician in an unrelated discipline—to understand the complexities and relative value of a colonoscopy. Congress sets its own wages, but somehow that’s not newsworthy. Dr. Siegel: Medicare is not secretly setting fees. The AMA has a committee made up of several specialists who establish the Current Procedural Terminology codes and try to set reasonable fees. Unfortunately, the codes do not reflect degree of difficulty: If a colonoscopy is more complex and several polyps are removed, the reimbursement is the same, more or less, and the reimbursement for an esophagogastroduodenoscopy (EGD) is only a few dollars less than for a colonoscopy. One can probably do four or five EGDs in the time it takes to perform one-and-a-half colonoscopies. So don’t burp too much or you’ll be getting an EGD! Colonoscopy, or any procedure, carries risks—including the likelihood of having a million-dollar lawsuit. Is it worth $220 to the doctor to take that risk? Dr. Rex: The RUC has a difficult job balancing the interests of and lobbying for many specialties. Certainly, the RVU for colonoscopy does not reflect the undue influence of gastroenterologists on the RUC, because gastroenterologists have not had a seat on the RUC for a long time. RVUs for procedures should not be based on time alone. The current RVU for colonoscopy is not out of line considering the intensity and risk of the procedure and the time that’s involved with preprocedure preparation, postprocedure patient instruction, pathology follow-up and other factors beyond the actual procedure. Reductions in colonoscopy RVUs might reduce the availability of colonoscopy for screening. In my own practice, I spend a lot of time performing complex endoscopic mucosal resections as well as colonoscopies in patients who have previously had incomplete colonoscopies with other doctors. Many gastroenterologists provide services of this type. Further reductions in the professional fee for colonoscopy will threaten our ability to provide these important and of a profession cost-saving services.

setting its own fee schedule

Dr. Allen: The article focuses on objectionable. One could not time as the leading factor in how values expect a layperson—or even are assessed, but time a physician in an unrelated is only a small component of the overall discipline—to understand equation. Physician the complexities and relative work and intensity during procedures, value of a colonoscopy.’ as well as the type —David Robbins, MD of patient treated, are valued more, and rightfully so. To say that procedures are Dr. Robbins: misvalued based on time calculations alone is inaccurate The idea of a profession setting its own fee schedule and does not adequately capture the process. is neither secretive nor objectionable. One could not The AMA and the RUC have provided an enormous

is neither secretive nor

service to the field of medicine, and the current process allows physicians’ input. One can argue with the outcome and the basic structure, but has anyone come up with a better alternative to balance the “relative” reimbursement of more than 7,000 service codes? We are working toward a value-based reimbursement system that recognizes the importance of primary care management. But when do I get to see the plan, and how can I help move this needle forward without disrupting current health care delivery?

‘RVUs for procedures should not be based on time alone. The current RVU for colonoscopy is not out of line considering the intensity and risk of the procedure and the time that’s involved with preprocedure preparation, postprocedure patient instruction, pathology follow-up and other factors beyond the actual procedure.’ —Douglas Rex, MD

GEN: Is cost linked to quality of health care? Dr. Nunn: The answer to this question depends on how you measure “quality.” If you’re referring to individual care—immediate care using the most tests and highest-tech equipment—we are the absolute best. But if you mean care of a population, then no, we’re not getting our money’s worth. For example, our ability to manage diseases, such as diabetes or hypertension, on a population level is not good. Additionally, costs that vary by location are not linked to quality of care: For instance, although a colonoscopy will cost five to eight times more if performed in a hospital versus a physician’s office, patients will not get an eightfold better product. Dr. Robbins: I am unaware of any convincing data linking the cost to quality of health care, to the extent that spending more money results in better outcomes. The problem with asking, “Does cost correlate with quality?” is the complexity of what defines both “costs” and “quality.” At first blush, it stands to reason that outcomes might improve if we reward folks for doing quality work rather than being paid on the volume of their work. But so many factors are at play. see Trillion-Dollar Bill, page 23

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

New Antibody Test Could Identify IBS BY DAVID WILD SAN DIEGO— —A first-of-its-kind blood test for irritable bowel syndrome (IBS) differentiated the syndrome from inflammatory bowel disease (IBD) in more than 90% of cases in a trial presented at the 2013 American College of Gastroenterology Annual Scientific Meeting. Researchers found that patients with IBS had significantly higher levels of anti-vinculin antibodies, which

are produced during acute gastroenteritis, compared with patients with IBD and healthy individuals. Brian Lacy, PhD, MD, professor of medicine and chief of the Section of Gastroenterology and Hepatology at the Geisel School of Medicine, DartmouthHitchcock Medical Center, Lebanon, N.H., said that, along with previous research conducted by the same investigators, the study helps frame IBS “in an entirely new way.”

“If the results of this pilot study are confirmed, measuring anti-vinculin antibodies could prove to be a safe, easy-touse and inexpensive aid in the diagnosis of IBS,” said Dr. Lacy, who was not involved in the study. Lead investigator Mark Pimentel, MD, director of the Gastrointestinal Motility Program and Laboratory at Cedars-Sinai Medical Center, Los Angeles, said increasing evidence is pointing to a post-infectious etiology

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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.

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in many cases of IBS (Halvorson AA et al. Am J Gastroenterol 2006;101:18941899). Prior research by Dr. Pimentel and his team showed that cytolethal distending toxin B, a byproduct of pathogenic gastroenteritis-causing bacteria, triggers the formation of antibodies to vinculin, a cell migration and adherence protein predominantly found

Series Editor Tarun Mullick, MD Clinical Faculty Rush-Copley Medical Center Aurora, Illinois Clinical Staff Delnor Hospital Geneva, Illinois Provena Mercy Medical Center Aurora, Illinois

Commentary by Dr. Mullick Finally, irritable bowel syndrome (IBS), a condition that for many patients is a diagnosis of exclusion, may have an identifiable biological cause for which there is a clinical diagnostic test. In this installment of “Found in Translation,” Mark Pimentel, MD, and his colleagues have unleashed a breakthrough biomarker, the anti-vinculin antibody. Many researchers believe that IBS has multiple potential causes and influences. Patients with IBS may have an altered brain–gut axis; ensuing IBS symptoms may result from that altered perception. Stressors or changes in emotional state may accentuate IBS symptoms. Changes in concentration of serotonin and other neurotransmitters

F O U N D I N T R A N S L AT I O N

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

developing. The three groups of patients were demographically similar. The investigators’ findings confirmed their previous results, showing that patients with IBS have significantly higher levels of anti-vinculin antibodies. Additional statistical analyses determined that using a minimum cutoff optical density of 0.8 was 43% sensitive and 81% specific in distinguishing patients with IBS from healthy controls, with a positive predictive value (PPV) of 93%. The cutoff was associated with a similar sensitivity and PPV in discriminating patients with IBS from those

with IBD, but it was slightly less specific, the investigators found. “The results indicate that there is a pathophysiologic mechanism of IBS that is tied to acute gastroenteritis,” Dr. Pimentel told Gastroenterology & Endoscopy Newss in an interview. The researchers could not rule out that the test identified a subgroup of IBS that is post-infectious in derivation, and “this will need to be determined in future studies,” they said. IBS is likely a mixture of disorders, Dr. Pimentel added, but it most often

develops following an episode of acute gastroenteritis. Approximately 60% of patients with IBS have anti-vinculin antibodies, he noted. Dr. Lacy said he expects ongoing research to improve the accuracy of the test. “The project is a work in progress, and I suspect that future versions of the assay will note an improved PPV and better sensitivity.” ■ Drs. Lacy and Pimentel reported no relevant financial conflicts of interest.

Assessing swallowing disorders can be challenging. on nerves and epithelial cells (Pokkunuri V et al. J Neurogastroenterol Motil 2012;18:434-442). In the current multicenter study, Dr. Pimentel’s team measured serum anti-vinculin antibody levels in 165 patients with Rome-positive IBS, 30 patients with IBD and 26 healthy controls, using an enzymelinked immunosorbent assay that they are

may relieve or heighten IBS symptoms. But now, is a post-infectious state the major cause of the physiologic changes that lead to IBS? Serum anti-vinculin antibodies, a consequence of gastroenteritis, have been found in a large proportion of patients with IBS. Although there has been much speculation that post-infectious gastroenteritis could precipitate IBS, these new findings from Dr. Pimentel and his colleagues may be the key to supporting that theory. Soon, there may be a diagnostic test offered to patients with suspected IBS, with a more than 90% ability to identify IBS right in the clinic. That’s not bad, given that previously we have not been able to differentiate IBS from inflammatory bowel disease, without the use of more invasive and expensive tests. With the good data this study has provided, it is likely that in only a few years from now, this assay will be part of a diagnostic panel of tests that help distinguish a patient’s type of bowel disease in an office-based setting. Thus, IBS will no longer be a diagnosis of exclusion—a “functional” gastrointestinal disorder, if you will—but rather a diagnosis made based on clinical pathophysiologic findings.

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The risks of catheter ca insertion into the nasal passage associated with ManoScan® ESO high resolution manometry inc include discomfort, nasal pain, minor bleeding, runny nose, throat discomfort, irregular heartbeat with dizziness and perforation. In rare instances, the catheter may be misdirected into the trachea causing causin coughing or choking, or the catheter may shift up or down causing false results. Medical, endoscopic endos or surgical intervention may be necessary to address any of these complications, should they occur. oc This system is not compatible for use in an MRI magnetic ﬁeld. Please refer to the product user manual m or www.givenimaging. com for detailed information. Copyright ©20 ©2001-2013 Given Imaging Ltd. GIVEN, GIVEN & Design, MANOSCAN, MANOSHIELD, MANOVIEW, and a THE MEASURE OF GI HEALTH are Trademarks and/or Registered Trademarks of Given Imaging Ltd., its subsidiaries and/or affiliates in the United States and/or other countries. All other company or product pr names are the trademarks or registered trademarks of their respective holders. All rights not expressly e granted are reserved.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Experts’ Picks:

Best of the ACG Annual Scientific Meeting: Focus on IBD COMPILED AND WRITTEN BY DAVID WILD

The 2013 American College of Gastroenterology Annual Scientific Meeting offered a trove of useful findings. On your behalf, Gastroenterology & Endoscopy News asked our roster of experts to select their favorite abstracts from the meeting. Here is the first of two parts in this series, this one including picks and insights on studies in IBD.

Ashish Atreja, MD, MPH Director of I-ROQ (Informatics for Research, Outcomes and Quality) Assistant Professor Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York

Early Responses in Patientreported Outcomes Are Predictors for Mucosal Healing in Patients with Moderately to Severely Active Ulcerative Colitis Treated with Golimumab—Results from Pursuit SC Induction (Sandborn W et al)

P445.

whose rectal bleeding persisted throughout the study (odds ratio [OR], 13.0; P<0.001). Similarly, 78.3% of patients with normalized stool frequency after week 2 achieved mucosal healing at week 6 compared with 30.2% of those with abnormal stool frequency throughout the study (OR, 8.3; P<0.001). Dr. Atreja: There is a lot of interest in identifying surrogate markers or predictors for mucosal healing in order to determine early response to treatment. In this post-hoc analysis of the golimumab PURSUIT-SC induction Phase II/Phase III study, Dr. Sandborn and his colleagues found an association between patient-reported outcomes of stool frequency and rectal bleeding with endoscopically observed mucosal healing in patients with active UC. The study suggests that a change in patientreported measures as early as two weeks after golimumab treatment can be used to inform treatment decisions and predict clinical outcomes, such as mucosal healing.

Risk of Cerebrovascular Accidents and Ischemic Heart This analysis of data from the randomized, doubleDisease in Patients with Inflammatory Bowel blind, placebo-controlled PURSUIT-SC (Program Disease: a Systematic Review and of Ulcerative Colitis Research Studies Utilizing and Meta-analysis (Singh S et al) Investigational Treatment) study included patients with moderate to severe ulcerative colitis (UC) who In this study, researchers set out to identify possible received an initial subcurisk factors for artetaneous injection of golirial thromboembolism mumab 200 or 400 mg at in patients with IBD. week 0 followed by golimTo this end, they conThe researchers found that within umab 200 or 100 mg at week ducted a systematic two weeks of the first injection, 2 (n=515) or two placebo review of cohort and injections (n=256). Patients case–control studies golimumab recipients had in the study had Mayo scores from several medical significantly greater improvements between 6 and 12, includdatabases and confering an endoscopy subence proceedings pubin measures of stool frequency score of at least 2. At lished before March and rectal bleeding compared with study outset, 99% of 1, 2013 that included placebo recipients. patients reported abnormal reports of cerebrostool frequency, and 86.9% vascular events, ischsaid they had rectal bleeding. emic heart disease The researchers found that and extraintestinal within two weeks of the first peripheral arterial injection, golimumab recipients had significantly greater events in patients with IBD. Inclusion criteria required improvements in measures of stool frequency and rectal comparison between IBD and non-IBD populations or bleeding compared with placebo recipients (P<0.001). historical controls. The investigators looked for events Additionally, 17.7% of the pooled group of golimumab including stroke, transient ischemic attack, acute cororecipients had normalization of stool frequency at week nary syndrome, myocardial infarction, angina, and acute 6 compared with 7% of placebo recipients (P<0.001). or chronic peripheral arterial insufficiency excluding the Similarly, 52.7% of golimumab recipients had no rec- intestinal vasculature. The final analysis included nine tal bleeding at week 6 compared with 34% of placebo studies, with 2,424 reports of cerebrovascular events and recipients (P<0.001). 6,478 reports of ischemic events. The investigators found that patients with no recCompared with patients without IBD, patients with tal bleeding after week 2 were 13 times more likely to UC and Crohn’s disease (CD) were 1.13 and 1.25 times achieve mucosal healing at week 6 compared with those more likely, respectively, to experience a cerebrovascular

P457.

event (95% confidence in nterval [CI], 1.05-1.23 for UC; 95% CI, 1.141.39 for CD). Women and younger patients had the most statistically significant risk for cerebrovascular events (women: OR, 1.28; 95% CI, 1.17-1.41; P<0.05; younger patients: OR, 1.84; 95% CI, 1.282.66; P<0.01). Patients with IBD had a 19% higher risk for ischemic heart disease compared with those without IBD (95% CI, 1.08-1.31); women with IBD had the highest risk, with a 26% increase in risk for ischisch emic events (95% CI, 1.18-1.35; P=0.02). P The investigators did not find an association between IBD and increased risk for peripheral arterial thromboembolic events. Dr. Atreja: Inflammation increasingly is being recognized as central to the pathogenesis of atherosclerosis, and studies have reported an increased risk for cerebrovascular accidents and ischemic heart disease in patients with chronic inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Dr. Singh and his colleagues compared incident cases of cerebrovascular accidents and ischemic heart disease in patients with and without IBD based on a metaanalysis of cohort and case–control studies. They found that IBD was associated with a modest increase in risk for cerebrovascular accidents and ischemic heart disease, especially in women. Future studies should look at which phenotype of IBD is linked to cardiovascular morbidity and which patients might benefit form aggressive risk factor modification. Impact of Breathing and Education Programs on Inflammatory Bowel Disease (IBD) Quality of Life (QOL) and Inflammatory Biomarkers (Jacob VE et al) Researchers from Weill Cornell Medical College in New York City randomly assigned 30 patients with IBD to participate in one breathing, movement, and meditation workshop (BBMW) followed by six weekly follow-up sessions; 30 similar patients were randomly assigned to attend an educational seminar. Both groups received similar clinical care during the six-week period and underwent clinical evaluation for quality of life, anxiety, depression, mood, perceived stress and laboratory inflammatory markers.

P1064.

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

At week 6, BBMW participants showed signifi- CD who underwent at least two endoscopies at their cant improvements in scores on the Brief Symptom institution and were found to have at least one mucoInventory (BSI) instrument, a measure of psychologi- sal ulceration. Patients were a median 25 years of age cal well-being, compared with patients who attended at baseline, and had CD for a median of 9.8 years. the educational seminar, who did not have significant Nearly all patients had received corticosteroids, 50.7% changes in BSI scores (P=0.02). Additionally, at the had received immunosuppressive drugs and 47.7% had end of the six-week intervention period, BBMW par- received anti-tumor necrosis factor (TNF) treatment; ticipants had decreases in scores on the Beck Anxiety 38.1% had undergone surgery. Inventory instrument and improvements in qualityThe researchers observed that, during a two-year of-life scores on the Inflammatory Bowel Disease period, 60% of patients had two consecutive endoscopies, Questionnaire relative to baseline (P≤ P 0.02 for both); 31% had three consecutive endoscopies and 9% had four attendees of the educonsecutive endoscopies, cational seminar did conducted a median of 23 not exhibit significant to 26 weeks apart. At the changes in these scores. conclusion of the two-year ‘Mindfulness techniques may play a Changes in symptom period, 50.7% of patients role in enhancing quality of life and measures in patients achieved mucosal healing psychological well-being in patients in the BBMW group compared with 49.3% who persisted at six months. did not. The likelihood of with IBD, and this change appears Furthermore, this group endoscopically observed to occur independently of changes also had improvements mucosal healing increased in disease activity.’ in scores on the Perfrom 12% at week 24, to ceived Disability Scale, 45% at week 52, to 62% —Ashish Atreja, MD, MPH Perceived Stress Scale at week 74, the researchers and the Beck Depresreported. sion Inventory at six According to multimonths (P≤ P 0.01 for all). variate analyses, baseline Univariate analyses revealed that educafactors, including prior or current use of immunosupprestional seminar attendees had significant improvements sives and anti-TNF agents, or a history of surgery, did not in fecal calprotectin levels at week 6 relative to baseline, predict mucosal healing. However, those who underwent whereas there was a trend toward improved fecal cal- repeat endoscopy within 26 weeks of the previous endosprotectin levels in the BBMW group; these changes did copy were more likely to have mucosal healing (hazard not persist at six months in either group. ratio [HR], 2.35; 95% CI, 1.15-4.97; P=0.019), as were those whose therapeutic regimen was adjusted if repeat Dr. Atreja: In this pilot randomized controlled trial, endoscopy revealed incomplete mucosal healing (HR, investigators found that a deep breathing intervention 4.28; 95% CI, 1.9-11.5; P=0.003). P had a durable effect on quality of life, anxiety and depression metrics, lasting up to six months. However, there was Dr. Sandborn: The idea of treating to a target of no significant effect on fecal calprotectin levels. Patients mucosal healing has intuitive appeal, but many critics assigned to the educational seminar group achieved short- raise the concern that it is not feasible with our curterm improvements in fecal calprotectin levels, perhaps rent armamentarium of medications because of the owing to an increase in medication adherence. This study low rates of mucosal healing obtained in clinical trials suggests that mindfulness techniques may play a role in of patients with CD. enhancing quality of life and psychological well-being in These real-world data from a tertiary care center patients with IBD, and this change appears to occur inde- demonstrate that mucosal healing can be achieved pendently of changes in disease activity. ■ in more than 50% of patients, and that the primary predictors of mucosal healing are followDr. Atreja reported no conflicts of interest. up endoscopy within six months, and if ulcers are present, intensification of therapy. It should be noted that therapeutic drug monitoring of infliximab levels was employed in this study, and more than 10% of patients were treated with ustekinumab. William J. Sandborn, MD This observational, proof-of-concept study provides preliminary evidence that treating to target is indeed Chief of the Division of feasible, and the results should pave the way for subGastroenterology sequent prospective, controlled trials to demonstrate University of California, San Diego that treating to target can change long-term outcomes La Jolla, California in patients with CD. Comparison of Long-term Outcomes of MMX Mesalamine Maintenance Treatment for Ulcerative Colitis (UC) between Patients (PTS) in Complete Remission (CR) and Partial Remission (Pr) Following Induction (Rubin D et al) In this study, investigators examined data from 459 patients with mild to moderately active UC who had achieved either complete (n=182) or partial (n=277) clinical and endoscopic remission following eight weeks

P439.

Feasibility of Endoscopic Assessment and Treating to Target to Achieve Mucosal Healing in Crohn’s Disease (Bouguen G et al)

25.

Investigators from the University of California, San Diego, reviewed medical records from 67 patients with

of open-label induction treatment with once-daily MMX mesalamine 4.8 g; this was followed by maintenance treatment with 2.4 g of the drug administered once daily for 12 months. Before induction treatment, participants had Ulcerative Colitis Disease Activity Index (UCDAI) scores in the range of 4 to 10, with endoscopy subscores of 1 or lower and Physician’s Global Assessment scores of at least 2. Complete remission (CR) was defined as a modified UCDAI score of 1 or lower, rectal bleeding and stool frequency scores of 0, and at least a 1-point reduction in the endoscopy subscore relative to either baseline or maintenance treatment outset. Partial remission (Pr) was defined as a UCDAI score of 3 or lower, and combined rectal bleeding and stool frequency scores of 1 or lower in the absence of CR. The researchers observed sustained CR after 12 months of maintenance treatment in 47.8% of patients with initial CR and progression to CR in 26% of patients with initial Pr. Furthermore, 76.4% of patients with initial CR and 63.5% of those with initial Pr had endoscopy scores of 1 or lower; and 65.4% and 57% of patients, respectively, had rectal bleeding scores of 0 at 12 months, and 62.6% and 42.6%, respectively, had stool frequency scores of 0 at 12 months. Forty patients discontinued treatment because of lack of efficacy. Safety data revealed that 37.2% and 50% of patients with initial CR or Pr, respectively, experienced one or more treatment-emergent adverse events (AEs), including relapse (7.7% and 10.4%, respectively), headache (3.3% and 3.6%, respectively), influenza (1.6% and 2.9%, respectively) and nasopharyngitis (2.7% and 2.2%, respectively). Twenty-four patients discontinued treatment due to AEs.

‘[This] provides preliminary evidence that treating to target is indeed feasible, and the results should pave the way for subsequent prospective, controlled trials to demonstrate that treating to target can change long-term outcomes in patients with Crohn’s disease.’ —William J. Sandborn, MD

Dr. Sandborn: An area of current discussion among gastroenterologists is whether to treat patients to CR (i.e., a composite of clinical remission and endoscopic remission) or whether Pr is sufficient. This study indicates that patients who achieve CR are highly likely to maintain CR over the subsequent 12 months. In contrast, patients who achieve Pr are unlikely to subsequently achieve CR over the next year. These data indicate the need for additional “treat-totarget” trials in which patients who achieve only Pr undergo intensification of therapy in an attempt to achieve complete CR. see Best of ACG, page 16

ACG 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Vedolizumab continued from page 1

The finding, based on data from more than 450 patients with ulcerative colitis (UC) and Crohn’s disease (CD), showed that UC patients were the most likely to successfully discontinue steroid use after one year of vedolizumab (Takeda Pharmaceuticals). “These results are very important, considering the importance of steroid-free remission rather than clinical remission only,” said Asher Kornbluth, MD, clinical professor of medicine, Icahn School of Medicine at Mount Sinai, New York City, who was not involved in the study. “Clinical remission while on steroids is not a treatment success.” Bruce Sands, MD, chief of the Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine, presented the study at the 2013 American College of Gastroenterology Annual Scientific Meeting. Dr. Sands and his colleagues examined data from a subgroup of 215 patients with UC and 244 patients with CD in the multicenter, double-blind, randomized, placebo-controlled GEMINI 1 and 2 trials who had achieved clinical response to either vedolizumab 300 mg or placebo at weeks 0 and 2, after entering the study with active disease despite treatment with corticosteroids. At week 6 of the study, all of these patients were randomized to receive either vedolizumab

‘These results are very important, considering the importance of steroid-free remission rather than clinical remission only.’ —Asher Kornbluth, MD

300 mg or placebo every four (Q4) or eight weeks (Q8) and also started tapering their corticosteroid doses. Dr. Sands and his team found that 45.2% and 31.4% of patients with UC in the vedolizumab Q4 and Q8 groups, respectively, achieved clinical remission and had discontinued steroids by week 52 compared with 13.9% of placebo

recipients who attempted to taper corticosteroids (P≤ P 0.012 for both groups vs. placebo). Among patients with CD, 28.8% and 31.7% of vedolizumab Q4 and Q8 recipients, respectively, achieved steroidfree clinical remission at week 52 compared with 15.9% of placebo recipients (P≤ P 0.45 for both groups vs. placebo). Patients with UC who achieved clinical

Best of ACG continued from page 15

‘Rectal therapies are well

Budesonide Foam for Inducing Remission in Active Mild to Moderate Ulcerative Proctitis or Ulcerative Proctosigmoiditis: Results of Two Randomized, Placebo-controlled Trials (Sandborn WJ et al)

known to be more effective

In two identically designed, double-blind, Phase III studies, 546 patients with mild to moderately active ulcerative proctitis or ulcerative proctosigmoiditis were randomized to receive six weeks of treatment with budesonide foam (2 mg/25 mL twice daily for two weeks, followed by 2 mg/25 mL daily for four weeks) or placebo (identical regimen). More than half of the patients had failed to respond to treatment with mesalamine. Participants had mean modified Mayo scores of approximately 8 at baseline, and a score of 2 or higher on both the endoscopic and rectal bleeding subscales. Approximately 56% of patients in both the treatment and placebo groups were women. At week 6 of the study, 38.3% and 44% of budesonide recipients in the ulcerative proctitis and ulcerative proctosigmoiditis groups, respectively, experienced clinical remission, defined as endoscopy scores of 1 or lower, rectal bleeding scores of 0, and either an improvement or no change in stool frequency; this was compared with 22.4% and 25.8% of

with side effects. Budesonide

P441.

than oral mesalamine, but many patients are unable to retain liquid enemas and conventional steroid enemas are associated foam provides an easy-to-retain, rectal formulation of a highly effective steroid, with firstpass hepatic metabolism and a favorable side-effect profile.’ —William J. Sandborn, MD

placebo recipients, respectively (P<0.05 for the treatment arms of both studies vs. placebo). Additionally, 55.6% and 56% of the two groups, respectively, of budesonide recipients had endoscopy subscores of 1 or lower at week 6 compared with 36.7% and 43.2%, respectively, of placebo recipients (P<0.05 for both treatment groups vs. placebo). Findings also showed

remission following induction treatment and who received vedolizumab Q4 had the highest rates of 52-week steroid-free remission (58.6% for vedolizumab Q4, 39.1% for vedolizumab Q8 and 17.4% for placebo; P P=0.003 for vedolizumab Q4 vs. placebo; P not significant for vedolizumab Q8 vs. placebo). Patients with CD who achieved post-induction clinical remission were more likely to have 52-week steroid-free clinical remission if they received vedolizumab, although the differences compared with placebo were not statistically significant (37.9% for vedolizumab Q4, 48.3% for vedolizumab Q8 and 28.6% for placebo). “Steroid-free remission is a very difficult end point to achieve, and the GEMINI 1 and 2 trials included a large number of treatment-refractory patients,” said Dr. Sands, noting that most patients who achieved steroid-free remission after 52 weeks discontinued use of these drugs for at least half of that time. For patients on vedolizumab without mucosal healing after six weeks of treatment, Dr. Kornbluth recommended “working with additional therapies to achieve mucosal healing.” ■ Dr. Sands has served as a consultant for Takeda Pharmaceuticals. Dr. Kornbluth has served as an advisory board member for AbbVie Inc., Janssen and Takeda. The GEMINI 1 and 2 trials were sponsored by Millennium Pharmaceuticals, Inc.

that 46.6% and 50%, respectively, of budesonide recipients in the trials had no rectal bleeding at six weeks compared with approximately 28% of both groups of placebo recipients (P≤ P 0.002 for both treatment groups vs. placebo). AEs occurred in 45.9% of all budesonide recipients and 36.3% of all placebo recipients during treatment. Five and three patients in the treatment and placebo groups, respectively, had serious treatment-emergent AEs. Dr. Sandborn: For patients with distal UC, treatment options include rectal mesalamine, rectal conventional steroid enemas, oral mesalamine and oral steroids. Rectal therapies are well known to be more effective than oral mesalamine, but many patients are unable to retain liquid enemas and conventional steroid enemas are associated with side effects. Budesonide foam provides an easy-toretain, rectal formulation of a highly effective steroid, with first-pass hepatic metabolism and a favorable side-effect profile. Budesonide foam was effective as first-line therapy, as well as in patients who had failed to respond to treatment with oral mesalamine. ■ Dr. Sandborn has received research support from and has served as a consultant for AbbVie, Janssen and UCB Pharma. He has served as a consultant for Salix and Shire Pharmaceuticals.

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UEGW 2013

Infliximab Dosing continued from page 1

the second phase of the TAXIT (Trough level Adapted infliXImab Treatment) trial, which previously demonstrated that dosage adjustment based on drug levels during initiation of infliximab is beneficial. “Our recommendation based on these data would be to dose-optimize when infliximab is started, but we did not show that further drug level–based dosing provides an advantage over clinically based adjustment,” said study author Niels Vande Casteele, PharmD, PhD, of the Laboratory for Therapeutic and Diagnostic Antibodies, University of Leuven, Belgium. The findings were presented during the Opening Plenary Session of the 2013 United European Gastroenterology Week.

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

in each dosing group achieved the primary end point (69.1% vs. 71.7% of drug level–based and clinically based dosing groups, respectively). “What this study tells us is that treat-to-target dosing of infliximab results in higher efficacy and better cost-effectiveness during the dose optimization phase of treatment. However, once treatment is optimized, clinicians can safely revert to clinical monitoring,” Dr. Vande Casteele said. He noted the results are similar for patients with ulcerative colitis (UC), slightly more than 25% of the study population, and for those with Crohn’s disease (CD). “We have been interested in determining whether inadequate drug levels is one of the reasons for nonresponse,” Dr. Vande Casteele said. The variability in drug metabolism with standard doses of infliximab was underscored in this study by the nearly 10% of patients with undetectable drug levels.

‘Our recommendation based on these data would be to dose-optimize when infliximab is started, but we did not show that further drug level–based dosing provides an advantage over clinically based adjustment.’ —Niels Vande Casteele, PharmD, PhD

Induction Phase Monitoring The underlying hypothesis of the TAXIT trial was that clinical outcomes of patients treated with infliximab could be improved by achieving serum trough levels between 3 and 7 mcg/mL. The lower boundary was selected to ensure clinical efficacy, and the upper boundary was chosen to avoid excess drug-related expense. After randomization, 123 patients were managed with clinically based dosing and 128 patients were managed with drug level–based dosing. In the dosage optimization phase— the major findings of which were presented at the 2012 Digestive Disease Week meeting—only 44% of patients who started treatment on the standard induction dose of infliximab 5 mg/kg had drug levels in the target range of 3 to 7 mcg/mL. Among the remaining patients, 26% had levels above this range, and 30% had levels below the range, including 9% with undetectable levels. According to these previously presented data, dose intensification in patients with low levels of infliximab provided improved disease control, whereas dose reductions in patients with levels of infliximab above 7 mcg/ mL significantly lowered treatment costs, without sacrificing disease control.

Maintenance Phase Monitoring In the newly reported data from the maintenance phase of the TAXIT trial, however, the investigators reported there was no advantage for the drug level dosing strategy. On the basis of the primary end point, which was clinical and biological remission (defined as C-reactive protein <5 mg/L) at week 52, drug level–based dosing did result in a higher percentage of patients in the target therapeutic range at one year (78% vs. 56%; P<0.001), but about the same percentage

the patients who received dosing based on drug level. Dr. Vande Casteele suggested this finding might explain the 3.8-fold greater risk for undetectable serum levels of infliximab in the clinically based versus the drug level– based dosing populations (95% confidence interval, 1.47.7; P<0.01). Although the most recent TAXIT results did not demonstrate an advantage for drug level–based dosing during the maintenance phase of infliximab therapy, Stephen B. Hanauer, MD, chief, Section of Gastroenterology, Hepatology and Nutrition, and co-director, Inflammatory Bowel Disease Research Center, University of Chicago Medicine, cautioned that this should not be considered a negative trial. Rather, the data from TAXIT showing the advantage of drug level–based dosing during induction is an important lesson for clinical practice. “These data are consistent with other reports that demonstrate treating to target levels at the conclusion of induction therapy with infliximab improves long-term outcomes,” said Dr. Hanauer, who was not involved in the TAXIT study. For example, he cited data from the ACCENT (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen in Patients With Fistulizing Crohn’s Disease) trial, in which optimization of infliximab levels at the end of induction therapy also produced high rates of deep clinical, biological and steroid-free remission at one year. As for the failure of continuous drug level monitoring to provide additional benefit during maintenance, Dr. Hanauer said, “There are a number of potential

‘These data are consistent with other reports that demonstrate treating to target levels at the conclusion of induction therapy with infliximab improves long-term outcomes.’ —Stephen Hanauer, MD

Although improving the risk–benefit ratio of infliximab therapy was one motivation the investigators had for evaluating drug level–based dosing, cost was another. According to Dr. Vande Casteele, the percentage of primary nonresponders to infliximab may be as high as 25%, with another 40% of initial responders losing clinical benefit over time. This suggests a substantial proportion of patients are receiving an expensive therapy from which they are not benefiting. Despite the inability of continuous drug level–based dosing to increase the proportion of patients who achieved the primary end point in this study, Dr. Vande Casteele’s team’s findings did not rule out potential benefits outside of the study end point. For example, three patients who received clinically based dose adjustments in the study developed antibodies to infliximab by the end of the maintenance phase compared with none of

explanations, including the more complete reduction in inflammatory burden early in the course, with eventual stabilization of drug levels and a regression toward the mean in maintenance therapy.” Regardless of the explanation, TAXIT still provides strong support for monitoring of infliximab levels during induction therapy. ■ Dr. Vande Casteele reported no relevant conflicts of interest. Dr. Hanauer reported financial relationships with Abbott Laboratories, Amgen, AstraZeneca, Baxter, Caremark/CVS, Coronado Bioscience, Eli Lilly, Ferring Pharmaceuticals, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co., Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Roche, Salix Pharmaceuticals, Santarus, Seres Health Inc., Takeda Pharmaceuticals and UCB.

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TNF Inhibitors Fail To Aid Stoma Reversal In Patients With Crohn’s Disease BY CHRISTINA FRANGOU For two decades, physicians have prescribed therapies that block tumor necrosis factor (TNF) for patients with Crohn’s disease (CD). But it has never been clear whether anti-TNF treatment affects the chances of stoma closure. Now, a study from the Cleveland Clinic suggests that anti-TNF therapy does not facilitate restoration of intestinal continuity in patients undergoing stoma diversion for severe perianal CD. “The results of our study contradict the assumption that we can select a group of patients with Crohn’s disease who require a stoma and start anti-TNF after the stoma is created, with the expectation that this will facilitate stoma closure. This is simply unrealistic in the context of the current use and indications for anti-TNF,” said lead author Luca Stocchi, MD, a colorectal surgeon at the Cleveland Clinic, in Ohio. The study, which was presented at the 2013 annual meeting of the American Society of Colon and Rectal Surgeons, suggests the site of disease involvement,

rather than anti-TNF therapy, strongly predicts the likelihood of stoma closure. Anti-TNF drugs have a proven record; about 80% of patients experience complete or partial responses to TNF inhibitors (Seminerio JL et al. Dig Dis Sci 2013;58:797-806). However, studies analyzing TNF inhibitors and surgical outcomes are lacking. Few studies have examined the longterm outlook of patients who have a diverting stoma for perianal CD, and only one of these studies included patients who received anti-TNF treatment. The study by Dr. Stocchi and his colleagues is the largest known study to evaluate the relationship between antiTNF use and closure of stomas. Dr. Stocchi and his colleagues conducted a retrospective review of all patients who had fecal diversion for complicated perianal disease at the Cleveland Clinic between 1994 and 2012. Of 162 patients in the study, 120 (72%) received TNF inhibitors. Patients who received biologics were slightly younger than those who did not (36 vs. 40 years). There were no other

demographic differences between the groups. Analysis revealed noo significant difference in rates of stoma closure betwe be en patients who used biologics and those who did not (28% vs. 24%, respectively; P=0.64). Proctectomy rates also were un unchanged by biologic use (39% vs. 37%, %, rrespectively; P=0.79). Once perianal disease sease ase has h progressed to the point of requirement ntt of a stoma to control symptoms, surgeons nss are ar rarely successful in getting the disease to heal sufficiently to reverse the stoma, said Emily Finlayson, MD, MS, assistant professor of surgery, Institute of Health Policy Studies at the University of California, San Francisco. “The confirmation of this finding is important in that it will impact how we counsel our patients. Many patients and doctors cling to the hope that treatment with anti-TNF agents will allow for future stoma reversal. We know now that this is unlikely.” The study showed that the site of disease strongly predicts rates of stoma closure. Patients with disease in the perianal

region onlyy had ad d the greatest likelihood of closure closure, at 75%. The presence of perianal disease diseas disea with small bowel wel el disease was associated associa with a 45% closure rate, ate, or three and a a half times less likely to have ve stom stoma closure. Patients with perianal and colon disease were the least likely to have stoma closure with a 15% closure rate, and an odds ratio of 18.5. Ninety-one percent of patients who received biologic therapy started the treatment before their diversion was created. The timing of anti-TNF treatment had no effect on stoma closure, the study showed. ■

Crohn or Crohn’s: What’s in a Name? Frederick L. Greene, MD Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina When I started medical school, I was always intrigued by the use of eponyms and enjoyed remembering the eponymous contributions and name recognition associated with both commonplace and arcane syndromes, diseases and triads. Terms like “Down’s syndrome” and “Addison’s, Crohn’s and Cushing’s” diseases, as well as many others, were fascinating to me and challenged me to learn something about the person associated with the process. Historically, an eponym has been used in medical terminology to commemorate the importance of an individual’s contribution. In recent years, there has been a vigorous debate over the issue of whether medical eponyms should be abandoned since they “lack accuracy, lead to confusion, and hamper scientific discussion in a globalized world” (Woywodt A, Matteson E. Br Med J 2007;335:424; Whitworth JA. Br Med J 2007;335:425). A more curious discussion has centered on whether the possessive or the nonpossessive form of the eponym should be used in spoken and written formats. A 1975 Canadian National Institutes of Health conference dealing with the naming of diseases was summarized in The Lancet, and concluded, “The possessive use of an eponym should be discontinued, since the

author neither had nor owned the disorder.” In our electronic age, the issues at stake are not trivial because the ability to retrieve data may depend on whether the “apostrophe s” is present or absent. Studies have shown that American publications have tended to prefer the nonpossessive form, leaving out the “apostrophe s,” whereas our European colleagues tend to gravitate more toward the possessive form of the eponym. In both my reading of medical and surgical articles and reviewing manuscripts for journals, it is interesting to note the haphazard use of the possessive and nonpossessive forms of eponyms, with seemingly no uniform standard being used. Recently, however, there has been a push to make the nonpossessive form of an eponym more journalistically correct as recommended by the American Medical Association’s AMA Manual of Style and other important reference works. The concept of using the term “Crohn disease” rather than “Crohn’s disease” will be difficult at best. We tend to think of the eponym in the possessive form, and it is abhorrent to avoid this norm in discussion at conferences and in our reading of and contributions to the medical literature. Thank goodness that in some circumstances, a nonpossessive form is irrelevant such as with ZollingerEllison syndrome. In the use of toponyms (naming after a place, such as Lyme disease), a nonpossessive form also is standard practice. The authorities who work for the World Health Organization (WHO) in naming diseases would suggest that the possessive forms of medical eponyms

are often unwarranted, redundant and confusing. In the WHO 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), a clear preference for avoiding the possessive form of eponyms appears. Proofreaders would suggest that the nonpossessive eponymous form is more efficient, with fewer letters and no punctuation. Although one might feel initially awkward dropping the “apostrophe s” from Parkinson’s disease or Barrett’s esophagus, we can take some solace in our acceptance of the terms Apgar score and Cochrane review. As you read the medical literature, it will be interesting to see whether the nonpossessive form of an eponym is catching on. I would suggest that those of us who contribute to the medical literature consider using the nonpossessive form since this is destined to be the benchmark in the not-toodistant future. The Council of Science Editors has been a staunch advocate for harmonization of stylistic standards and has adopted the posture that “the possessive form be eliminated altogether from eponymic terms so that they can be clearly differentiated from true possessives.” Alas, I admit that the possessive form of the eponym that we grew up using will be difficult to abandon. We will, however, ultimately need to accept the audible and visual effect of Crohn disease, Hodgkin lymphoma and Alzheimer disease as we use these terms in our everyday lexicons. It is hard to know what’s right. I know for myself, I have already started missing the apostrophe!

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Controlled Breathing Relieves IBD Symptoms in Small Pilot Study BY MONICA J. SMITH SAN DIEGO—Patients with inflammatory bowel disease (IBD) may experience significant improvements in psychological and physical symptoms by practicing a controlled breathing technique, according to a pilot study conducted by researchers at the Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medical Center, New York City. “When you think about how potent the immune-modulating and biologic medications we offer are, it is nice to consider nonmedical alternatives for improving quality of life,” said Vinita Jacob, MD, lead author of the study, which was presented as a poster at the 2013 American College of Gastroenterology Annual Scientific Meeting. “We know that stress absolutely affects the sympathetic nervous system to negatively impact the gastrointestinal tract [GI] by increasing secretions, motility and visceral pain perceptions, and that patients have worsened symptoms of abdominal pain, diarrhea and a sense of urgency,” she explained.

With that in mind, Dr. Jacob and her colleagues investigated a breathing technique designed to stimulate the parasympathetic nervous system to decrease GI secretions, GI motility and a patient’s overall perception of stress. They randomized 30 patients with IBD (mainly mild) to attend a breathing, movement, and meditation workshop (BBMW) or an educational seminar while continuing their conventional IBD medications. The BBMW consisted of nine hours of group instruction over two days, during which time participants were instructed in a coherent breathing technique—gently inhaling and exhaling five times per minute—Qigong movements and brief meditation. “It’s a wonderful nonmedical route we hope will be helpful for the patients and also give them a sense of control over this very complicated disease that can flare for no rhyme or reason,” Dr. Jacob said. The investigators assessed patients at baseline and at weeks 6 and 26 for physical and psychological symptoms; depression and anxiety; IBD quality of life (QoL); perceived disability; perceived stress; and fecal calprotectin and C-reactive protein (CRP) levels.

At weeks 6 and 26, patients in the BBMW group experienced significant relief of psychological and physical symptoms and inflammation, and improvement in QoL scores, whereas patients in the education group reported no such improvements. At week 26, CRP levels of the BBMW group, but not the control group, were significantly reduced. “Many of the patients whom I spoke with afterward felt empowered by being able to control their symptoms by practicing these breathing techniques,” Dr. Jacob said. “There is a real potential physiology to this—it is not just some random breathing technique that might help you, but [it is] very purposeful in stimulating the parasympathetic nervous system to help IBD patients with the physiologic symptoms they experience.” The researchers’ next step is to extend the study to a larger population of patients that will include individuals with moderate to severe IBD, and to examine

other objective criteria, such as endoscopic remission. “As gastroenterologists, we are concerned about mucosal healing and reducing inflammation, but most often our patients’ primary goal is to feel better and improve their quality of life, so they are always looking for alternative therapies that could help them ameliorate their chronic symptoms,” said Bincy Abraham, MD, MS, assistant professor of medicine, Baylor College of Medicine, Houston, who was not involved in the study. “The mind–body connection is quite fascinating,” Dr. Abraham said. “This study tapped into this interconnection using relaxation techniques that ultimately improved both physical and psychological symptoms. If additional techniques like these help control these chronic diseases, physicians as well as patients can add them to the treatment armamentarium as adjunctive therapies that offer huge benefit with minimal or virtually no risk,” she concluded. ■

Vercirnon ‘Not Safe and Effective’ For Induction in Crohn’s Disease Positive Phase II Findings Not Borne Out in Phase III Trial BY MONICA J. SMITH SAN DIEGO—Despite the findings of a Phase II trial suggesting that high doses of vercirnon, an oral CCR9 antagonist, might be efficacious as an induction and maintenance therapy for patients with Crohn’s disease (CD), the results of a Phase III trial presented at the 2013 American College of Gastroenterology Annual Scientific Meeting showed the drug to be neither safe nor effective. The earlier trial of vercirnon— which included doses of 250 mg once daily, 250 mg twice daily and 500 mg once daily—missed its primary end point of clinical response at week 8; however, at week 12, clinical response was significant in patients taking the 500-mg dose. “The placebo rate was relatively high in that earlier trial and may have confounded the ability to see a treatment effect,” explained study author William J. Sandborn, MD, professor of medicine, University of California San Diego, La Jolla. “The conclusions of the earlier study were that vercirnon might be effective for the treatment of active CD, but would require higher doses, a longer treatment period and minimization of the placebo treatment response.”

To investigate that theory, Dr. Sandborn and his colleagues evaluated the higher dose, 500 mg, in 608 patients with active CD. Patients were randomized to receive 500 mg once daily, 500 mg twice daily or placebo, with the primary end point defined as a reduction of at least 100 points in the Crohn’s Disease Activity Index (CDAI) score at week 12. The secondary end point was remission, defined as a reduction in CDAI score of 150 points or more by week 12. “In order to minimize the placebo response rate, we required that patients have both elevated C-reactive protein (CRP) concentration and fecal calprotectin concentration, or ulceration seen at colonoscopy,” Dr. Sandborn said. Demographics and disease status were similar among the three groups of patients, who had mean CDAI scores of 313 (range, 123-450) and median CRP concentrations of 13.5 mg/L (range, 0.2-157). About 75% of patients completed the study. The dropout rate was similar among the three groups and was mainly related to adverse events (AEs). The primary end point (CDAI score reduction ≥100) was achieved by 27.2% of patients in the vercirnon twice-daily group, 27.6% in see Vercirnon, page 44

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Trillion-Dollar Bill continued from page 10

Dr. Siegel:

Dr. Robbins:

Cost is not linked to quality of care. The United States simply is not the best. Too many of our colleagues are performing more procedures than are indicated, perhaps because they are getting paid $220 when the overhead exceeds the payment. There’s also a crazy quirk in Medicare reimbursement where procedures performed in an accredited office are reimbursed at 100% to the practitioner, but there is no facility reimbursement; however, the physician receives 50% of the professional fee when he or she performs the same procedure in an ASC or hospital.

I believe there is little disagreement that colonoscopy is the gold standard for CRC screening. The cheaper and less-invasive tests Ms. Rosenthal refers to are inferior and do not afford the opportunity to treat cancer at its earliest stages. That said, it is important to respect a patient’s preferences, and ultimately the best test is the one that actually gets done.

‘Too many of our colleagues are performing more procedures than are indicated, perhaps because they are getting paid $220 when the overhead exceeds the payment.’ —Jerome Siegel, MD

Dr. Rex: It is obviously not the case that cost is linked to quality of care in the United States. There is no evidence that we have better care or outcomes compared with a number of other developed countries. Dr. Allen: There are very few examples of successful linkage of cost to quality. We have struggled for a generation simply to define “quality.” Is quality patient satisfaction, reduction of mortality, or restoration of health? A gastroenterologist on call can end up in an emergency room at 2 a.m. performing a high-risk endoscopy on someone with a piece of steak blocking his or her esophagus. For this, the payment is the same as a simple endoscopy performed during usual waking hours. One could argue that this represents a nonlinkage of cost to outcome. I realize that the overall cost of health care in the United States is substantially more than in other developed countries, but one has to carefully analyze the methodologic derivation of those data. Additionally, the political and social mandates in the United States, the devastating lifestyle choices so prevalent here and the fact that tens of millions of people do not have insurance and lack access to care— our lack of universal health care is shameful.

GEN: Should colonoscopy be the gold standard for CRC screening, or as Ms. Rosenthal questioned, are other cheaper and less-invasive tests equally effective? Dr. Nunn: I think if you look at the data, colonoscopy is the best screening test for CRC. The other tests do appear to represent a step down in their ability to detect lesions. But is the difference between them worth the costs and the risks? Now, that’s a value judgment.

Dr. Siegel: I think we know that colonoscopy is the gold standard. Computed tomographic colonography requires the same bowel preparation; exposes patients to radiation; cannot detect small lesions; and if there is a lesion, requires a subsequent colonoscopy. Sigmoidoscopy is good for part of the left side of the colon—like having a one-breast mammogram. Fecal tests don’t identify the source of bleeding. Dr. Rex: We’ve got strong evidence that colonoscopy both prevents CRC and causes a decline in cancer incidence rates, and there is no solid evidence that other, cheaper tests, such as flexible sigmoidoscopy and fecal immunochemical testing (FIT), are equally effective. For example, the first randomized controlled trial comparing FIT and colonoscopy showed that colonoscopy identified more patients with advanced lesions (Quintero E et al. N Engl J Med 2012;366:697-706). Dr. Allen: This is the wrong question. Some people may prefer other screening tests, which is their absolute right and there is evidence to validate these choices. However, colonoscopy is the final common pathway of all positive screening tests.

GEN: What is your opinion of Dr. Welch’s op-ed piece, “Diagnosis: Insufficient Outrage,” published in The New York Times?

providers,” the facility fee that hospitals and other health care centers legally charge is not an extra payment— rather it covers the ever-increasing cost of delivering health care, including staff salaries, rent, equipment, etc.

‘Set a reasonable fee to cover the physician’s fee, not like the ridiculously low Medicare payment, and safeguard the guidelines.’ —Jerome Siegel, MD

Dr. Siegel: Regarding the Welch article, it’s a shame, but he’s right: Set a reasonable fee to cover the physician’s fee, not like the ridiculously low Medicare payment, and safeguard the guidelines. Dr. Rex: I agree with many of Dr. Welch’s points. It’s absolutely true that hospitals are trying to buy up ASCs and other practices. Hospitals, through their lobbying efforts, have managed to have reimbursement to ASCs reduced. ASCs became less profitable, and many sold out to hospitals. As a result, hospital-owned, former ASCs often bill like hospitals. Hospitals are interested in controlling market share and want to have a large percentage of patients, physician practices and ASCs in their control. Dr. Allen: Dr. Welch’s piece is inflammatory, perhaps rightly so, but it does not really add to a constructive discussion or solution. The article seems to cast dedicated physicians, providers, nurses and administrators together in a single, damning light.

Dr. Nunn: Dr. Welch has many valid points. The prices in our health care system are out of control. As Dr. Welch explained, GEN: What are potential solutions to hospitals are buying up physician the rising cost of practices and converting them into health care in the hospital outpatient facilities where ‘The fee-for-service United States, and they can charge exorbitant hospital model is antiquated what are some of rates for the same services instead of more reasonable office fees. I see this the impediments to and has the potential trend happening in specialties like implementing them? to reward people for cardiology, urology and oncology.

essentially gaming the Dr. Nunn: Dr. Robbins: system.’ I think Dr. Welch raises some In his book “Remedy and —David Robbins, MD excellent points. There is no denyReaction: The Peculiar Ameriing we are facing runaway health can Struggle Over Health Care care costs, and it is a multifactorial Reform,” Paul Starr, PhD, pandemic. I agree that the fee-fordescribed three major reasons service model is antiquated and has the potential to why it’s so difficult to make changes in our medical reward people for essentially gaming the system. Dr. system: 1) complexity—our system is so complicated Welch also makes an excellent point about the overuse and convoluted that no one person can tackle it; 2) an of routine tests, including colonoscopy. Although I agree overabundance of special interest groups—everyone that “medical care is intended to help people, not enrich see Trillion-Dollar Bill, page 30

COLORECTAL CANCER:

The “Right” Perspective

Adenocarcinoma Detection and Prevalence in the Proximal Colon

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

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

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

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

Flat lesion

Serrated lesion

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

Number of interval cancers†

35 33.6

30 25

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

25.5 22.1

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

15 10

‡ Proportion

2.4

5 0

<11%

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

of subjects in whom at least one polyp was identiﬁed.

≥20%

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

Screening colonoscopy: adenoma ﬁndings

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

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

>10 adenomas

Sessile adenomas removed piecemeal

Recommended timing of follow-up

5-10 years

3 years

<3 years; consider possibility of familial syndrome

2-6 months to verify complete removal

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

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

SU-13899

May, 2013

Brought to you as an educational service by

Colonoscopy Costs continued from page 1

followed by The Washington Post’ss exposé “How a Secretive Panel Uses Data that Distort Doctors’ Pay.”1,2 Many gastroenterologists expressed concern and dismay at this negative focus on colonoscopy. “It’s unhelpful and misleading to single out colonoscopy to make points about U.S. health care costs because the large cost disparities for colonoscopy are hardly unique,” said Douglas Rex, MD, Distinguished Professor of Medicine, Indiana University School of Medicine, and director of endoscopy, Indiana University Hospital, both in Indianapolis. “These disparities are essentially the rule for medical procedures and services in the United States.” With so many other inefficiencies and abuses to highlight, Gastroenterology & Endoscopy Newss asked: Why is colonoscopy under fire? And why now?

Overuse and Abuse Although colonoscopy has been subject to relatively greater scrutiny this year, the procedure is just one of many routine, high-cost medical tests, procedures and therapies to receive national attention. In fact, since President Barack Obama assumed office in 2009 and signed the Affordable Care Act into law on March 23, 2010, the U.S. health care system has been put under the microscope on a variety of fronts. As early as October 2009, Reuters released a report estimating that the United States wastes between $505 billion and $850 billion annually in health care spending.3 The report outlined some of the main culprits of wasteful practices: Overuse of antibiotics and lab tests topped the list, accounting for 37% of the total; fraudulent Medicare claims and other types of medical fraud accounted for 22% of wasteful spending; administrative inefficiency and redundant paperwork made up 18%; medical mistakes explained 11%; and a paper-based medical records system, which discourages sharing of patient information, and preventable conditions, such as diabetes, both accounted for 6%. Colonoscopy screening did not make the list. The following year, the use of medical technologies came under fire. In June 2010, the Boston Globe published an editorial calling out the misuse of computed tomography (CT) scans, revealing an estimated 70 million scans are performed in the United States each year, many of which are unnecessary.4 Although careful to point out the benefit of CT scans for medically necessary reasons, the Globe noted instances when

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

CT scans are employed too frequently and could cause harm to patients through excessive exposure to radiation. Furthermore, a CT scan can cost from $1,080 to $1,520, adding to mounting health care costs. The New York Times published its own series on the overuse off medical imag imaging, including a reportt exploring the problem of repeat CT scans in hospital settings.5 Based on Med dicare outpatient claims from 2008, the reeporters found that hospitals performeed repeat scans on 75,000 paatients, costing Medicare approoximately $25 million th hat year. Several months later, The Times pub-lished a report on another overused technology: magnetic resonance imaging (MRI).6 Although fees for MRI scans can vary, the costs are often high, rangingg from $875 to $1,225. A commentary that folllowed in The Atlantic noted a main driver of MRI overuse may be fear of liitigation, a common motivattor that can lead physicians to practice “defensive medicine.”7

Choosing Wisely initiative in early 2012. Partnering with the American Gastroenterological Association (AGA) and a host of other professional specialty societies, the ABIM brought attention to a list of more than 130 overused tests and procedures.11 Some items on the ABIM’ss list overlapped with those on ABIM

Killing Us.”12 Mr. Brill expounded on the chargemaster list, a hospital’s internal price list, revealing that “no hospital’s chargemaster prices are consistent with those of any other hospital, nor do they seem to be based on anything objective—like cost— that any hospital executive I spoke with was able to explain. explain.” The chargemaster

With so many inefficiencies and abuses in the U.S. health care system to highlight, why is colonoscopy under fire? And why now?

‘It’s unhelpful and misleading to single out colonoscopy to make points about U.S. health care costs because the large cost disparities for colonoscopy are hardly unique. These disparities are essentially the rule for medical procedures and services in the United States.’ —Douglas Rex, MD In January 2012, the American College of Physicians (AC CP) named 37 medical tests that physicians routinely overuse and could be harming instead of helping patients.8 The report, subsequently covered by Reuters9 and The Huffington Post,10 pointed to a range of tests, including CT scans for lung disease, MRI scans for paatients with low back pain, cardiac evalu uations such as routine electrocardioggrams (EKGs) and stress tests in heealthy patients, and coronary angiography phy for patients with chronic but controlled chest pain. Although not on the ACP’s list, Reuters pointed out colorectal cancer screening—comparing colonoscopy’s $3,000 price tag to the much lower $10 cost for stool testing—but the commentary stopped there. In a wide-reaching effort to call attention to screening overuse and misuse, the American Board of Internal Medicine (ABIM) launched the

the ACP’s list, including the routine use of EKGs and stress tests to evaluate cardiovascular health in asymptomatic patients, CT scans of the brain and chest, and MRIs to evaluate low back pain. Other items highlighted by the ABIM included overprescribing of antibiotics for mild sinusitis, proton pump inhibitors for heartburn, and opioids for migraines; overuse of CT scans to evaluate minor head injuries in children; annual Pap smears for healthy women between the ages g of 30 and 65 years; and dual-energy x-ray absorptiometry scans in young individuals and those with no signs of osteoporosis.

The Chargemaster More recently, a spotlight on hospitals revealed the extent to which hospital fees contribute to health care costs. In February 2013, journalist Steven Brill wrote a scathing account of hospital charges in “The Bitter Pill: Why Medical Bills Are

prices have no relationship to the cost of a service and can be more than 10 times higher than prices charged at doctor’s offices and surgical centers, Mr. Brill reported. p Shortly after publication of Mr. Brill’s article, the Centers for Medicare & Medicaid Services released a list of prices that hospitals throughout the country charge for the 100 most common inpatient medical services and the 30 most common outpatient services, revealing huge variations among institutions.13 The media responded, highlighting price discrepancies in hospitals located mere see Colonoscopy Costs, page 28

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

Colonoscopy Costs continued from page 26

miles apart. In one example, the cost of treating chronic obstructive pulmonary disease at Bayonne Hospital Center in New Jersey was $99,690, whereas the same service just 30 miles away in New York City’s Lincoln Medical and Mental Health Center was just $7,044. The Washington Postt responded with an interactive feature on its website where consumers could compare prices for different services in different locations.14

Colonoscopy Price Tag In light of all of this, colonoscopy is but one of the many examinations and procedures singled out by the media in an ongoing discussion of mounting health care costs in the United States. For the most part, the debate surrounding colorectal cancer screening has focused on identifying which test is the best, with colonoscopy among them. Chalmers Nunn, MD, CEO of Gastroenterology Associates of Central Virginia, Lynchburg, suspects the reason

colonoscopy has been singled out recently is multifactorial. “First, there are large numbers of colonoscopies being performed each year, and the procedure has received attention from persuasive screening campaigns. Second, although it is the best test we have, it’s not a perfect test. And third, because Ms. Rosenthal singled it out in her piece,” he noted. Dr. Rex believes that “colonoscopy is a target because of its enormous success and the high volume of procedures performed.

‘Colonoscopy is a target because of its enormous success and the high volume of procedures performed. In the United States, the incidence and mortality of colorectal cancer are falling as in no other country, and much of this can be directly attributed to widespread use of colonoscopy.’ —Douglas Rex, MD “In the United States, the incidence and mortality of colorectal cancer are falling as in no other country, and much of this can be directly attributed to widespread use of colonoscopy,” he said. “Of course, we have improvements to make in quality of performance and correct use, but these facts can’t change the overall great achievement of colonoscopy.” Jerome Siegel, MD, clinical professor of medicine, Albert Einstein College of Medicine, New York City, pointed to the fact that some gastroenterologists perform “too many colonoscopies” based on

Patients Care About Cost, Even When They’re Not Paying BY TED BOSWORTH

RESEARCH Advancing Genomic Medicine To Create Precision Therapies.

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

CHICAGO—Two studies indicate that a substantial proportion of patients want their physicians to include the costs of care in their discussion of treatment options. Both studies evaluated patients with cancer and were presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO). One study was designed to evaluate the issue of cost in the context of financial distress. All of the 300 patients surveyed had health insurance, but the median out-of-pocket expenses were $592 per month. This expense led, on average, to “moderate” distress when evaluated with a standardized instrument for assessing financial well-being. The median annual income for the study population was $60,000. For 17% of

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

misinterpretation of indications and nonadherence to society guidelines. “The fact that some gastroenterologists are overusing colonoscopy and not following our organization’s guidelines is likely what prompted Ms. Rosenthal’s article. Gastroenterologists really need to be more careful to adhere to guidelines of screening and surveillance,” Dr. Siegel said. The AGA guidelines recommend colonoscopy screening for colorectal cancer once every 10 years beginning at age 50 in healthy asymptomatic individuals, and earlier for individuals with a family history of colon cancer or other notable risk factors.15 ■

References 1. Rosenthal E. “The $2.7 Trillion Medical Bill: Colonoscopies Explain Why U.S. Leads the World in Health Expenditures.” The New York Times. June 1, 2013. 2. Whoriskey P, Keating D. “How a Secretive Panel Uses Data that Distort Doctors’ Pay.” The Washington Post. July 20, 2013. 3. Fox M. “Healthcare system wastes up to $800 billion a year.” Reuters. Oct. 26, 2009. 4. Editorial: “To stop overuse of CT scans, consistent rules are needed.” Boston Globe. June 19, 2010. 5. Bogdanich W, McGinty JC. “Medicare Claims Show Overuse for CT Scanning.” The New York Times. June 17, 2011.

individuals with cancer, the financial distress was considered “high” or “overwhelming.” Among the key findings: • Although 52% expressed a desire to discuss costs of cancer care, only 19% reported actually discussing costs with their oncologist. • The desire to discuss costs rose to 62% of those with the highest financial distress. • Of those who discussed costs with their physicians, 57% reported that this led to lower costs. Perhaps the most important message of the study is that financial distress “is prevalent even among insured cancer patients,” for whom “cost does matter,” said lead study author, S. Yousuf Zafar, MD, of Duke Cancer Institute in Durham, N.C. He noted that 51% of those surveyed want physicians to account for costs in therapeutic decisions. A second study suggested that patients are mindful of costs even when they do not directly affect see Cost, page 32

6. Kolata G. “Sports Medicine Said to Overuse M.R.I.’s.” The New York Times. Oct. 28, 2011.

By American College Of Physicians Guidelines.” The Huffington Post. Feb. 22, 2012.

7. Tenner E. “Who’s to Blame for the Overuse of MRI Scans: Doctors or Patients?” The Atlantic. Oct. 29, 2011.

11.Helwick C. “AGA Asks: Are You Choosing Wisely? Overutilization of Colonoscopy, CT Scans Questioned.” Gastroenterology & Endoscopy News. October 2013;64:1,32-34.

8. Snyder L, American College of Physicians Ethics, Professionalism, and Human Rights Committee. American College of Physicians Ethics Manual: sixth edition. Ann Intern Med. 2012;156:73-104. 9. Sherman D. “Stemming the tide of overtreatment in U.S. healthcare.” Reuters. Feb. 16, 2012. 10.Young J. “Health Care Spending Targeted

12.Brill S. “The Bitter Pill: Why Medical Bills Are Killing Us.” Time. Feb. 20, 2013. 13.The Centers for Medicare & Medicaid Services. “Medicare Provider Charge Data.” https://www.cms.gov/ Research-S tatistics-Data-and-S ystems/Statistics-Trends-and-Reports/

Medicare-Provider-Charge-Data/index. html. Accessed Nov. 21, 2013. 14. Wilson A, et al. “Disparity in medical billing.” The Washington Post. May 8, 2013. http://www.washingtonpost.com/wp-srv/ special/national/actual-cost-of-medicalcare. Accessed Nov. 21, 2013. 15. Levin 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.

EXPERT ROUNDTABLE

Trillion-Dollar Bill

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

‘The United States is built on principles that focus on

continued from page 23

the individual (independence and capitalism), which has a vested interest in the health care system, which means that even a small change will benefit some and hurt others; and 3) values—the United States is built on principles that focus on the individual (independence and capitalism), which makes it difficult to manage populations; however, we need a population approach to managing health care.

One potential solution would be to do away with fee-for-service: If doctors were salaried, our decision making, regarding the most prudent tests and procedures, would change. Dr. Robbins: How much time do you have? The traditional fee-for-service model needs

makes it difficult to manage populations; however, we need a population approach to managing health care.’ —Chalmers Nunn, MD

to be overhauled and replaced with a system that fairly compensates providers for delivering health care in a

cost-conscious, but not cost-limited, fashion. This needs to take place alongside tort reform; medical school education debt reform; competitive and open market pricing for medical products and services; and training programs for new providers to deliver it all. Dr. Siegel: We really should be more careful as physicians to adhere to the guidelines of screening and surveillance. Some doctors are overusing colonoscopy and not following screening guidelines. It is imperative that we reprimand gastroenterologists who do so. Another idea is to adjust physicians’ fees according to the cost-ofliving index. Dr. Rex: I’m not a health care economist, but I see a few potential solutions. Importantly, there needs to be transparency in pricing. People need to be able to understand what a procedure or test will cost before they have it so they can shop around. Patients also should understand the basis for pricing. In terms of colonoscopy, reference pricing—like what Safeway implemented—or bundled pricing could help make colonoscopy prices reasonable. Additionally, reference or bundled pricing could put financial incentives in place for gastroenterologists to once again administer sedation—including propofol—themselves, and to institute the resect-and-discard policy for diminutive colon polyps. Such changes would help reduce cost and improve effectiveness of colonoscopy. Dr. Allen: Potential solutions include an emphasis on people taking responsibility for their own health, which means controlling the true drivers of health care costs: obesity, smoking, traumatic accidents and alcohol use. Another solution would be to slowly transition to a system that pays for outcomes and emphasizes clinical integration. Impediments to reaching these goals can be traced, in part, to the federal government, which has taken over regulation of health care. We have, essentially, a single regulatory system that rests within a dysfunctional and politically divided governing body. ■

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

‘Bitter Pill’ Should Be a Wake-Up Call for Surgeons Mitchell Roslin, MD Chief of Bariatric Surgery Lenox Hill Hospital/ North Shore-LIJ New York, New York

When I was growing up, the names DeBakey, Cooley and Starzl were household names. It was international news when Christian Barnard did the firstever heart transplant and when Leonard Bailey performed a heart transplant on Baby Fae. Although quite well educated and interested in health care, I doubt my parents knew who the CEOs of Baylor, Texas Heart, University of Colorado or the University of Pittsburgh were, or any institution in which these esteemed surgeons worked. Neither of my parents was a physician and their knowledge base was representative of well-informed individuals. Every day they watched the news with interest, and our surgical pioneers were a source of pride and were widely revered. That is why Steven Brill’s article “Bitter Pill: Why Medical Bills Are Killing Us” (Feb. 20, 2013) in Time magazine is a must read for every surgeon, and should serve as a rapid wake-up call. Most importantly, it should make us realize the importance of working as a collective entity and make us insist that our societies and lobbying groups represent our real interests. Surgeons should be compensated fairly for each procedure we perform, and we need to reassume the role as the central focus of our health care facilities. Patients travel to and revere those of us who have special skills and perform high-risk procedures. We need to regain control and not allow the respect that the public has for us to decline. We are not interchangeable parts, and we cannot allow hospital administrators to make us a commodity. In his front-page article, Mr. Brill details the high collective pay of hospital and health care system CEOs. More importantly, he describes our health system as one in which there are no real rate sheets. Hospitals charge inflated rates to entities that do not have prearranged contracts. Thus, what Medicare or Blue Cross pays for medical services or for surgical procedures is far less than what a patient would pay if he or she wants to pay for his or her own services. Mr. Brill got a lot of things right in his article, but he did not discuss the implications and what has happened to surgeons. Where does the CEO’s money come from? The unfortunate answer is it comes

from us. What has happened in the past several decades is that payments have increased for facilities and have been reduced to providers. It is essentially a wealth redistribution plan. The justification for this system is that physicians would not otherwise provide for the poor or those who require government assistance. To make sure the indigent receive care, decision-making power on reimbursement was given to the facility, which

would then hire physicians. As a result, an artificial, inefficient market was created. In New York state, Article 28 allows for an inflated facility fee to any center with this designation. If a physician sees a patient in his or her own office, the physician is paid a small fraction of the fee, with the bulk of the reimbursement going to the facility. As a result, it is impractical for any physician to see Medicaid or subsidized patients in a private setting.

Similarly, Medicare has subtly followed a similar system. The facility payment, or Part B, is much higher than the Part A payment or the physician payment. A cardiac surgeon gets paid $1,900 for coronary artery bypass grafting. In cities such as New York, no one could survive on private practice revenue alone. A Whipple procedure pays even less. And yet the conditions for which these procedures are performed see “Bitter Pill”, page 32

OPINION

“Bitter Pill” continued from page 31

have high-paying diagnosis-related groups that reimburse the hospital well. Private insurance is beginning to follow a similar model. This means that the majority of money is being paid to the hospital or the health care system, which then redistributes the money. To date, many of us have done well in this model. For disclosure, I am a full-time employee of North Shore-LIJ, a large health system in New York City, and I

“

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

have been treated well and compensated fairly. That being said, I realize that the bariatric program that I run could not survive without hospital support. This means as surgeons, if things remain the way they are, we are going to lose leverage and have fewer options. Physicians also have manipulated the system for their own self-interest. Surgeons should have the right to set rates and get fair compensation for a procedure. But the idea that patients go to an emergency room and then get seen by a physician who is out of network and then

The reason [hospital] CEOs are getting paid is that they control the revenue. It is not hard to improve your bottom line as a nonprofit hospital. collects a fee beyond what is reasonablee is also not right. This practice is unjustlyy rationalized by the feeling that it compensates for treating the patients for whom we get paid very little. Mr. Brill has paved the road for us to

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gather h public support and change the system before it is too late. The reason CEOs are getting paid is that they control the revenue. It is not hard to improve your bottom line as a nonprofit hospital. One popular way is to merge with other hospitals so you reduce the common costs and gain leverage in contract negotiations. As a collective entity, we need to campaign so that we get paid a fair rate for each case. We should not tolerate a system in which the facility is overcompensated and the surgeon’s fee is undervalued for either public or private reimbursement. Nor should we encourage a system in which we are either under- or overpaid. It is not too late, but soon it will be. Currently, every patient knows the name of the surgeon who performs his or her operation. But they don’t know the CEO of the hospital. Few remember who the anesthesiologist was, but everyone can recall and speak about the surgeon who treated them. Before another day passes, we need to draw attention to these facts. We undergo the most training, take the highest risk and have the most responsibility. An analogy can be made to sports. Fans want to see the players. Coaches and general managers are compensated

Cost continued from page 29

their pocketbook. In this survey, 169 patients with prostate cancer were questioned. “We conducted the survey because this issue has come up repeatedly. Anecdotally, it seemed that even patients with full health coverage were interested in cost,” said study coauthor Jeremy Cetnar, MD, a medical oncologist at the University of Wisconsin Carbone Cancer Center in Madison. This study, like the other, suggests that a substantial proportion of patients want cost discussed, and that this discussion may influence therapeutic decisions, even

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

We do not want fees artificially raised for the facility and lowered for the provider in either the public or private sector. We do not want large sums going to the hospital and then have the CEO redistribute.

need to go to our societies and make clear that we want fair compensation for every case. We do not want bundled fees going to hospitals. We do not want fees artificially raised for the facility and lowered for the provider in either the public or private sector. We do not want large sums going to the hospital and then have the CEO redistribute. Additionally, we have no issue with our rates being transparent. I am certain that our public wants our best and brightest to grow up and be physicians. They want great surgeons who cure cancer, reverse

heart disease and allow them to grow old with joints that work. The public understands the years of training and the skill required to be a top surgeon. If they do not, we need to educate them. I believe that they want us to be well compensated and believe we deserve fair rates. They do not understand a system that reimburses vastly different sums for the same procedure. Most of all, they do not care who the hospital CEO is and what system merges with which. We need to take these facts to the public and deliver our message before the window closes. ■

well, but certainly not close to star players. Also, sports provides an excellent model. Before the formation of the players associations and collective bargaining, owners kept the majority of revenue. That formula has really changed and shows the power of organization. Another misconception is that those who perform surgery are overcompensated and that more money should be diverted to keep people healthy. There are many problems with this viewpoint. Can we really makee people healthy? Can we force them to exercise, to not smoke, to lose weight and to eat healthier foods? Also, does it take extensive education to be aware of these facts? No, people should take care of themselves and we should exist to assist them and fix things when they happen. Again, returning to sports, I am sure the Washington Redskins have an excellent training staff that attempts to keep their players healthy. Yet, all of our attention was on Dr. James Andrews when star quarterback Robert Griffin III reinjured his knee. Who was ultimately responsible for R.G. III’s million-dollar knee and whose judgment was questioned? Steven Brill has laid a foundation in his Time article. Now it is our turn. We

when patients are not responsible for payment. Among the findings: • 79% agreed that a discussion of costs is appropriate, although only 69% reported that they wanted to have that discussion. • 82% agreed that prognosis provides an important context for discussing costs. • 37% agreed that national health care costs should be taken into consideration by oncologists or patients selecting a therapy. “We need more data … but we hypothesize that patients do want to consider value even if they will not directly bear the cost,” Dr. Cetnar said.

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*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.

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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.

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OPINION

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

The Constitution and the ACA Jon C. White, MD Professor of Surgery George Washington University Chief of Surgical Services VAMC Washington, DC When people mention the Constitution and the Affordable Care Act (ACA) in the same sentence, they are usually commenting on the legality of the ACA and

whether its methods are consistent with laws either contained or derived by the Constitution. This commentary usually comes in the form of a tribute to the legislative genius behind the ACA or a vitriolic denunciation of the scoundrels who trampled the U.S. Constitution. This editorial is neither. Rather, it is a reflection on how these two documents have historical similarities, suggesting that the ACA will ultimately be accepted and

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) bisacodyl n (% = n/N) 5-mg 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.

tablets (N=298) n (% = n/N)

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

How the ACA Is Like The Constitution The U.S. Constitution was negotiated and written over the course of four months by the Second Constitutional Convention. It was based

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.

DRUG INTERACTIONS

The p Th ph hiillosop oso os op ph phi hiica cal de dep ptth an a nd e erru ud diitttio ion o io off th he e Fede Fe dera ali list st Pap ape errs p pu uts s to sha sh sham am me tth he ca cate terw rwau auli ling ng on o n TV a an nd in nd in the he pre res ss s today to day th da that hat at pa as sse ses ffo or in nte tell tell llig gen ent di disc scus scus ussi ussi sion on abo abou ab ou ut he he ea allth a th ca arre. e.

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.

fine-tuned like the Constitution. On the other hand, their dissimilarities point out certain critical weaknesses of Obamacare.

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,

on the core principles of natural rights, espoused by the English philosopher John Locke, and republicanism, championed by the French philosopher Montesquieu. Although the convention had drafted a constitution by fall 1787, it did not become the law of the land until 1789 when the required nine states had ratified it. The final state to ratify, Rhode Island, took three years to elect delegates who at first rejected but finally accepted the Constitution. For many, it was the first time they had experienced the concept of bending to the will of the people and not to the will of a capricious and arbitrary monarch. Does this all sound familiar? The ACA also was negotiated and written over the course of months and, like the Constitution, it is based on a core principle; this time it is universal or near-universal health care coverage. It gained enough support by 2010 that it became law of the land, but three years later it is still being debated and challenged in courts. Only about half of the states are fully on board with some of its basic strategies such as Medicaid restructuring. There are many in the country who have not yet signed on and are bending to the will of the people. After 200 years, however, the will of the people is not a novel concept and has become an important part of the democratic process. As the Constitution was being ratified, there were two factions at work: the federalists who believed in a strong central government and supported the Constitution and the anti-federalists who

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

be read in half an hour and both its underlying principles and intent were clear. It created the process by which we are governed, how decisions are made and how our body of laws could be added to and amended. Using its formulas, our laws have been greatly expanded and are recorded as the U.S. Code of Laws, which is published every two years and currently contains 200,000 pages. The ACA, at 1,900 pages, is almost unreadable, and its true intent is still opaque. House Speaker Nancy Pelosi’s

were suspicious of an over-reaching government and were concerned about the potential for tyranny by a central authority. After circulation of early drafts of the Constitution, articles began to show up in the most widely circulated newspapers of the day that were critical of its powerful central authority. James Madison, Alexander Hamilton and John Jay launched a counteroffensive in the form of the Federalist Papers, a series of skillfully written essays explaining and defending both federalism and the Constitution. These essays, also circulated by the lay press, are now considered some of the most astute political writings ever published. Today, members of the Democratic Party, who support a strong central government, might be considered modernday Federalists. Republicans, on the other hand, are suspicious of “big government” and in this regard are more like the antiFederalists. The media outlets these days regularly air these dissenting points of view regarding the ACA. Unfortunately, this is one area where the current debate falls short of the Constitutional debate. The philosophical depth and erudition of the Federalist Papers puts to shame the caterwauling on TV and in the press today that passes for intelligent discussion about health care.

Why the ACA Is Not Like The Constitution When the U.S. Constitution was finally completed, it was three pages long and the Bill of Rights added a fourth. It could

comment that we will have to pass it to see what is in it has turned out to be prophetic. In its three-year history, we are witnessing not a gradual accretion of functionality as we have with the Constitution, but a systematic deconstruction of its content. I think that part of the confusion lies in its poorly chosen title. Most of its strategies are designed to increase coverage although its title seems to suggest that it addresses affordability. Affordability is the weakest argument for the ACA, and whether it will be more or less expensive is largely unknown and much debated. Its

proponents should cling to the reality that it insures more people rather than try to convince a skeptical public that it is less expensive. There is another point that distinguishes the ACA from the Constitution. When the Constitutional Convention was proposed, most proponents agreed that the purpose of the convention should not be to amend or fix the Articles of Confederation, but to create an entirely new government based on the philosophical principles of democracy see ACA, page 38

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

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.

OPINION

ACA continued from page 37

and republicanism. The architects of the Constitution were not new to this task. Each of the 13 colonies had already drawn up its own version of a constitution after independence and those who framed the U.S. Constitution had been engaged in similar efforts for more than 10 years. Starting with only philosophical principles and theories of political science, they presented their arguments, debated and ultimately arrived at compromises. The end product was a document that has created the longeststanding and most successful democracy in the modern world. By contrast, the ACA was intended to make small adjustments to the existing system rather than consider a new vision. In my view, this is its greatest fault. Our health care system is functioning at present but headed for a precipice. A minor adjustment will not change its course quickly or sharply enough. At this moment we should be thinking along the lines of the Constitutional Convention. We could start with core principles such as universal coverage, competition, personal financial incentives, promotion of prevention, and so on, and create a new health care system that would be the longest-standing and most successful in the world.

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

years. The details of how these principles are applied have been amended, added to and sometimes subtracted from and have resulted in the U.S. Code of Laws. I think that the underlying principle of the ACA, near-universal coverage, will be preserved. We will not go back to having 15% of the population uninsured and, in this regard, the ACA has been a great accomplishment. The particulars of how we do it, such as government subsidies, tax incentives, insurance exchanges, changes in Medicare coverage and mandatory participation are being debated. They are being challenged

in state courts, the Supreme Court and in the court of public opinion. Some of these details will be retained, some will be altered and others will be abandoned. It is, simply put, democracy at work. On the other hand, I think that the ACA is a bandage approach to a much larger problem. Opinion is divided as to whether it will increase or decrease the expense of our health care system. Opinion is less divided on whether it will solve our main problem, which is the approaching insolvency of our health care industry and the government that it will drag down

with it. Most people recognize that it does not address the fact that we spend twice the percentage of gross domestic product on health care than most Organization for Economic Cooperation and Development (OECD) countries and achieve no better health care results. Fortunately, the ACA is like the Constitution in some regards but, regrettably, it is not in others. Both documents were written in response to significant national problems. In the 1780s, the Articles of Confederation had not created a central government with the authority to

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

History Will Be the Judge The principles of the Constitution have remained intact for more than 200

gastroendonews

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

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

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

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

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

The small way in which the ACA affects health care spending will not come close to solving the problem of its unsustainable economics. We can’t just amend our current system. We should get our best minds together [and] can come up with an entirely new plan. negotiate international treaties, establish a national military or even levy taxes to pay for its minimal role. People were suspicious of central authority, however, because they had just fought for their independence

from a colonial power that they considered tyrannical. The Constitution had to address these two competing problems. In the same way, the ACA was written to address two competing problems: the lack

of access to the health care system by an increasing percentage of the population and the unsustainable cost of this lessthan-adequate coverage. The Constitution solved its dilemma with negotiated strategies such as separation of powers and checks and balances. The ACA does not seem to have struck such a successful balance. Although it does increase coverage to almost all of the population, its effect on health care spending and the economy is unknown. Some argue it will slow health care inflation, whereas others insist it will make the economy worse.

Through the UCERIS Savings Program

Now 90% of patients with commercial insurance will pay only $252 *†

ulary New Forme and g Covera avings S Expanded ram Prog

UCERIS : ®

A POWERFUL, LOCALLY ACTING STEROID1-3 •

MMX® technology targets delivery of budesonide throughout the full length of the colon1,3

•

3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo2‡

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

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

www.UCERIS.com

Regardless of which argument is correct, the small way in which the ACA affects health care spending will not come close to solving the problem of its unsustainable economics. We can’t just amend our current system. We should get our best minds together in a room in Philadelphia for another four months. This time they can come up with an entirely new plan that incorporates centuries-old economic and political philosophies as well as the realities of our rapidly changing health care demographics. That kind of a health care plan would truly be constitutional. ■

F D A U P D AT E & P R O D U C T N E W S

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

USGI Medical Cleared To Launch Blinded, Head-to-Head, ShamControlled Study To Evaluate Endoscopic Weight Loss Procedure USGI Medical, Inc., recently announced conditional approval by the FDA of its investigational device exemption (IDE) application to launch what the company is calling the largest, multicenter, randomized, shamcontrolled study of an endoscopic procedure for weight loss ever conducted. USGI plans to enroll approximately 350 individuals at up to nine

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)

centers across the United States. At press time, the study was set to begin in December 2013. Investigators in the study, known as the ESSENTIAL Trial, will use USGI Medicalâ&#x20AC;&#x2122;s g-Cath EZ Suture Anchor Delivery Catheter to place tissue anchors across folds of tissue in strategically located parts of the stomach to reduce its size and ability

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

to stretch to accommodate a meal. The g-Cath, which is used in general, non-obesity indications, is the first endoscopic suturing technology proven to create a durable, healed fold in the stomach, USGI said. The incisionless outpatient procedure already has been

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. ÂŠ 2013 Santarus, Inc.

1-UCE13033 V1

Tissue anchors are placed using the g-Cath EZ Suture Anchor Delivery Catheter across folds of tissue in strategically located parts of the stomach to reduce its size and ability to stretch to accommodate a meal. Photo courtesy of USGI Medical

performed in more than 2,000 patients, mostly in Europe, where the procedure is known as POSE (Primary Obesity Surgery Endolumenal). It is performed entirely by passing the device through the mouth, without any incisions in the abdomen. Many patients have returned to work without bandages or signs of surgery within two to three days.

â&#x20AC;&#x2DC;Surgery for weight loss has been studied with positive results, but this will be one of the first major trials to prospectively compare the effectiveness of an endoscopic procedure against a sham procedure plus diet and exercise.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Thomas E. Lavin, MD

â&#x20AC;&#x153;Although published data show significantly superior weight loss results from bariatric surgery than from diet and exercise alone, a major open or laparoscopic operation still poses risks and longer recovery times, and surgery is not right for every patient,â&#x20AC;? said study investigator Thomas E. Lavin, MD, founder of The Surgical Specialists of Louisiana, Covington. â&#x20AC;&#x153;Surgery for weight loss has been studied with positive results, but this will be one of the first major trials to prospectively compare the effectiveness of an endoscopic procedure against a sham procedure plus diet and exercise,â&#x20AC;? Dr. Lavin said. â&#x20AC;&#x153;Based on preliminary studies conducted in Europe, we believe that this

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

F D A U P D AT E & P R O D U C T N E W S

First Generic Versions of Aciphex Tablets Approved To Treat GERD On Nov. 8, the FDA announced the approval of the first generic versions of Aciphex (rabeprazole sodium) delayed-release tablets for the treatment of gastroesophageal reflux disease (GERD) in adults and adolescents aged 12 years and older. “Health care professionals and consumers can be assured that FDAapproved generic drugs have met the same rigid standards of quality as the brand-name drug,” said Kathleen Uhl, MD, acting director of the Office of Generic Drugs, FDA Center for Drug Evaluation and Research, in a statement. “This medication is widely used by people who have GERD, so it is important to have access to affordable treatment options.” Rabeprazole is a proton pump inhibitor that works by decreasing the amount of acid produced in the stomach. The medication is

used to treat symptoms of GERD, as well as Zollinger-Ellison syndrome, a condition in which the stomach produces too much acid. Additionally, rabeprazole is used to treat peptic ulcers and in combination with other medications to eliminate Helicobacter pylorii infection. Manufacturers that have received approval from the FDA to market generic rabeprazole include Dr.

Reddy’s Laboratories Ltd., Kremers Urban Pharmaceuticals Inc., Lupin Pharmaceuticals Inc., Mylan Pharmaceuticals Inc., Teva Pharmaceuticals USA and Torrent Pharmaceuticals Ltd. In clinical trials, the most common adverse events (AEs) reported by adults taking Aciphex were sore throat, flatulence, infection and constipation. In adolescents, the most

frequently reported AEs were abdominal pain, diarrhea and headache. More information about generic Aciphex can be obtained from the manufacturers. —Based on a press release from the FDA

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new approach may help patients feel full sooner during meals, improving satiety and reducing hunger cravings so they can control their portions, consume fewer calories and lose weight,” he added. “If the data are positive and consistent with smaller trials, it could mean that tens of thousands of patients may have an incredibly compelling option to consider if they’ve struggled to lose weight with diet and exercise, but aren’t prepared to accept the risk of traditional bariatric surgery.” “We look forward to working with many of the country’s leading bariatric surgeons and advanced endoscopists, both at top academic medical institutions and well-respected private centers, to enroll patients in this study,” said John Cox, chief operating officer of USGI Medical. “Based on our experience to date, we believe our new incisionless approach to treating obesity may offer promise to patients who have struggled to lose weight through diet and exercise.” Initial safety and efficacy results of European studies of POSE are positive, according to USGI. For additional details about the ESSENTIAL Trial, visit ClinicalTrials.gov (identifier: NCT01958385). For more information about USGI Medical, visit www.usgimedical.com. ■ —Based on a press release from USGI Medical

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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 • DECEMBER 2013

FDA Approves Expanded Use for Alvimopan On Oct. 21, Cubist Pharmaceuticals, Inc., announced that the FDA granted approval of its supplemental new drug application (sNDA) for Entereg (alvimopan). This approval expands the indication for use of Entereg to accelerate the time to upper and lower gastrointestinal (GI) recovery following alll surgeries that

include partial bowel resection with primary anastomosis. The FDA originally approved Entereg in 2008 to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis. The original indication was supported by trials in patients

undergoing bowel resection for benign and malignant colorectal or small bowel disease. Primary support for the expanded indication was based on data from a Phase IV randomized, placebo-controlled, double-blind trial in patients undergoing radical cystectomy, an extensive surgical procedure that

Photo courtesy of Cubist Pharmaceuticals, Inc.

includes resecting a segment of the bowel to reconstruct the lower urinary tract. “Delayed GI recovery is one of the most common causes of prolonged hospital stays in patients undergoing major abdominopelvic surgery. We are pleased that doctors will have the best option to help speed GI recovery for appropriate patients who have undergone surgeries that included a bowel resection,” said Steven Gilman, PhD, executive vice president of research and development, and chief scientific officer at Cubist Pharmaceuticals. For further information, visit www.entereg.com. —Based on a press release from Cubist Pharmaceuticals, Inc.

RESEARCH Advancing Genomic Medicine To Create Precision Therapies.

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

Gastroenterology & Endoscopy News’

FDA Update & Product News column is compiled by the editors based on press releases from manufacturers and the U.S. Food and Drug Administration.

Please send product news to:

cgordon@mcmahonmed.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

NEW PRODUCT ANNOUNCEMENT

‘Ulcerative Colitis for Dummies’: Free Resource for Patients Now Available During the 2013 American College of Gastroenterology (ACG) Annual Scientific Meeting, Salix Pharmaceuticals Ltd., announced the availability of “Ulcerative Colitis for Dummies,” a free book offering patientfocused information on ulcerative colitis (UC). The book is available in print and online. Authored by Francis A. Farraye, MD, MSc, clinical director in gastroenterology and co-director of the Center for Digestive Disorders at Boston Medical Center, and professor of medicine at the Boston University School of Medicine, the book is written for patients as an easy-to-use guide that offers basic information including tips for living with UC and answers to commonly asked questions about the condition.

Colitis for Dummies’ will empower patients to talk openly with their clinicians about their condition and potential treatment options,” said Matt Mitcho, brand director, Salix Pharmaceuticals. “Informing patients about UC can further expand the dialogue by getting patients to ask the right questions, become more aware of symptoms and make the best use of the time with their provider. The goal is to help patients

better understand and manage their condition,” Mr. Mitcho said in a press release. Dr. Farraye, an expert on topics related to the diagnosis and management of inflammatory bowel disease, has authored or co-authored more than 300 original scientific manuscripts, books, chapters, reviews and abstracts. He is a fellow of the ACG, the American College of Physicians, the American Society

of Gastrointestinal Endoscopy, and the American Gastroenterological Association, and has served on numerous committees, including the Crohn’s and Colitis Foundation of America Professional Education Committee. Visit www.ucfordummies.com to download a copy of ‘Ulcerative Colitis for Dummies.’ —Based on a press release from Salix Pharmaceuticals Ltd.

presents

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

Podcast

Now Available @ www.gastroendonews.com Photo courtesy of Salix Pharmaceuticals Ltd.

“When it comes to educating patients, it is critical that providers are able to connect in a relatable way to ensure patients have an understanding of their diagnosis,” said Dr. Farraye in a press statement. “‘Ulcerative Colitis for Dummies’ can be used as a conversation tool for patients at all stages to empower better understanding and management of UC.” The book is sponsored by Salix Pharmaceuticals Ltd., and was distributed at the ACG meeting in San Diego. It is available through Salix representatives and also for download online at www.ucfordummies.com. “We hope that ‘Ulcerative

Dr. Johnson discusses defining a successful colonoscopy, standard-of-care guidelines, and how quality regulation may improve adenoma detection rate and cancer detection.

Parameters That Define a Successful Colonoscopy Podcast is supported by Braintree Laboratories.

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

New Bite Block Helps Oxygen Delivery During Endoscopic Procedurees clinician may need to relocate the oxygen cannula to the mouth or bite block. When the cannula is repositioned, it can interfere with the procedure by falling out of position or getting in the way of the endoscope, US Endoscopy said in a press release. “The challenges many clinicians face during these procedures can extend procedure time

US Endoscopy recently announced the full market release of the Respa O2 delivery bite block, which is designed to hold the nasal cannula in place during upper gastrointestinal procedures. During endoscopic procedures, patients may switch from breathing through their nose to breathing through their mouth, according to US Endoscopy. If this occurs, the

and create additional costs for the facility,” said Tony Siracusa, vice president and general manager of US Endoscopy, a subsidiary of STERIS Corporation. “Unlike others on the market, the Respa bite block is specifically designed to house the nasal cannula, helping to eliminate frustrations and ensure delivery of oxygen to patients is uninterrupted.”

The Respa O2 delivery bite block helps to ensure uninterrupted delivery of oxygen to patients during endoscopic procedures. Photo courtesy of US Endoscopy

The Respa O2 delivery bite block has a dental retention rim, latex-free strap and an opening size of 20 mm/60 FR. For more information, visit www.usendoscopy.com.

Optimizing the Prevention and Management of Postsurgical Adhesions

—Based on a press release from US Endoscopy

Vercirnon continued from page 22

To participate in this FREE CME activity, log on to

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

Chair

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

Faculty

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

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

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

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

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

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

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

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

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.

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

the vercirnon once-daily group and 25.1% in the placebo group. Remission occurred in 15.3%, 13.3% and 12.9% of patients, respectively. There was no difference in CRP and fecal calprotectin levels from baseline to week 12. “In addition, important AEs, including cardiac toxicity, were observed,” Dr. Sandborn said. “These data demonstrate that vercirnon is not safe and effective for the induction treatment of CD.” These findings were certainly disappointing given the promise suggested by the Phase II trial, but nevertheless they provide a clear example of the purpose of thorough research and the need for reproducible outcomes in the quest for a better and broader range of therapies for complicated conditions like CD. “Everyone needs to be aware that positive Phase II results from limited patient numbers, doses and subgroups do not always translate into positive Phase III results in larger and/or more heterogeneous patient populations,” said Stephen B. Hanauer, MD, the Joseph B. Kirsner Professor of Medicine and Clinical Pharmacology, University of Chicago Medicine, who was not involved in this study.

NEW PRODUCT ANNOUNCEMENT

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2013

EndoChoice Introduces Newly FDA-Approved Fuse Gastroscope Offering Full-Spectrum Field of View On Oct. 28, EndoChoice announced FDA 510(k) clearance of its Fuse Gastroscope for use in the upper gastrointestinal (GI) tract. With a field of view of 245 degrees, the Fuse system allows endoscopists to see nearly twice as much surface area as they can with traditional endoscopes, the company stated in a press release. The new approval gives doctors performing upper GI flexible endoscopy a new tool to help them see more of the anatomy and facilitate diagnoses in the upper GI tract. According to EndoChoice, traditional gastroscopes provide a field of view limited to about 140 degrees. The new Fuse Gastroscope joins the line of products released earlier this year by EndoChoice under the Fuse brand, including the Fuse Colonoscope. The Fuse Gastroscope has two cameras and the Fuse Colonoscope has three, whereas traditional systems have only one camera, according to EndoChoice. Because of the folds that occur naturally in the colon and stomach anatomy, problem areas may go undetected with the use of traditional endoscopes. The Fuse system allows endoscopists to see into and behind those folds. Endoscopic images are displayed on high-definition screens that are specially arranged to give endoscopists a full-spectrum view. Data supporting Fuse were presented simultaneously at the 2013 American College of Gastroenterology Annual Scientific Meeting and at the 2013 United European Gastroenterology Week meeting. Researchers showed that the Fuse system allows for detection of significantly more adenomas and precancerous lesions compared with traditional single-view endoscopes. “The data from the Full Spectrum Endoscopy Tandem study would indicate that Fuse is a radical improvement over the tools we’ve used in the past to fight GI disease,” said Douglas K. Rex, professor of

medicine at Indiana University, Bloomington. For more information about Fuse Full Spectrum Endoscopy, visit www. endochoice.com/fuse.

The newly approved Fuse Gastroscope has a field of view of 245 degrees. Photo courtesy of EndoChoice

—Based on a press release from EndoChoice

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.

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 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 mgtreated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

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

Hepatic Encephalopathy XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age. In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed. XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores > 25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions (5.4), Use in Speciﬁc Populations (8.7), Clinical Pharmacology (12.3)].

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

WARNINGS AND PRECAUTIONS Travelers’ Diarrhea Not Caused by Escherichia coli XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered. XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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

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

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

Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean

MedDRA Preferred Term

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

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

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

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

The following adverse reactions, presented by body system, have also been reported in the placebocontrolled 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.

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.

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.

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

XIFA3X0139_I_Thin_Ice_Digest_Ad_BS_r8.indd 1

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 13/11

11/14/13 12:53 PM

Request samples at Xifaxan550.com/samples

Hepatic Encephalopathy:

ARE YOUR PATIENTS LIVING ON THIN ICE? Overt hepatic encephalopathy (HE) should be considered in any patient with cirrhosis.1 Once a cirrhotic patient has developed HE, experts in hepatology recommend maintenance drug therapy to reduce the risk of unpredictable recurrences.2

Treat continuously with a Xifaxan 550 mg pill twice daily

58% proven reduction in the risk of overt HE breakthrough * 50% proven reduction in the risk of HE-related hospitalizations 3

3†‡

The most common adverse reactions occurring (≥12% incidence) in the clinical trial with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.3

*Over a 6-month period; P<0.0001 vs placebo.3 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 †

Prescribe. Protect. Repeat.

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

Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Important Safety Information About XIFAXAN 550 mg

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.

XIFAXAN (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of The most common adverse reactions occurring in ≥10% of patients and at a the components in XIFAXAN. Hypersensitivity reactions have included exfoliative higher incidence than placebo in the clinical study were peripheral edema (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%). 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.

Xifaxan 550 mg is not available for sale outside the U.S.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores <25.

References: 1. Starr SP, Raines D. Cirrhosis: diagnosis, management, and prevention. Am Fam Physician. 2011;84(12):1353-1359. 2. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis. 2012;16(1):73-89. 3. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2011.

Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see brief summary on reverse.

DECEMBER 2013 Brought to You by

REPORT ACG 2013: Advancing the Accuracy Of IBD Diagnostics and Monitoring For Biologic Therapy I

nflammatory bowel disease (IBD) or prognosis for patients with atypical is a common and debilitating confindings.3 Additionally, there are disFaculty dition caused by a complex intertinct differences between pediatric play between host genetic factors, and adult IBD regarding presentation, David T. Rubin, MD the immune system, and commenlocation, and severity.4 Consequently, 1 Professor of Medicine sal enteric bacteria. In the United patients with suspected IBD may Co-Director, Inflammatory Bowel require a battery of tests to assess States, an estimated 1.4 million indidisease subtype, prognosis, and viduals have been diagnosed with Disease Center treatment course. IBD,1 and yet its pathogenesis and Associate Section Chief for In an effort to improve diagnostic clinical presentations are not well Educational Programs accuracy and streamline the process, defined. The designation of Crohn’s University of Chicago Medicine serologic markers have been investidisease (CD) or ulcerative colitis (UC) Chicago, Illinois gated as a method to diagnose and may be a simplification of more comsubtype IBD, as well as to inform its plex inflammatory processes, but an phenotype.1,2 Early research focused accurate diagnosis and early initiation of targeted therapy can yield sustained outcomes.2 on 2 biomarkers in particular: anti–Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil Historically, the diagnosis of IBD has been plagued by cytoplasmic antibodies (pANCA).1,2 The first generation symptom overlap between its 2 subtypes, CD and UC, as well as non–IBD-related conditions such as infectious coliof serologic assays for IBD focused on these biomarkers; tis or irritable bowel syndrome.3 Clinical confirmation of however, there is overlap in about 25% of patients, thus compromising their clinical accuracy.2,5 Ongoing research IBD may require multiple invasive diagnostic exams, such as endoscopy and advanced imaging, with associated led to the identification of additional biomarkers involved shortcomings and costs.1,2 These exams inform clinicians in the pathogenesis of IBD and its specific subtypes, such as antibody to outer membrane porin C (anti-OmpC) and about mucosal inflammation, polyps, lesions, and disease anti-flagellin (anti-CBir1) antibodies.2 location, but they offer little information about IBD subtype

Supported by

REPORT

The scientific community also has begun to unravel the synergistic effect of serologic, genetic, and inflammatory biomarkers in the pathogenesis of IBD. Certain genetic profiles may represent dysregulated mucosal responses to commensal enteric pathogens, thus resulting in the trademark inflammatory responses of IBD.6 Specific genes are implicated in susceptibility to IBD and its subtypes. For example, mutations in autophagy-related 16-like 1 gene (ATG16L1) lead to defective handling of enteric microorganisms and have been implicated in the development of CD.1,6 Extracellular matrix gene 1 (ECM1) is an epithelial barrier gene that inhibits matrix metalloproteinase 9, and mutations in ECM1 have been associated with UC.1,6 These discoveries have led to the development of an advanced diagnostic test incorporating serologic, genetic, and inflammatory biomarkers, all within a single assay. Compared with previous biomarker tests, this test offers superior sensitivity and specificity for IBD and its subtypes.7 There is great interest in the utility of such serologic and genetic markers for enhanced disease classification and prognosis, and their utility is currently being confirmed in multiple clinical trials. The therapeutic management of IBD also continues to evolve. With diagnostic improvements and advances in the prediction of disease progression, clinicians now are able to individualize treatment decisions. For patients who do not require surgical intervention, therapy continues to move away from the use of corticosteroids due to related adverse events, lack of sustained efficacy, and the risk for steroid dependence.8 Biologic therapy with agents such as infliximab (IFX), adalimumab (ADA), certolizumab pegol, golimumab (GLM), and natalizumab has shown efficacy in the treatment of IBD, but historically, optimizing the dose to both induce and maintain disease

remission was plagued by loss of response and subsequent recurrences.8 Loss of response may occur in up to 50% of initial responders.9-11 Several factors have been uncovered that collectively affect the pharmacokinetic and pharmacodynamic profiles of biologic therapy, including high baseline levels of tumor necrosis factor alpha (TNFÎą) or C-reactive protein (CRP), high body weight, concomitant use of immunosuppressive agents, and the presence of antibodies to IFX (ATI) and ADA (ATA).12 Antidrug antibodies can cause hypersensitivity reactions and, more importantly, increased production reduces the efficacy of biologic agents. They accelerate serum drug clearance and inhibit drug binding ability, thus leading to loss of response and reduced remission rates.12 Other assays, such as enzyme-linked immunosorbent assays (ELISAs) and derivatives thereof, such as electrochemiluminescence immunoassays (ECLIAs), have limitations attributed to solid-phase methodology, including increased likelihood of false-negative and -positive results.13 Liquid-phase homogeneous mobility shift assays (HMSAs) that can accurately measure serum drug and antidrug antibody levels are now commercially available. These assays aid IBD management by providing valuable information about serum drug and drug antibody levels, and clinical research continues to validate the importance of such information regarding disease activity and patient outcomes.14 The confluence of advances in the diagnosis of IBD and its subtypes and improved monitoring capabilities for biologic therapy may usher in a new era of patient care. This review features selected highlights of the latest research on the use of biomarker and drug monitoring tests for IBD. All of the abstracts were accepted for presentation at the American College of Gastroenterology 2013 Annual Scientific Meeting.

Combined Serological IBD Markers Correlate With High Inflammatory Burden in a Large Cohort of Patients Presenting IBD-Like Gastrointestinal Symptoms Fred Princen, Steven Lockton, Jordan Stachelski, Cheryl Triggs, Michelle Brown, and Sharat Singh

Background

Aim

Some patients with IBD will experience a benign clinical course. However, other patients face a progressive disease course, which can include high inflammatory burden leading to complicated disease that ultimately requires surgery. Several studies have shown that early aggressive therapy can benefit patients with aggressive disease. It is also established that both the presence and magnitude of serologic markers are correlated with specific phenotypes and with the need for intestinal surgery.

The aim of this study was to investigate the relationship between serologic markers and inflammatory burden in patients with a suspected diagnosis of IBD.

Methods Marker data from 43,679 de-identified patients between the ages of 2 and 85 years old were collected from Prometheus Labs CLIA laboratory. The patient diagnosis was unknown. The prevalence of serologic markers (ASCA-IgA,

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ASCA-IgG, ANCA, pANCA, and anti-OmpC), anti-flagellins (CBir1, A4-Fla2, and FlaX) and inflammatory markers (CRP, SAA, ICAM, VCAM, and VEGF) were compared. Quartile Sum Scores (QSS) were calculated from serologic markers by assigning a score from 0 to 3 for each marker based on the quartile the marker value was followed by summation of these per-marker scores. Inflammatory markers were combined to form an inflammatory index by centering their values at the reference range for each assay, scaling each marker, then summing them on a per-patient basis.

Results QSS values combining the 8 serologic markers ranged from 0 to 19. High QSS score ≥16 or ≥17 represented 22.4% and 11.5% of the population, respectively. Higher QSS was correlated with an increased acute inflammation as assessed by CRP. High CRP prevalence increased from 66.7%, 71.8% to 77.5%, in individuals presenting with QSS values of 17, 18,

and 19, respectively. When the ASCA markers were removed from the QSS calculation (QSS range 0 to 13 for combining the remaining 6 markers), the top 2 QSS values ≥12 and ≥13 still correlated with a high CRP prevalence of 64.2% and 70.2%, respectively. Similarly the higher QSS correlated with higher inflammatory indices. High inflammatory index prevalence increased from 28.1%, 33.3% to 41.6%, in individuals presenting QSS values of 17, 18, and 19, respectively.

Conclusion In this large cohort of patients presenting IBD-like gastrointestinal symptoms, we observed a relationship between serologic value (QSS) with both acute inflammation and high inflammatory index scores. These results demonstrated the benefit of a multimarker diagnostic panel for detecting those patients with a high chance of developing aggressive disease. Our results also showed the minimal contribution of ASCA in the QSS correlation with inflammation.

A Unique Serological Marker Signature Can Help To Identify Difficult To Diagnose Colonic IBD Fred Princen, Steven Lockton, Jordan Stachelski, Cheryl Triggs, Michelle Brown, and Sharat Singh

Introduction Colonic IBD is a unique form of IBD that behaves differently from typical CD or UC. Current multimarker diagnostic panels can discriminate between CD and UC by classifying patients based on an expected marker profile for each IBD subtype. However, a subset of patients possesses a marker signature that conforms to neither subtype, but appears to have a unique signature, featuring CD-specific anti-flagellin markers like antiCBir1 combined with the UC-specific marker ANCA.

Aim The aim of this study was to investigate serologic marker patterns that may help to differentiate and subtype colonic IBD-like subjects.

Methods Serum samples from 518 patients with well-characterized IBD, collected from 6 academic and 42 community medical practices, were evaluated with serologic markers (ASCA-IgA, ASCA-IgG, ANCA, anti-OmpC, anti-CBir1, anti–A4-Fla2, and anti-FlaX). Using a marker pattern of ANCA positivity and high titers of the anti-flagellin (CBir1, A4-Fla2, and FlaX) antibodies, 53 IBD patients were identified as serologically inconclusive for CD versus UC.

Results The majority (91%) of these 53 patients had colonic disease involvement. Twenty-seven were originally diagnosed as

CD (51%) and 26 as UC (49%). These 53 patients were profiled by their specific serologic marker patterns. The first group (n=21) had ASCA and anti-flagellin markers reminiscent of a CD pattern, but also had high ANCA and pANCA (median values in EU/mL: ASCA-IgA, 11.2; ASCA-IgG, 11.6; ANCA, 67.1; anti-OmpC, 7.9; anti-CBir1, 51.5; anti–A4-Fla2, 53.2; anti-FlaX, 51.7): so were classified “CD-like.” The second group (n=13) had a marker pattern resembling UC with high ANCA and pANCA and low ASCA, but also had high anti-flagellin markers (median values in EU/mL: ASCA IgA, 3.0; ASCA IgG, 3.0; ANCA, 100.1; anti-OmpC, 4.2; anti-CBir1, 34.7; anti–A4-Fla2, 35.5; anti-FlaX, 30.3); and so were classified as “UC-like.” The third group (n=19) had a truly intermediate marker pattern (median values in EU/mL: ASCA-IgA, 3.1; ASCA-IgG, 5.4; ANCA, 47.5; anti-OmpC, 37.3; anti-CBir1, 37.3; anti–A4-Fla2, 34.5; anti-FlaX, 25.5); so were classified as “IBD-indeterminate.” A total of 7 CD and 12 UC cases have been reclassified based on their marker pattern as IBD-indeterminate.

Conclusions Multimarker diagnostic panels containing ANCA and antiflagellin serologic markers can help to identify patients who can be hard to diagnose and subtype into CD or UC. Moreover, the serologic markers can identify colonic disease involvement and identify subtypes such as UC-like, CDlike, or truly indeterminate within this group. The clinical significance of these subtypes will need to be evaluated in a larger study.

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Anti-Flagellin Serological Markers Are Earlier Markers of CD Progression Than ASCA Serological Markers Fred Princen, Steven Lockton, Jordan Stachelski, Cheryl Triggs, Michelle Brown, and Sharat Singh

Background Up to 1.4 million Americans of all ages suffer from IBD. IBD tends to be more aggressive in younger people, however, more often resulting in complicated disease phenotypes. Serologic markers to predict complicated clinical CD phenotypes are extensively described in the literature. Interestingly, not all these markers have equal immunogenicity. Indeed, evidence suggests that glycans (ASCA-like structure) are relatively weakly immunogenic. Conversely, flagellins are strongly recognized by the specific innate immune receptor toll-like receptor 5 (TLR5) and have high immunogenic potential. These observations suggest that longer maturation times are required to develop ASCA response in IBD compared with anti-flagellin response. Finally, in CD patients, serologic positivity of ASCA and flagellins is additionally influenced by the age of diagnosis.

(ASCA-IgA, ASCA-IgG, ANCA, pANCA, and anti-OmpC), antiflagellins (CBir1, A4-Fla2, and FlaX), and inflammatory markers (CRP, SAA, ICAM, VCAM, and VEGF) were calculated. Per-subject QSS was calculated from serologic markers. This was achieved by assigning a score from 0 to 3 for each marker based on which quartile the marker value was in, followed by summation over these per-marker scores. Markers were deemed positive if they were in the fourth quartile.

Results

Aim

In this young adult CD cohort, elevated anti-flagellins were associated with aggressive CD behavior (P<0.05), while ASCAIgA and ASCA-IgG were not (P>0.05). Patients with complications have a significantly higher QSS (P=0.0157). When ASCAâ&#x20AC;&#x2122;s contributions are removed from the QSS, the relationship between QSS and the complications is even stronger (P=0.0053). High QSS are also associated with a higher disease burden: Median CRP for high QSS (â&#x2030;Ľ16) was 12.14 mg/L, while for low QSS (<16) median CRP was 2.33 mg/L (P<0.001). In contrast, no relationship was found between ASCA-IgA or ASCA-IgG and CRP.

To study the prevalence and magnitude of serological markers in relation to inflammation and complicated CD.

Conclusion

Methods Samples from well-characterized patients, including data on disease complications, were collected from 15 North American gastrointestinal centers. Samples from 147 young adult patients with CD were analyzed. The prevalence of serologic markers

These results show that anti-flagellin serologic markers are strongly associated with inflammatory burden and complicated disease phenotype. ASCA markers did not correlate with inflammation or with disease complications in this young adult cohort. This suggests that anti-flagellin serological markers are earlier markers of CD progression than ASCA.

Infliximab Therapeutic Drug Monitoring in Clinical Practice: Indications and Utility Michael McTigue, William J. Sandborn, Barrett Levesque, and Derek Patel

Purpose IFX is effective for the treatment of CD and UC. Measurement of serum IFX levels and ATI have shown utility in the management of IBD patients with inadequate/loss of response (LOR) to IFX or infusion reactions. Evolving evidence suggests additional indications for therapeutic drug monitoring using IFX and ATI concentrations in patients without specific response-related issues and in patients restarting IFX after drug holiday may help predict and optimize response to IFX. Here we report the spectrum of use of IFX and ATI testing at an academic IBD center, including novel indications such as reintroduction of IFX and therapeutic drug monitoring.

Methods We conducted a retrospective review of the electronic medical records of all IBD patients at our institution who underwent IFX/ATI testing between 1/1/2010 and 12/31/2012. The testing date, results, indication for testing, and clinical management based on test results all were obtained.

Results One hundred forty-two IBD patients (83 with CD, 58 with UC, 1 with indeterminate colitis) underwent 205 IFX/ATI tests. Sixtyone percent (87/142) of patients received concomitant immunosuppression (IS). The most common indications for testing were inadequate/LOR (50%) and therapeutic drug monitoring (19%). Of 49 patients with confirmed LOR, 50% (25/49) had nontherapeutic IFX levels and 16% (8/49) had detectable ATI. Thirty-eight patients underwent testing for therapeutic

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drug monitoring: 16% (6/38) had nontherapeutic IFX levels, 3% (1/38) had detectable ATI, and 3% (1/38) had measurable IFX with detectable ATI. Of 7 patients tested before reintroduction of IFX, 43% (3/7) were found to have detectable ATI. Of 11 patients tested after rechallenge with IFX, 55% (6/11) had nontherapeutic IFX concentrations and 36% (4/11) had detectable ATI. Concomitant IS therapy was significantly associated with negative ATI status (P=0.0026). Nontherapeutic IFX concentration was

associated with higher CRP (P<0.0001). Testing resulted in changes in therapy in 50% of patients with LOR and 21% of patients undergoing routine therapeutic drug monitoring.

Conclusions The measurement of IFX and ATI concentrations in IBD patients receiving IFX can aid decision making in multiple clinical scenarios and frequently results in changes in clinical care.

Clinical Utility of Next Generation Infliximab and Antibodies to Infliximab Assay Michael McTigue, William J. Sandborn, Barrett G. Levesque, and Derek Patel

Purpose An assay to measure serum IFX and ATI has been available since 2006. The first-generation test was an ELISA and could only measure ATI in the absence of IFX, due to interference of the drug with the assay. A novel liquid-phase mobility shift assay was developed recently, allowing for the measurement of IFX and ATI levels even when IFX is present in the serum. The aim of this study is to investigate the clinical utility of this new test.

Methods We conducted a retrospective review of the electronic medical records of all IBD patients at our institution who underwent IFX/ATI testing between 1/1/2010 and 12/31/2012. The type of assay, test date, results, indication for testing, and clinical management based on test results were obtained.

Results One hundred forty-eight tests were performed using the ELISA assay and 57 tests were performed with the Anser IFX assay. The results of testing are summarized in the Table. Fiftytwo percent (77/148) of the ELISA tests and 47% (27/57) of the

Anser IFX tests were performed to evaluate inadequate/LOR to IFX. Overall, 48% (49/103) of patients experiencing LOR had therapeutic IFX levels. Using the ELISA assay, 11/31 patients (35%) with undetectable IFX levels were ATI-positive as compared with 10/11 patients (91%) tested using the Anser IFX assay. In addition, 2/13 (15%) of patients with subtherapeutic IFX concentrations found using the Anser IFX assay were ATI-positive (ATIs could not be measured in the 41 patients with subtherapeutic IFX concentrations tested using the ELISA assay). In total, 11/72 patients (15%) with undetectable or subtherapeutic IFX concentrations as measured by ELISA, as compared with 12/24 of patients (50%) with undetectable or subtherapeutic IFX concentrations as measured by Anser IFX, had detectable ATI.

Conclusions Use of the Anser IFX assay is associated with a marked increase in the proportion of patients with undetectable or subtherapeutic IFX concentrations who are found to be ATIpositive. These preliminary findings should be confirmed prospectively in a study with paired ELISA and Anser IFX assays in the same patients. If confirmed, these findings suggest that the Anser assay may explain the underlying reason (immunogenicity) for undetectable or subtherapeutic IFX concentrations in a larger proportion of patients.

Table. Comparison of Anser IFX Versus Standard ELISA ELISA Undetectable IFX

Undetectable/Unable to Confirm ATI

Low ATI

High ATI

Subtherapeutic IFX

Therapeutic IFX

Undetectable ATI

Low ATI

High ATI

Undetectable IFX

Subtherapeutic IFX

Therapeutic IFX

Anser IFX

ATI, antibodies to infliximab; ELISA, enzyme-linked immunosorbent assay; IFX, infliximab

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Post-Marketing Review of Serum Adalimumab and Antibodies to Adalimumab Using the Mobility Shift Assay Platform David T. Rubin, Scott Hauenstein, and Sharat Singh

Introduction A commercial assay for serum ADA levels and ATA was recently released. We reviewed the use of these assays in order to analyze clinical practice patterns and glean additional insight about performance of ADA in IBD and other conditions.

Methods All available records of requests for ADA/ATA levels using the Anser ADA assay were obtained and reviewed. Data available include the results of the assay and provider-reported information on the test requisition. The requisition for this test includes queries for patient diagnosis and International Classification of Diseases codes, initial dose and date of therapy, current dose and last injection date, as well as the reason for ordering the assay. We also reviewed any Anser ADA tested patients who had previously had IFX assays performed. Simple statistics were performed to describe these findings.

Results Two hundred and thirty-eight tests were ordered. Diagnoses were for CD (121), UC (27), and other diagnoses including diarrhea, abdominal pain, rheumatoid arthritis, psoriasis, or not identified (24). One hundred and eighty-five tests had an indication for order and final test results. Of these 185, 154 (83%)

had detectable ADA levels, 52 (28%) had positive ATA, and 34 of these 52 (65%) also had detectable ADA levels. ADA levels were greater in patients who were ATA negative compared to those who were ATA positive (11.64 vs 4.9 mcg/mL, P<0.0001). Twenty-four of 64 (38%) patients who had an indication of “LOR” or “relapse” had positive ATA. In addition, the ADA level was lower in patients with an indication of relapse compared to the “LOR” and no info groups (median 4.4 vs 10.5, 9.85 for LOR and no info, respectively; P=0.0078, 0.023). When exploring dosing differences, ADA levels were not significantly different between patients on qw and qow dosing (median 9.7 vs 8.5 mcg/mL), but there were significant differences in ATA for patients on 40 mg qw compared to qow (median 1.05 vs 0 U/ mL, P=0.013, Mann-Whitney). Eight patients had both ADA assessment and prior IFX assessment performed; 5/8 were ATI positive and 3/5 of these now tested ATA positive.

Conclusions In post-marketing review, patients with detectable ATA had significantly lower ADA levels and ADA levels in patients who had these assays for “loss of response” or “relapse” were more likely to have ATA. Patients receiving ADA qw were more likely to have ATA, as were patients who had previously developed ATI. These findings inform future studies and treatment strategies.

HMSA Overcomes the Limitations of ELISA and ECLIA Assays for Monitoring IFX, ADA, and Associated Antidrug Antibodies in Serum Laia Egea-Pujol, Rukmini Reddy, Shruti Patel, Raymond Christie, Jared Salbato, Shawn Shah, Scott Hauenstein, and Sharat Singh

Purpose Commercial ELISA/ECLIA for monitoring IFX and ADA have many shortcomings, including the inability to detect antidrug antibodies in the presence of drug. For drugs given by subcutaneous injection, this is of particular importance because drug is usually present in patient serum. Further, secondary LOR caused by antidrug antibodies is common, warranting an assay that can accurately measure antidrug antibody levels in the presence of drug. This study compares the analytical capabilities of ELISA/ECLIA to HMSA in detecting drug and antidrug antibody levels in serum.

Methods ELISA/ECLIA assays were developed and validated for IFX, ADA, ATI, and ATA. Validation was performed according to

industry recommendations and included the following parameters: sensitivity, accuracy, precision, and serum interference (normal serum, hemolyzed, lipemic, icterus, rheumatoid factor, and drug). The values derived for ELISA/ECLIA were compared to published results for HMSA.

Results Precision and accuracy for ELISA/ECLIA drug and antidrug antibody assays were within acceptable limits at greater than 10 mcg/mL of drug or antidrug antibody (coefficient of variation [CV] <20%, error <25%). However, CVs and error rates increased significantly at concentrations less than 10.0 mcg/mL. Concentrations ≤1.5 mcg/mL for ATI and ATA were not detectable or not accurately measurable by ELISA/ECLIA, but were measurable by HMSA. Drug concentrations as low as 1.0 mcg/mL compromised the accuracy of the ATI/ATA ELISA and ECLIA assays, similar to published work. In contrast, ATI/ATA HMSA tolerated up to 60 mcg/mL of drug. IFX and ADA ELISA/ECLIA showed high sensitivity in buffer

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(3.12-31 ng/mL); however, sensitivity in serum was less than in buffer (up to 300x). HMSA showed superior accuracy and precision from 0 to 10 mcg/mL drug in serum. In serum with interfering agents, HMSA was able to accurately measure IFX and ADA drug levels at low concentrations (<5.0 mcg/mL), whereas ELISA/ECLIA failed. No significant interference was observed at the physiologic level of serum substances in the ATI/ATA HMSA, whereas ELISA/ECLIA showed high error rates (30%-233%).

Conclusion ELISA/ECLIA assays for IFX/ATI and ADA/ATA were developed and validated to meet industry standards. HMSA accurately measures drug levels in both normal serum and serum with interfering agents where ELISA/ECLIA do not. We confirm the results of publications showing that ELISA/ECLIA cannot measure antidrug antibodies in the presence of drug. HMSA has better sensitivity, precision, and accuracy for drug and antidrug antibodies.

Validation of an HSMA for the Measurement of Golimumab and Antibodies to Golimumab in IBD Patient Serum Jared Salbato, Jonathan Parnell, Rukmini Reddy, Raymond Christie, Steven Lockton, Scott Hauenstein, Gordon R. Greenberg, and Sharat Sing

Purpose GLM is a therapeutic monoclonal antibody recently approved for use in moderate to severe UC patients. Previous work has demonstrated that up to 40% of patients may experience loss of response to anti-TNF therapies commonly used in IBD. Therapeutic drug monitoring has been shown to be advantageous for patient care in IBD patients losing response. Here we describe the analytical validation of the HMSA for GLM and antibodies to GLM (ATG) and its clinical utility.

Methods The HMSA for GLM and ATG was performed as previously described. For the ATG assay, standard curves were created by incubating normal human serum containing known amounts of rabbit ATG with fluorescently labeled GLM; bound and free GLM were then separated by SE-HPLC [size-exclusion highperformance liquid chromatography]. Internal standards and controls were included to ensure accuracy and precision. Validation was performed according to industry recommendations. Eighty-eight serum samples from IBD patients receiving GLM therapy were used to evaluate clinical utility. Serial serum samples were drawn prior to drug therapy and concentrations of GLM and ATG measured by HMSA.

Results Method validation was performed for both GLM and ATG. Sensitivity for GLM was 1.0 mcg/mL and for ATG was 3.13 U/mL in undiluted serum. The upper limit of quantitation was determined to be 30 mcg/mL for GLM and 75 U/mL for ATG. The standard curves generated for each assay showed high reproducibility, dynamic range, and sensitivity. Inter- and intra-assay precision showed less than 10% CV for both the GLM and ATG assays and accuracy was within 20%. Drug tolerance in the ATG assay was >20 mcg/mL of GLM. The reference range (mean +2 SD) was determined to be 0.60 mcg/mL using serum from 40 healthy human controls. The median concentration of GLM in the 88 IBD patient samples was 15.01 mcg/mL and was significantly higher than in healthy controls (P<0.0001). Patients with â&#x2030;Ľ8 mcg/mL GLM had significantly lower CRP than those with <8 mcg/mL (3.9 vs 18.1 mg/L, P<0.0001).

Conclusions This study describes the validation of an HMSA for GLM and ATG. These assays showed high accuracy and precision across a wide dynamic range. The HMSA platform allowed detection of antidrug antibodies even in the presence of interfering agents, which are known to limit the utility of ELISA methods. The development of the HMSA platform represents an improvement in anti-TNFÎą monitoring assays and may help guide treatment decisions for patients who lose response to therapy.

Discussion The research highlighted in this report may help guide the diagnosis and management of IBD. The use of assays that can measure serologic, genetic, and inflammatory markers enables clinicians to identify patients with more aggressive IBD phenotypes, thus helping inform patient treatment decisions.15 For patients with more difficult-to-diagnose disease presentations, such as colonic IBD, these multibiomarker diagnostic panels may provide improved accuracy, leading to disease reclassification in some patients.16 Moreover, anti-flagellin biomarkers

may appear earlier in the progression of CD than ASCA, thus offering clinicians information about disease phenotype due to their high immunogenic profile.17 These abstracts also provide important findings about the use of HMSAs to monitor biologic therapy. In patients receiving IFX therapy, measuring IFX and ATI levels may affect therapeutic decisions, particularly in patients experiencing loss of response.18 These assays may also show that immunogenicity caused by ATI is the cause of inadequate or lost responses

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in patients receiving IFX therapy.19 These diagnostic tests offer improvements over ECLIA and ELISA regarding their sensitivity, precision, and accuracy for serum drug and drug antibody levels.20,21 Rubin and colleagues used HMSAs to assess ADA and ATA levels in patients with IBD.22 Higher ADA levels were observed in patients with undetectable ATA levels, and ATA was associated with relapse or loss of response; patients receiving weekly ADA were more likely to have ATA than those receiving biweekly doses. Of particular interest, the investigators reported that patients who previously received IFX and developed detectable ATI were more likely to develop ATA following ADA therapy. Taken together, these abstracts help advance the clinical landscape for patients with IBD, aggressive subtypes, and those receiving biologic therapy for disease management. The use of multibiomarker panels and HMSAs has enabled these improvements in the care of patients with IBD.

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Wolf DS, Bincy BP, Afzali A, et al. Community perspectives: combining serology, genetics, and inflammation markers for the diagnosis of IBD and differentiation between CD and UC. Gastroenterol Hepatol. 2012;8(6 suppl 2):S1-S16.

Scherl EJ, Seidman EG, Wolf DC. Emerging prognostic markers in IBD. Gastroenterol Hepatol. 2007;3(12 suppl 36):S1-S11.

Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. 2007;133(5):1670-1689.

Sauer CG, Kugathasan S. Pediatric inflammatory bowel disease: highlighting pediatric differences in IBD. Gastroenterol Clin North Am. 2009;38(4):611-628.

Kuna AT. Serological markers of inflammatory bowel disease. Biochem Med. 2013;23(1):28-42.

Lees CW, Satsangi J. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol. 2009;3(5):513-534.

Plevy S, Silverberg MS, Lockton S, et al. Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn’s disease, and ulcerative colitis patients. Inflamm Bowel Dis. 2013; 19(6):1139-1148.

Yanai H, Hanauer SB. Assessing response to biological therapies in IBD. Am J Gastroenterol. 2011;106(4):685-698.

Hanauer SB, Feagan BG, Lichtenstein GR, et al; the ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet. 2002;359(9317):1541-1549.

10. Wang SL, Hauensten S, Ohmund L, et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by homogenous mobility shift assay. J Pharm Biomed Anal. 2013;78-79:39-44. 11. Molnár T, Farkas K, Nyári T, et al. Frequency and predictors of loss of response to infliximab or adalimumab in Chron’s disease after one-year treatment period—a single center experience. J Gastrointestin Liver Dis. 2012;21(3):265-269.

12. Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91(4):635-646. 13. Wang SL, Ohrmund L, Hauenstein S, et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods. 2012;382(1-2):177-188. 14. Plevy S, Lockton S, Princen F, et al. Clinical research highlights in IBD: diagnosis and anti-tumor necrosis factor monitoring. Gastroenterol Hepatol. 2013;9(8 suppl 4):S1-S16. 15. Princen F, Lockton S, Stachelski J, et al. Combined serological IBD markers correlate with high inflammatory burden in a large cohort of patients presenting IBD-like gastrointestinal symptoms. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 16. Princen F, Lockton S, Stachelski J, et al. A unique serological marker signature can help to identify difficult to diagnose colonic inflammatory bowel disease. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 17. Princen F, Lockton S, Stachelski J, et al. Anti-flagellin serological markers are earlier markers of Crohn’s disease progression than ASCA serological markers. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 18. McTigue M, Sandborn W, Levesque B, et al. Infliximab therapeutic drug monitoring in clinical practice: indications and utility. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 19. McTigue M, Sandborn W, Levesque B, et al. Clinical utility of next generation infliximab and antibodies to infliximab assay. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 20. Egea-Pujol L, Reddy R, Patel S, et al. Homogeneous mobility shift assay (HMSA) overcomes the limitations of ELISA and ECLIA assays for monitoring infliximab (IFX), adalimumab (ADA) and associated anti-drug antibodies in serum. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 21. Salbato J, Parnell J, Reddy R, et al. Validation of a homogeneous mobility shift assay (HMSA) for the measurement of golimumab (GLM) and antibodies-to-golimumab (ATG) in inflammatory bowel disease (IBD) patient serum. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA. 22. Rubin DT, Hausenstein S, Singh S. Post-marketing review of serum adalimumab and antibodies to adalimumab using the mobility shift assay platform. Presented at: 2013 American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013; San Diego, CA.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Prometheus Laboratories Inc., 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. 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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Disclosures: Dr. Rubin reported that he serves as a consultant for AbbVie Pharmaceuticals, Bristol-Myers Squibb, Elan Pharmaceuticals, Emmi Solutions, Given Imaging, Ironwood Pharmaceuticals, Lifecore Biomedical, LLC, Prometheus Laboratories Inc., Santarus, UCB Pharma, Telsar Pharmaceuticals, and Vertex Pharmaceuticals. He also has received grant support from AbbVie Pharmaceuticals, Elan Pharmaceuticals, Prometheus Laboratories Inc., and Warner Chilcott.