The June 2012 Digital Edition of Gastroenterology and Endoscopy News

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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 6 • June 2012

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40th AN N IVER SARY

Patients Prefer Colonoscopy

GI Quality Improvement Consortium Catching on Across the Country

By David Wild

Program a Win-Win-Win for Physicians, Patients, Payers

San Diego—Patients undergoing screening for colorectal cancer (CRC) experience less pain and have less anxiety with colonoscopy compared with patients undergoing computed tomographic colonography (CTC) screening, according to findings from a prospective questionnairebased study presented at the 2012 Digestive Disease see Colonoscopy, page 14

Fly and Flare Air Travel Linked to IBD Flares

By David Wild San Diego—Fly and flare. This was the link discovered by Swiss researchers who found that patients with inflammatory bowel disease (IBD) who embarked on high-altitude flights or journeys had higher relapse rates than those who stayed closer to the ground. see Flares, page 15

By Monica J. Smith In an effort to facilitate the pursuit of quality in the evolving context of American health care, the American College of Gastroenterology (ACG) and the American Society for Gastrointestinal Endo­ scopy (ASGE) launched the GI Quality Improvement Consortium (GIQuIC), a database of quality measures in endoscopy that will allow participants to measure themselves against national benchmarks, satisfy demands for transparency, and possibly reap some financial rewards.

“I think there is more and more emphasis from payers and CMS [the Centers for Medicare & Medicaid Services] for us to document that we are complying with quality measures,” said Karen L. Woods, MD, a gastroenterologist in Houston. “This is see GIQuIC, page 24

I N S I D E

Physician Rallies Colleagues To Help Shape Future of Health Care Reform

EXPERT ROUNDTABLE The Use of JCV Antibody Assay in Treating Patients With Crohn’s Disease ������������������ page 11

By Kate O’Rourke Houston—In the next five to 10 years, health care will change dramatically, and if physicians don’t lead the process of health care reform, the politicians will, Robert Pearl, MD, told physicians at the recent annual meeting of the Society of Critical Care Medicine. The prospect of politicians leading the way will not bode well

Stephen B. Hanauer, MD

Uma Mahadevan, MD

David T. Rubin, MD

see Health Care, page 38 PRODUCT ANNOUNCEMENT see page 53 for product information

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Gastroenterology & Endoscopy News • JUNE 2012

Vol. 63, No. 6 Medical Advisory Board Manoop S. Bhutani, MD

Gary R. Lichtenstein, MD

Alan F. Cutler, MD

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Houston, Texas

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Elizabeth City, North Carolina

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Christopher Jolley, MD Gainesville, Florida

Myron Lewis, MD Memphis, Tennessee

Philadelphia, Pennsylvania

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Joel E. Richter, MD

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Gastroenterology & Endoscopy News • JUNE 2012

From the Literature

ACP Guidance Recommends Screening Blacks for Colon Cancer at Younger Age

By Monica J. Smith A recently published guidance statement on colon cancer screening compiled by the American College of Physicians (ACP) differs little from the guidelines with which gastroenterologists are all familiar, with one notable exception: a lower age at first screening for blacks than previously had been recommended by multisociety or individual guidelines (Qaseem A et al. Ann Intern Med 2012;156:378-386).

“It kind of caught me by surprise, and I’m encouraged that another society has agreed, after reviewing the evidence, that African Americans should be screened earlier than age 50,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, Norfolk. “But basically their recommendations ran parallel with those established by the U.S. Preventative Services Task Force [USPSTF].”

Based on the premise that it is more helpful to physicians to provide a thorough review of existing guidelines than to create new ones when multiple or conflicting guidelines exist, the ACP identified and analyzed four current guidelines: a joint guideline compiled by the American Cancer Society, the U.S. MultiSociety Task Force on Colorectal

Cancer and the American College of Radiology (ACS/USMSTF/ACR) as well as individual guidelines developed by the USPSTF, the ACR and the Institute for Clinical Systems Improvement.

After reviewing and assessing each guideline, the ACP suggested screening for average-risk adults beginning at age 50, and for highrisk adults beginning at age 40, or 10 years younger than the age at which the youngest relative with colorectal cancer was diagnosed. The guidance statement includes blacks in the high-risk category, noting that “African Americans have the highest incidence of colorectal cancer compared with other races.”

Follow-up screening is recommended at 10 years for optical colonoscopy and five years for stool-based screening tests and flexible sigmoidoscopy, and every five years for people at high risk for colorectal cancer. Optical colonoscopy is recommended in patients with a positive finding after a noncolonoscopic screening test. The ACP also recommends physicians cease screening adults older than age 75 and those not expected to live 10 years more.

Dr. Johnson, who co-authored the ACS/USMSTF/ACR joint guideline (Levin B et al. Gastroenterology 2008;134:1570-1595), as well as the 2009 American College of

Gastroenterology guideline (which recommends screening for averagerisk blacks beginning at age 45; Rex DK et al. Am J Gastroenterol 2009;104:739-750), has long been in favor of lowering the age to begin screening in blacks.

“There is a lower mean age of cancer onset, a higher incidence rate at any age in African Americans and the disease tends to be more aggressive,” he said. “The age 40 is somewhat curious to me, but that’s not to say it’s wrong; clearly, earlier than 50 is better.”

Also of note in the ACP guidance are the recommended screening

modalities. The society advised use of stool-based testing, flexible sigmoidoscopy or optical colonoscopy in average-risk patients, and optical colonoscopy in high-risk patients.

Fecal DNA tests and computed tomographic colonography (CTC) were left off the list.

“They did not condone CTC or fecal DNA tests as an option,” Dr. Johnson said. Although the ACP statement noted that CTC is an option included in some guidelines, the USPSTF had not found sufficient evidence to assess the potential harms or benefits of that screening modality. n

From the Literature

New Study Finds More Patients Adhere to CRC Screening When Given a Choice of Screening Methods

By Margaret W. Crane Today, most clinicians consider colonoscopy the gold standard for detecting, and often preventing, colorectal cancer (CRC). Unique among screening procedures, colonoscopy is both diagnostic and therapeutic, allowing for the immediate excision of precancerous polyps. By contrast, fecal occult blood testing (FOBT), still valued as a screening method, is purely diagnostic.

It would seem to be a no-brainer: Patients should simply follow physicians’ recommendations and get screened regularly via colonoscopy—the most thorough, most successful CRC screening method available.

At least that’s what John Inadomi, MD, and his research team thought when they launched a randomized clinical trial to compare three

different approaches by which physicians can Cyrus E. Rubin Professor of Medicine & Head at the University of Washington make screening recommenin Seattle. dation to patients, and their The researchers enrolled respective impact on adher- ‘We expected to receive nearly 1,000 patients in the ence. One group of physiconfirmation of our original trial and divided them into cians recommended FOBT; a hypothesis: that patients three groups, as outlined second group steered patients toward colonoscopy; and a would by and large do what we above. At the end of the year-long study period, the third group offered patients told them to do. But what we researchers tallied the numa choice between FOBT and bers and found that only 38% colonoscopy. Reported in the found was quite the opposite.’

April 9 issue of the Archives of —John Inadomi, MD of patients who received a recommendation of coloInternal Medicine, the findings noscopy alone completed were surprising, said Dr. Inadomi. screening compared with 67% of those who were “We expected to receive confirmation of our original hypothesis: that patients would by and advised to complete FOBT alone and 69% of large do what we told them to do. But what we those given a choice between the two procedures. see Choice, page 8 found was quite the opposite,” said Dr. Inadomi,

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Gastroenterology & Endoscopy News • JUNE 2012

From the Literature

Choice continued from page 6

“You’d think that offering a choice might cause confusion, leading patients to defer making a decision.

But as the numbers show, patients offered a choice completed CRC screening at a significantly higher rate than those who received a recommendation of colonoscopy alone,” Dr. Inadomi said.

Promoting Screening Strategies for Diverse Patient Populations

interviews were conducted in their native language followed their physicians’ recommendations at significantly higher rates than did those who preferred to speak English.

The “why” behind these differences remains to be explored by social scientists, says Dr. Pochapin. “What matters is that important differences exist, and that they have everything to do with patients’ health-care beliefs, behavior and decision-making.

“Even if we strongly favor colonoscopy as the gold standard for

Americans than any other racial or ethnic group,” noted Mark Pochapin, MD, director of the Division of Gastroenterology at New York University Langone Medical Center in New York City. “The question is, how can we encourage all of our patients to follow our recommendations—recommendations that could save lives?”

Latino and Asian patients sought screening at the highest rates of all, a result that the researchers believe has more to do with language than ethnicity. Interestingly, those whose

colorectal cancer screening, we may lose the opportunity to screen an important subset of patients if we push the procedure too strongly,” he continued. “Clearly, there is no one-size-fits-all answer. The age of personalized medicine is here.

If there are patients who will not undergo colonoscopy—and clearly, there are—we need to find ways to bring them into the fold by being aware of differences and offering alternatives.”

Lawrence Cohen, MD, professor

In the words of Sidney Winawer, MD, a pioneering gastroenterologist and author of a seminal 1993 study linking polypectomy with colorectal cancer prevention, “Any screening is better than no screening.”

Thank s.com

ndonew

gastroe Volume

‘You’d think that offering a choice might cause confusion, leading patients to defer making a decision. But as the numbers show, patients offered a choice completed CRC screening at a significantly higher rate than those who received a recommendation of colonoscopy alone.’

—John Inadomi, MD

With national CRC screening rates hovering at less than 50%, clinicians should be prepared to change the way they recommend screening in light of racial, ethnic and cultural differences among their patients—differences that were shown to affect adherence, according to the current study’s findings.

For example, nonwhite participants were far less likely to undergo colonoscopy than their white counterparts, with African Americans seeking the procedure at the lowest rates of all.

“It’s well known that colorectal cancer rates are higher among African

Questions, comments, suggestions?

Contact the Editor 212.957.5300 x277 cgordon@mcmahonmed.com

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Gastroenterology & Endoscopy News • JUNE 2012

and clinical researcher at the Mount Sinai School of Medicine, in New York City, agreed. The data on adherence, he feels, are extremely useful, especially in the context of the changing demographics of the United States. However, he said, the study focused on patients at relatively low levels of income and education. For example, only 20% of those enrolled had a college degree, with another 20% reporting that they had had “some college or technical school.”

Only 2% had an annual household income of more than $30,000, with

us boost the numbers and prevent more and more deaths from this highly preventable type of cancer.’

—Lawrence Cohen, MD

the majority subsisting well under the poverty line.

“The low socioeconomic status of the study’s participants may be a confounder that limits the extent to which we can generalize the results,”

Dr. Cohen noted. “Also, when you consider the study design with its three arms, the actual number of participants turns out to be quite low. So even though the conclusions are statistically valid, they’re valid for a small

k you for consistently making

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APRIL 2012

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REPORT

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Jack A. Di Palma, MD

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Lawrence B. Cohen, MD Russell W. Pelham, PhD

Professor of Medicine Director of Division of Gastroenterology University of South Alabama College of Medicine Mobile, Alabama

Professor of Medicine Director of Endoscopy Division of Gastroenterology and Hepatology Indiana University Hospital Indianapolis, Indiana

Associate Professor Department of Medicine Mount Sinai Medical Center New York, New York

Important Safety Information

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SUPREP ® Bowel Prep Kit is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.

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roundtable discussion among leading colorectal surgeons on the appropriate use of medical therapy for the management of hemorrhoidal disease was held on July 28, 2011 in Chicago, Illinois. The discussion resulted in a consensus that there is a need to redefine the role of medical therapy as the foundation of the management of hemorrhoidal disease. the science behind positive patient outcomes

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Glenn Parker, MD, FACS, FASCRS Chief, Division of Colon and Rectal Surgery Director, Gastrointestinal Oncology Jersey Shore University Medical Center Oakhurst, New Jersey

of mesalamine within protective, ph-dependent coatings. 2 because each dosing formulation has specific medication-release properties, multipledaily administration may be required to maintain therapeutic concentrations of mesalamine within the colon.2 however, multiple-daily dosing may affect adherence to prescribed pharmacologic regimens. this article briefly reviews the impact of nonadherence to mesalamine therapies for uc and provides practical advice for improving therapeutic compliance.

(crc)7 because of the increased inflammation associated with uc. mesalamine is thought to be chemoprotective through reduction of colon inflammation8; therefore, nonadherence to mesalamine therapy may result in an increased risk for crc. in support of this hypothesis, a metaanalysis of 9 studies demonstrated a protective association between the use of mesalamine and crc in patients with uc.9 concomitant with a reduction in flares, adherent patients have higher healthrelated quality of life10 and may be more likely than nonadherent patients to avoid the stress and worry associated with flares that may occur immediately before the weekend (so-called Friday flares). given these observations, increasing adherence to medication regimens is paramount in terms of clinical, economic, and psychological well-being.

Importance of Adherence

a significant percentage of patients with uc (ie, ≥40%) are nonadherent to their prescribed maintenance therapy3 despite evidence that nonadherence may significantly influence the clinical course of their disease. For example, after 2 years, 89% of adherent patients maintained uc remission compared with only 39% of those who were nonadherent (Figure).4 an increased occurrence of flares in nonadherent patients can translate into an increased need for hospitalization and medications such as prednisone, thereby resulting in higher medical costs.5,6 additionally, patients with uc may have a greater risk for developing colorectal cancer

Science of Adherence

Patients Remaining in Remission, %

24

Time, mo Figure. maintenance of clinical remission after 2 years in adherent and nonadherent patients with ulcerative colitis. a greater percentage of patients who were adherent to their maintenance treatment regimen (89%) remained in clinical remission than nonadherent patients (39%). Figure adapted from Kane s, huo d, aikens J, hanauer s. medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med. 2003;114(1):39-43. with permission from elsevier.

20 gastroenterology & endoscopy news • october 2011

compliance typically is greater with oral than with topical mesalamine formulations14 and negatively correlates with treatment duration (ie, compliance with treatment regimens for the induction of remission [short-treatment duration] is greater than that for maintenance therapy [long-term duration]). dosing frequency also significantly affects compliance. more frequent dosing (eg, 3 times daily) may be considered more disruptive because patients are required to take medication in the middle of the day when they are at work or school. they may feel embarrassed about taking medication outside of their home or they may forget entirely. thus, it is not surprising that patient compliance was less with 3-times-daily treatment regimens than with once- or twice-daily regimens.16,17 however, patient preference and cost13 also should be taken into account. some studies have reported no significant difference in adherence between different dosing regimens,12,14,18 and patients may prefer increased dosing frequency if it is concomitant with lower pill burden at each administration.

Disease status

Quiescence of symptoms14 longer duration of disease10,11 less-extensive disease (eg, proctitis, proctosigmoiditis)3

factors (eg, patient perception, treatment formulations, and demographic and disease characteristics) can guide health care professionals in their discussions and educational efforts with patients, with the ultimate goal of increasing clinical remission and patient well-being.

the frequency and cost of ulcerative colitis flares. patients who experience frequent flares their situation is understood but also may Aliment Pharmacol Ther. 2009;29(3):247-257. despite medication may be suspected of provide physicians with valuable insight nonadherence, but, given the relapsing regarding the patients’ disease course, 6. Kane s, shaya F. medication non-adherence is associated with increased medical health care and remitting nature of uc and the adherence, and barriers to adherence. costs. Dig Dis Sci. 2008;53(4):1020-1024. observation that patients who receive patients’ attitude toward medications, no treatment may not experience a flare their belief and support systems, and 7. eaden Ja, abrams Kr, mayberry JF. the risk of colorectal cancer in ulcerative colitis: a metafor years, flares may be a poor indicator knowledge of their disease should be analysis. Gut. 2001;48(4):526-535. of compliance. Frank questioning of explored.19 physicians also should review patients verbally or through the use the patient’s disease and therapeutic 8. lyakhovich a, gasche c. systematic review: molecular chemoprevention of colorectal maligof questionnaires may provide some history and examine the efficacy and nancy by mesalazine. Aliment Pharmacol Ther.

2010;31(2):202-209. insight into patient adherence and disruption associated with previous may act as a catalyst for discussions treatments (eg, switching from a multiple- 9. velayos Fs, terdiman Jp, walsh Jm. effect of about compliance.20 although patients daily to a once-daily medication).19 these 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalmay inflate their adherence rate and types of discussions can lead to dialogue ysis of observational studies. Am J Gastroenterol. self-reporting techniques are limited concerning treatment alternatives and 2005;100(6):1345-1353. by patients’ recollections, subjective distribution of educational materials that assessment of patients’ responses and are pertinent to the patient and, therefore, 10. lopez san román a, bermejo F, carrera e, pérezabad m, boixeda d. adherence to treatment in body language during questioning may are more likely to be remembered and inflammatory bowel disease. Rev Esp Enferm Dig. 2005;97(4):249-257. be informative. prescription refill rates followed. may provide a more definitive perspective 11. bernal i, domènech e, garcia-planella e, et al. on patient adherence, but they do not Conclusion medication-taking behavior in a cohort of patients with inflammatory bowel disease. Dig Dis Sci. accurately reflect actual medication patient adherence to mesalamine 2006;51(12):2165-2169. consumption. however, failure to refill treatment directly affects the clinical prescriptions for long periods of time likely outcome of uc, the overall health care 12. ediger Jp, walker Jr, graff l, et al. predictors of medication adherence in inflammatory bowel disease. tHe science BeHind positive patient outcoMes indicates noncompliance. pill counting cost associated with the disease, and the Am J Gastroenterol. 2007;102(7):1417-1426. and comparison with patients’ prescribed development of long-term complications. dose also is hindered by the lack of understanding the factors that contribute 13. Kane sv. systematic review: adherence issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther. definitive information, but asking patients to treatment nonadherence may help 2006;23(5):577-585. to bring in their medication and inspecting identify at-risk patients and allow the the remaining doses may be beneficial in development of appropriate strategies to 14. d’incà r, bertomoro p, mazzocco K, vettorato mg, rumiati r, sturniolo gc. risk factors for non-adherinitiating a dialogue about adherence21 target less-adherent patient populations. ence to medication in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2008;27(2):166-172. and may be seen by the patient as a gesture the physician–patient relationship of the physician’s interest and compassion. is essential to this process, and open 15. rubin dt, siegel ca, Kane sv, et al. impact of ulcermore objective measurements of patient discussions about the patient’s disease ative colitis from patients’ and physicians’ perspectives: results from the uc: normal survey. compliance include biologic assays that may provide insight into adherence Inflamm Bowel Dis. 2009;15(4):581-588. education, measure blood or urine concentrations barriers, a forum for disease the benefit to screening colonoscopy), subsequent crc mortality when used in reduction in crc incidence was significant 16. shale mJ, riley sa. studies of compliance with and evaluation of treatment options that of the medications or their metabolites.

Douglas J. Robertson, MD, MPH across the entire colon. 19 conjunction with FoBts. combined with seminal studies confirming delayed-release mesalazine therapy in patients with (eg, although effective, these tests provide may increase patient compliance wide-scale screening Pharmacol Recent RCTs16,17 of flexible sigmoidoscopy the feasibility of inflammatory bowel disease. Aliment Associate Professor of Medicine once-daily vs multiple-daily medications). time-limited adherence information Ther. 2003;18(2):191-198. colonoscopy,6,7 led to a marked increase provide clear proof of the principle that Prospective Studies of Colonoscopy (eg, adherence only within the Dartmouth previous Medical School & in use. subsequently, in 2002, the uspstF endoscopy as a primary screening strategy Some studies have reported on 17. bermejo F, lópez-san román a, algaba a, et al. FacThe Dartmouth Institute 24 hours), and their cost-effectiveness has Acknowledgment tors that modify therapy adherence in patients can reduce mortality. the most definitive individuals who received colonoscopy, changed its position, endorsing colonoscopy Chief, Section of Gastroenterology with inflammatory bowel disease. Crohns Colitis. not been ascertained. thus, identification medthink communications provided 8 as a screening option. in the united states, of 3 recent rcts compared 57,099 where cancer was not detected, but were VA Medical Center 2010;4(4):422-426. of patients who are nonadherent remains editorial assistance under the direction White River Junction, Vermont based on surveys9 and Medicare data,10 persons randomized to screening with later followed up for the development of challenging, and the principal strategy to of dr. osborn with support from salix 18. Kane s, huo d, magnanti K. a pilot feasibility endoscopy is the dominant modality for CRC sigmoidoscopy compared with 112,939 cancer over the next several years. the study of once daily versus conventional dosing 17 overcome this problem may be the use of pharmaceuticals, inc. controls. a subsequent analysis showed findings on baseline colonoscopy are an screening. mesalamine for maintenance of ulcerative colitis.

Introduction practical measures to augment adherence Clin Gastroenterol Hepatol. 2003;1(3):170-173. that screening with flexible sigmoidoscopy important predictor of the subsequent References in all patients with uc. reduced mortality from crc by 31% (hazard observed cancer risk. For those not identified Colorectal cancer (CRC) ranks as the Evidence Supporting 19. lakatos pl. prevalence, predictors, and clini1. carter mJ, lobo aJ, travis spl. guidelines for the ratio [Hr], 0.69; 95% confidence interval with adenomas at baseline colonoscopy, second most common cause of cancer death Colonoscopy’scal consequences of medical adherence in Use for Screening Practical Tips for Increasing management of inflammatory bowel disease in 1 ibd: how to improve it? World J Gastroenterol. [ci], 0.59-0.82).17 However, the benefit was subsequent risk for crc is very low. For in the united states. in fact, the lifetime adults. Gut. 2004;53(suppl 5):v1-v16.

2009;15(34):4234-4239.

Adherence Improving Survival Curves risk is approximately 6% in average-risk confined to the left colon, where cancer example, imperiale performed colonoscopy 2. lichtenstein gr, Kamm ma. review article: a strong physician–patient relationship 20. hommel Ka, davis cm, baldassano rn. objective individuals.1 From the screening standpoint, Regular CRC screening is vital in preventing incidence was reduced by 46% (Hr, 0.64; on 1,256 average-risk individuals and a 5-aminosalicylate formulations for the treatment is paramount for ensuring proper disease versus subjective assessment of oral medication of ulcerative colitis—methods of comparing second exam approximately 5 years later early identification of crc is crucial, as crc.11 Recent trends in CRC incidence 95% ci, 0.57-0.72).17 adherence in pediatric inflammatory bowel disease. management and medication adherence. release rates and delivery of 5-aminosalicylate 2 2 in which no cancers were found.20 in survival is directly related to stage of disease. and mortality rates Inflammare Bowelencouraging.

Dis. 2009;15(4):589-593. to the colonic mucosa. Aliment Pharmacol Ther. discord with the physician22 or feeling 2008;28(6):663-673.

Screening also leads to the identification For example, from 1997 to 2006, the crc Case-Control Studies of Colonoscopy contrast, the crc risk observed in a higher- 21. tindall wn, boltri Jm, wilhelm sm. mild-touneducated about the disease17 correlate and removal of a cancer precursor—the mortality rate dropped in the united states A number of studies have directly risk entirely adenoma-bearing population moderate ulcerative colitis: your role in patient with nonadherence. patients often feel 3. Kane sv, cohen rd, aikens Je, hanauer sb. prevalence compliance and health care costs. J Manag Carecolonoscopy as a tool to reduce of nonadherence with maintenance mesalamine colorectal adenoma. currently, colonoscopy annually on an average of approximately evaluated with close colonoscopic follow-up is that the disease disrupts their daily life, Pharm. 2007;13(7 suppl a):s2-s12; quiz s13-s14. in quiescent ulcerative colitis. Am J Gastroenterol. is recommended by some as the preferred 3%.2 the downward trajectory of these the burden of crc. two large case– significantly greater. in one pooled cohort 2001;96(10):2929-2933. although their physicians may not agree. sewitch mJ, abrahamowicz m, barkun a, et al. screening method for CRC prevention in curves predate22. the “colonoscopy boom” control studies found that exposure to of 9,167 adenoma-bearing patients who they also may feel that their physicians 4. Kane s, huo d, aikens J, hanauer s. medication nonpatient nonadherence to medication in inflam3 the united 2001. therefore, colonoscopy is associated with reduced were followed for approximately 4 years, 58 Colonoscopy plays that occurred around 15 adherence and the outcomes of patients with quiesdo not fully appreciate their situation.

To states. matory bowel disease. Am J Gastroenterol. colonoscopy as a2003;98(7):1535-1544. primary screening tool crc incidence and mortality.18,19 The first cancers were observed.21 vital role in CRC prevention and Jearly cent ulcerative colitis. Am Med. 2003;114(1):39-43. overcome these perceptions, a physicians disease detection, as well as reduction in cannot account entirely for the improvement. study used administrative data comparing Perhaps the most representative study should actively listen to patients talk about 5. higgins pd, rubin dt, Kaulback K, schoenfield crc mortality rates. although there are However, given that colonoscopy is the final 10,292 cases of crc death with controls.18 of the benefit of screening colonoscopy ps, Kane sv. systematic review: impact of nontheir disease and ask questions accordingly. other less-invasiveadherence to 5-aminosalicylic acid products on or noninvasive options common pathway when other screening overall, previous exposure to colonoscopy was performed by Kahi and colleagues,22 this not only may make patients feel that available, colonoscopy remains the final tests are positive for disease, its use certainly was associated with a 31% reduced risk in which 715 individuals underwent a pathway when other methods test positive. contributes to the recent gains. for crc mortality (odds ratio [or], 0.69; baseline screening colonoscopy and were This article summarizes some of the current 95% ci, 0.63-0.74).18 The study revealed an subsequently followed up to determine gastroenterology & endoscopy news • october 2011 21 finding—the risk reduction long-term outcome. in this “mixed Extension of FOBT and evidence supporting the use of colonoscopy unexpected in CRC screening and considers challenges Sigmoidoscopy Trials was limited to the left colon (or, 0.33; population” (some patients with adenomas for the technology going forward.

Although there are no randomized 95% ci, 0.28-0.39) with no benefit on the at baseline and some without), 7 cancers controlled trials (RCTs) of colonoscopy right (or, 0.99; 95% ci, 0.86-1.14).18 it is were identified after baseline. the observed CRC Screening Guidelines and completed to date, there are definitive rcts possible that colonoscopy detects left- cancer rate was then compared with the of CRC screening that indirectly support sided neoplasia better than right-sided expected cancer rate using data from Colonoscopy colonoscopy’s effectiveness as a screening neoplasia for reasons such as the biology of surveillance, epidemiology and end results National guidelines for cancer care and tool. three large rcts of FoBt12-14 suggest the right-sided tumor, colonic preparation cancer registry.22 screening colonoscopy was prevention communicate clinical information screening can reduce colorectal mortality of the patient, and technician’s skill level. associated with a significant reduction in to facilitate the decision-making processes in the range of 15% to 33% (table 1). Finally, a more recently published case– crc incidence (standardized incidence ratio, of physicians, patients, and other individuals although designs across these trials varied, control study (1,688 cases per 1,932 0.33; 95% ci, 0.10-0.62) and a near-significant involved in health care. in 1980, the american a positive FoBt required a colonoscopy to controls) drawn from a german screening reduction in mortality (standardized Cancer Society (ACS) recommended digital locate the source of blood in each study. if colonoscopy program, found a 77% mortality ratio, 0.35; 95% ci, 0.0-1.06).22 rectal exam, proctoscopy, and fecal occult an FoBt is positive, repeating the test or reduction in crc incidence (or, 0.23; 95% blood testing (FoBt) for screening.4 Since using other follow-up tests are inadequate; ci, 0.19-0.27).19 Although there remained The Future of Colonoscopy then, however, recommendations have consequently, a colonoscopy always is a gradient between effectiveness in the Colonoscopy remains the definitive changed substantially reflecting both required as a follow-up method.15 thus, left colon (or, 0.16; 95% ci, 0.12-0.20) and approach when other screening modalities technologic developments and evidence colonoscopy has had a role in reducing right colon (or, 0.44; 95% ci, 0.35-0.55), are positive and therefore will have a key supporting various screening modalities. in 1996, the united states preventive services task Force (uspstF) did not recommend Table 1. Large Randomized Controlled Trials of CRC Screening colonoscopy as a screening test for CRC due to lack of supporting evidence. instead, Intervention, N/ CRC Deaths Intervention/ the uspstF recommended annual FoBt, Study Intervention Control, N CRC Deaths Control RR CRC Mortality (95% CI) periodic sigmoidoscopy, or a combination Mandel et al (1993)14 FoBt 15,534/15,364 82/121 0.67 (0.50-0.87) of both. However, shortly after, a guideline

Chief, Division of Colon and Rectal Surgery Patient Perception Director, Gastrointestinal Oncology Jersey Shore University Medical Center Oakhurst, New Jersey

Adherent (n=40)

25

12

Medication Formulation and Dosing

Glenn Parker, MD, FACS, FASCRS

Nonadherent (n=59)

0

Treatment-specific

rectal therapy14 multiple-daily dosing3,11 prescription drug costs13

multiple factors contribute to how well patients adhere to their medication regimen (table).3,10-14 insight into these

Colorectal Surgeon 100 North Shore University Hospital Manhasset, New York 75

0

Demographic male sex3 unmarried status3 Full-time employment3,11,12 large number of concomitant medications3

Colorectal Surgeon Colorectal Surgical Associates Houston, Texas

Sanjay Jobanputra, MD, FACS

50

Table. Factors contributing to nonadherence with mesalamine treatments

Anne Le, MD

patients’ perception of the incapacitating nature of their disease, their expectations of treatment, and the perceived inconvenience of their treatment regimen all affect medication compliance. in an internet survey conducted among us patients with uc (55% of whom were receiving mesalamine to treat the disease), 95% reported that their uc was disrupting their lives, but they believed that flares were normal (74%) and that feeling ill (73%) and making numerous bathroom visits (84%) were to be expected.15 thus, patients may not see the benefit of complying with medications that do not relieve all of their disruptive symptoms. indeed, patients with inflammatory bowel disease in the united Kingdom who were receiving mesalamine and perceived their medication to be ineffective were significantly more likely than their peers to be noncompliant.16 this may be especially true when patients perceive their dosing regimen to be challenging. in the internet survey mentioned previously, 49% of patients reported that managing their medication was difficult and 46% admitted that they were less than fully compliant with the prescribed treatment.15

Demographic and Disease Characteristics

on the basis of data from questionnaires addressing medication-taking behavior, specific patient populations or characteristics may be associated with a greater risk for noncompliance (table). young age,12,14,16 male sex,3 unmarried status, 3 full-time employment, 12,14,16 disagreeable temperament, 12 multiple concomitant medications, 3,16 and advanced education16 were associated with noncompliance. additionally, nonadherence was greater in patients with inactive disease,14 those without a history of complex disease (ie, steroid dependency, steroid refractoriness, intestinal resection, infliximab requirement, or uc-related hospitalization),11 and patients with leftsided uc.3 these demographic and clinical characteristics may aid in the identification of patients who are at increased risk for nonadherence and thus help focus interventional and educational efforts accordingly.

Supported by

Identification of Patients at Risk for Poor Adherence Practical Tips for Assessment assessing medication compliance in clinical practice can be difficult, and no gold standard for doing so exists.19

Gary Siemons, MD, FACS, FASCRS

Colorectal Surgeon Virtua Health System Centennial Surgical Center Voorhees, New Jersey

Supported by

Evidence and Use of Colonoscopy For Colorectal Cancer Screening

Hardcastle et al (1996)13

FoBt

75,253/74,998

360/420

0.85 (0.74-0.98)

Kronborg et al (1996)12

FoBt

30,967/30,966

205/249

0.82 (0.68-0.99)

atkin (2010)17

Sigmoidoscopy

57,099/112,939

189/538

0.69 (0.59-0.82)

segnan (2011)16

Sigmoidoscopy

17,148/17,144

65/83

0.78 (0.56-1.08)

CI, confidence interval; CRC, colorectal cancer; FOBT, fecal occult blood test; RR, relative risk Based on references 12-14 and 16-17.

16 gastroenterology & endoscopy news • MarcH 2012

Table 2. Large Randomized Controlled Trials of Colonoscopy in Process or Planning role in any screening program. the biggest challenge for future practice is refining colonoscopy performance so that it is consistent in effectively detecting neoplasia.

Recent studies have demonstrated some decreased effectiveness in cancer prevention in the right colon,18,23 likely related to both biologic and technologic factors. Biologically speaking, some right-sided crcs appear to have different genetic signatures and some may be the end result of flat, serrated lesions that are more endoscopically “missable” than their conventional polypoid counterparts.

Heightened attention to both detecting and effectively removing these potentially fastgrowing lesions may improve colonoscopy performance.

From the technology standpoint, incomplete colonoscopy contributes to the occasional right-sided failure of the test. evidence dictates that endoscopists with higher colonoscopy completion rates have lower rates of missed cancer.24 Careful examination of the mucosa by the endoscopist also is critically important. endoscopists with high adenoma detection rates outperform those with low detection rates in preventing cases of missed crc.25 similarly, neoplasia detection is clearly linked to adequate colonic preparation. decreasing the interval between the last dose of colonic prep and colonoscopy improves preparation quality.26 in one trial, the efficacy of split- and standarddose regimens was compared. the splitdose regimen consisted of polyethylene glycol electrolyte (peg-e) with no dietary restrictions while the standard dose required whole-dose peg-e with a liquid diet the day before the colonoscopy.a results showed that split-dose preparations were superior to standard dosing.27 therefore, endoscopists should consider split-dose regimens as a means of improving performance of colonoscopy in crc prevention.

Less-Invasive Options Although colonoscopy is the dominant primary screening strategy in the united states, recent acs/multisociety guidelines28 recommend a panel of tests that include less-invasive options. although stool testing with conventional FoBt has declined in the united states over the past decade,9 the fecal immunochemical test (Fit) has brought new interest into this approach. unlike conventional FoBt, Fit specifically tests for human hemoglobin in the stool and dietary restriction before testing is not required.

Because some Fits are quantitative, test characteristics can be titrated to maximize performance. although Fits must be conducted regularly to be effective,15 there is good evidence of improved compliance with screening by Fit compared with a

Trial

NCT Trials Registration No.

Proposed N

Control

nordicc30

00883792

Average-risk adults scandinavia, the (aged 55-64) netherlands, poland

66,000 (colonoscopy vs control in 1:2 ratio)

Standard care

ColonPrev31

00906997

Average-risk adults Spain (aged 50-69)

55,498 (colonoscopy vs Fit in 1:1 ratio)

Biennial iFoBt

va csp #57732

01239082

us veterans (aged 50-75)

50,000 (colonoscopy vs Fit in 1:1 ratio)

annual iFoBt

Participants

Setting

us veterans hospitals

FIT, fecal immunochemical test; iFOBT, immunochemical fecal occult blood test; NCT, National Clinical Trial Based on references 30-32.

FoBt.29 Of the 3 large RCTs presently under way to assess colonoscopy (table 2),30-32 2 directly compare Fit-based strategies with colonoscopy. when Fit results are positive for hidden blood, a colonoscopy is still needed for further analysis.15 Computed tomography colonography is another available noninvasive approach recommended by current guidelines. largescale studies in screening populations suggest that the test performs well particularly when identifying large-sized neoplasia.33 However, potential limitations of the technology include operator variability, extracolonic findings, and radiation exposure. additionally, if polyps or other suspect areas are discovered, a colonoscopy is required for further investigation.15 Efforts continually are being made to improve lessinvasive screening strategies.

Conclusion colonoscopy is widely recommended and utilized as a primary screening modality and is the definitive study when other screening methods are positive. colonoscopy screening frequently detects crc at an early stage, when it is still treatable and can prevent crc through polypectomy. there is substantial evidence demonstrating that colonoscopy as a primary screening tool significantly reduces crc incidence as well as crc mortality. definitive long-term trials will determine the magnitude of that benefit relative to other approaches.

Note: the contents of this work do not necessarily represent the views of the department of veterans affairs or the us government.

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32. us national institutes of Health. Colonoscopy versus fecal immunochemical testing in reducing mortality from colorectal cancer. http://www.clinicaltrial.gov/ ct2/show/nct01239082?term=01239082&rank=1. accessed January 2, 2012.

20. imperiale tF, glowinski ea, lin-cooper c, larkin gn, rogge Jd, ransohoff dF. Five-year risk of colorectal neoplasia after negative screening colonoscopy.

N Engl J Med. 2008;359(12):1218-1224.

33. Johnson cd, chen MH, toledano ay, et al.

Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med. 2008;359(12):1207-1217.

gastroenterology & endoscopy news • MarcH 2012 17

not Fda-approved for split dosing.

GI FELLOW

21. robertson dJ, lieberman da, winawer sJ, et al. interval cancer after total colonoscopy: results from a pooled analysis of eight studies. Gastroenterology.

2008;134(4):a111-a112.

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GI Tract Examiner A diagnostic publication for gastroenterologists and radiologists

Technology Advances Improve Accuracy of Diagnosis

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hen current gastroenterology fellows at major teaching hospitals complete their training in the management of esophageal disorders, they will be the first graduates able to incorporate several previously experimental forms of technology into routine clinical practice.

One of the advantages that fellows see from gaining experience and familiarity with emerging advanced technology is that better tools help frame a more logical series of diagnostic studies.

“I think gastroenterology is a specialty that attracts individuals who like technology and gadgets, but the new tools are permitting a better understanding of how acid and motility issues are contributing to symptoms, and this is why they are being adopted relatively rapidly,” said Anish Sheth, MD, PhD, former Director, Gastrointestinal Motility Program at Yale University School of Medicine, now a practicing gastroenterologist at Princeton Medical Group in New Jersey.

As the ongoing transition in areas such as pH monitoring and manometry gains momentum, the question at many teaching

hospitals is whether the older technology should be included in the teaching curriculum. Teaching institutions have taken various approaches to the implementation of new technology.

“At this point, we continue to teach standard manometry. Not all centers have been equipped with high-resolution devices, so fellows need to learn both,” said Satish S.C. Rao, MD, Chief, Section of Gastroenterology and Hepatology, Director, Digestive Health Center at Georgia Health Sciences University in Augusta.

“It can be argued that the old technology encourages the pattern recognition useful in understanding esophageal muscle function.” However, Dr. Rao admitted that because of the multiple advantages of high-resolution manometry, “it will not be long before the old technology will be completely forgotten.”Volume In other words, 1 • Issue 1 a transition seems to be under way. www.gitractexaminer.com At Yale, fellows are not routinely instructed about standard manometry. As the superior diagnostic tool,1 high-resolution manometry is considered the emerging standard so that training on

Brian Lacy, PhD, MD Director, GI Motility Laboratory Dartmouth Medical School Lebanon, New Hampshire

Most otherwise healthy individuals experience occasional episodes of heartburn. This makes an accurate diagnosis of gastroesophageal reflux (GER) difficult as it depends, in part, on the relative frequency and severity of symptoms. Defined as at least weekly episodes of moderate to severe symptoms that also may include regurgitation, up to 20% of US adults have gastroesophageal reflux Brought to you from the publishers of

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disease (GERD) on an empirical basis1; however, the termext empirical Uga quae ommoldeserves emphasis. Heartburn is a nonspecific complaint that can oreped molupis mi, corebe variably interpreted by patients to refer to an array of pro symptoms qui corepel lacerum emanating from different areas of the gastrointestinal (GI) tract, and quo et volque lautate eum volorio as such, may not always correlate with underlying GER. The potenorum voluptatiamupaque qui beriae. tial for alternative diagnoses, even when symptoms are relatively Et magnimus, inienia estrum sunt characteristic, is well represented by a patient assunt. recently referred to our unit for anti-reflux surgery.

The Case A 27-year-old non-obese man in good health presents to the GI Motility Laboratory at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, for evaluation of his unrelieved heartburn.

The patient has been experiencing heartburn for the past 5 years.

See CASE STUDY, page 2

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Id quassuntur, suntesti conecep udipidest hario ium alit apientempe volupta sa idem sunda voloreh enditiam, quo exceata tusandunte laccus, volessimus as inci dolori sinturibus id ut aspel ipiendigni optatem et ea cus voluptis molor rercius sectum il idistiam aceatur aut aut am volo tem alignim natquam facerumquis quia dolescieni aute pos est oditatur am, alit aut harcima volumquam, cum qui conseque es maios adit laborum acillab incto dipisquat. see Jump, page 7

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ulcerative colitis (uc) is a chronic inflammatory bowel disease of the colon characterized by exacerbation and remission of core symptoms, including bloody diarrhea, abdominal pain, urgency, and tenesmus.1 pharmacologic treatment is necessary to induce remission, and protracted therapy often is required to maintain remission. First-line therapeutic options for induction of remission in patients with mild to moderate uc include 5-aminosalicyclic acid (5-asa) and steroids, whereas various oral and topical formulations of 5-asa (ie, ph-dependent mesalamine, balsalazide, sulfasalazine, and olsalazine) generally are prescribed for the long-term maintenance of remission.1,2 differences among these formulations revolve around the mechanisms that prevent absorption of 5-asa within the small intestine.2 these include attachment of the parent 5-asa molecule to protective moieties (eg, sulfapyridine or benzoic acid derivatives) or encapsulation

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Most current treatment algorithms present hemorrhoid management in a linear fashion, starting with medical therapy and progressing to office or surgical procedures depending on the type and severity of symptomatic hemorrhoids. This approach gives the impression that medical therapy is reserved only as an initial therapy for mild hemorrhoidal disease.

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Most current treatment algorithms present hemorrhoid management in a linear fashion, starting with medical therapy and progressing to office or surgical procedures depending on the type and severity of symptomatic hemorrhoids. This approach gives the impression that medical therapy is reserved only as an initial therapy for mild hemorrhoidal disease.

However, as Glenn Parker, MD, chief of the Division

roundtable discussion among leading colorectal surgeons on the appropriate use of medical therapy for the management of hemorrhoidal disease was held on July 28, 2011 in Chicago, Illinois. The discussion resulted in a consensus that there is a need to redefine the role of medical therapy as the foundation of the management of hemorrhoidal disease.

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Financial Disclosures Jack Di Palma, MD: Braintree Laboratories, Centocor Ortho Biotech, Takeda Pharmaceuticals NA (lecture honoraria); Braintree Laboratories (consultant directorship); Bovie Medical Corporation (technical advisor); Braintree Laboratories, Takeda Pharmaceuticals NA (research support).

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The good news, he said, is that the larger issue of adherence is ripe for future research through larger, multicenter studies.

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‘Adding our patients’ preferences into the equation should help

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Gastroenterology & Endoscopy News • JUNE 2012

11

The Use of JCV Antibody Assay in Treating Patients With Crohn’s Disease How the Test Will Influence Treatment With Natalizumab Stephen B. Hanauer, MD

Uma Mahadevan, MD

David T. Rubin, MD

Professor of Medicine and Clinical Pharmacology Chief, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medical Center Chicago, Illinois

Associate Professor of Medicine Center for Colitis and Crohn’s Disease University of San Francisco San Francisco, California

Associate Professor of Medicine Co-director, Inflammatory Bowel Disease Center University of Chicago Medical Center Chicago, Illinois

William J. Sandborn, MD

Corey A. Siegel, MD, MS

Professor of Clinical Medicine Chief, Division of Gastroenterology Director, Inflammatory Bowel Disease Center University of California, San Diego School of Medicine La Jolla, California

Section of Gastroenterology and Hepatology Director, Inflammatory Bowel Disease Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Compiled and written by Monica J. Smith

I

n early clinical trials, natalizumab showed promise for the treatment of Crohn’s disease (CD).

Patients did well on the drug and did not lose response over time. Researchers soon learned, however, that long-term use of the drug resulted in a cumulative increased risk for reactivation of

the JC polyoma virus (JCV), which causes the fatal brain infection progressive multifocal leukoen-

cephalopathy (PML) in people who are immunosuppressed.

The risk for developing PML was thought to be about one in 1,000, but the knowledge that only about half of the population has antibodies for JCV altered that understanding: People who are JCV antibody–negative have very low risk, possibly zero risk, for developing PML, whereas those who have antibodies for the virus have a risk profile closer to one in 500, and this risk increases with longterm exposure to natalizumab. With this knowledge, the drug’s manufacturer developed a clinical assay to detect JCV antibodies. The assay became available mid-2011. In January 2012, the FDA approved revision of natalizumab’s label to reflect the availability of the assay. Gastroenterology & Endoscopy News asked experts in CD what their take was on treatment with natalizumab, now that an assay for JCV is available.

GEN: How has the availability of JCV antibody assay influenced your use of natalizumab in patients with Crohn’s?

Dr. Rubin: I have been an avid user of natalizumab for some time, prior to the availability of the assay, because our patients need therapeutic options when other

mechanisms of control don’t work. The availability of the assay has given me a tool to help patients understand their overall risks, but it hasn’t changed my decision regarding who is eligible for this therapy or when I offer it.

Dr. Hanauer: The availability of the JCV antibody assay has influenced our use of natalizumab in CD in two ways. First, patients are much more likely

to accept natalizumab as a treatment if they are negative for the antibody. The correlated problem is that when patients who are already on natalizumab therapy test positive for the virus, they are much more likely to want to discontinue treatment.

Dr. Siegel: The data that we’ve seen regarding the assay are very helpful, and certainly have changed the way that I’m going to use natalizumab. Very specifically, before starting treatment I will get a test and use that to guide my management decision on whether or not to use natalizumab. I am now testing all of my patients already taking natalizumab to determine if it is safe for them to continue.

Dr. Mahadevan: [The assay] has had a strong impact in two ways, affecting both use and discontinuation of the drug. We now consider natalizumab for a much wider range of patients because we can test for the antibody; if they are antibody-negative, we feel more comfortable going down that pathway. But if patients are positive, we are much more hesitant to start them on it. If they had been in remission, doing well and it has been more than a year, we will often try to find ways to get them off the drug if they are antibody-positive.

Dr. Sandborn: Our current understanding is that patients who are antibody-negative have a very low risk for getting PML with natalizumab therapy, while patients who are antibody-positive have a risk higher see Crohn’s Roundtable, page 12

12

E x p er t R o u nd t a b l e

Crohn’s Roundtable continued from page 11

than the overall risk we had attributed to natalizumab therapy. This is a way to stratify patients who have quite a high cumulative risk from those who have a low cumulative risk and might find the therapy more acceptable.

Gastroenterology & Endoscopy News • JUNE 2012

‘I would be uncomfortable treating patients for more than six

continued anyone past two years if they are JCV antibody–positive. At that point the risk gets so high because all these patients have been patients with CD really need a on prior immunomodulators. We tell them that long-term strategy, I don’t see much utility the clock really begins to tick at 12 months, so they have the option of trying to get into remisGEN: Would you consider treating a in using this for short-term therapy.’ sion at one year, after which we will try to find patient with natalizumab if they test —William J. Sandborn, MD something else to maintain them. positive for the JCV antibody?

Dr. Sandborn: When a patient has 18 Dr. Rubin: Definitely. We know from the multo 24 months of natalizumab therapy, has used tiple sclerosis (MS) data and the two cases of PML immune suppressants and is antibody-positive, the risk Dr. Sandborn: I would be uncomfortthat occurred in the CD population that the develop- able treating patients for more than six months for PML could go up to one in 150 to one in 250, which ment of PML is a complication of long-term exposure to a year, and since patients with CD really need is really quite high. I would probably advise discontinuto natalizumab. So far, no case has occurred sooner than a long-term strategy, I don’t see much utility in ation unless the patient is willing to accept that high a nine months after treatment intiation. In patients who using this for short-term therapy. The risk factors risk, and I think most patients—if you put it in those are positive for JCV antibodies, our evaluation of the for getting PML are 18 months or more on natalizumab, terms—would ultimately stop. risks and benefits of their staying on this therapy beyond previous exposure to immunosuppressive drugs and nine months to a year or longer will be informed based being positive for the antibody. Everyone with CD who GEN: What would you do with that on whether or not they are in remission. If the therapy gets treated with natalizumab will have been treated with patient’s treatment at that point, and what doesn’t work, the discussion of a risk that may occur after immunosuppressive drugs, and natalizumab is used for factors would influence your decision? prolonged exposure is a moot point. Also, other therapies long-term treatment. The combination of antibody-posare in development that we expect to be available in the itive [status], previous immunosuppressive treatment and Dr. Rubin: In general, I encourage patients to stay on next 12 to 24 months. Having good disease control will long-term treatment puts patients at quite a high risk. the therapy that’s working, although I am cautious about help patients feel better and reduce the likelihood they this and see them frequently in the office. Once they’re will suffer irreversible damage from their disease. in stable remission, I would strongly consider stopping GEN: If a patient who is already on Dr. Hanauer: We certainly could consider treat- natalizumab tests positive for JCV natalizumab and going back to another maintenance ment, but the risk–benefit [ratio] is less in favor of those strategy because the mechanisms and effectiveness of antibodies, how do you educate him individuals. therapies for maintaining remission are sometimes difor her about the risk of continued ferent from what is required to induce successful remisnatalizumab treatment? sion. In certain patients, a surgical solution may still be an option. In my own experience, those patients would ‘I’d really be thinking of Dr. Rubin: If they are antibody-positive, they rather stay on therapy than consider a permanent ileosnatalizumab as a bridge to an have a different risk estimate for developing tomy. That said, the patient group that does best with PML than the general population who are on natalizumab is not the one with terrible rectal disease alternative therapy we hope to therapy. Therefore, it is important to tell them who is just trying to avoid an ileostomy. The people have available in the future, or that because they are JCV antibody–positive, who have done best with natalizumab have been more their risk is higher than what we previously had typically defined as failing tumor necrosis factor (TNF) to delay surgery in patients who discussed. An important question is whether we therapy and not progressing to irreversible fibrotic damare not ready for it.’ might stop natalizumab and transition them to age; from a purely mechanistic decision analysis, we go —Corey A. Siegel, MD, MS another therapy that did not work previously, but on to natalizumab early. might work once they are in remission. Clearly, Dr. Hanauer: You have to reassess patients’ prior in a patient who was sick enough to be on natali- history, what drugs they were treated with and their Dr. Siegel: Patients offered natalizumab zumab, stopping natalizumab and doing nothing is sta- experience with those drugs prior to natalizumab. We recently had a young man who had done very well on have very few treatment alternatives. If a patient tistically riskier than staying on therapy. starting natalizumab tested positive, I would Dr. Hanauer: The education has to come before infliximab therapy, but lost response to it and had no consider using natalizumab for less than two you even order the antibody test. As soon as you order response to adalimumab. He did well on natalizumab for two years, but tested positive on the assay and decided to years. After this time, the risk goes up. I’d really the test, you’re essentially saying that if the be thinking of natalizumab as a bridge to an alternative test is positive we’re going to stop treattherapy we hope to have available in the future, or as a ment, and if it’s negative we’re going to conway to delay surgery in patients who are not ready for tinue. If you’re not going to do that, there’s no ‘As soon as you order the test, it. Beyond the short term, if the patient really wanted to reason to order the test. you’re essentially saying that if the Dr. Siegel: I would lay out the risks very continue and truly understood the risks for PML, I think carefully.

Within the first year or two it appears I would consider it, but it would take a lot for me to allow test is positive we’re going to stop that they have a one per 1,000 chance of developa patient to continue beyond two years. treatment, and if it’s negative we’re Dr. Mahadevan: We do that right now, know- ing PML, and after that it’s about a one in 125 chance.

I talked to a patient recently who said she’s ing the risks go up after nine to 12 months. Patients who going to continue. If you’re not going to do go on natalizumab have failed all other available thera- not sure what she’ll do if she tests positive, because that, there’s no reason to order the test.’ pies and are very ill. Even if we find them positive for she was so sick and she’s finally feeling well. In the —Stephen B. Hanauer, MD JCV antibodies, we will often start the patient on natali- majority of patients who test positive, we will have zumab, if they are willing, to get them under control for to stop therapy, but that will require an alternative. that first year until we can find another option. If they And that alternative might be surgical manageare on natalizumab already and are in remission at one ment; it might be a clinical trial; it might be another discontinue treatment. We have evidence that patients year, we’re very hesitant to take them off. That said, most medication that we’re using off label. There are always who have done well on infliximab for several years can go of our patients beyond the one-year point who are posi- options for these patients; it’s just a matter of how help- back to infliximab therapy as long as they’re on immunosuppressants. So we restarted an immunosuppressant tive for antibodies have discontinued the drug because ful we think those options will be.

Dr. Mahadevan: At this point we have not and put him back on infliximab, and he responded to of concern over PML.

months to a year, and since

Gastroenterology & Endoscopy News • JUNE 2012

E x p er t R o u nd t a b l e

13

‘In a JCV antibody–negative patient, that treatment again. Most patients are ending up going into clinical trials, because that’s the alternative.

Dr. Siegel: If a patient had been on treatment two years or more, I would recommend stopping treatment as long as we had some reasonable alternatives.

The factors that would influence my decision would be the potential severity of their CD, how sick they were before starting natalizumab, how effective it had been and the availability of clinical trials. Many of us have been taught to avoid surgery, but surgery can be a very effective treatment for CD. In patients whose disease has settled with natalizumab, what might previously have been a very extensive segment for bowel surgery is now a much more limited surgery.

Dr. Mahadevan: In a patient who is JCV antibody–positive, the factors influencing my decision would be how long they’ve been on natalizumab, whether or not they’ve been on immunomodulators, how severe their illness was before and what other options are available.

Some patients absolutely do not want a colectomy with ileostomy and are willing to accept the risk for PML. If patients are educated and making an informed choice, we will continue the drug, although we have so far not gone past two years. But if it comes down to a question of uncontrollable CD in the small bowel, where you really don’t have the option of long-term remission with surgery, the dynamics change. If they’ve been on the drug less than 12 months we would go to 12 months, and if at 12 months patients are in a solid remission, we would try to put them on something they may not have tried in order to maintain remission. Alternatively, we can switch them to ustekinumab [a psoriasis treatment], which has shown some benefit in clinical trials for IBD [irritable bowel disease].

Dr. Sandborn: My understanding of the data we have now is that continuing beyond 18 months might pose an absolute risk of one in 150 to one in 250, so my advice to the patient probably would be to stop.

But if the patient has no other options and they’re doing really well and are willing to accept that level of risk, the patient could have the final call. In the MS setting, I imagine there are patients who do continue despite being antibody-positive. My sense is that CD patients, who don’t have a neurologic illness, are going to be less willing to accept that kind of risk.

GEN: If a JCV antibody test is negative, do you do a second test within a short interval to ensure against the possibility of a false-negative?

Dr. Rubin: In patients who test negative, I would repeat the test in nine months or so, and subsequently annually.

Dr. Hanauer: We have not done so.

Dr. Siegel: This is a two-phase test. The first part is a fairly sensitive test that might pick people up who don’t really have the virus. If the test is positive, they will automatically have a second confirmatory test that is very specific, meaning if it is positive, they probably have had exposure to JCV. Theoretically, the test will pick up most if not all people who have exposure to JCV. But we don’t know about the importance of doing a second test [if they are negative]. I have not been doing it, but plan to check annually in those who continue on natalizumab.

Dr. Mahadevan: There is no guideI think it would be reasonable to line on this, so this is my anecdotal pracstart with natalizumab and move on tice: If it’s negative, I check it once a year. to vedolizumab if they lose response.

Dr. Sandborn: We’re not so worried about that. We know there is a seroconIn a JCV antibody–positive patient, version rate of about 1% a year of patients I would probably go straight to vedolizumab.’ going from JCV-negative to positive. The right algorithm has yet to be defined, but —David T. Rubin, MD I think checking every six to 12 months is a good safety strategy. Even if the original therapy in a disease class is extremely importest was a false-negative and the patient actually had latent JCV, the patient’s risk doesn’t really tant. Therefore, in a JCV antibody-negago up until after a year. If the patient really was nega- tive patient, I think it would be reasonable tive six months ago and seroconverted, you may want to to start with natalizumab and move on to vedolizumab if they lose response. In a JCV consider stopping. antibody–positive patient, I would probably go straight to vedolizumab. We are hopeful and optimistic that GEN: If you begin treatment with vedolizumab is not going to cause PML even in JCV natalizumab in a patient whose JCV antibody–positive patients, but we need to know the antibody test is negative, when should follow-up of a large population of clinical trial patients. you retest that patient to assess for a new Dr. Hanauer: We don’t expect to see any PML with primary infection? vedolizumab. Assuming we don’t, it’s going to provide another important option with a different mechanism Dr. Rubin: I think annually. In the 1% chance that from the anti-TNF biologics. As effective as the latter patients develop a primary infection in the previous year, have been, there is a great clinical need for alternative that doesn’t change the likelihood of their getting PML. mechanisms of action because patients lose response.

They are now positive and the cumulative effectiveness Dr. Siegel: At this point we don’t have any indiof their therapy has to be weighed immediately. The cation that vedolizumab is associated with PML and we hope that will continue to be the case. If it is [associated], patients who are positive for the JCV antibody will be candidates for vedolizumab ‘If patients are educated and over natalizumab. If they’re negative, both those making an informed choice, we medications will be options. As we’ve learned, it’s will continue the drug, although very rare that biologics are persistently active in a patient over the long term, and having more than we have so far not gone past two one drug in a class has been a benefit. years.’

Dr. Mahadevan: Assuming there is no JCV infection risk, I think most of us would go straight —Uma Mahadevan, MD to vedolizumab in patients who would be candidates for natalizumab. Right now, a patient who fails an anti-TNF therapy will often go to another anti-TNF before getting to natalizumab. [In the future] you may be more likely to have a primary nonclock doesn’t start when the JCV infection occurs, but responder to anti-TNFs go straight to vedolizumab when the natalizumab is initiated. rather than trying another biologic.

Dr. Hanauer: I don’t think the answer to that quesDr. Sandborn: Our understanding of how natalition has been established. It appears that the assimilazumab leads to PML is that it blocks lymphocyte traftion of JCV occurs early in childhood, so adults are not ficking to the brain, which diminishes or removes the highly likely to develop positivity, but we don’t have a cohort of individuals who have been followed after a immune surveillance function for the JCV. We expect negative test to see what the incidence of new positiv- that vedolizumab, which does not impede lymphocyte ity is. We assume it’s going to be very low, but we really trafficking in the brain, will not lead to PML. I imagine don’t know. I would suggest maybe two years, but that’s that [IBD] patients and physicians will prefer a selecan out-of-the-blue grab for an answer. tive agent that can block lymphocyte trafficking to the Dr. Siegel: My plan will be to test annually. gut while preserving lymphocyte trafficking to the brain.

Dr. Mahadevan: Once a year is my practice, but That said, for JCV [antibody–negative] patients, natalithere is no hard and fast rule on that. zumab is likely to be a reasonably safe and good treatDr. Sandborn: I’m beginning with testing every six ment option. n months. Whether that is overkill, time will tell.

Dr. Rubin is a consultant for Elan and Takeda. Dr. Hanauer is a past consultant for Elan and Biogen. Dr. SieGEN: How would the approval of gel is a consultant for Elan, Abbott, UCB and Janssen; has vedolizumab affect your future received educational grants from Abbott, UCB and Janssen; management of these patients? and has received honoraria from Abbott and Janssen for lecDr. Rubin: In IBD and other disease states, loss of tures. Dr. Mahadevan is a consultant for Elan. Dr. Sandresponse with biologics is common and neutralizing born is a consultant for and receives research support from antibody development can occur. Having more than one Elan, Takeda, Genentech and Pfizer.

14

Gastroenterology & Endoscopy News • JUNE 2012

Colonoscopy continued from page 1

Week meeting (abstract 445).

Researchers asked 90 patients being screened for CRC to undergo both CTC and colonoscopy on the same day and found that 77% said they would prefer colonoscopy for repeat screening.

The findings are important “in that they allow me say with confidence that colonoscopy is not less comfortable than CTC, but that most patients would find it more comfortable,” said Douglas

Faigel, MD, professor of medicine at Mayo Clinic in Scottsdale, Ariz., who was not involved in the study.

“Along with these findings, and given that colonoscopy has been shown to prevent CRC incidence and mortality while similar data are lacking on CTC, I would recommend colonoscopy as the best test for detecting and preventing CRC,” Dr. Faigel added. “I would reserve CTC for the subset of patients who are truly unwilling to undergo colonoscopy but [are] willing to have a CTC.” Patient preference may affect

adherence to a CRC screening schedule, said lead investigator Greg Rosenfeld, MD, clinical assistant professor in the Department of Family Practice and a gastroenterology fellow at the University of British Columbia’s Department of Medicine in Vancouver. To better understand the question, Dr. Rosenfeld and his colleagues enrolled 90 patients (mean age, 55 years) to undergo CTC and subsequent colonoscopy on the same day. Participants received midazolam and fentanyl or meperidine during colonoscopy, but no sedation or analgesia during

‘Along with these findings, and given that colonoscopy has been shown to prevent CRC incidence and mortality while similar data are lacking on CTC, I would recommend colonoscopy as the best test for detecting and preventing CRC.’ —Douglas Faigel, MD

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CTC. The subjects completed a 13-item patient satisfaction questionnaire following each procedure.

The findings showed that 36% of patients felt less anxious during colonoscopy, whereas 14% reported experiencing less anxiety with CTC (P<0.0001). Additionally, 69% of patients said they felt less pain or discomfort during colonoscopy, whereas only 4% said they felt more comfortable during CTC (P<0.0001).

In terms of overall satisfaction, 30% of participants preferred colonoscopy rather than CTC in contrast to 4% who were more satisfied with CTC (P<0.0001).

The remainder of respondents to the three questions did not demonstrate a strong preference either way.

Notably, 77% of patients said they would rather undergo colonoscopy for repeat screening.

Although the palatability of CTC may be improved if patients were to receive sedation and analgesia, Dr. Rosenfeld insisted the conclusions point to the continued place of colonoscopy as the gold standard in screening for CRC. “I think that, overall, colonoscopy is a better test than CTC for screening and CTC should be reserved for cases where patients are unwilling to undergo colonoscopy or it cannot be safely completed,” Dr. n Rosenfeld concluded.

Drs. Rosenfeld and Faigel have no conflicts of interest.

15

Gastroenterology & Endoscopy News • JUNE 2012

Flares continued from page 1

Lead investigator Stephan Vavricka, MD, chief of the Division of Gastroenterology and Hepatology at Triemli Hospital in Zurich, presented these findings at the 2012 Digestive Disease Week (DDW) meeting (abstract 303).

He believes clinicians should advise IBD patients in remission not to ascend beyond 2,000 meters (approximately 6,500 feet) above sea level.

“We believe patients should avoid going to high altitudes if they are in remission as a way to prevent relapse,” Dr. Vavricka said during a press conference held prior to the DDW meeting.

Prior research has shown oxygendeprived mice have impaired immune function and hampered mucosal barrier protection (Chen LW et al. Nat Med 2003;9:575-581). In a study of healthy volunteers, ascents to elevations higher than 3,400 meters (approximately 11,000 feet) increased levels of circulating proinflammatory cytokines and serum C-reactive protein (Hartmann G et al. Cytokine 2000;12:246-252).

high-altitude journeys compared with 20.7% (six of 29) of remitted respondents with CD (P=0.024). Approximately 42% (13 of 31) of relapsed UC patients reported recent high-altitude travels compared with 20.7% (six of 29) of UC patients in remission (P=0.077). Controlling for age, gender, smoking status and medication use did not affect the correlation, Dr. Vavricka said.

Interestingly, the researchers found that most relapsed high-altitude travelers experienced symptom aggravation after returning from high altitudes rather than

during their stays in high altitudes.

Peter Higgins, MD, PhD, an expert not involved in the study, said the findings have potential clinical utility but need to be validated in a prospective study.

“There is some risk for recall bias when using a retrospective questionnaire,” said Dr. Higgins, who is assistant professor of gastroenterology in the Department of Internal Medicine at the University of Michigan Health System in Ann Arbor.

“In terms of future research, I would like to know if there is a dose–response

relationship,” he said. “For example, is there a minimum altitude or time spent at high altitude that is associated with increased flare risk? Are patients with tenuous remission at greater risk than those with mucosal healing and a fecal calprotectin below 50? Future randomized studies also should examine interventions, for example, comparing administration of supplemental oxygen versus supplemental n air during travel.”

Drs. Vavricka and Higgins have no relevant conflicts of interest.

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Gastroenterology & Endoscopy News • JUNE 2012

Infliximab Not Associated With Increased Risk for Cancer Ongoing Evaluation of TREAT Registry Shows Infliximab Safe at Five-Year Follow-up Dr. Lichtenstein said. “Crohn’s disease patients may have a higher lymphoma risk than the general U.S. population,” which he has attributed to azathioprine/6MP use or potentially disease activity. Chromosomal changes that occur in users of azathioprine and 6-MP have been well described in the literature. Dr. Lichtenstein hypothesized that it is possible that taking azathioprine and 6-MP induces these mutations and may play a causal role in lymphoma.

with the medication compared with the risk.

“We have good data to show that anti-TNF therapy is very effective, so knowing infliximab did not increase the National Harbor, Md.—The use of infliximab does risk for lymphoma when compared with conventional not appear to increase the risk for cancer in patients with therapy is comforting; however, work will be ongoing to Crohn’s disease (CD), although several other indepenlook at this with longer use.” dent factors may, according to the latest findings from Stephen Hanauer, MD, who was not involved in Dr. the TREAT (Crohn’s Therapy, Resource, Evaluation Lichtenstein’s study, also considers these recent findings and Assessment Tool) registry presented at the Americomforting. can College of Gastroenterology’s annual “This is an important ongoing study meeting, held last November. that continues to add evidence regardGary Lichtenstein, MD, professor ‘We found that baseline age, disease duration, smoking and ing the long-term safety of infliximab of medicine, University of Pennsylva- immunomodulator therapy—but not infliximab use—were therapy,” said Dr. Hanauer, professor of nia School of Medicine, Philadelphia, medicine and clinical pharmacology, and and colleagues prospectively evalu- significant predictors of malignancy.’ chief of the Section of Gastroenterology, ated patients in the registry to examine —Gary Lichtenstein, MD Hepatology & Nutrition, at the Univerwhether an association between maligsity of Chicago Medical Center. nancies and use of anti-tumor necrosis “We’re probably approaching 10 years factor (TNF) therapy exists. of experience, and the numbers aren’t The TREAT registry, set up primarily shifting dramatically,” Dr. Hanauer said. to examine the safety of infliximab com“We are not seeing accumulating toxpared with other treatment therapies for icities over time. The more immunosupCD, now includes 6,273 patients from pressants you give someone, the greater more than 200 different centers (80% the risk for both infection and neoplasia, community centers, 20% academic cenbut overall, I look at this as very reassurters), with a mean length of time in the ing that we do not see an independent registry of 5.2 years. During that time, risk related to long-term therapy with records have been kept on 3,674 patients infliximab.”

Table. Risk for Malignancy Associated With Treatments receiving infliximab and 2,509 receiving The recent findings, he said, are conFor Crohn’s Disease in the TREAT Registry other treatments, including azathioprine, sistent with what’s been reported in the 6-mercaptopurine (6-MP), methotrexate, past.

Treatment Adjusted Hazard P value Ratiob corticosteroids, mesalamine and antibiot“The story continues to follow the ics, at the discretion of their physician. same theme, which is that the major risks 1.60 0.011 Immunomodulatora “There was no difference in incidence for patients are not the biologic therapies, vs. no immunomodulator per 100 patient-years of malignancy or but the steroid therapies, which have Infliximab vs. no infliximab 0.79 0.17 lymphoma in the two groups,” said Dr. been associated with risks for infection Narcotic analgesics 1.14 0.48 Lichtenstein, also director of the Cenand death.” vs. no narcotic analgesics ter for Inflammatory Bowel Diseases, The complexity, Dr. Hanauer added, is Prednisone vs. no prednisone 0.84 0.28 University of Pennsylvania Health Syshow to separate the risks of immunosuptem, Philadelphia. “We found that basepressant agents from the risks of biologic TREAT, Crohn’s Therapy, Resource, Evaluation and Assessment Tool a Includes azathioprine, 6-mercaptopurine and methotrexate line age, disease duration, smoking and therapy, since many patients are treated b Adjusted for age, gender and race; based on time to first malignancy from exposure at any time immunomodulator therapy—but not concomitantly with both. infliximab use—were significant predic“My interpretation of the literature, tors of malignancy.” including the TREAT registry, is that the Although patients taking azathio- ‘We have good data to show that anti-TNF therapy is very biggest risk is that of steroid therapy, that prine or 6-MP have an increased risk for effective, so knowing infliximab did not increase the risk for immunosuppressants are associated with malignancy, the addition of infliximab a greater risk for lymphoma. That risk to other treatments did not increase this lymphoma when compared with conventional therapy may be associated with anti-TNF therapy risk in patients on other treatments alone is comforting.’ as well, but it’s really hard to separate that (Table). Dr. Lichtenstein’s group previindividual risk with the risk associated —Gary Lichtenstein, MD ously reported a meta-analysis highlightwith immunosuppressants,” he said. ing a fourfold increase in the standard “Although these data are reassuring, incidence ratio of patients with lymthere are limitations to this observational phoma who were exposed to azathioprine or 6-MP. “But to date no one has done an adequately sized study and we still need to acknowledge that the FDA Comparing findings from the TREAT registry with study of this, because the current belief among gastro- has placed a warning on all anti-TNF agents regardthose in the National Institutes of Health Surveillance, enterologists is that it is still safe to use azathioprine and ing the risk for lymphoma, in particular for young males Epidemiology and End Results (SEER) database, which 6-MP as a general treatment in patients with Crohn’s; who are susceptible to the very rare hepatosplenic T-cell examines cancer incidence in the general population, the although the risk for lymphoma in patients is elevated it lymphomas, which also have an increased risk with researchers found that breast cancer was less common still represents a rare event,” Dr. Lichtenstein said. combination therapy with immunosuppressants. In all in the TREAT registry, but the standardized incidence Based on a recent population-based meta-analysis his cases, the risks of combination therapy must be balanced ratio for lymphoma was twice that of the background group conducted, Dr. Lichtenstein estimates that one against the benefits of the combination of infliximab and population in individuals in both the infliximab-treated in 500 to one in 600 patients using azathioprine and azathioprine observed in the SONIC [Study of Biologic and other treatment–only cohorts.

6-MP may develop a lymphoma. But, he added, “There and Immunomodulator-Naive Patients in Crohn’s Disn “This is consistent with other reports in the literature,” are certainly many more patients who gain an advantage ease] trial,” Dr. Hanauer concluded.

By Monica J. Smith

17

Gastroenterology & Endoscopy News • JUNE 2012

Vitamin D May Be Easy, Low-risk Way To Relieve Symptoms of Crohn’s Disease

By Monica J. Smith National Harbor, Md.—Could something as simple and safe as vitamin D supplementation help ameliorate symptoms in patients with Crohn’s disease (CD)?

“For some time, there has been a description of a north–south gradient in CD—an association between the location of populations in relation to the equator and the frequency of CD. One postulated reason for this is the impact of vitamin D,” said Dustin Boothe, thirdyear medical student at Weill Cornell Medical College, New York City, and primary author of the study, which was presented at the 2011 American College of Gastroenterology meeting.

Mr. Boothe and colleagues reviewed data on CD patients at their center and found that most of the patients had vitamin D levels below normal, and that the lower the vitamin D levels, the higher the patient’s Harvey-Bradshaw Index (HBI) scores and vice versa.

“The question with any retrospective study that shows an association like that is, which is the chicken and which is the egg? Is their clinical score low because their vitamin D is high, or is their vitamin D high because their disease is in remission?” asked Brian Bosworth, MD, senior study investigator.

To test their theory that high-dose vitamin D supplementation could improve clinical outcomes in patients with CD and low vitamin D levels, the researchers randomized 15 patients in an observer-blind fashion to receive either a standard dose of 1,000 IU vitamin D per day or a high-dose supplementation of 10,000 IU vitamin D per day. For the most part, patients continued on whatever drug treatment regimen they had already been taking. Patients also were monitored for serum hypercalcemia.

“The basis of this study is that we know vitamin D is an immunomodulator, that it has an effect on the immune system; that’s been studied for more than a decade now,” Mr. Boothe said. “Since CD has an inflammatory component, we thought that vitamin D supplementation might be able to influence it in a way that could improve clinical scores on the HBI.” The researchers were concerned about high amounts of vitamin D, but the American Society of Nutrition had done a retrospective study and determined that up to 10,000 IU per day was a safe dose (Hathcock JN et al.

Am J Clin Nutr 2007;85:6-18).

“Given the fact that if you’re out in the sun for a day you could produce 25,000 units on your own, 10,000 seems like a reasonable dose,” Dr. Bosworth said.

HBI scores were assessed at day 1 and at weeks 8 and 26.

“We found that the patients receiving 1,000 IU per day increased their vitamin D levels to above 30 ng/mL, but that was not a statistically significant increase,” Dr. Bosworth said. “Those on 10,000 IU per day, however, increased their vitamin D levels from around 25 [ng/ mL] up to 72 [ng/mL], a very large increase.”

At week 26, vitamin D levels in the low-dose group reached 26 ng/mL (±5.6 ng/mL), and 64.2 ng/mL (±29.8 ng/mL) in the high-dose group. HBI scores for

‘The question with any retrospective study that shows an association like that is, which is the chicken and which is the egg? Is their clinical score low because their vitamin D is high, or is their vitamin D high because their disease is in remission?’

—Brian Bosworth, MD

‘Since CD has an inflammatory component, we thought that vitamin D supplementation might be able to influence it in a way that could improve clinical scores on the HBI.’ —Dustin Boothe

‘What’s interesting is that, by and large, medications were held constant during the course of the study; this one nutritional supplementation actually made a real clinical impact without any toxicity.’

—Brian Bosworth, MD the two groups were 7.6 (±3.9) and 3.25 (±2.2), respectively (P<0.04). Although the goal of the study was not to induce remission, the drop in HBI scores was indicative of a meaningful response to current medication and reduced need to escalate drug therapy.

“The patients on higher doses of vitamin D had a clinically relevant reduction of about three points in their clinical activity,” Dr. Bosworth said. “What’s interesting is that, by and large, medications were held constant during the course of the study; this one nutritional supplementation actually made a real clinical impact without any toxicity.”

The study is limited by its small size, but the research is ongoing. “The data so far is promising, and we’re excited about it,” Mr. Boothe said. “We’re hoping this study will snowball into more studies that further evaluate the impact of vitamin D on CD. It’s a debilitating disease, and the more tools we have to help our patients have a better quality of life, the better.”

Andrea Branch, PhD, associate professor of medicine,

Mount Sinai School of Medicine, New York City, was excited by the short-term findings of the small study.

“I’m very pleased this study was done in patients. If we’re interested in accelerating the pace of treatment development, it’s really important that innovative interventions get tried out in patients if they are logical and there are no safety issues,” she said. “You would need to know the long-term consequences—if this is an improvement in the disease that would be sustained over time—but I think as an early study it makes a lot of sense and I find it really encouraging.”

Because vitamin D reduces levels of tumor necrosis factor (TNF)-α, a characteristic of drug interventions beneficial in treating CD, it seems logical to try a nutritional supplement that may have some of the same effects, Dr. Branch explained.

“It certainly makes sense that a natural molecule that reduces TNF-α might be beneficial and potentially less toxic than some of the pharmaceutical interventions n directed at reducing TNF-α levels.”

18

Gastroenterology & Endoscopy News • JUNE 2012

Allopurinol Mitigates Thiopurine Toxicity In IBD Patients, Large Study Confirms

By Monica J. Smith National Harbor, Md.—The addition of allopurinol to thiopurine therapy appears to be an effective and well-tolerated long-term maintenance strategy for patients with inflammatory bowel disease (IBD) who fail monotherapy with thiopurine, according to research presented at the 2011 American College of Gastroenterology annual meeting.

“As many of you know, thiopurine therapy is important to maintain remission in IBD. But many patients have to discontinue this therapy due to [either] lack of remission or side effects,” said lead researcher Frank Hoentjen, MD, PhD, assistant professor of medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

A substantial proportion of patients maintained on thiopurines have trouble with the drugs due to a skewed thiopurine metabolism, Dr. Hoentjen explained.

“When we look at the metabolites of these patients, we sometimes see grossly elevated 6-MMP [6-methylmercaptopurine] levels that can cause toxic side effects, whereas 6-TGN [6-thioguanine nucleotide], which is the metabolite that keeps patients in remission, is very low.”

Prior studies have found that in this subset of patients, the addition of allopurinol can help invert that ratio, reducing 6-MMP and raising 6-TGN. But those studies were relatively small, with a short follow-up. “Our goal was to design a larger study with more patients and a longer follow-up,” Dr. Hoentjen said.

To assess the effectiveness of combination therapy, Dr. Hoentjen and colleagues administered allopurinol and low-dose thiopurine to 85 patients with the disease from two tertiary referral IBD centers. The patients previously had failed monotherapy with thiopurines. The researchers determined effectiveness by calculating the cumulative number of patients still using combination therapy at six, 12, 24 and 60 months, while staying in clinical remission.

efficacy, which usually occurred within two months of induction. The percentages of patients still using combination therapy at six, 12, 24 and 60 months were 88%, 84%, 76% and 73%, respectively.

The authors concluded that combination therapy with allopurinol and lowdose thiopurines is effective and well tolerated, and that it is an alternative long-term maintenance strategy for this subset of patients who fail conventional monotherapy with thiopurines.

‘We confirmed previous data showing that combination therapy is very effective at reducing the side effects and at achieving remission in this group of patients, and we also see good effectiveness with this therapy long term.’

—Frank Hoentjen, MD, PhD The researchers found that the mean 6-TGN concentrations increased from 268 at baseline to 484, and that the mean 6-MMP concentrations fell from 12,721 to 803. Laboratory results showed that leukocyte counts dropped from 6.8 to 5.4, and that platelets fell from 310 to 275.

Liver function tests showed that alanine aminotransferase levels, which were about 75 U/L on monotherapy, normalized in 85% of patients after initiating combination therapy.

Eleven patients experienced leukopenia, but all were able to continue combination therapy after receiving appropriate dose adjustments; 17 patients (20%) discontinued combination therapy, mainly due to adverse reactions or lack of

“We confirmed previous data showing that combination therapy is very effective at reducing the side effects and at achieving remission in this group of patients, and we also see good effectiveness with this therapy long-term,” Dr. Hoentjen said.

Miles Sparrow, MBBS, consultant gastroenterologist, The Alfred Hospital, Melbourne, Australia, noted that this study represents the largest cohort of patients receiving combination allopurinol-thiopurine therapy reported to date.

“The biochemical findings are identical to previous reports of this combination therapy, most noticeably the precipitous drop in 6-MMP metabolite levels after allopurinol is added,” he said. “What is most impressive is the proportion of

patients remaining on long-term maintenance combination therapy, with almost three-fourths of the patients still on allopurinol-thiopurine therapy at five years.”

Dr. Sparrow noted that the researchers did not provide disease activity scores or information regarding infections in the patients who became leukopenic, and that thiopurine methyltransferase activity was not reported. Nonetheless, “this report does contribute to the small but expanding evidence base showing that adjunctive allopurinol successfully salvages the subgroup of perhaps 15% of patients who otherwise produce 6-MMP when taking thiopurines,” he said.

“Recent reports from different groups have shown that allopurinol also may reduce thiopurine intolerances regardless of an individual’s metabolite profile, but confirmation of this with further data is required,” Dr. Sparrow noted. “Given that treatment alternatives to thiopurine failures may be expensive (e.g., biologics) or associated with other toxicities (e.g., biologics, methotrexate), the role of combination therapy in maximizing all possible thiopurine responders is a costeffective, safe and efficacious addition to treatment alternatives in IBD.” At this point, Dr. Hoentjen and colleagues are working on a genetic analysis of blood collected from all trial subjects to determine why their metabolism differs from that of other patients.

“We are going to explore whether there is a genetic basis for this specific metabolism,” he said. “A couple of mutations are already known, but now, with a larger cohort—we are collaborating with a lab in the United Kingdom—we are trying to find new gene mutations that might help us understand why this group of patients is not able to sufficiently metabolize thion purines toward 6-TGN.”

From the Literature

NSAIDs, but Not Aspirin, May Increase IBD Risk

By Monica J. Smith The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may raise the risk for developing inflammatory bowel disease (IBD), but aspirin does not appear to have a similar influence, according to research first presented at the 2011 annual meeting of the American College of Gastroenterology (ACG) and recently published in the Annals of Internal Medicine (2012;156:350-359).

Ashwin N. Ananthakrishnan, MD, of Massachusetts General Hospital in Boston, and colleagues reviewed data on 76,795 women enrolled in Nurses’ Health Study (NHS) to clarify the effect of aspirin and other NSAIDs on the risk for developing Crohn’s disease (CD) and ulcerative colitis (UC).

“Most of the prior studies looked at the safety of these drugs in people with established IBD,” Dr. Ananthakrishnan told Gastroenterology & Endoscopy News after the ACG meeting. “We know there are mechanisms to support that aspirin and NSAIDs are bad for the GI tract, but there also are some benefits in terms of preventing adenoma recurrence and colon cancer recurrence. So we looked at what the effect of pre-IBD use [of aspirin and other NSAIDs] would be on IBD risk.”

In 1990, when the NHS first began to include biennial information on NSAID use (aspirin use had been documented since

1980), 44% of the women used aspirin on a regular basis and 37% used NSAIDs. During the 18-year follow-up, the researchers confirmed 123 cases of CD and 117 cases of UC. see NSAIDs, page 20

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7HEN USED ")$ BASED ON ABSOLUTE CHANGE IN HOUR AVERAGE PAIN INTENSITY FROM BASELINE TO BETWEEN DAYS AND AS MEASURED BY A MM VISUAL ANALOG SCALE 6!3 -EAN 6!3 SCORE AT BASELINE WAS MM FOR 2%#4)6 AND MM FOR PLACEBO MEAN 6!3 SCORE BETWEEN DAYS AND WAS MM FOR 2%#4)6 AND MM FOR PLACEBO $IFFERENCE IN MEAN CHANGE IN PAIN SCORE BETWEEN THE GROUPS WAS MM P #) MM MM "ASED ON A HYBRID ANALYSIS OF BASELINE OBSERVATION CARRIED FORWARD LAST OBSERVATION CARRIED FORWARD 2

Indication and Usage s 2%#4)6 NITROGLYCERIN /INTMENT IS INDICATED FOR THE TREATMENT OF MODERATE TO SEVERE PAIN ASSOCIATED WITH CHRONIC ANAL lSSURE Important Safety Information s 2%#4)6 IS CONTRAINDICATED IN PATIENTS TAKING PHOSPHODIESTERASE TYPE 0$% INHIBITORS EG SILDENAlL VARDENAlL AND TADALAlL

WHICH CAN POTENTIATE THE HYPOTENSIVE EFFECT OF ORGANIC NITRATES AND IN PATIENTS WITH SEVERE ANEMIA INCREASED INTRACRANIAL PRESSURE

OR KNOWN HYPERSENSITIVITY TO NITROGLYCERIN OTHER NITRATES AND NITRITES OR ANY COMPONENTS OF THE OINTMENT s 0ATIENTS WITH CARDIOVASCULAR DISORDERS SHOULD BE CLOSELY MONITORED WHILE USING 2%#4)6 ┬И 6ENOUS AND ARTERIAL DILATION AS A CONSEQUENCE OF NITROGLYCERIN TREATMENT CAN RESULT IN HYPOTENSION s %XERCISE CAUTION IN PATIENTS WITH ANY OF THE FOLLOWING CONDITIONS BLOOD VOLUME DEPLETION EXISTING HYPOTENSION CARDIOMYOPATHIES

CONGESTIVE HEART FAILURE ACUTE MYOCARDIAL INFARCTION OR POOR CARDIAC FUNCTION FOR OTHER REASONS s 4HE ADVERSE REACTIONS OF 2%#4)6 ARE LIKELY TO BE MORE PRONOUNCED IN THE ELDERLY s .ITROGLYCERIN PRODUCES DOSE RELATED HEADACHES WHICH MAY BE SEVERE s 4HE FOLLOWING DRUG INTERACTIONS MAY OCCUR IN PATIENTS TAKING 2%#4)6 ┬И 0$% INHIBITORS POTENTIATION OF HYPOTENSIVE EFFECTS OF ORGANIC NITRATES CONCOMITANT USE IS CONTRAINDICATED ┬И !NTIHYPERTENSIVES POSSIBLE ADDITIVE HYPOTENSIVE EFFECTS ┬И !SPIRIN INCREASED NITROGLYCERIN LEVELS ┬И 4ISSUE TYPE PLASMINOGEN ACTIVATOR T 0! DECREASED THROMBOLYTIC EFFECT ┬И (EPARIN ANTICOAGULANT EFFECT OF HEPARIN MAY BE REDUCED -ONITOR ACTIVATED PARTIAL THROMBOPLASTIN TIME !044 ┬И %RGOTAMINE INCREASED BIOAVAILABILITY OF ERGOTAMINE ┬И !LCOHOL ADDITIVE VASODILATORY EFFECTS TO NITROGLYCERIN #ONSUMPTION OF ALCOHOL SHOULD BE AVOIDED _ ARE HEADACHE AND DIZZINESS s 4HE MOST COMMON ADVERSE REACTIONS > s 2%#4)6 OINTMENT IS FOR INTRA ANAL USE AND NOT FOR ORAL OPHTHALMIC OR INTRAVAGINAL USE Please see brief summary of US Prescribing Information for RECTIV on the following page.

References: 1. 2%#4)6 53 0RESCRIBING )NFORMATION *UNE 2. $ATA ON lLE !PTALIS 0HARMA 53 )NC

Aptalis Pharma US, Inc. 22 Inverness Center Parkway Birmingham, Alabama 35242 USA Tel (800) 472-2634 Fax (205) 991-8426 www.aptalispharma.com

01/12

RE010-1211

┬й2012 Aptalis Pharma US, Inc.

RECTIV is a trademark used under license by Aptalis Pharma US, Inc.

20

Gastroenterology & Endoscopy News • JUNE 2012

From the Literature

NSAIDs continued from page 18

“The incidence of CD in NSAID users was nine in 100,000, and this stayed the same until about 14 days per month of use,” Dr. Ananthakrishnan said. But when women used NSAIDs for 15 or more days per month, the incidence of CD increased to 15 in 100,000; a similar pattern was observed in UC. This association was not seen with aspirin.

“Essentially, we found the highest frequency of NSAID duration,

six years or more, and the highest frequency of tablets per week, five or more, correlated with a twofold increase in both CD and UC,” Dr. Ananthakrishnan said.

Concerned that subjects might be using the drugs to treat their symptoms, which could result in a false association, they looked at acetaminophen use within the same cohort.

“There was no association with acetaminophen, and no association with aspirin—both analgesics,” Dr. Ananthakrishnan said. “This suggests a fairly specific association

RECTIV (nitroglycerin) Ointment 0.4%, for intra-anal use Rx Only Initial U.S. Approval: 1955 Brief summary of Prescribing Information. Please consult package insert for full Prescribing Information.

INDICATIONS AND USAGE: RECTIV™ (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.

CONTRAINDICATIONS: PDE5 inhibitor use - Administration of RECTIV is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see DRUG INTERACTIONS]. Severe anemia - RECTIV is contraindicated in patients with severe anemia. Increased intracranial pressure - RECTIV is contraindicated in patients with increased intracranial pressure. Hypersensitivity - RECTIV is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites.

Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

WARNINGS AND PRECAUTIONS: Cardiovascular disorders - Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly. Headache - RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

ADVERSE REACTIONS: 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 most common adverse reaction of RECTIV (nitroglycerin) Ointment 0.4% applied to the anal canal is headache. Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment. In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1): Table 1: Incidence of Adverse Reactions (≥ 2%) in Study REC-C-001 RECTIV Placebo N = 123 N = 124 System Organ Class Patients Events Patients Events Preferred term n (%) n n (%) n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0

Hypotension: Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Allergic Reactions: Flushing, allergic reactions and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely.

Methemoglobinemia: In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia (see OVERDOSAGE).

DRUG INTERACTIONS: PDE5 inhibitors - Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of RECTIV within a few days of PDE5 inhibitors is contraindicated. Antihypertensives - Patients receiving antihypertensive drugs, betaadrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.

Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with RECTIV in patients with angina pectoris, additional hypotensive effects may occur. Aspirin - Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of RECTIV may be enhanced by concomitant administration of aspirin. Tissue-type Plasminogen Activator (t-PA) - Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving RECTIV during t-PA therapy. Heparin - Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and RECTIV concurrently, the anticoagulation status of the patient must be checked. Ergotamine - Oral administration of nitroglycerin

with NSAID use.”

Biologically, these data indicate that there are pathways affected by NSAIDs, but not by aspirin, that may play a role in the pathogenesis of IBD. “If we understand this [process] better, we may shed some light on potential new avenues for treatment,” Dr. Ananthakrishnan said.

Importantly, the findings of the study do not imply that aspirin is safer for people with established IBD. “We are concerned that use of these agents can contribute to flares; our study did not look at that question

markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris.

Therefore the possibility of ergotism in patients receiving RECTIV should be considered. Alcohol - The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C - Animal reproduction and teratogenicity studies have not been conducted with RECTIV. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. RECTIV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin. Nursing Mothers - It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECTIV is administered to a nursing woman. Pediatric Use - The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established. Geriatric Use - Clinical studies of RECTIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting.

Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSAGE: Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of RECTIV overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemia: Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information and Instructions for Use) in the full prescribing information. Interaction with PDE5 inhibitors - Advise patient not to use RECTIV with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of RECTIV and other nitrate drugs. Hypotension - Advise patients that treatment with RECTIV may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly. Headaches - Advise patients that headaches sometimes accompany treatment with RECTIV. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops.

Advise patients that if they experience headache they should not alter the schedule of their RECTIV treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches. Dizziness - Advise patients that dizziness has been reported as a side-effect of treatment with RECTIV. Advise patients not to drive or operate machinery immediately after applying RECTIV. Aptalis Pharma US, Inc, 22 Inverness Center Parkway, Birmingham, Alabama 35242 USA, Tel (800) 472-2634, Fax (205) 991-8426, www.aptalispharma.com Revised: June 2011

and does not suggest that aspirin is safer than NSAIDs in people with IBD, so it’s important not to conclude that [our findings] are a reflection of safety,” Dr. Ananthakrishnan said.

The study’s value lies in its potential to shed some light on the pathogenesis of IBD. “We have a greater understanding of genetics, but genetics seem to explain less than a third of the risk for either form of IBD, so this suggests a strong role for environmental risk factors,” Dr. Ananthakrishnan said. “I think we need to continue to do highquality studies to better understand what these risk factors are and how they affect CD and UC.”

‘The results seem to be quite clear and uniform, which enhances the reliability of the study.’

—Lawrence Brandt, MD

Lawrence Brandt, MD, emeritus chief of gastroenterology at Montefiore Medical Center and professor of medicine and surgery at Albert Einstein College of Medicine, New York City, appreciated the motives of the research, but said it perhaps raises more questions than it answers.

“This was a pretty good study,” he said. “It did not evaluate the effect of NSAIDs on patients with established IBD, but looked at the risk for developing CD and UC in patients being treated with aspirin and NSAIDs. That had not been done before.”

But because aspirin itself is an NSAID, Dr. Brandt is curious about the different effects of two types of NSAIDs on the risk for IBD. “Why do patients treated with NSAIDs exhibit an increased risk for UC and CD, while those treated with aspirin do not? Maybe it’s the biology of the disease rather than the biology of the drug,” he suggested.

He did believe the study established a true result.

“There was a correlation between the dosage, duration and frequency with NSAID use, and not with aspirin use,” he said. “So the results seem to be quite clear and uniform, which enhances the reliability of the study.” n Drs. Ananthakrishnan and Brandt reported no relevant conflicts of interest.

Q & A

Gastroenterology & Endoscopy News • JUNE 2012

21

A D V E R T I S E M E N T

Genii Introduces the Revolutionary gi 4000

Q.

People say the gi 4000 is the most exciting endoscopy product in at least 15 years. Why?

A.

One word: solutions. Genii knows the pressure our customers face to stretch resources while reducing errors and improving quality measures. When it comes to electrosurgical therapies, we provided the solution. Endoscopists needed a single device that could perform bipolar, monopolar, argon and lavage functions, because if they had those four things in every treatment room and on every travel cart, they would be prepared for whatever presents without disrupting throughput by dragging specialty generators from room to room.

Such a standardizable device had to be compact enough to fit on booms, travel carts or shelves. Finally, the price could not present a cost barrier to having it everywhere.

Q.

Will the introduction of the gi 4000 make argon therapy more widely available?

A. Absolutely. Since our argon-capable unit costs about the same as many standard generators and there is no up-front cost for reusable gas tanks or regulators, the cost barrier has disappeared for

many small hospitals and ASCs that felt unable to offer this therapy option before.

Q.

Tell us more about Genii, the company.

A.

manufactured in the USA. Engineers and executives with Genii have over 75 years of combined experience in endoscopy AND electrosurgery.

Visit Genii at www.genii-gi.com.

Founded in 2007, Genii exploded into view in 2011 with the launch of the very successful TouchSoft Coagulator®.

The TouchSoft and the gi 4000 are both

Touch the future today!

Genii met standardization and price goals with a patented compact design with internal argon canister. To reduce errors, Genii built the unit just for flexible endoscopy with a revolutionary user interface that is completely intuitive. It is incredibly simple to use. In testing, users set up procedures with 100% accuracy after only one, five-minute group training session. In addition, evidence-based power defaults are used for consistent and reproducible tissue effects. Physicians can, of course, make their own per-case adjustments, but they have the confidence of using a completely transparent display that lets them know exactly what type of cutting or coagulation waveform is selected and the power setting being delivered.

It was a tall order, but we did it. The gi 4000 is everything our customers need to meet these challenges. Solution delivered!

Q. A.

What does it mean to be truly standardized and why is that a good thing?

Being truly standardized means that any center has only one type of generator. It is not enough to just have the same brand in each room or on each cart because that doesn’t solve the problem of having every “tool” available everywhere. Also, some brands have several different models that vary greatly in their output characteristics. All of the cost and efficiency gains from standardization are only fully realized when a center has only one model to learn to operate, maintain and have available wherever, whenever.

True standardization is recognized as the best path to reducing costs while reducing errors.

Introducing the Genii® gi 4000 the world’s easiest, most intuitive electrosurgical generator.

Finally, a generator that thinks the way you do! A revolution in ease of use that does every procedure and fits anywhere. Touch, confirm and treat! Do every procedure with confidence, from basic to complex. Advanced tissue sensing, ArC Smart™ beam, smart-cut pulse modes, best endo bipolar, exclusive safety features, always ready lavage—and a patented compact argon system that fits right into the all–in-one unit. Designed only for flexible endoscopy, it’s a whole new electrosurgery future.

The future is here. Call today to touch it.

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22

Gastroenterology & Endoscopy News • JUNE 2012

Journal Club Links United States and Russia on IBD Issues Participants Hope AGA-Backed Project Will Foster Interactive Exchange

By Christina Frangou American and Russian gastroenterologists have teamed up to create an international journal club focused on inflammatory bowel disease (IBD).

Backed by the American Gastroenterological Association (AGA) and the Gastroenterological Scientific Society of Russia, the club was launched by Ellen J. Scherl, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease, NewYork-Presbyterian Hospital, in New York City.

The journal club provides an online forum to discuss clinical evidence about IBD and exchange treatment experiences. Participants from both countries screen, read and discuss a selected group of relevant journal articles, including clinical studies that address controversial topics. The club is open to all gastroenterologists in the United States and Russia. Registered users can sign on to the service, available online at http://ibdjournalclub.com, and critique and comment on the selected articles or watch the video presentations.

“It’s a very exciting project where both [countries] have much to learn and teach each other, particularly younger investigators,” said Oksana Stefanyuk, of the Department of International Scientific Collaboration at the Central Scientific Research Institute of Gastroenterology, in Moscow. “It’s a chance to have direct communication with other gastroenterologists around the world.”

Peter R. Holt, MD, senior research scientist at The Rockefeller University, in New York City, called the club “an opportunity for an interactive dialogue, rather than lectures. It’s important to recognize that what’s done here in the United States is not always done in other countries.”

As chair of the AGA’s International Committee, Dr. Holt traveled to Russia several times in recent years to attend its gastroenterology society’s annual meeting. In March 2010, he invited Dr. Scherl to join him and speak with young Russian investigators about IBD. “As part of the mission of the AGA’s International Committee, I like to encourage communication with younger people, not as a seminar, but as something more interactive,” said Dr. Holt.

“When Ellen and I were there, we were peppered with questions. … It became clear that what they are interested in is some scientific practical approach to IBD.”

Out of that meeting, the idea for an international journal club was born. Dr. Scherl spearheaded the venture, with the Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medical Center and Columbia University Medical Center providing support.

“This support and commitment was critical and pivotal to our success,” she

said, adding that the project would not have been completed without the efforts of Jill Roberts, Oksana Stefanyuk, Columbia University GI fellow Rupa Mukherjee, MD, and Cornell University GI IBD fellow Melissa Rosen, MD. Both Americans and Russians involved with the project wanted an interactive

Inadequate Bowel Preps: A Problem With Potentially Serious Consequences

Colonoscopic view of cecum in patient using a split-dose bowel prep1

Colonoscopic view of cecum in patient using a single-dose bowel prep1

In Bowel Cleansing, Location Matters Inadequate bowel cleansing can compromise detection of lesions in the right colon,2 where cancer often develops3

23

Gastroenterology & Endoscopy News • JUNE 2012

forum to discuss debates in the field, and to learn about scientific and clinical efforts in the other country.

“The breadth of treatment for IBD that’s available in Russia is very broad because, on one hand, premier institutions involved in research have used stem cell treatment for IBD long before many other places, including the [United States],” said Dr. Holt.

In contrast, most of Russia does not have access to biologics that are available in the United States.

‘It’s a very exciting project where both [countries] have much to learn and teach each other, particularly younger investigators.’

—Oksana Stefanyuk

How Common Are Inadequate Bowel Preps?

• In a review of over 236,000 outpatient colonoscopies, bowel preparation was inadequate in almost 24% of procedures4 • In another review of over 93,000 colonoscopies, bowel preparation was inadequate in 23% of procedures5

The Impact of Inadequate Bowel Preps on Colonoscopy: • Liquid residues remaining in the colon4 • Incomplete cleaning of right side of colon2 • Longer mean cecal intubation time6 • Higher rate of difficult colonoscopies6 • Greater likelihood of aborted examination6 Figure 1. Association of bowel cleansing quality with difficulty of colonoscopy (% of patients)6 Colonoscopy Quality

50

Low*

49.1

Intermediate*

% of Patients

40 30 20

High*

34.2

33.1

20.0 15.4

10 0

Easy†

12.4

Difficult† Difficulty of Colonoscopy

* Cleansing quality was determined by endoscopist grading using a 5-point scale. High = completely clean (score 5) or clear liquid present (score 4); Intermediate = liquid plus solid stool present that can be aspirated (score 3); Low = liquid and solid stool present that cannot be totally aspirated (score 2) or solid stool preventing visualization (score 1). † Degree of difficulty of procedure was determined by endoscopist grading with a 6-point scale: extremely easy, easy, fairly easy, fairly difficult, difficult, extremely difficult.

The Impact of Inadequate Bowel Preps on Diagnosis: • In a survey of patients with poor/fair bowel preps (N=3047), 42% of adenomas found in a follow-up colonoscopy had not been detected in the first colonoscopy7 • 27% of advanced adenomas, which have a greater premalignant potential, were missed in the first colonoscopy7 • Smaller adenomas (<10 mm) were missed nearly twice as often as adenomas ≥10 mm when the prep was poor7 References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Baxter N, Rabeneck L. ICES report: new findings about the risks and limitations of colonoscopy used in the early detection of colorectal cancer. Healthcare Quarterly. 2009;12:24-25. 3. Cappell MS. The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. Med Clin N Am. 2005;89:1-42. 4. Crispin A, Birkner B, Munte A, Nusko G, Mansmann U. Process quality and incidence of acute complications in a series of more than 230 000 outpatient colonoscopies. Endoscopy. 2009;41:1018-1025. 5. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58:76-79. 6. Froehlich F, Wietlisbach V, Gonvers J-J, Burnand B, Vader J-P. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc. 2005;61:378-384. 7. Lebwohl B, Kasinos F, Glick M, Rosenbaum AJ, Wang T, Neugut AI. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc. 2011;73:1207-1214. ©2012 Braintree Laboratories, Inc.

SU-12873RV

March, 2012

Brought to you as an educational service by

“As a result, this journal club has a very broad audience. We have to recognize that agents that are readily available here in the [United States] are not always available [elsewhere],” Dr. Holt said.

The first meeting focused on appropriate use of corticosteroids in Crohn’s disease, discussing two consequential papers on corticosteroids and biologic therapy. The former was a review (Irving PM et al. Aliment Pharmacol Ther 2007;26:313-329), the latter a landmark randomized clinical trial (Colombel JF et al. N Engl J Med 2010;362:13831395). In Moscow, the physicians signed in at 3 p.m.; at the same time, Dr. Scherl and colleagues logged on at 7 a.m. in New York City. The physicians talked about resolving the conflict between the two strategies, namely the older strategy of treating symptoms with corticosteroids and the newer approach, which uses a more proactive individualized therapy with biologics.

“We’re trying to work toward best practices and correct use of steroids and biologics,” said Dr. Scherl. “The aim is to make current therapies safer by using them correctly. These two articles were selected because they challenge us to ask what the role of steroids, immunosuppression and biologics is in the management of moderate to severe Crohn’s diseases in the 21st century.”

In the future, organizers plan to launch an IBD case teleconference. Physicians from both countries will present interesting cases, followed by discussion of relevant teaching points and treatment options.

“This will allow for an active exchange and an appreciation of the different types of cases that may emerge in New York and/or Moscow, and will allow for further collaboration ultimately in terms of epidemiologic studies,” said Ms. Stefanyuk.

Leonid Lazebnik, MD, PhD, director of Moscow’s Central Scientific Research Institute of Gastroenterology, said he hopes the journal club will strengthen scientific research in Russia through allowing young investigators an opportunity to converse with leaders in IBD therapy.

“We would like more people to join our IBD club. It’s an opportunity for thousands of people to see our journal,” he said.

This may be the first in a series of gastroenterology journal clubs for the two countries as organizers hope to branch into other areas.

“We are continuing to learn, and maybe the lessons we learn and how the endeavor ends up might provide lessons that others can utilize in similar sorts of n activities,” said Dr. Holt.

24

Gastroenterology & Endoscopy News • JUNE 2012

GIQuIC continued from page 1

going to become the type of data they will want to see from us, so we feel as though we spearheaded it, took the initiative and are telling them, ‘This is what you should look at in gastroenterology.’ ” Since the initiative was launched, 60 sites with more than 500 physicians have signed contracts, registered hardware and software and implemented the program, estimated Thomas M. Deas Jr., MD, medical director, Fort Worth Endoscopy

Center, Texas, and a member of the GIQuIC advisory board.

“We’ve already exceeded my expectations,” Dr. Deas said. “Any type of IT [information technology] program will be slow to catch on. There is typically some physician resistance and pushback to change. But there are incentives for physicians to get involved.”

One incentive is to demonstrate to public and private regulatory bodies that

a practice is actively involved in tracking quality measures. Indianapolis Gastroenterology and Hepatology, in Indiana, a single-specialty, private practice group with 14 gastroenterologists, joined GIQuIC about a year-and-a-half ago in order to have a full year of data collected by 2012.

“We’re seeking accreditation this year and I’m trying to get ready for that, to make sure we’re in good shape,” said

Laura Allen, RN, a clinical director for the group. “A lot of accrediting agencies look for practices to do some sort of benchmarking, and this is a great way to do it.”

Another incentive is to streamline the process by which physicians report data to Medicare’s Physician Quality Reporting System (PQRS).

‘I think there is more and more emphasis from payers and CMS for us to document

“

that we are complying with

Our surveyors are active health care professionals.

They bring ‘real world’ understanding to the process.

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quality measures. This is going to become the type of data they will want to see from us, so we feel as though we spearheaded it, took the initiative and are telling them, “This is what you should look at in gastroenterology.”’

—Karen L. Woods, MD

“Right now, to report that information, you have to click on a certain code with your EMR [electronic medical record], which is tedious and not very reliable— you tend to forget or don’t report often enough, and then you fail to qualify for the incentive. GIQuIC users will be able to report some of these measures via the registry, and Medicare has a small percentage fee increase for that,” Dr. Deas said.

With an ever-increasing emphasis on quality and outcomes in health care, participation in GIQuIC may make participants more attractive to commercial payers as well.

“We’ve had conversations with some payers about using participation in the quality registry to identify preferred providers,” Dr. Deas said.

Currently, GIQuIC participants are able to report data relative to colonoscopy procedures, focusing on well-established quality indicators including adenoma detection rate, cecal intubation rate, quality of bowel preparation, indications for procedure and screening surveillance intervals. Soon they will be able to report on a broader array of endoscopic procedures and in other clinical areas as well.

The Pilot

Improving Health Care Quality through Accreditation

The concept of GIQuIC was tested over the course of two years in a pilot

25

Gastroenterology & Endoscopy News • JUNE 2012

program involving more than 20 sites, including about 60 physicians, from around the country. Those participants reflected the endoscopists who would be involved down the road, “some in academic practice, some in private practice, some in big group practices, and some in small practices like myself,” said Dr. Woods.

The goals of the pilot were to validate the collection of quality data as a computerized report, to determine if the data could be collated and examined in a large group sample across all participants,

force (Bjorkman DJ, Popp JW Jr. Am J Gastroenterol 2006;101:864-865; Faigel DO et al. Gastrointest Endosc 2006;63[4 suppl]:S3-S9).

“We were trying to meet those standards and see if this data report collecting system would work; could people get it done? Could they give 100% of their data? Did the data look useful once it was collated and reports given?” Dr. Woods said. “We found that it was very successful. We validated the ability to do it.”

GIQuIC was rolled out nationally in mid-2010 and is now available to any site

After a year-and-a-half trying to do so, The Methodist System changed its mind.

“They finally said, ‘We simply can’t get this done; GIQuIC looks like a good, low-cost investment to get back a lot of quality data in return.’ That’s when they allowed me to

Hepatology started tracking quality measures long before GIQuIC was available, said Michael S. Morelli, MD, president of the group.

“One of the endeavors we’ve embarked on over the past few years is to stay at

GIQuIC was rolled out nationally in mid-2010 and is now available to any site where endoscopy procedures are performed, including offices, ambulatory surgery centers and hospitals.

The concept of GIQuIC was tested over the course of two years in a pilot program involving more than 20 sites, including about 60 physicians, from around the country. and to see if this type of benchmarking effort could suggest trends in the real-world performance of endoscopists.

How long are colonoscopies taking? How many polyps are endoscopists detecting?

What surveillance intervals are they recommending? Are patients adequately prepped? Are procedures matching up with indications?

Throughout the course of the pilot, participants submitted data through manual data entry or endoscopy report writers (endowriters) to the data registry. They had periodic meetings and received reports on how each compared to one another and how well they met the standards of care for colonoscopy as established by an ASGE and ACG task

where endoscopy procedures are performed, including offices, ambulatory surgery centers (ASC) and hospitals. Fees for participation in the service are based on the number of physicians in the practice.

Getting Set Up When Dr. Woods first approached her institution, The Methodist Hospital System in Houston, with the idea of installing a quality data collection system, they approved of the idea, but not of GIQuIC. “They said, ‘This doesn’t look like it would be that hard to do: We have our own IT people, so we can set this up, but we don’t want to share our data outside the hospital system, so we’ll set up a data collecting system on our own,’ ” she said.

bring GIQuIC to the table.”

During the pilot project, Dr. Woods’ husband, who works in her office as a researcher, uploaded all of her data manually. But the GIQuIC system The Methodist System has purchased for all hospitals in its system will link to the endowriter they use. “We’ll all do the same type of report so that it’s standardized, and we’ll upload our data whenever it requires us to do so, then get our reports back—so no more manual data entry,” she said.

GIQuIC may seem a natural direction for groups that already have been investigating ways to capture quality indicators or actually have implemented ways to do so. Indianapolis Gastroenterology and

the forefront of the movement in medicine toward demonstrating quality,” he said, noting that his group published a paper on colonoscopy performance and benchmarking around the time the ACG and ASGE were rolling out GIQuIC (Morelli MS et al. J Clin Gastroenterol 2010;44:152-153). “This system really worked well with what we were trying to accomplish, which was to start measuring how well we were performing endoscopy services, specifically our colonoscopy quality outcomes.”

Prior to adopting GIQuIC, Dr. Morelli’s group had extracted a lot of their data manually. “With this program, we’re able to do it electronically. We can see GIQuIC, page 26

26

Gastroenterology & Endoscopy News • JUNE 2012

GIQuIC continued from page 25

get almost any type of information we need with the touch of a button through the GIQuIC program,” he said. “It is helping us accomplish what we want to do—to measure our quality—and it’s helping us support the professional societies we belong to.”

“The quality measures being gathered by the GIQuIC registry are the same as those being collected for the endoscopy reports, so when we enter information for the endoscopy reports, we’re entering information for the benchmarking registry program as well,” he said.

Identifying Gaps It took a little time to implement and fine-tune GIQuIC, to identify individuals in the endoscopy center to manage it and to get everyone on board using it, but at this point Indianapolis Gastroenterology and Hepatology has accu-

ways to close them; the next step is to set up quality improvement programs for the practice.

“Thus far, we’ve been giving information to individual physicians and it’s up to them to devise their own strategies for improvement, but we want to standardize that a little bit,” Dr. Morelli said.

Selling Points ‘We’ve been able to use this data not only to start to devise ways to improve, but we’ve also started marketing to our patients—showing them that we’re doing better than the national

‘We can get almost any

benchmarks.’

type of information we

—Michael S. Morelli, MD

need with the touch of a button through the GIQuIC program. It is helping us accomplish what we want to do—to measure our quality—and it’s helping us support the professional societies we belong to.’

—Michael S. Morelli, MD David Greenwald, MD, gastroenterology fellowship training director and associate division director, Montefiore Medical Center, New York City, has been enthusiastic about benchmarking, registries and GIQuIC for years through his leadership in the ASGE Endoscopic Unit Recognition Program.

“We’ve been promoting the use of databases and benchmarking for many years now, because we think quality is critical,” he said. “It’s not enough to just do a colonoscopy for cancer screening—it has to be high quality each and every time.”

The Advanced Endoscopy Center in the Bronx, N.Y., of which Dr. Greenwald is the medical director, implemented the program about six months ago. So far it’s running smoothly. “It’s been going great because the required data collection is truly behind the scenes,” Dr. Greenwald said. “It’s seamless. You don’t actually know it’s happening.”

Dr. Greenwald’s center already was using an endowriter to create endoscopy reports after procedures, and as such, involvement in GIQuIC does not require an extra step.

That information is then uploaded electronically at regular intervals to the registry, which is run by a CMS-qualified vendor. The data are stripped of all identifiable information, encrypted and batched for use in reporting and benchmarking. Participants can generate reports on anything in the registry to benchmark themselves against local, regional or national groups.

Dr. Greenwald’s group found the program relatively easy to establish. “We needed some assistance from the software manufacturer of our endoscopic report, but they are familiar with GIQuIC, helped us set it up and customized it for our needs,” Dr. Greenwald said.

Indianapolis Gastroenterology and Hepatology spent a few months setting up GIQuIC, making sure the interface worked with their endowriter and that they were entering the data they needed to be entering and doing so in the right way. “We did find some bugs, but that’s what it’s all about,” Ms. Allen said. “I think we were one of the first practices to do this with CORI [Clinical Outcomes Research Initiative], and it’s been working really well.”

mulated enough information to put it to use. “We now have six to nine months, enough data to be meaningful,” Dr. Morelli said.

With the reports from GIQuIC, the group has been able to pinpoint stronger and weaker areas of performance. “This program has really helped identify certain gaps we’ve had in services we’re providing,” Dr. Morelli said. “In some areas, it’s really been a surprise to some of the physicians how well they are or are not doing compared with what they thought.”

Just as most drivers consider themselves at least as good if not better than others behind the wheel, most physicians think they’re doing an above-average job.

“But when you look and see that you’re actually performing below the standard benchmark for polyp detection, then you can go back and try to figure out why that is,” Dr. Morelli said. “Is your prep inadequate? Are you withdrawing the scope too fast? You try to look at variations in what you’re doing and how you could improve.”

The group has now established a committee to identify gaps and think about

Of course, most physicians want to do a good job, and it seems many are open to using a tool that will help them identify areas of weakness if it helps them toward the goal of improving in order to provide the best service they can for their patients. But a little financial incentive doesn’t hurt.

“We’ve been able to use this data not only to start to devise ways to improve, but we’ve also started marketing to our patients—showing them that we’re doing better than the national benchmarks,” Dr. Morelli said. “We want to prove our quality to them and make them comfortable coming to us, to differentiate us from others who do colonoscopy.”

Indianapolis Gastroenterology and Hepatology also has started talking with insurance companies about how they can use this information to get paid according more to how well they’re doing rather than how much they are doing.

“The current status of medicine is fee for services, but the future of medicine will be based on cost-effectiveness— doing the right thing, demonstrating high quality with good outcomes,” Dr. Morelli said.

Ms. Allen found participation in GIQuIC worked to the group’s advantage during recent contract negotiations with an insurance payer. “I think they were very impressed with the results and with the fact that we had the data, which shows them we are committed to quality,” she said. “They appreciate the fact that we have statistics like that, so I think that’s very helpful.”

Programs like GIQuIC may help all parties win, said Dr. Morelli. “[They are] good for the patient because they’re cost-effective, demonstrate high quality and help doctors to improve; good for the physician because it helps them practice high-quality medicine and, hopefully, get reimbursed for quality rather than volume; and good for insurance companies to not pay for needless procedures or procedures that are not done effectively,” Dr. Morelli said.

“They’re going to be paying for quality, which is what everyone wants. I think these types of programs really help propel medicine, in particular our specialty, n toward that type of future.”

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Gastroenterology & Endoscopy News • JUNE 2012

Lynch Syndrome Cancer Risks Clarified Known Associations Confirmed, Pancreatic Cancer Risk Suggested

By Christina Frangou A new prospective study of patients with Lynch syndrome provides the strongest evidence yet that relatives without the characteristic mutation face no greater risk for cancer than the general population.

“Family members who do not have the mutation will not need any more surveillance than anybody out on the street, based on these findings. That, of course, is a very, very big advantage not only for the patients’ peace of mind but also money-wise for the health system,” said Albert de la Chapelle, MD, PhD, professor of molecular virology, immunology and medical genetics at the Ohio State University in Columbus.

The findings, which were published Feb. 13 in the Journal of Clinical Oncology, may have implications for screening and early detection of cancers in patients who do have this mutation (Win AK et al.

2012;30:958-964).

Additionally, the study provides clearer estimates of the risks for cancers already known to be associated with Lynch syndrome, including colon, uterus, ovary, kidney, stomach and bladder malignancies (Table). It also suggests that people with this inherited disorder may have increased risks for breast and pancreatic cancers.

This is the first study to show a possible link between breast cancer and Lynch syndrome, contrary to previous studies that found no association between the two (Buerki N et al. Genes Chromosomes Cancer 2012;51:83-91; Walsh MD et al. Clin Cancer Res 2010;16:2214-2224).

The finding will need confirmation in larger studies, according to investigators.

“Further clarification of the risk for breast cancer for women at various ages is needed to determine the recommended age for mammography for each patient, and to determine whether additional tests such as MRI [magnetic resonance imaging] are warranted for women with Lynch syndrome,” said Mark A. Jenkins, PhD, the senior author of the study and associate professor at the University of Melbourne, in Australia.

Lynch syndrome is an inherited condition characterized by a mutation in one of the four key mismatch repair (MMR) genes—MLH1, MSH2, MSH6 and PMS2. Carriers are already known to be at high risk for developing some cancers, particularly colon cancer, and are diagnosed at younger ages than the general population. Previous research has suggested that three to five out of every 100 colon cancers are caused by Lynch syndrome.

In this study, researchers followed a group of 446 carriers with one of four mismatch repair gene mutations related to Lynch syndrome and 1,029 of their relatives who did not have these mutations. The participants were evaluated at five-year intervals at research centers in the United States, Canada and Australia.

At a median follow-up of five years, the researchers found that compared with the general population, mutation carriers had a 20-fold greater risk for colorectal cancer (standardized incidence ratio [SIR],

20.48; 95% confidence interval [CI], 11.7133.27; P<0.001); a 30-fold higher risk for endometrial cancer (SIR, 30.62; 95% CI, 11.24-66.64; P<0.001); a 19-fold greater risk for ovarian cancer (SIR, 18.81; 95% CI, 3.8854.95; P<0.001); an 11-fold greater risk for renal cancer (SIR, 11.22; 95% CI, 2.31-32.79; P<0.001); and a 10-fold greater risk for pancreatic, stomach and bladder cancers (SIR, 10.68; 95% CI, 2.68-47.70; P=0.001; SIR, 9.78; 95% CI, 1.18-35.30; P=0.009; SIR, 9.51; 95% CI, 1.15-3.37; P=0.009, respectively).

The analysis also showed a fourfold greater risk for breast cancer (SIR, 3.95; 95% CI, 1.59-8.13; P=0.001). However, experts have Table. Standardized Incidence Ratios questioned the significance of that find- Of Cancers in Patients With Lynch Syndromea ing. Only seven cases of breast cancer were Endometrial cancer 30.62 reported in the study and only two cases of pancreatic cancer. Although the analysis Colorectal cancer 20.48 showed a statistically significant increased risk Ovarian cancer 18.81 for breast cancer, the numbers may be too few Renal cancer 11.22 to be definitive.

C. Richard Boland, MD, the chief of gasPancreatic cancer 10.68 troenterology at Baylor University Medical Stomach cancer 9.78 Center in Dallas, said larger studies have not Bladder cancer 9.51 shown a link between Lynch syndrome and Breast cancer 3.95 these two cancers. The nine cases reported in a W

in AK, Young JP, Lindor NM, et al.

Colorectal and other cancer risks for carrithis study are not enough to counter the preers and noncarriers from families with a DNA mismatch repair gene mutation: vious studies, he said. a prospective cohort study. J Clin Oncol. 2012;30:958-964.

“There is nothing wrong with this study, but I will not change any aspect of my clinical practice evidence supports screening for pancreatic cancers, so it is unlikely that MMR gene mutation carriers would based on this work,” he said.

Dr. de la Chapelle said the numbers “absolutely call” undergo pancreatic screening.

“There is no data demonstrating that screening for for this question to be reexamined in future studies. these other cancers is beneficial, in part due to the “Even if there is an increased risk, I don’t consider absence of effective screening tests,” said Dr. Jenkins. the risk very high,” he said.

The researchers are continuing to follow this cohort.

“If somebody asked about the risk, I would say ‘yes, Since much larger numbers of carriers are needed to there may be one but it is not possible today to give a determine the cancer risks specific to each of the four definitive answer,’ ” he continued. “This may call for genes for Lynch syndrome, the researchers are estabgreater alertness to the possibility. In other words, lishing the International Mismatch Repair Consortium maybe these people should see their doctor a tad more to pool data from 51 clinical research centers around often than they would otherwise regarding breast the world.

Collectively, these centers treat more than cancer.”

7,500 families with Lynch syndrome and over 13,000 The study confirmed that mutation carriers who mismatch mutation carriers. developed cancer were generally diagnosed at a younger In 2009, the Evaluation of Genomic Applications age than the general population. The median age for in Practice and Prevention Working Group, which was diagnosis of colorectal cancer was 49 years. supported by the U.S. Centers for Disease Control and Most previous studies of Lynch syndrome famiPrevention (CDC), recommended that all individuals lies have been retrospective. This new study is one of with a new diagnosis of colorectal cancer, regardless the first to prospectively quantify the risks for cancer of age or family history, be offered genetic testing for for MMR gene mutation carriers and their family Lynch syndrome in order to help prevent cancer in members. their close relatives.

Close biological relatives such as parents, children, The primary benefit will be the identification of sisters and brothers of people with Lynch syndrome are relatives who also are carriers of a gene mutation for at a 50% risk for also having Lynch syndrome. Other Lynch syndrome.

Affected relatives can be offered relatives such as grandparents, aunts, uncles, nieces and appropriate screening beginning at ages 20 to 25 years, nephews are at increased risk as well. according to their report.

The question now is what these results mean for The working group is independent, and recompeople who have the gene mutations.

For colorectal cancer, these individuals are already mendations are not official positions of the CDC or undergoing increased surveillance and should con- the U.S. Department of Health and Human Services tinue to do so, the researchers said. But for pancre- [Evaluation of Genomic Applications in Practice and atic and breast cancers, as well as other cancers, the Prevention (EGAPP) Working Group. Genet Med appropriate course of action is less clear. Very limited 2009;11:35-41]. n

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Gastroenterology & Endoscopy News • JUNE 2012

Constipation: What Can Sisyphus Teach Us About Regularity?

Gary H. Hoffman, MD

Am I Constipated?

Attending Surgeon, Division of Colorectal Surgery Cedars-Sinai Medical Center Los Angeles, California Attending Surgeon, Division of General Surgery Associate Clinical Professor of Surgery David Geffen School of Medicine University of California, Los Angeles

Remember Sisyphus, the Greek king of Ephyra? Punished for his hubris, he was condemned to roll a boulder uphill for eternity. Just before reaching the top of the hill, the boulder would roll down to the bottom and Sisyphus would have to begin anew. Interminable activities often are described as Sisyphean. And so it is with constipation: It seems interminable and unbearable.

Everyone claims to be constipated at some time. The constipation may be an acute episode or a chronic condition. Yet, ask the average person to describe constipation and all the answers are different.

Does a rock-hard bowel movement or a sense of fullness after evacuation qualify?

What about straining to have a bowel movement? To further complicate matters, when science defines constipation, few people meet the criteria. Are constipation sufferers doomed to the Sisyphean struggle of pushing rocks? Can the full feeling and inability to go be remedied?

An acute change in bowel habits requires an explanation. Finding none, constipation is diagnosed when a patient reports having less than three bowel movements per week, with severe constipation diagnosed with less than one bowel movement per week. Statisticians tell us that 95% of adults have between three and 21 bowel movements per week. The median is one bowel movement per day. Unfortunately, one bowel movement per day seems to be the “holy grail” of bowel movement frequency and patients often are frustrated in their attempts to achieve this average. In fact, natural irregularity is the true normal.

Most true constipation has an idiopathic etiology and the treatment of the psychological and physical distress associated with idiopathic constipation is usually in the form of symptomatic relief. What is available for those patients who must “do something” about their bowel habits?

A Kind Word Might Help The first step in relieving patient anxiety is through education, with an effort to dispel the myth of stool regularity. Verbal reassurance is the best first medicine.

“What goes in will come out ... relax.”1 This advice actually helps occasionally.

Failing this advice, patient education will allow the seeker to choose from a panoply of available options. It is important

that the patient discuss all of the following options with a physician before beginning any treatment programs. Some of these preparations can decrease the absorption of important prescription medications and alter their effectiveness.

Want the Hulk? Eat the Bulk!

In our Westernized diet, we often fall short of the recommended consumption of 25 g of fiber per day, but this requirement varies with age and gender. Fiber binds up to 30 times its own weight in water and allows for a bulkier, softer and easier movement. Fiber is found in fruits and vegetables or in bran, and when ingested in sufficient quantities, often relieves constipation. Some cereals contain 15 g of fiber per half cup. Some actually taste good. As patients see dietary changes as “natural,” the psychological burden of having to take a daily “medication” is avoided. Not uncommonly, side effects such as abdominal bloating and flatulence may occur.

Different preparations affect individuals differently, both in stool bulk and flatulence. A trial-and-error approach is used.

Patience is advised as the body begins to adjust. Water must be consumed with each preparation. Excessive flatulence may be removed by rectal transport or by ingesting a different fiber preparation.

Psyllium seeds are derived from plants.

Table. Treatment Options for Constipation Treatment Option

Pros

Cons

Lubricants/Mineral oils

•F acilitates bowel movements • Promotes soft bulk

• Fat-soluble vitamins may not be absorbed • Patient may become deficient in vitamins A, D, E, K • Larger doses may cause rectal leakage • Oil may interact with warfarin and birth control pills

Emollients (Colace, Dialose, Docusate, Surfak)

• Penetrates, wets stool • Often effective for painful anal fissures

• May cause bloating and flatulence

Hyperosmolar laxatives (GlycoLax, lactulose, Miralax, sorbitol)

• Promotes water retention in stool • Does not alter electrolyte balance

• May cause bloating and flatulence

Saline laxatives (Fleet, Milk of Magnesia, Magnesium Citrate, Visicol)

• Softens, bulkens stool • Rapid acting, used in bowel cleansing

• Potenitally dangerous electrolyte distrubance, dehydration or hypovolemia • Rare nephrocalcinosis and renal failure possible

Stimulants (Aloe, Cascara, Castor oil, Correctol, Dulcolax, Ex-Lax, prunes, Senna, Senokot)

• Increases water in stool

• Prolonged use may lead to peristaltic dependence

Herbs (Green tea)

• May contain polyphenol stimulant laxative or anthranoid stimulant

• May lead to colonic peristaltic dependence • May reduce water absorption in colon

Bulking agents (Benefiber, Citrucel, Equilactin, Fiberall, Fibercon, Konsyl, Metamucil, Modane Bulk, psyllium, Serutan)

• Often relieves constipation • Absorbs water, bulkens and softens stool

• Abdominal bloating, flatulence

When taken as 7 g per serving with 8 ounces of water three times daily, the seeds absorb water and increase bulk. The seeds and the stool become surrounded by mucilage, a thick glue-like substance, promoting softening. Psyllium preparations are marketed under brand names such as Fiberall, Konsyl, Metamucil, Modane Bulk or Serutan. Benefiber contains wheat and dextrin, a type of sugar and also a bulking agent.

Cellulose is found in the cell walls of green plants. Methylcellulose is a synthetic compound created from cellulose. Methylcellulose strongly attracts and holds water, bulking and softening the stool. It is marketed under the brand name of Citrucel, and also is available in a generic form. It must be taken with water.

Polycarbophil is a synthetic chemical that also attracts water, increasing stool bulk and softness. It is marketed as Equilactin, Fibercon or Konsyl Fiber. As always, it should be ingested with at least 8 ounces of water.

Lubricants Mineral oil serves as an excellent facilitator of bowel movements. The oil coats the stool and traps water within it, promoting soft bulk. The various commercial preparations are supplied as the plain oil or as an emulsion of oil and water.

There are several potential problems with ingesting mineral oil preparations.

The first is that fat-soluble vitamins may become dissolved in the oil rather than being absorbed, and patients taking oil on a long-term basis might become deficient in vitamins A, D, E or K. Lipoid pneumonia might occur if patients, especially the elderly, aspirate the oil preparation when taking it at bedtime. Both of these complications may be more of a theoretical concern than a true hazard. Taking large doses of mineral oil may lead to an embarrassing rectal leakage of the oil.

Finally, there are reports of oil interactions with warfarin and birth control pills, with the effect that both of these medications may exhibit decreased effectiveness.

Emollients: Gentle but Unpredictable Emollients are wetting agents or chemical substances that lower the surface tension of liquids such as water and increase their spreading and penetrating properties. As a result, water more easily penetrates and softens the stool. The most common chemical in this class of softeners is docusate (butanedioic acid, sulfo-1,4-bis[2-ethylhexyl] ester, sodium salt, sodium 1,4-bis[2-ethylhexyl] see Constipation, page 32

ONLY† 1 PROBIOTIC HAS 3 CLINICALLY TESTED STRAINS Lactobacillus gasseri supports nutrient absorption and lactose digestion*1

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E XP E R T R E V I E W

Constipation continued from page 30

sulfosuccinate, or C20H37NaO7S). It can be found in Colace, Surfak, Dialose, Docusate and other commercially available preparations, which may cause bloating and flatulence. Results are not as predictable as with other medications and dosing may be changed to achieve the desired effect. This class of compounds often is used to soften the stool in patients with painful anal fissures and after various anal operations.

Gastroenterology & Endoscopy News • JUNE 2012

Hyperosmolar Laxatives: Hold Your Water

Saline Laxatives: Potentially Harmful

The best-known preparations in this group of laxatives are Miralax and glycolax, which contain polyethylene glycol (PEG) powder that is mixed with liquid. Taken on a regular basis, they promote the retention of stool water. PEG is not digested or absorbed and does not alter electrolyte balance. Lactulose and sorbitol, both sugars, function in a similar manner. Bloating and flatulence are not uncommon side effects, and are dose-related.

Phosphate, citrate, magnesium and sulfate are ions that cause water to be drawn into the stool, resulting in softening and bulking. They are rapid acting and also are used in bowel cleansing before colonoscopy or colonic operations.

Serious, potentially life-threatening electrolyte disturbances, dehydration and hypovolemia may occur. The phosphate preparations also are associated with rare nephrocalcinosis and renal failure, especially in those patients taking

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angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Preparations include Fleet Phosphosoda, which has been recalled, and the pill form of the compound Visicol, which has fallen out of favor because of potential renal side effects. Other saline laxatives are marketed under the names of Milk of Magnesia, Magnesium Citrate and others.

Stimulants: Popular, but Not Advised for Regular Use Stimulants stimulate. Stimulants are chemicals. They work by increasing the rate and intensity of intestinal peristalsis and they promote water secretion into the small intestine. They also may increase the amount of water in the stool by decreasing water absorption.

Dulcolax and Correctol contain bisacodyl (triphenylmethane). Cascara, Aloe, Senna, Senokot and Ex-Lax contain the organic hydrocarbon anthraquinone. Castor oil contains ricinoleic acid. Prunes contain the stimulant phenolphthalein but also may promote peristalsis through the osmolar action of sorbitol.

Prolonged usage of these compounds may lead to peristaltic dependence and should be avoided. Melanosis coli is seen endoscopically in the colon. It is a brown-spotted, benign discoloration of the mucosa and is an indicator of chronic stimulant use.

Herbs? No!

♦ 13,477 gastroenterologists

Most herbal or “natural” products (including green tea) contain a polyphenol stimulant laxative or an anthranoid stimulant. These can lead to colonic peristaltic dependence. Herbal preparations may promote secretion of water into the small intestine or reduce water absorption in the colon. These are not recommended for regular use as laxatives.

♦ 1,532 colon and rectal surgeons ♦ 982 pediatric gastroenterologists ♦ 798 physician assistants ♦ 219 nurse practitioners ♦ 109 hepatologists

The Bottom Line? Listen to Your Father

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4/4 (monthly) readers

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cover-to-cover readers

Most people are not truly constipated.

For those wishing to avoid the uncomfortable feeling associated with a lack of regularity, numerous preparations are available. Some are innocuous and some must be used with caution. However, the best bowel movement is a natural bowel movement, delivered on nature’s time table. Remember, “What goes in will come out … relax.” n

Reference 1. Norman N. Hoffman, MD. Overheard in discreet personal communications to thousands of constipatees during the past 24 years.

Dr. Hoffman is a senior member of Los Angeles Colon and Rectal Surgical Associates (www.lacolon.com).

F OU N D I N T R A N S LAT I O N

Gastroenterology & Endoscopy News • JUNE 2012

33

Methylnaltrexone Effective for Opioid-induced Constipation Researchers Pushing for Nonmalignant Pain Indication, Investigating Oral Formulation

By Rosemary Frei, MSc Virtually all the data on methylnaltrexone (Relistor, Progenics Pharmaceuticals Inc.) seem to confirm the drug can bring fast, effective and relatively side effect– free relief to patients suffering from opioid-induced constipation. The potential

significant adverse events are gastrointestinal (GI) perforation and abdominal pain, but these do not appear to be a large concern.

The subcutaneous form of methyl­­­ naltrexone, an opioid antagonist, was approved by the FDA in April 2008 for add-on therapy for patients receiving palliative care for advanced illnesses and

those who have opioid-induced constipation but have not responded sufficiently to laxatives. Salix Pharmaceuticals is now seeking an indication for patients with nonmalignant pain based on data from 2011, and recently presented the results of a Phase III trial of oral methylnaltrexone at the 2012 Digestive Disease Week meeting.

The 2008 approval was based largely on two randomized, placebo-controlled studies funded by Progenics Pharmaceuticals, one of which was later published in The New England Journal of Medicine (Thomas J et al. 2008;358:2332-2343).

The results demonstrated that 48% and 52% of patients, respectively, treated see Methylnaltrexone, page 34

Spring Issue Now Available

GI FELLOW

ADVISOR

An educational newsletter for physicians in training

‘Our results show that if a patient responds early on, it’s a good sign that they’re going to continue responding.’

—Edward Michna, MD

www.GIFellowAdvisor.com Sponsored by:

34

F OU N D I N T R A N S LAT I O N

Methylnaltrexone continued from page 33

with one or two to four daily injections of methylnaltrexone had a rescue-free bowel movement (RFBM) within four hours. The respective rates for patients receiving placebo were 15% and 8%,

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

Commentary by Dr. Mullick

T

reatments for constipation are of all varieties. There are water and fiber supplements.

We have many forms of laxatives, ranging from osmotic or stimulant laxatives. But there are patients who do not respond well to these medications. One of the classes of medicines that can make it difficult to treat constipation is narcotics. Let’s take a look at a breakthrough in treatment of narcotic-induced constipation.

Methylnaltrexone will be useful for patients who have chronic pain issues or have been treated with narcotics for diseases like pancreatitis. Additionally, patients with cancer often are on narcotics. Thus this medicine can be useful in that case.

Physicians should be careful to be aware of any signs of mechanical bowel obstruction; methylnaltrexone is contraindicated in this case. Finally, if there are any signs of worsening pain with this medicine, it may be necessary to stop the medication. Naturally, methylnaltrexone, while helping with the narcoticinduced constipation may cause a reversal of the effects of narcotics resulting in worsening pain.

Overall, this is a useful medication, but it has a specific group of patients in whom it can be useful.

respectively (P<0.001, for both comparisons). Moreover, the median time to laxation was significantly shorter among patients receiving methylnaltrexone compared with placebo.

Results of a more recent randomized controlled trial indicate that approximately 30% of injections of subcutaneous methylnaltrexone in patients with chronic, noncancer pain and opioidinduced constipation treated once a day or once every other day experienced RFBM within four hours of treatment (Michna E et al. J Pain 2011;12:554-562). The

Gastroenterology & Endoscopy News • JUNE 2012

four-week trial involved 150 patients randomized to receive 12 mg of subcutaneous methylnaltrexone daily, another 148 randomized to receive 12 mg of subcutaneous methylnaltrexone every other day and 162 given daily placebo injections. The results indicated the medication is effective and also safe, although the patients in the methylnaltrexone groups suffered from more abdominal pain, nausea, diarrhea and hyperhidrosis than did the placebo subjects.

A post hoc analysis of the trial published three months later showed that

42.3% of patients responded to at least two of the first four daily treatments, and those patients averaged 4.8 RFBMs per week compared with two RFBMs per week among the other 57.7% of subjects (Michna E et al. Pain Med 2011;12:12231230). Both analyses were funded by Progenics.

Edward Michna, MD, lead investigator of both studies, said that he and his colleagues use methylnaltrexone primarily in cancer patients who have been admitted to the hospital for severe constipation, and one or two doses are

Indication INCIVEK (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment naïve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers.

The following points should be considered when initiating treatment with INCIVEK: INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with INCIVEK combination treatment INCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or other HCV NS3/4A protease inhibitors

Important safety information Contraindications

Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.

INCIVEK combination treatment is contraindicated in women who are or may become pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. If ribavirin is used during pregnancy or in the event of a pregnancy while on treatment, inform the patient of the potential hazard to a fetus. INCIVEK combination treatment is also contraindicated in men whose female partners are pregnant.

INCIVEK is contraindicated when combined with drugs that 1) are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events and 2) strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVEK. Contraindicated medications are alfuzosin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, sildenafil (Revatio®) or tadalafil (Adcirca®) for pulmonary arterial hypertension, oral midazolam, and/or triazolam.

Anemia has been reported with peginterferon alfa and ribavirin treatment.

Adding INCIVEK is associated with an additional decrease in hemoglobin compared to peginterferon alfa and ribavirin alone. Hemoglobin values of ≤10 g per dL were observed in 36% of patients, and <8.5 g per dL in 14% of patients who received INCIVEK combination treatment compared to 17% and 5%, respectively, with peginterferon alfa and ribavirin alone.

Hemoglobin should be monitored at baseline and at weeks 2, 4, 8, and 12, or as clinically appropriate. Use the labeled ribavirin dose modification guidelines to manage anemia; if ribavirin dose reductions are inadequate, consider discontinuing INCIVEK. If ribavirin is permanently discontinued, INCIVEK must also be permanently discontinued. The dose of INCIVEK must not be reduced and must not be restarted if discontinued

Warnings and precautions

Pregnancy: Ribavirin may cause defects and/or death of the exposed fetus.

Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained just before initiation of therapy Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during combination treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping all treatment.

Female patients may continue hormonal contraceptives but they may not be reliable during INCIVEK dosing and for up to 2 weeks after stopping INCIVEK. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome (SJS) were reported in <1% of patients receiving INCIVEK combination treatment compared to none with peginterferon alfa and ribavirin alone. These serious reactions required hospitalization and all patients recovered. Presenting signs of these reactions may include rash, fever, facial edema, target lesions, mucosal ulcerations, and evidence of internal organ involvement. If serious skin reactions occur, all components of INCIVEK combination treatment must be discontinued immediately and the patient referred for urgent medical care Rash developed in 56% of patients who received INCIVEK combination treatment compared to 34% with peginterferon alfa and ribavirin alone. Severe rash was reported in 4% of patients treated with INCIVEK combination treatment compared to <1% with peginterferon alfa and ribavirin alone. Severe rash may have a prominent eczematous component.

Patients with mild to moderate rash should be followed for progression of rash or development of systemic symptoms. If rash becomes severe or systemic symptoms develop, discontinue INCIVEK. Peginterferon alfa and ribavirin may be continued.

Adverse reactions

The most common adverse reactions seen with an incidence ≥5% with INCIVEK over controls were rash (56% vs 34%), fatigue (56% vs 50%), pruritus (47% vs 28%), nausea (39% vs 28%), anemia (36% vs 17%), diarrhea (26% vs 17%), vomiting (13% vs 8%), hemorrhoids (12% vs 3%), anorectal discomfort (11% vs 3%), dysgeusia (10% vs 3%), and anal pruritus (6% vs 1%) Please see the Brief Summary on the adjacent pages to this ad. a

ADVANCE was a randomized, double-blind, parallel-group, placebo-controlled, Phase 3 trial in treatment-naïve patients with genotype 1 chronic HCV and compensated liver disease (N=1088). INCIVEK was given for the first 8 weeks of treatment (T8 arm) or the first 12 weeks of treatment (T12 arm) in combination with pegIFN-RBV for either 24 or 48 weeks. Patients who had undetectable HCV RNA (target not detected) at Weeks 4 and 12 (eRVR) received 24 weeks of pegIFN-RBV, and patients who did not have undetectable HCV RNA at Weeks 4 and 12 (no eRVR) received 48 weeks of pegIFN-RBV treatment. The control regimen had a fixed treatment duration, with telaprevir-matching placebo for the first 12 weeks and pegIFN-RBV for 48 weeks. SVR in all trials was defined as HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. b REALIZE was a randomized, double-blind, placebo-controlled, Phase 3 trial in patients with genotype 1 chronic HCV and compensated liver disease who were previously treated with pegIFN-RBV (N=662). The trial enrolled prior relapsers and prior nonresponders (including partial responders and null responders). Patients received INCIVEK combination treatment for 12 weeks (with and without a 4-week lead-in of pegIFN-RBV alone) followed by treatment with pegIFN-RBV alone for a total of 48 weeks. The control regimen received a telaprevir-matching placebo for the first 16 weeks followed by pegIFN-RBV alone for a total of 48 weeks. Immediate-start and lead-in arms delivered comparable rates of SVR, relapse, and virologic failure; therefore, data were pooled. SVR in all trials was defined as HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. c Adult patients with genotype 1 chronic hepatitis C virus and compensated liver disease.

HCV = hepatitis C virus. INCIVEK combination treatment = INCIVEK + pegIFN-RBV for 12 weeks, and an additional 12 or 36 weeks of pegIFN-RBV alone. pegIFN = peginterferon alfa. RBV = ribavirin. SVR (virologic cure) = sustained virologic response; defined as HCV RNA <25 IU/mL at 24 weeks after the planned end of treatment. RVR = undetectable HCV RNA (target not detected) at Week 4; the first milestone toward eRVR. eRVR = undetectable HCV RNA (target not detected) at Weeks 4 and 12. Treatment-naïve = received no prior therapy for HCV, including interferon or pegylated interferon monotherapy. Partial responder = ≥2 log10 reduction in HCV RNA at Week 12, but not achieving undetectable HCV RNA at the end of a prior pegIFN-RBV therapy. Relapser = undetectable HCV RNA at the end of a prior pegIFN-RBV regimen, but detectable HCV RNA within 24 weeks of follow-up. Null responder = <2 log10 reduction in HCV RNA at Week 12 during a prior pegIFN-RBV therapy.

References: 1. IMS Health, IMS NPA Market DynamicsTM, 05/2011 to 03/2012, extracted 04/2012. 2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.

F OU N D I N T R A N S LAT I O N

Gastroenterology & Endoscopy News • JUNE 2012

‘From an evolutionary standpoint, it seems more conceivable that the plethora of opioid receptor types expressed in the gut serve not only to modulate motility of the smooth muscles of the bowel, but also to participate in antinociception.’

—Xiulu Ruan, MD often all that’s required to “get them moving.”

“Progenics asked for the post hoc analysis because [the company] wanted

to find out which patients have the highest chance of success, since it’s an expensive medication,” said Dr. Michna, director of the Pain Trials Center and

assistant professor at Harvard Medical School, Boston. “Our results show that if a patient responds early on, it’s a good sign that they’re going to continue responding.”

Another Progenics-supported study confirmed that when methylnaltrexone is administered subcutaneously, it has a high bioavailability at therapeutic dose levels. It also has a terminal half-life of eight to nine hours, is metabolized only to a limited extent before being excreted and has a limited number of drug–drug interactions.

1

THE # PRESCRIBED

DIRECT-ACTING ANTIVIRAL

IN ADULTS WITH GENOTYPE 1 CHRONIC HEPATITIS C VIRUS 1

In adults with genotype 1 chronic hepatitis C virus (HCV) and compensated liver disease

POWERFUL RESULTS

Superior SVR (virologic cure) rates across all patient types studied with INCIVEK combination treatment vs pegIFN-RBV alone 79% (285/363) of treatment-naïve patients achieved SVR vs 46% (166/361) with pegIFN-RBV alonea 86% (246/286) of prior relapsers achieved SVR vs 22% (15/68) with pegIFN-RBV aloneb 59% (57/97) of prior partial responders achieved SVR vs 15% (4/27) with pegIFN-RBV aloneb 32% (47/147) of prior null responders achieved SVR vs 5% (2/37) with pegIFN-RBV aloneb – A high proportion of previous null responders (particularly those with cirrhosis) did not achieve SVR and had telaprevir resistanceassociated substitutions emerge on treatment with INCIVEK combination treatment

START TRIPLE THERAPY DAY 1 All patientsc start Day 1 with triple therapy for 12 weeks

RAPID VIROLOGIC RESPONSE

Rapid achievement of undetectable HCV RNA in treatmentnaïve patients—68% (246/363) of treatment-naïve patients achieved

undetectable HCV RNA at Week 4 (RVR) vs 9% (34/361) with pegIFN-RBV alonea,2 12 weeks of triple therapy and an additional 12 or 36 weeks of pegIFN-RBV alone is required

Majority of treatment-naïve patients and prior relapsers achieved eRVR—58% (212/363) of treatment-naïve patients and 76% (218/286) of prior relapsers achieved eRVR in the ADVANCE and REALIZE trials, respectivelya,b

In the ADVANCE trial, 8% (29/361) achieved eRVR with pegIFN-RBV alone 24-week total treatment duration is recommended in treatment-naïve patients and prior relapsers who achieve eRVR – Treatment-naïve patients with cirrhosis who have undetectable HCV RNA at Weeks 4 and 12 may benefit from a total treatment duration of 48 weeks A confirmed “detectable but below limit of quantification” should not be considered equivalent to an “undetectable” (target not detected) result

An additional 12 or 36 weeks of pegIFN-RBV alone is required

SAFETY PROFILE

1797 patients were included in safety evaluations Most common adverse reactions with an incidence ≥5% with INCIVEK over controls were rash, fatigue, pruritus, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal discomfort, dysgeusia, and anal pruritus Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK 14% of patients overall discontinued INCIVEK due to adverse drug reactions INCIVEK and the Blue Arrow logo are trademarks of Vertex Pharmaceuticals Incorporated.

The brands listed are trademarks of their respective owners. ©2012 Vertex Pharmaceuticals Incorporated | All rights reserved | VX12-3593 | 5/12

35

“The onset of activity is fairly quick, and the practical half-life is short—in fact, the clinically relevant half-life is only two to three hours because the concentration drops so quickly after that,” confirmed Robert Israel, MD, senior vice president of medical affairs, Progenics, Tarrytown, N.Y., and senior author of The New England Journal of Medicine paper. “That means that you don’t get accumulation if you give it according to the instructions on the label, and you can give it as often as daily.” see Methylnaltrexone, page 36

36

F OU N D I N T R A N S LAT I O N

Gastroenterology & Endoscopy News â&#x20AC;˘ JUNE 2012

Methylnaltrexone continued from page 35

nonsteroidal anti-inflammatory drugs and steroids. The FDA stated that physicians should use methylnaltrexone with caution in patients with known or suspected lesions of the GI tract, and that patients who develop severe, persistent and/or worsening abdominal symptoms should be advised to discontinue therapy and immediately notify their physicians.

Several specialists weighed in on why methylnaltrexone may produce certain

â&#x20AC;&#x2DC;For opioid-induced constipation, methylnaltrexoneâ&#x20AC;&#x2122;s almost like a diagnostic test, because if patients present with constipation as their gastrointestinal disorder and also are put on narcotics for something else, I may not know if the constipation is related to the narcotics or not. But if they respond to methylnaltrexone, then itâ&#x20AC;&#x2122;s likely narcotic-related.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Douglas Drossman, MD

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Ergot derivatives

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia

GI motility agent

Cisapride

Potential for cardiac arrhythmias

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St. John's wort (Hypericum perforatum)

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Lovastatin, simvastatin

Potential for myopathy including rhabdomyolysis

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Pimozide

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PDE5 inhibitor

4JMEFOBGJM 3FWBUJPÂŽ PS UBEBMBGJM "EDJSDBÂŽ) [for Potential for PDE5 inhibitor-associated treatment of pulmonary arterial hypertension] adverse events, including visual abnormalities, a hypotension, prolonged erection, and syncope

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Orally administered midazolamb, triazolam

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b

34%

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47%

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3BTI BOE BOFNJB CBTFE PO 44$ 4QFDJBM 4FBSDI $BUFHPSZ HSPVQFE UFSNT Description of Selected Adverse Drug Reactions Rash. In controlled clinical trials, rash events (all grades) were reported in 56% of subjects who received INCIVEK combination treatment and in 34% of subjects XIP SFDFJWFE QFHJOUFSGFSPO BMGB BOE SJCBWJSJO 3BTI NPTU GSFRVFOUMZ CFHBO EVSJOH UIF GJSTU XFFLT CVU DPVME PDDVS BU BOZ UJNF EVSJOH */$*7&, DPNCJOBUJPO treatment. Improvement of rash occurs after INCIVEK dosing completion or discontinuation; however, rashes may take weeks for complete resolution.

3BTI FWFOUT MFE UP EJTDPOUJOVBUJPO PG */$*7&, BMPOF JO PG TVCKFDUT BOE EJTDPOUJOVBUJPO PG */$*7&, DPNCJOBUJPO USFBUNFOU JO PG TVCKFDUT Anemia. In controlled clinical trials, the overall incidence and severity of anemia increased with INCIVEK combination treatment compared to peginterferon alfa and ribavirin alone. The incidence of anemia adverse events was 36% with INCIVEK combination treatment compared to 17% with peginterferon alfa and SJCBWJSJO BMPOF " EFDSFBTF JO IFNPHMPCJO MFWFMT PDDVSSFE EVSJOH UIF GJSTU XFFLT PG USFBUNFOU XJUI MPXFTU WBMVFT SFBDIFE BU UIF FOE PG */$*7&, EPTJOH )FNPHMPCJO WBMVFT HSBEVBMMZ SFUVSOFE UP MFWFMT PCTFSWFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO BGUFS */$*7&, EPTJOH XBT DPNQMFUFE Anorectal Signs and Symptoms. In the controlled clinical trials, 29% of subjects treated with INCIVEK combination treatment experienced anorectal adverse events, compared to 7% of those treated with peginterferon alfa and ribavirin alone. The majority of these events (e.g., hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate in severity; less than 1% led to treatment discontinuation and all resolved during or after completion of INCIVEK dosing.

Laboratory abnormalities White Blood Cells: Treatment with peginterferon alfa is associated with decreases in mean values for total white blood cell, absolute neutrophil, and absolute lymphocyte count. More INCIVEK-treated subjects had decreases in lymphocyte counts to 499/mm3 or less (15% compared to 5%). Decreases in total white cell counts to 1,499/mm3 PS MFTT XFSF DPNQBSBCMF DPNQBSFE UP 5IF JODJEFODF PG EFDSFBTFT JO BCTPMVUF OFVUSPQIJM DPVOUT UP NN3 or less was 15% in subjects treated with peginterferon alfa and ribavirin alone compared to 12% among those treated with INCIVEK combination treatment.

Platelets: Treatment with peginterferon alfa is associated with decreases in mean platelet counts. More patients treated with INCIVEK combination treatment had decreases in mean platelet values of all grades: 47% compared to 36% treated with peginterferon alfa and ribavirin alone. Three percent of INCIVEK combination treatment subjects had decreases to 49,999/mm3 or less compared to 1% of those treated with peginterferon alfa and ribavirin-treated alone.

Bilirubin: 'PSUZ POF QFSDFOU PG */$*7&, USFBUFE TVCKFDUT DPNQBSFE UP PG QFHJOUFSGFSPO BMGB BOE SJCBWJSJO USFBUFE TVCKFDUT IBE BMM HSBEF FMFWBUJPOT JO CJMJSVCJO levels; 4% and 2% of subjects, respectively, had greater than or equal to 2.6 x ULN elevations. Bilirubin levels increased most steeply during the first 1 to 2 weeks of INCIVEK dosing, stabilized and between Weeks 12 and 16 were at baseline levels.

Uric Acid: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg per dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation.

DRUG INTERACTIONS Potential for INCIVEK to Affect Other Drugs */$*7&, JT BO JOIJCJUPS PG $:1 " $P BENJOJTUSBUJPO PG */$*7&, XJUI ESVHT UIBU BSF QSJNBSJMZ NFUBCPMJ[FE CZ $:1 " NBZ SFTVMU JO JODSFBTFE QMBTNB concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. INCIVEK is also an inhibitor of P-gp.

Co-administration of INCIVEK with drugs that are substrates for P-gp transport may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. If dose adjustments of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK is completed.

Potential for Other Drugs to Affect INCIVEK */$*7&, JT B TVCTUSBUF PG $:1 " BOE 1 HQ UIFSFGPSF ESVHT UIBU JOEVDF $:1 " BOE PS 1 HQ NBZ EFDSFBTF */$*7&, QMBTNB DPODFOUSBUJPOT BOE SFEVDF UIF UIFSBQFVUJD FGGFDU PG */$*7&, $P BENJOJTUSBUJPO PG */$*7&, XJUI ESVHT UIBU JOIJCJU $:1 " BOE PS 1 HQ NBZ JODSFBTF */$*7&, QMBTNB DPODFOUSBUJPOT Established and Other Potentially Significant Drug Interactions The table below provides effect of concentration of INCIVEK or concomitant drug with INCIVEK. These recommendations are based on either drug interaction USJBMT JOEJDBUFE XJUI PS QSFEJDUFE JOUFSBDUJPOT EVF UP UIF FYQFDUFE NBHOJUVEF PG JOUFSBDUJPO BOE QPUFOUJBM GPS TFSJPVT BEWFSTF FWFOUT PS MPTT PG FGGJDBDZ Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction Concomitant Drug Class: Drug Name

Effect on concentration of INCIVEK or Concomitant Drug

Clinical Comment

ANTIARRHYTHMICS Co-administration with telaprevir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir.

digoxin

Concentrations of digoxin were increased when co-administered with telaprevir.

The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.

telaprevir antibacterials

Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin.

or warfarin

Concentrations of warfarin may be altered when co-administered with telaprevir.

5IF JOUFSOBUJPOBM OPSNBMJ[FE SBUJP */3 TIPVME CF NPOJUPSFE XIFO XBSGBSJO JT co-administered with telaprevir.

telaprevir carbamazepine or phenytoin or phenobarbital

Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin.

Telaprevir may be less effective in patients taking these agents concomitantly.

Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response.

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antiarrhythmics

â&#x17E;&#x17E;

lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine

telaprevir escitalopram desipramine trazodone

Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir.

Concomitant use of trazodone or desipramine and telaprevir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with telaprevir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.

ANTIBACTERIALS clarithromycin erythromycin telithromycin ANTICOAGULANT warfarin

â&#x17E;&#x17E;

ANTICONVULSANTS carbamazepine phenobarbital phenytoin

â&#x17E;&#x17E; â&#x17E;&#x17E;

See table under Drug Interactions for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction.

See table under Drug Interactions for parenterally administered midazolam.

WARNINGS AND PRECAUTIONS Pregnancy: Use with Ribavirin and Peginterferon Alfa. 3JCBWJSJO NBZ DBVTF CJSUI EFGFDUT BOE PS EFBUI PG UIF FYQPTFE GFUVT &YUSFNF DBSF NVTU CF UBLFO UP BWPJE QSFHOBODZ JO GFNBMF QBUJFOUT BOE JO GFNBMF QBSUOFST PG NBMF QBUJFOUT 3JCBWJSJO UIFSBQZ TIPVME OPU CF TUBSUFE VOMFTT B SFQPSU PG B OFHBUJWF QSFHOBODZ UFTU has been obtained immediately prior to initiation of therapy.

Because INCIVEK must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male QBUJFOUT BT TJHOJGJDBOU UFSBUPHFOJD BOE PS FNCSZPDJEBM FGGFDUT IBWF CFFO EFNPOTUSBUFE JO BMM BOJNBM TQFDJFT FYQPTFE UP SJCBWJSJO 3FGFS BMTP UP UIF QSFTDSJCJOH information for ribavirin.

Female Patients-)PSNPOBM DPOUSBDFQUJWFT NBZ CF DPOUJOVFE CVU NBZ OPU CF SFMJBCMF EVSJOH */$*7&, EPTJOH BOE GPS VQ UP UXP XFFLT GPMMPXJOH DFTTBUJPO PG INCIVEK. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Examples may include barrier methods or intrauterine devices (IUDs). Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives.

Serious Skin Reactions. 4FSJPVT TLJO SFBDUJPOT JODMVEJOH %SVH 3BTI XJUI &PTJOPQIJMJB BOE 4ZTUFNJD 4ZNQUPNT %3&44 BOE 4UFWFOT +PIOTPO 4ZOESPNF (SJS) were reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin BMPOF 5IFTF TFSJPVT TLJO SFBDUJPOT SFRVJSFE IPTQJUBMJ[BUJPO BOE BMM QBUJFOUT SFDPWFSFE 5IF QSFTFOUJOH TJHOT PG %3&44 NBZ JODMVEF SBTI GFWFS GBDJBM edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).

If a serious skin reaction occurs, all components of INCIVEK combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care.

Rash. 3BTI EFWFMPQFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU 4FWFSF SBTI F H B HFOFSBMJ[FE SBTI PS SBTI XJUI WFTJDMFT PS CVMMBF PS ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component.

Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended.

Anemia. "OFNJB IBT CFFO SFQPSUFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO UIFSBQZ 5IF BEEJUJPO PG */$*7&, UP QFHJOUFSGFSPO BMGB BOE SJCBWJSJO JT BTTPDJBUFE XJUI BO BEEJUJPOBM EFDSFBTF JO IFNPHMPCJO DPODFOUSBUJPOT )FNPHMPCJO WBMVFT MFTT UIBO PS FRVBM UP H QFS E- XFSF PCTFSWFE JO PG TVCKFDUT XIP SFDFJWFE */$*7&, DPNCJOBUJPO USFBUNFOU DPNQBSFE UP PG TVCKFDUT XIP SFDFJWFE QFHJOUFSGFSPO BMGB BOE SJCBWJSJO )FNPHMPCJO WBMVFT MFTT UIBO H QFS E- XFSF observed in 14% of subjects who received INCIVEK combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin.

In subjects receiving INCIVEK combination treatment, 4% discontinued INCIVEK, 1% discontinued INCIVEK combination treatment, and 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia. In subjects treated with peginterferon alfa and ribavirin alone, there were two discontinuations and 12% underwent ribavirin dose modification due to anemia. )FNPHMPCJO TIPVME CF NPOJUPSFE QSJPS UP BOE BU MFBTU FWFSZ XFFLT EVSJOH */$*7&, DPNCJOBUJPO USFBUNFOU 'PS UIF NBOBHFNFOU PG BOFNJB SJCBWJSJO EPTF reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of INCIVEK should be considered. If ribavirin is permanently discontinued for the management of anemia, INCIVEK must also be permanently EJTDPOUJOVFE 3JCBWJSJO NBZ CF SFTUBSUFE QFS UIF EPTJOH NPEJGJDBUJPO HVJEFMJOFT GPS SJCBWJSJO 5IF EPTF PG */$*7&, NVTU OPU CF SFEVDFE BOE */$*7&, NVTU OPU be restarted if discontinued.

Drug Interactions. See the table under Contraindications for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening BEWFSTF FWFOUT PS QPUFOUJBM MPTT PG UIFSBQFVUJD FGGFDU UP */$*7&, 3FGFS UP UIF UBCMF JODMVEFE VOEFS Drug Interactions for established and other potentially significant drug-drug interactions.

Laboratory Tests. )$7 3/" MFWFMT TIPVME CF NPOJUPSFE BU XFFLT BOE BOE BT DMJOJDBMMZ JOEJDBUFE 6TF PG B TFOTJUJWF SFBM UJNF 35 1$3 BTTBZ GPS NPOJUPSJOH )$7 3/" MFWFMT EVSJOH USFBUNFOU JT SFDPNNFOEFE 5IF BTTBZ TIPVME IBWF B MPXFS MJNJU PG )$7 3/" RVBOUJGJDBUJPO FRVBM UP PS MFTT UIBO *6 QFS N- BOE B MJNJU PG )$7 3/" EFUFDUJPO PG BQQSPYJNBUFMZ *6 QFS N- 'PS UIF QVSQPTF PG BTTFTTJOH SFTQPOTF HVJEFE UIFSBQZ FMJHJCJMJUZ BO iVOEFUFDUBCMFw )$7 3/" 5BSHFU /PU %FUFDUFE SFTVMU JT SFRVJSFE B DPOGJSNFE iEFUFDUBCMF CVU CFMPX MJNJU PG RVBOUJGJDBUJPOw )$7 3/" SFTVMU TIPVME OPU CF DPOTJEFSFE FRVJWBMFOU UP BO iVOEFUFDUBCMFw )$7 3/" SFTVMU SFQPSUFE BT i5BSHFU /PU %FUFDUFEw PS i)$7 3/" /PU %FUFDUFEw

)FNBUPMPHZ FWBMVBUJPOT JODMVEJOH XIJUF DFMM EJGGFSFOUJBM DPVOU BSF SFDPNNFOEFE BU XFFLT BOE PS BT DMJOJDBMMZ BQQSPQSJBUF UIFSFBGUFS $IFNJTUSZ FWBMVBUJPOT FMFDUSPMZUFT TFSVN DSFBUJOJOF VSJD BDJE IFQBUJD FO[ZNFT CJMJSVCJO BOE 54) BSF SFDPNNFOEFE BT GSFRVFOUMZ BT UIF IFNBUPMPHZ FWBMVBUJPOT PS BT DMJOJDBMMZ JOEJDBUFE 3FGFS UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO JODMVEJOH QSFHOBODZ UFTUJOH SFRVJSFNFOUT General. INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with INCIVEK. 5IFSF BSF OP DMJOJDBM EBUB PO SF USFBUJOH QBUJFOUT XIP IBWF GBJMFE BO )$7 /4 " QSPUFBTF JOIJCJUPS CBTFE USFBUNFOU OPS BSF UIFSF EBUB PO SFQFBUFE DPVSTFT of INCIVEK. Hepatic Impairment. INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal UP PS QBUJFOUT XJUI EFDPNQFOTBUFE MJWFS EJTFBTF 3FGFS UP QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO XIJDI NVTU CF DP BENJOJTUFSFE with INCIVEK. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: t 1SFHOBODZ 6TF XJUI 3JCBWJSJO BOE 1FHJOUFSGFSPO BMGB t 4FSJPVT 4LJO 3FBDUJPOT 3BTI t "OFNJB */$*7&, NVTU CF BENJOJTUFSFE XJUI QFHJOUFSGFSPO BMGB BOE SJCBWJSJO 3FGFS UP UIFJS SFTQFDUJWF QSFTDSJCJOH JOGPSNBUJPO GPS UIFJS BTTPDJBUFE BEWFSTF SFBDUJPOT 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 clinical practice.

The safety assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received INCIVEK combination treatment and 493 who received peginterferon alfa and ribavirin.

Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK combination treatment compared to none of the subjects treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with INCIVEK combination treatment were skin disorders (rash BOE PS QSVSJUVT BOE BOFNJB 'PVSUFFO QFSDFOU PG TVCKFDUT EJTDPOUJOVFE */$*7&, EVF UP BEWFSTF ESVH SFBDUJPOT 3BTI BOFNJB GBUJHVF QSVSJUVT OBVTFB BOE vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK. a

56%

â&#x17E;&#x17E;

"MQIB BESFOPSFDFQUPS BOUBHPOJTU

3BTI

â&#x17E;&#x17E;

Clinical Comments

Peginterferon alfa and ribavirin

â&#x17E;&#x17E; â&#x17E;&#x17E;

Drugs within Class that are Contraindicated with INCIVEK

INCIVEK, peginterferon alfa, and ribavirin Combination Treatment N=1797

â&#x17E;&#x17E;

Drug Class

INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in INCIVEK-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone.

Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK

â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;

INCIVEKTM (telaprevir) Tablets Brief Summary of Prescribing Information. See package insert for full prescribing information.

INDICATIONS AND USAGE INCIVEKTM (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naĂŻve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers.

The following points should be considered when initiating treatment with INCIVEK: t */$*7&, must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. t " IJHI QSPQPSUJPO PG QSFWJPVT OVMM SFTQPOEFST QBSUJDVMBSMZ UIPTF XJUI DJSSIPTJT EJE OPU BDIJFWF B 4VTUBJOFE 7JSPMPHJD 3FTQPOTF 473 BOE IBE UFMBQSFWJS resistanceâ&#x20AC;&#x201C;associated substitutions emerge on treatment with INCIVEK combination treatment. t */$*7&, FGGJDBDZ IBT OPU CFFO FTUBCMJTIFE GPS QBUJFOUT XIP IBWF QSFWJPVTMZ GBJMFE UIFSBQZ XJUI B USFBUNFOU SFHJNFO UIBU JODMVEFT */$*7&, PS PUIFS )$7 /4 " QSPUFBTF JOIJCJUPST CONTRAINDICATIONS Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.

INCIVEK combination treatment is contraindicated in: t XPNFO XIP BSF PS NBZ CFDPNF QSFHOBOU 3JCBWJSJO NBZ DBVTF GFUBM IBSN XIFO BENJOJTUFSFE UP B QSFHOBOU XPNBO *G UIJT ESVH JT VTFE EVSJOH QSFHOBODZ or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus. t NFO XIPTF GFNBMF QBSUOFST BSF QSFHOBOU */$*7&, JT DPOUSBJOEJDBUFE XIFO DPNCJOFE XJUI ESVHT UIBU BSF IJHIMZ EFQFOEFOU PO $:1 " GPS DMFBSBODF BOE GPS XIJDI FMFWBUFE QMBTNB DPODFOUSBUJPOT BSF associated with serious and/or life-threatening events (narrow therapeutic index). INCIVEK is contraindicated when combined with drugs that strongly JOEVDF $:1 " BOE UIVT NBZ MFBE UP MPXFS FYQPTVSF BOE MPTT PG FGGJDBDZ PG */$*7&, $POUSBJOEJDBUFE ESVHT BSF MJTUFE CFMPX

â&#x17E;&#x17E; â&#x17E;&#x17E;

Methylnaltrexone, however, is contraindicated in patients with known or suspected mechanical GI obstruction.

In 2010, the FDA issued a warning on methylnaltrexone because cases of GI perforation were reported in patients with complex confounding factors who received methylnaltrexoneâ&#x20AC;&#x201D;such as cancer, GI malignancy, GI ulcer, and Ogilvieâ&#x20AC;&#x2122;s syndrome and medications such as bevacizumab (Avastin, Genentech),

ANTIDEPRESSANTS FTDJUBMPQSBN

desipramine trazodone

F OU N D I N T R A N S LAT I O N

Gastroenterology & Endoscopy News â&#x20AC;˘ JUNE 2012

side effects. In a letter to the editor of the Journal of Opioid Management (2011;7:167,170), Xiulu Ruan, MD, director of clinical research at Physiciansâ&#x20AC;&#x2122; Pain Specialists of Alabama, PC, in Mobile, cited a study that showed another peripherally restricted opioid antagonist, naloxone methiodide, â&#x20AC;&#x153;when administered subcutaneously, blocked the antinociception of systemically and centrally administered methadoneâ&#x20AC;? (He

Effect on concentration of INCIVEK or Concomitant Drug

Clinical Comment

Effect on concentration of INCIVEK or Concomitant Drug

Clinical Comment

DZDMPTQPSJOF sirolimus UBDSPMJNVT

â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;

Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir.

Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, IJHI EPTFT PG JUSBDPOB[PMF PS LFUPDPOB[PMF HSFBUFS UIBO NH EBZ BSF OPU recommended.

Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole.

QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole.

Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use.

cyclosporine sirolimus tacrolimus

Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied.

â&#x17E;&#x17E;

itraconazole posaconazole or voriconazole â&#x17E;&#x17E;

ketoconazole telaprevir

ANTI GOUT

salmeterol

Concentrations of salmeterol may be increased when co-administered with telaprevir.

Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

3 NFUIBEPOF

Concentrations of methadone were reduced when co-administered with telaprevir.

No adjustment of methadone dose is required when initiating co-administration of UFMBQSFWJS )PXFWFS DMJOJDBM NPOJUPSJOH JT SFDPNNFOEFE BT UIF EPTF PG NFUIBEPOF during maintenance therapy may need to be adjusted in some patients.

PDE5 inhibitors

Concentrations of PDE5 inhibitors may be increased when co-administered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not FYDFFEJOH NH JO IPVST WBSEFOBGJM BU B TJOHMF EPTF OPU FYDFFEJOH NH EPTF JO IPVST PS UBEBMBGJM BU B TJOHMF EPTF OPU FYDFFEJOH NH EPTF JO IPVST DBO CF used with increased monitoring for PDE5 inhibitor-associated adverse events.

QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended.

Co-administration of sildenafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated.

Co-administration of tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is not recommended.

INHALED BETA AGONIST salmeterol

â&#x17E;&#x17E;

NARCOTIC ANALGESIC colchicine

Patients with renal or hepatic impairment should not be given colchicine with UFMBQSFWJS EVF UP UIF SJTL PG DPMDIJDJOF UPYJDJUZ " SFEVDUJPO JO DPMDIJDJOF EPTBHF PS an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function.

Treatment of gout flares: co-administration of colchicine in patients on telaprevir: NH UBCMFU GPS EPTF GPMMPXFE CZ NH IBMG UBCMFU IPVS MBUFS /PU UP CF repeated before 3 days.

If used for prophylaxis of gout flares: co-administration of colchicine in patients on telaprevir: *G UIF PSJHJOBM SFHJNFO XBT NH UXJDF B EBZ UIF SFHJNFO TIPVME CF BEKVTUFE UP NH PODF B EBZ *G UIF PSJHJOBM SFHJNFO XBT NH PODF B EBZ UIF SFHJNFO TIPVME CF BEKVTUFE UP NH PODF FWFSZ PUIFS EBZ Treatment of familial Mediterranean fever (FMF): co-administration of colchicine in patients on telaprevir: .BYJNVN EBJMZ EPTF PG NH NBZ CF HJWFO BT NH UXJDF B EBZ

NFUIBEPOF

â&#x17E;&#x17E;

colchicine

the smooth muscles of the bowel, but also to participate in antinociception,â&#x20AC;? Dr. Ruan said. â&#x20AC;&#x153;I wonder what the outcome would be when patients on methadone for analgesia were given methylnaltrexone and alvimopan.â&#x20AC;?

Douglas Drossman, MD, professor and co-director of the Center for Functional GI & Mobility Disorders, University of North Carolina Health Care System, Chapel Hill, said Dr. Ruanâ&#x20AC;&#x2122;s

IMMUNOSUPPRESSANTS â&#x17E;&#x17E; â&#x17E;&#x17E;

LFUPDPOB[PMF itraconazole posaconazole voriconazole

â&#x17E;&#x17E; â&#x17E;&#x17E; â&#x17E;&#x17E;

ANTIFUNGALS

Concomitant Drug Class: Drug Name

PDE5 INHIBITORS sildenafil tadalafil vardenafil

â&#x17E;&#x17E;

Concomitant Drug Class: Drug Name

L et al. J Pain 2009;10:369-379). Methadone is dependent on peripheral opioid receptors, and Dr. Ruan contends that these data strongly support the argument that peripheral opioid receptors also may play an important role in antinociception. â&#x20AC;&#x153;From an evolutionary standpoint, it seems more conceivable that the plethora of opioid receptor types expressed in the gut serve not only to modulate motility of

BMQSB[PMBN parenterally administered NJEB[PMBN

Concomitant use of alprazolam and telaprevir increases exposure to alprazolam.

Clinical monitoring is warranted.

midazolam

Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Co-administration of oral midazolam with telaprevir is contraindicated.

â&#x17E;&#x17E;

zolpidem OPO CFO[PEJB[FQJOF TFEBUJWF

zolpidem

Exposure to zolpidem was decreased when co-administered with telaprevir.

Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response.

Exposure to amlodipine was increased when co-administered with telaprevir. Caution should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended.

Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered.

Caution is warranted and clinical monitoring of patients is recommended.

â&#x17E;&#x17E; â&#x17E;&#x17E;

calcium channel blockers

â&#x17E;&#x17E; â&#x17E;&#x17E;

diltiazem felodipine nicardipine nifedipine nisoldipine verapamil

amlodipine

prednisone methylprednisolone

4ZTUFNJD DPSUJDPTUFSPJET TVDI BT QSFEOJTPOF BOE NFUIZMQSFEOJTPMPOF BSF $:1 " TVCTUSBUFT 4JODF UFMBQSFWJS JT B QPUFOU $:1 " JOIJCJUPS QMBTNB DPODFOUSBUJPOT PG these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended.

â&#x17E;&#x17E;

BNMPEJQJOF

telaprevir

4ZTUFNJD EFYBNFUIBTPOF JOEVDFT $:1 " BOE DBO UIFSFCZ EFDSFBTF UFMBQSFWJS QMBTNB concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered.

â&#x17E;&#x17E; â&#x17E;&#x17E;

CALCIUM CHANNEL BLOCKERS

fluticasone budesonide

Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

CORTICOSTEROIDS Systemic prednisone methylprednisolone Systemic dexamethasone Inhaled/Nasal fluticasone budesonide

bosentan

â&#x17E;&#x17E;

ENDOTHELIN RECEPTOR ANTAGONIST bosentan

Concentrations of bosentan may be increased when co-administered with telaprevir.

Caution is warranted and clinical monitoring is recommended.

Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir.

telaprevir fosamprenavir

Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir.

â&#x17E;&#x17E;

MPQJOBWJS SJUPOBWJS

telaprevir darunavir

â&#x17E;&#x17E; â&#x17E;&#x17E;

GPTBNQSFOBWJS SJUPOBWJS

Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.

â&#x17E;&#x17E; â&#x17E;&#x17E;

EBSVOBWJS SJUPOBWJS

telaprevir atazanavir

telaprevir lopinavir

Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir.

â&#x17E;&#x17E;

BUB[BOBWJS SJUPOBWJS

â&#x17E;&#x17E;

HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs)

HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS â&#x17E;&#x17E; â&#x17E;&#x17E;

FGBWJSFO[

â&#x17E;&#x17E;

UFOPGPWJS EJTPQSPYJM GVNBSBUF

telaprevir efavirenz telaprevir tenofovir

Concomitant administration of telaprevir and efavirenz resulted in reduced steadystate exposures to telaprevir and efavirenz.

Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities.

atorvastatin

â&#x17E;&#x17E;

HMG-CoA REDUCTASE INHIBITORS atorvastatin

Plasma concentrations of atorvastatin are markedly increased when co-administered XJUI UFMBQSFWJS "WPJE DPODPNJUBOU BENJOJTUSBUJPO PG UFMBQSFWJS BOE BUPSWBTUBUJO

HORMONAL CONTRACEPTIVES/ESTROGEN â&#x17E;&#x17E;

FUIJOZM FTUSBEJPM norethindrone

ethinyl estradiol norethindrone

Exposure to ethinyl estradiol was decreased when co-administered with telaprevir.

Two effective non-hormonal methods of contraception should be used during treatment with telaprevir.

Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.

â&#x17E;&#x17E;

â&#x17E;&#x17E; â&#x17E;&#x17E;

alprazolam

BENZODIAZEPINES

5IFTF JOUFSBDUJPOT IBWF CFFO TUVEJFE 5IF EJSFDUJPO PG UIF BSSPX = increase, = decrease, â&#x17E;&#x17E;

Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.

â&#x17E;&#x17E;

telaprevir rifabutin

â&#x17E;&#x17E;

ANTIMYCOBACTERIAL rifabutin

37

= no change) indicates the direction of the change in PK.

In addition to the drugs included in the table above, the interaction between INCIVEK and the following drug was evaluated in clinical trials and no dose adjustment is needed for either drug: esomeprazole.

Pregnancy Because INCIVEK must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.

INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment Pregnancy Category X: "OJNBM TUVEJFT IBWF TIPXO UIBU SJCBWJSJO DBVTFT CJSUI EFGFDUT BOE PS GFUBM EFBUIT XIJMF QFHJOUFSGFSPO BMGB JT BCPSUJGBDJFOU 4FF the prescribing information for ribavirin.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant (see also ribavirin prescribing information). Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information).

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. Systemic hormonal contraceptives may not be as effective in women while taking INCIVEK. Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with INCIVEK and concomitant ribavirin.

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Health care providers and patients are encouraged to report such cases by calling 1-800-593-2214.

INCIVEK (telaprevir) Tablets Pregnancy Category B: Telaprevir treatment alone in mice and rats did not result in harm to the fetus. The highest doses tested produced exposures equal to BOE GPME UIF FYQPTVSFT JO IVNBOT BU UIF SFDPNNFOEFE DMJOJDBM EPTF SFTQFDUJWFMZ 5FMBQSFWJS USFBUNFOU BMPOF IBE FGGFDUT PO GFSUJMJUZ QBSBNFUFST JO SBUT 5IF OP PCTFSWFE BEWFSTF FGGFDU MFWFM /0"&- GPS UFTUJDVMBS UPYJDJUZ XBT FTUBCMJTIFE BU FYQPTVSFT GPME UIF IVNBO FYQPTVSFT BU UIF SFDPNNFOEFE clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile sperm count) were observed in a rat fertility study at FYQPTVSFT GPME UIF IVNBO FYQPTVSFT BU UIF SFDPNNFOEFE DMJOJDBM EPTF "EEJUJPOBM FGGFDUT PO GFSUJMJUZ JODMVEF NJOPS JODSFBTFT JO QFSDFOU QSFJNQMBOUBUJPO loss, in percent of dams with nonviable embryos and percent of nonviable conceptuses per litter. These effects are likely associated with testicular toxicity in male but contributions of the female cannot be ruled out. There are, however, no adequate and well-controlled trials in pregnant women.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patientsâ&#x20AC;&#x201D;both during treatment and for 6 months after the completion of all treatment. INCIVEK combination treatment should not be started unless a female patient has a negative pregnancy test immediately prior to initiation of treatment. Pregnancy testing should occur monthly during INCIVEK combination treatment and for 6 months after all treatment has ended. Pregnancy testing in non-pregnant female partners is recommended before INCIVEK combination therapy, every month during INCIVEK combination therapy, and for 6 months after ribavirin therapy has ended. )PSNPOBM DPOUSBDFQUJWFT NBZ CF DPOUJOVFE CVU NBZ OPU CF SFMJBCMF EVSJOH */$*7&, EPTJOH BOE GPS VQ UP UXP XFFLT GPMMPXJOH DFTTBUJPO PG */$*7&, %VSJOH UIJT time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples may include barrier methods or IUDs. 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS SJCBWJSJO Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; IPXFWFS TQFDJGJD QSFTDSJCJOH JOGPSNBUJPO SFDPNNFOEBUJPOT TIPVME CF GPMMPXFE GPS UIF DPOUSBDFQUJWFT 3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS SJCBWJSJO Nursing Mothers It is not known whether telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in milk compared to UIPTF PCTFSWFE JO QMBTNB 3BU PGGTQSJOH FYQPTFE UP UFMBQSFWJS JO VUFSP TIPXFE OP FGGFDUT PO CPEZ XFJHIU BU CJSUI )PXFWFS XIFO GFE WJB NJML GSPN UFMBQSFWJS USFBUFE EBNT CPEZ XFJHIU HBJO PG QVQT XBT MPXFS UIBO QVQT GFE NJML GSPN DPOUSPM EBNT "GUFS XFBOJOH SBU QVQ CPEZ XFJHIU HBJO XBT TJNJMBS JO PGGTQSJOH GSPN telaprevir-treated and control dams. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment. See also the prescribing information for ribavirin.

Pediatric Use The safety, efficacy and pharmacokinetic profile of INCIVEK in pediatric patients have not been established.

Geriatric Use Clinical trials of INCIVEK did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, caution should be exercised in the administration and monitoring of INCIVEK in geriatric patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy.

Hepatic Impairment INCIVEK is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) because no QIBSNBDPLJOFUJD PS TBGFUZ EBUB BSF BWBJMBCMF SFHBSEJOH UIF VTF PG */$*7&, JO )$7 JOGFDUFE QBUJFOUT XJUI NPEFSBUF PS TFWFSF IFQBUJD JNQBJSNFOU BOE BQQSPQSJBUF EPTFT IBWF OPU CFFO FTUBCMJTIFE /P EPTF BEKVTUNFOU PG */$*7&, JT OFDFTTBSZ GPS QBUJFOUT XJUI NJME IFQBUJD JNQBJSNFOU $IJME 1VHI " TDPSF

3FGFS BMTP UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS QFHJOUFSGFSPO BMGB BOE SJCBWJSJO XIJDI NVTU CF DP BENJOJTUFSFE XJUI */$*7&, Renal Impairment /P EPTF BEKVTUNFOU JT OFDFTTBSZ GPS */$*7&, JO )$7 JOGFDUFE QBUJFOUT XJUI NJME NPEFSBUF PS TFWFSF SFOBM JNQBJSNFOU */$*7&, IBT OPU CFFO TUVEJFE JO )$7 JOGFDUFE QBUJFOUT XJUI $S$M MFTT UIBO PS FRVBM UP N- QFS NJO 5IF QIBSNBDPLJOFUJDT PG UFMBQSFWJS XFSF BTTFTTFE BGUFS BENJOJTUSBUJPO PG B TJOHMF EPTF PG NH UP )$7 OFHBUJWF TVCKFDUT XJUI TFWFSF SFOBM JNQBJSNFOU $S$M MFTT UIBO N- QFS NJO */$*7&, IBT OPU CFFO TUVEJFE JO TVCKFDUT XJUI FOE TUBHF SFOBM EJTFBTF &43% PS PO IFNPEJBMZTJT 3FGFS BMTP UP UIF QSFTDSJCJOH information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK. Co-infection 5IF TBGFUZ BOE FGGJDBDZ PG */$*7&, IBWF OPU CFFO FTUBCMJTIFE JO QBUJFOUT DP JOGFDUFE XJUI )$7 )*7 PS )$7 )#7 Solid Organ Transplantation The safety and efficacy of INCIVEK have not been established in solid organ transplant patients.

OVERDOSAGE 5IF IJHIFTU EPDVNFOUFE EPTF BENJOJTUFSFE JT NH FWFSZ IPVST GPS EBZT JO IFBMUIZ TVCKFDUT XJUI */$*7&, BMPOF *O UIBU USJBM UIF GPMMPXJOH DPNNPO BEWFSTF FWFOUT XFSF SFQPSUFE NPSF GSFRVFOUMZ XJUI UIF NH R I SFHJNFO DPNQBSFE UP UIF NH R I SFHJNFO OBVTFB IFBEBDIF EJBSSIFB EFDSFBTFE appetite, dysgeusia, and vomiting. No specific antidote is available for overdose with INCIVEK. Treatment of overdose with INCIVEK consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required. It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

Manufactured for Vertex Pharmaceuticals Incorporated $BNCSJEHF ."

6 4 1BUFOU /P ÂŞ 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE "MM SJHIUT SFTFSWFE */$*7&, BOE UIF #MVF "SSPX MPHP BSF USBEFNBSLT PG 7FSUFY 1IBSNBDFVUJDBMT *ODPSQPSBUFE 7&35&9 BOE UIF 7&35&9 USJBOHMF MPHP BSF SFHJTUFSFE USBEFNBSLT PG Vertex Pharmaceuticals Incorporated. The brands listed are the registered trademarks of their respective owners and are not trademarks of Vertex Pharmaceuticals Incorporated.

79

explanation is plausible, especially based on related research he is conducting on narcotic bowel syndrome (Grunkemeier DM et al. Clin Gastroenterol Hepatol 2007;5:1126-1139). This condition leads to abdominal pain from narcotics, which activates glial cells and upregulates pain.

However, Dr. Drossman noted, he has not seen abdominal pain develop de novo in any patients he has treated with methylnaltrexone, and that he has found it be quite effective, â&#x20AC;&#x153;although I am cautious when using it in patients who have predominant abdominal pain with their constipation. â&#x20AC;&#x153;For opioid-induced constipation, methylnaltrexoneâ&#x20AC;&#x2122;s almost like a diagnostic test, because if patients present with constipation as their gastrointestinal disorder and also are put on narcotics for something else, I may not know if the constipation is related to the narcotics or not. But if they respond to methylnaltrexone, then itâ&#x20AC;&#x2122;s likely narcotic-related,â&#x20AC;? said Dr. Drossman.

Overall, however, the gastroenterology community and Progenics appear optimistic about methylnaltrexone, not only for terminally ill cancer patients but also for those with chronic, nonmalignant n pain.

38

Gastroenterology & Endoscopy News • JUNE 2012

Health Care continued from page 1

for doctors and patients, according to Dr. Pearl, who is executive director and CEO of The Permanente Medical Group, Oakland, Calif. He encouraged physicians to take action.

“If together we don’t lead change, we will pay a price, but more importantly, our patients will pay a bigger price,” said Dr. Pearl.

Since the inception of Medicare and Medicaid in the 1960s, the cost of health care has risen between 7% and 8% per year and the ability to pay for it, the gross domestic product (GDP), has risen only 3% to 4% per year. Health care as a percent of GDP has doubled every 20 years.

“Today, health care is 18% of everything that is produced, sold and provided in this country,” said Dr. Pearl. “If nothing changes between now and 2030, health care will become 36%. If health care consumes more than one out of $3 in the United States, there will be no money for schools, infrastructure, police or fire.”

Dr. Pearl continued, “Everyone in medicine understands that health care is not affordable, but none of us believe that we are the source of the problem; or, maybe if we recognize our contribution, we don’t want to do anything about it.”

He pointed out that Stanford University has a newly constructed pediatric building on its campus, and 25 miles away the University of

California, San Francisco has built a new pediatric hospital. Most likely, Dr. Pearl said, individuals involved in these business decisions on both campuses planned for an increased volume, revenue and profit margin, not a decrease in the health care cost trajectory.

Anyone driving from San Francisco to San Jose, a distance of 50 miles, will pass 10 hospitals that provide cardiovascular surgery, three of which perform fewer than 300 cases a year.

“I question whether you can provide quality medical care when you are doing one case a day on average, but one can assume that when you are doing one case a day … it is impossible to run that service in a cost-effective way,” said Dr. Pearl.

Consolidating cardiovascular services would raise quality and lower costs, but “I don’t think that any of the hospital CEOs are talking about closing their cardiovascular services, so that the health care trajectory can go [down],” said Dr. Pearl.

Although Dr. Pearl believes the health care reform law has many good aspects, he also predicts that as more people with severe health problems have coverage, costs are likely to rise in the short term.

Montefiore Einstein Center for Transplantation

A World-Class Center of Excellence Dedicated to Liver Disease The Comprehensive Liver Program at Montefiore Medical Center in New York City is a multidisciplinary integrated practice bringing experts together in hepatology, advanced hepatobiliary surgery and liver cancer.

One-Year Adult Patient Survival Rate The Marion Bessin Liver Research Center at Albert Einstein College of Medicine is one of the oldest continuously funded National Institutes of Health Liver Centers in the United States and has 40 faculty investigators.

More than 200 adult and pediatric patients have been evaluated in Montefiore’s new liver transplant program.

90%

93%

Montefiore 89%

85

%

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The Children’s Hospital at Montefiore has a dedicated hepatology and transplant program and is ranked among America’s top pediatric hospitals by U.S. News & World Report.

80%

To refer or discuss an outpatient, please call 888-RX-LIVER (888-795-4837) or 718-920-2800 for inpatient transfers.

Scientific Registry for Transplant Recipients, www.srtr.org

To watch our vignette on stem cell research or to learn more about the Montefiore Einstein Center for Transplantation, visit www.montefiore.org/transplant

39

Gastroenterology & Endoscopy News • JUNE 2012

He described multiple ways that in the longer run, the law might lower costs.

These include the creation of accountable care organizations (ACOs), which bring physicians together to care for patients; the reimbursement incentive for meaningful use of electronic health records; and the creation of a comparative-effectiveness research group. The effect of these items, however, remains to be seen. For example, although Lipitor has no advantage over a generic statin for the majority of patients, it became the most commonly prescribed lipid-lowering drug because of direct-to-consumer advertising, despite its dramatically higher cost.

Future Initiative for Health Care To date, said Dr. Pearl, a plan has not been put into place to address the fundamental underlying problem with U.S. health care: affordability.

He outlined four possible scenarios for the future of health care. The first is that the fundamental health care system does not change, and the cost issues are addressed by freezing Medicare payments and raising patient-paid deductibles. This option will lead to a two-tiered system, one in which the rich have health insurance and the middle and lower classes do not. Few physicians will treat Medicare patients because of declining reimbursement, and in many cases, individuals will have only catastrophic insurance because of everincreasing deductibles.

The second scenario is rate regulation, the establishment of the maximum increase in health care premiums. This plan is on the ballot in a variety of states this year. In this scenario, there would be a limit on insurance rates, leading to growing access problems and undermining of medicine, as has been seen in a number of European countries, said Dr. Pearl. This scenario also would produce a two-tier system as physicians and hospitals refuse the governmentally determined payments, similar to Medicaid today.

The third scenario is health care being transferred overseas. “Much of medicine can be outsourced. If you look at places like India and Thailand, you have U.S.trained surgeons doing procedures, such as heart surgery and coronary bypass for $10,000, total joint replacement for $5,000 and cataracts for $1,000—high volume with excellent outcomes,” said Dr. Pearl. But whether health care costs in these countries will stay reasonable in the future is uncertain.

The fourth scenario is that physicians are going to lead the process of change.

“Together we will form the

organizations that are like the ACOs, not the hospitals and not the insurance companies, but the medical professionals will come together and we will make those difficult decisions. We will say that it doesn’t make sense to do one heart surgery a day. We will lead the process of consolidation, coordination and integration,” said Dr. Pearl.

Dr. Pearl pointed out that much of U.S. health care resembles a 19th-century cottage industry. It is fragmented,

with doctors working in small offices unconnected from their colleagues in the community. It is paid at the delivery system on a piecemeal, fee-for-service basis, rewarding volume over outcomes. It is paper-based and devoid of structure and effective leadership, and that is what Dr. Pearl hopes will change.

“If physicians and national societies can come together, create integrated structures that pay more for higher quality and better service and use

21st-century technology effectively, we can overcome the health care challenges of today,” he said. “Left to its own, the process will be led by for-profit insurance companies and elected officials, and the solutions are unlikely to provide the excellence in health care we all want.” In contrast, Dr. Pearl believes that physicians working together “can transform medical care and in the process provide mission-driven medicine n for this country.”

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2012 Audiovisual Award Honorable Mention Endoscopic Submucosal Dissection of Colon Lateral Spreading Tumors (DV054) This DVD is an evidence-based comprehensive review of the indications, technical aspects and complications of performing endoscopic submucosal dissection of colonic lateral spreading tumors. This DVD incorporates the when, why, how and when not to perform this procedure with multiple video clips demonstrating the techniques and tools used to perform ESD in the colon. AMA PRA Category 1 Credits™: 0.75

Endoscopic Mucosal Resection – LGI (DV051) This DVD identifies and discusses the different types of Endoscopic Mucosal Resections (EMR), such as lift and cut, suck and cut with a cap or using a band ligation. View actual video demonstrations of these techniques within the colon. A section on managing EMR complications related to bleeding, perforations and stricture is also included.

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40

OP I N I O N

Gastroenterology & Endoscopy News • JUNE 2012

The Private Practice Model of Medicine Must Survive more leverage to negotiate higher reimbursement from insurance companies and less fear of competing with independent venues offering inpatient care. This move toward regionalized health care delivery structures is well under way and appears to have strong support As a nation, our spending on health care is clearly out from the advocates of the PPACA. It is also the case of control. The United States faces an unfunded Medithat once a provider monopoly has been created, the care mandate that, by some estimates, totals more than controlling hospital corporation may purchase and own $90 trillion. This debt burden represents a financial a major insuring entity to further the goal of attaining black hole into which our federal and state governhegemony in the regional health care economy. ments will collapse, unless some major steps are taken The intensive efforts hospitals put forth to hire prito avoid the pending budgetary catastrophe. mary care physicians (PCPs) also may be based on the However, as the federal government moves to impleunderstanding that physicians could ultimately become ment the measures contained in the Patient Protection effective competitors by aggregating into larger inteand Affordable Care Act (PPACA), it is grated groups that direct referrals and important to carefully assess the direcutilization according to their own tion this important legislation will take judgment and to their own advantage. the delivery of health care services and Unfortunately, hospitals are currently the profound effect this will have on the positioned such that they can use public American public. We are concerned that dollars in their attempts to put private governmental actions are taking place so physicians out of business, and are able rapidly that there may not be adequate to use powerful and well-funded polititime to evaluate the outcomes of such cal lobbies to achieve their goals. changes, including significant uninBut what effects does this trend have tended consequences of emerging legison patients? Patients may not be aware lative and regulatory mandates. that physicians who work directly for the A major thrust of the PPACA is to hospital often transition to the mindset implement new, alternative payment of shift workers, and once they complete plans that are designed to reduce curtheir stint they then relinquish patient rent inefficiencies. This aim is thought care to the next shift. This practice can to be achievable through a combination have potentially detrimental effects on of financial incentives and disincentives a patient, both emotionally and physito health care providers. It is a worthy The most recent trend in medical practice has been the ologically. Such shift work inevitably objective: The overall cost of health care leads to a lack of continuity of care and explosive growth of the hospital-employed physician. This will be reduced while quality of care will also may increase the potential for medidevelopment has moved so quickly that, in 2011, the number cal errors. improve.

However, at the heart of this plan is An important ethical issue that of employed physicians exceeded the number of physicians in eliminating the Fee-for-Service/Pripatients are generally unaware of is who private practice for the first time in our nation’s history. owns or employs their physician. It is easy vate Practice Model (FFS/PPM). This cohort of independent FFS physicians to understand how, in practice, a physihas been incorrectly targeted as the culcian subjected to significant employer prit for escalating health costs, and is even described Employed Physicians pressures may feel the need to act in compliance with as the main source of our full spectrum of health care– The most recent trend in medical practice has been the goals of the employer (the hospital) rather than in the explosive growth of the hospital-employed physi- the best interest of the patient. The inherent conflict related financial problems.

Although not perfect, FFS/PPM has been an inte- cian. This development has moved so quickly that, in of interest in referrals (internal self-referrals within an gral part of the health care landscape in this country 2011, the number of employed physicians exceeded the owned entity) made by employed physicians serves to throughout our history. Americans feel most com- number of physicians in private practice for the first eliminate competition from independent and in many fortable choosing their own doctor—someone often time in our nation’s history. instances better-qualified providers and venues. Patient Why should hospitals be so motivated to employ choice of primary physicians and specialists often is viewed as a family member, and one in whom they can trust their lives. FFS/PPM has historically allowed physicians? There are several possibilities. One likely limited. The traditional patient–physician trust that is patients to obtain health care services from the health explanation is that hospitals are acting in anticipation an essential dimension of quality care is undermined. care professionals and hospitals of their own choos- of the Accountable Care Organization (ACO) model Hospitals claim that their move to employ doctors ing. Patients can see doctors wherever needed, and can of hospital reimbursement, wherein hospitals and par- results in lower health care costs. One element of such choose specialists without an unreasonable waiting ticipating providers assume financial risk for the care cost reductions is reducing unnecessary medical proceperiod or requirement to see a doctor within network, of their patients. Hospital administrators realize that dures. However, this often comes as a result of reducing a person who often is unknown to the patient. His- when they receive a fixed payment for managing the the volume of appropriate consults or by underpaying torically, the FFS/PPM has been a major component health of a specified population, it is better to own the specialty physicians. Although streamlining services in helping to ensure independence and flexibility with physicians involved in the care of patients. Although can theoretically improve quality and translate into the outcomes include the potential for more money lower costs, it often does neither. respect to health care options.

Furthermore, there is a large (and expensive) gray As physicians, FFS/PPM provides the greatest being available for distribution to participating parties, autonomy in making recommendations based on medi- it also is highly likely that less physician autonomy will zone of medical necessity when dealing with clinical cal appropriateness without overriding monetary con- be present in the health care recommendations made decision making in real time. The value sets of those cerns. Attention to patient care issues and competition to patients. who place top priority on costs and profits stand in The potential for hospitals to convert greater market sharp contrast to those who hold patient care as their among providers help facilitate and promote quality of care. FFS/PPM medicine encourages adherence to power into higher prices and less competition creates top priority. Patient care and outcomes may vary signifstrict ethical principles. Doctors act as I would like to a strong incentive for hospitals to employ physicians. icantly, and this dissimilar perception of how to achieve By having physicians as employees, hospitals have be treated if I were the patient. see Private Practice, page 44

Barry Roseman, MD Thomas Flake, MD Dan Kopen, MD

Furthermore, the FFS system insures that the patient remains the driving force in the health care landscape, by keeping physicians accountable to their patients.

The knowledge that patients can take their business elsewhere if unhappy with their care also is a source of great comfort to patients and contributes to their sense of well-being.

Other payment models have been tried over the past few decades with mixed success and variable patient satisfaction, including HMOs, managed care organizations, preferred provider networks and other capitated payment systems. Private insurers quite successfully have carved out a portion of Medicare reimbursements intended for physicians, under the name of controlling costs.

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Gastroenterology & Endoscopy News • JUNE 2012

Private Practice continued from page 40

optimal patient outcomes often leads to different styles of medical care.

In preparation for implementing the PPACA, hospitals are positioning themselves by hiring scores of personnel who work to ensure compliance with quality measures, core measures and other such standards that will be tied to reimbursement. Hospitals likely will force new practice patterns on physicians who work in the hospital, forcing providers to

comply with the latest government mandates. Unfortunately for patients, such measures are based on aggregate population studies and usually fail to take into consideration the many dimensions of patient variation, which affect individual health care outcomes. In many cases, compliance with broad statistical mandates has and will continue to result in suboptimal care, and in some instances, significant harm to the individual patient.

Ultimately, patients will potentially suffer the most under this increasingly common reimbursement system. In a salaried format, specialists tend to have long waiting lists because there is no financial incentive for doctors to put in the extra work that would be necessary to keep patients waiting times short.

Staff personnel often direct patients with acute issues to urgent care centers or emergency rooms. Physicians working in

shifts have minimal incentive to increase productivity, and patients wait longer for medical interventions. The often unrecognized and unstated reality of shiftwork reimbursement plans is that the employee gets paid more per unit of service the less service provided per shift.

This outcome fits well with the drive to ration care in order to reduce costs.

FFS/PPM Is Not the Problem Despite the fact that all health care costs have continued to rise unabated in the face of decreasing numbers of FFS/PPM practitioners (who now constitute a minority of practicing physicians), FFS/PPM is still continually blamed for escalating health care costs. This ongoing mantra of finger pointing at the FFS/PPM deflects attention from more highly influential elements of rising costs—hospitals, for-profit private insurance companies, the pharmaceutical and medical equipment manufacturers, patients’ own poor lifestyle choices and health behaviors, defensive medical practices and institutional fraud.

The FFS/PPM for medical practice has been vilified by many as the root cause of spiraling health care costs. “It drives up costs” is often repeated by editorialists and health care reformers, “because it rewards quantity and not quality.” This mantra is espoused and repeated, despite data that undermine the commonly held belief that increased physician reimbursement is the major contributing factor in rising health care costs. The truth is, physicians now receive about $0.08 of every health care dollar expended, down from nearly twice that figure in 1960.

The assertion that FFS/PPM rewards quantity and not quality is somewhat harder to disprove. It seems logical to suspect that some physicians are recommending care to patients based on monetary concerns without proper regard for what is medically indicated. Because certain categories of physicians, especially specialists, are paid for performing procedures, the assertion is that such specialists overuse services for their own benefit.

There is no question that, as in every profession, there are sporadic practitioners whose greed may impair their medical judgment, but these individuals constitute a minority of providers, compared with the vast majority of FFS/ PPM physicians engaged in the honorable practice of medicine. Among this majority group, the busiest physicians are usually, quite simply, the best. Medicare and private insurers routinely audit outliers—the one of many external pressures that limit physicians’ abuse of the FFS system.

OP I N I O N

Gastroenterology & Endoscopy News • JUNE 2012

This ongoing mantra of finger pointing at the Fee-for-Service/ Private Practice Model deflects attention from more highly influential elements of rising costs—hospitals, for-profit private insurance companies, the pharmaceutical and medical equipment manufacturers,

only emergent conditions are guaranteed to receive prompt attention.

Elective medical conditions, such as joint replacements (as in the Canadian system) can carry waiting times of up to two years because of the previously noted lack of financial incentive to keep waiting times short. For a majority of conditions listed as urgent, there also is a tendency to delay service provision based on the

same reimbursement principles as they apply to human behaviors.

Don’t Throw the Baby Out With the Bath Water It is understandable that the federal government is looking for ways to control health care costs, but the current direction of attempting to decrease the physicians’ share of the health care pie is a mistake. Pointing a finger primarily

at physician payments in general, and private practice FFS reimbursements in particular, as a means to control health care cost escalation is a misguided policy that will have adverse unintended consequences.

Eliminating FFS/PPM would remove the only remaining practice model in which the professional and economic autonomy of the physician is preserved. see Private Practice, page 46

patients’ own poor lifestyle choices and health behaviors, defensive medical practices and

your fingertips. Call us at 1-800-440-PATH or visit us at plusdx.com.

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institutional fraud.

Lost in the discussion of unnecessary service provision is the issue of defensive medicine. In the FFS/PPM, the harsh reality of the threat of a lawsuit for underdiagnosis adds significant conscious and subconscious pressures on providers to order additional testing and procedures. Combined with the legal recognition of patient autonomy and resulting patient demands for complete evaluation, the overuse of testing and procedures is largely the result of a reasonable approach to the real-time realities of patient care. Although the pressure to practice litigious medicine may be less on employed physicians, it is unreasonable to suggest that the FFS/ PPM, rather than insufficient progress in tort reform, should be the focus of this problem.

There are many beneficial aspects of FFS/PPM that are often overlooked when discussing this model. FFS encourages efficiency in medical care, in that physicians have an incentive to provide services in a timely manner, much to the satisfaction and benefit of their patients and referring physicians.

Perhaps this efficiency is at odds with the suggested goal of slowing down the system—an attempt to reduce costs by dramatically decreasing the volume of overall work done. It has become common knowledge that one of the easiest methods of introducing and maintaining rationing without referring to the word rationing itself is to create longer waiting lines for those seeking care. The concept is called rationing by queue in medical economics textbooks. This is a common element of all socialized medical systems and has been shown to be successful in lowering health care costs, especially among the elderly.

When specialists are salaried, as in many other systems around the world,

45

46

OP I N I O N

Gastroenterology & Endoscopy News • JUNE 2012

Private Practice continued from page 45

FFS/PPM doctors are the owners of their own businesses who cannot be easily pressured into compliance with suboptimal directives, unlike employees who are beholden to the boss. In order to understand how important this is, one must be aware of the ethical precepts on which the practice of medicine is based.

For example, surgeons, upon entry to the American College of Surgeons, pledge “to pursue the practice of surgery with honesty … to place the welfare and the rights of my patient above all else, and … to deal with each patient as I would wish to be dealt with if I was in the patient’s position.” They also promise they will “take no part in any arrangement, such as fee splitting or itinerant surgery which induces referral or treatment for reasons other than the patient’s best welfare.”

The FFS/PPM model, as it exists today, allows physicians to remain in control of making recommendations for the care his or her patient receives and to move promptly to implement such care. FFS/PPM frees physicians from the potentially compromising financial sanctions that can be imposed by ACOs

The Fee-for-Service/Private Practice Model importantly promotes the ethical practice of medicine by keeping the physician accountable to patients as individuals and not the system, the institution or the insurer.

or other payment models, and thus effectively avoids situations that arise when there is conflict between what is best for the system, the physician and the patient. FFS/PPM importantly promotes the ethical practice of medicine by keeping the physician accountable to patients as individuals and not the

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system, the institution or the insurer.

Attacks on the FFS/PPMs of health care delivery will undoubtedly continue in many forms, including implementation of new reimbursement models and new government regulations. These assaults currently stem from such entities as the sustainable growth rate, Independent Payment Advisory Board, ACOs, bundling schemes and pay-forvalue, outcomes, performance, quality and other measures removed from the basic ethical principle of reasonable payment for appropriate service provision.

Perhaps our focus should be on improving FFS/PPM, rather than attempting to replace it. In this regard, individual physicians must take a greater interest in collaborating with other doctors to solve the perceived problems with FFS/PPM and fend off the trend toward a monopolistic hospital/corporation-owned practice model. Physician societies must take a strong and open stance in favor of FFS/PPM in an effort to protect the best interests of patients and their member physicians. Physicians must have systems in place to continually police themselves to avoid the perception of self-serving overuse by strictly adhering to acceptable ethical rather than financial standards of care, while keeping patients’ interests first on the list of priorities.

FFS/PPM physicians must demonstrate the ability to deliver cost-effective care, although in a purely professional sense, the cost of care is not the physician’s primary concern. At the end of the day, what is best for patients must be the primary focus of all health care decisions.

FFS/PPM Will Survive The FFS/PPM allows the physician to evaluate each patient on his or her

individual merits and make decisions and recommendations based on what is medically appropriate, and move promptly to implement care. Who, other than the physician, has devoted anywhere from 12 to 16 years of rigorous education and training, in conjunction with the patient or patient surrogate, should be making medical decisions? Although doctors should consider the most cost-effective care for patients, ultimately it is the doctor’s ethical duty to do what is best for the health of the patient, relegating other concerns to secondary status.

Attacks on the FFS/PPMs of health care delivery will undoubtedly continue in many forms, including implementation of existing and new reimbursement models, and existing and new government regulations. However, a systematic and organized comparison of FFS/PPM with other practice models demonstrates that it remains the most efficient, ethically sound and highest-quality form of medical care, with a long history of physicians successfully self-regulating medical spending while keeping the individual patient and patient concerns at the center of every treatment decision.

It is understandable that the federal government is looking for ways to control health care costs, but focusing on physicians’ share of the health care pie is a mistake. Direct physician costs are not a leading contributor to our escalating health care budget. Neither owning physicians through hospital-based employment, nor attempting to control their behaviors through legislative and regulatory rules is going to ultimately reduce our nation’s overall cost of health care by any significant degree.

Health care reform should be about fixing what is wrong with our current health care system, while retaining and building on what works well. The FFS/ PPM is one of the good things about American medicine. It works and must be preserved so that physicians can help decide what care their patients should receive based on resources, ethical guidelines, and especially patients’ wishes, while placing the individual patient’s well-being at the top of the list of provider priorities.

It is time for Americans to look themselves in the mirror and ask: Who do I want my doctor to be working for—the insurance company, the hospital, the govn ernment, or for me, the patient?

The authors are general surgeons. Dr. Roseman practices in Maryville, Tennessee and Atlanta, Georgia; Dr. Flake practices in Detroit, Michigan; and Dr. Kopen practices in Forty Fort, Pennsylvania.

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Gastroenterology & Endoscopy News • JUNE 2012

AAAHC Announces New Accreditation Program for Hospitals On April 24, the Accreditation Association for Ambulatory Health Care (AAAHC) announced it will launch a new pilot hospital accreditation program for small hospitals this year.

“With our experience as the leader in ambulatory care accreditation, we saw an opportunity to improve patient care by offering a program that addresses both outpatient and inpatient hospital care and the ambulatory care offered by small hospital systems,” said John Burke, PhD, AAAHC president and CEO, in a statement.

The hospital accreditation program will evaluate health care services against nationally recognized standards of care; provide an educational, consultative

program approach; help develop the skills of hospital staff; offer opportunities for quality improvement based on best practices; and include a peer-based on-site survey conducted by surveyors who themselves are hospital leaders.

The accreditation will be offered through the Accreditation Association for Hospital/Health Systems

Inc. (AAHHS). The AAHHS and AAAHC will have separate governing boards and function independently to ensure that the AAAHC “will continue unhindered in what it does best, which is ambulatory health care accreditation,” Dr. Burke said.

Jack Egnatinsky, MD, immediate past chair, AAAHC board of directors, praised the new accreditation

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program: “Our research suggests that health care providers desire and will benefit from the unique accreditation model that AAAHC has developed for its ambulatory accreditation programs.”

For more information about the program, visit www.aaahc.org.

—Based on a press release from the AAAHC

48

E S S AY

Gastroenterology & Endoscopy News • JUNE 2012

Dragonflies Mark R. Fleisher, MD Gastroenterologist The Borland-Grover Clinic Jacksonville, Florida

We rode Bus “T” bound for Brooklyn Day Camp, which was over the bridge and somewhere in Queens, naturally. Supposedly, the original camp had become too popular for its own good. With no room to grow in compact Brooklyn, it merely shifted over one borough and kept the name. Its misnomer was part of its charm. The bus that shuttled me and my siblings was the only blue one in the camp. Driven and owned by Bernie, The Bluebird picked us up first and dropped us off last. After a hard day at camp, this seemed truly unfair, even though my parents probably paid an exorbitant sum for such choice placement. As camp neared, we always passed the same elderly black woman. She would just be hanging laundry or sitting in a chair. We’d wave to her and she’d wave back. It seems so simple now. Just a hello. Just people.

Six days a week, Monday through Saturday, every day was the same at Brooklyn Day Camp. Leading off was baseball, my passion. Every morning I’d check the skies. I can recall many a day after a deluge, playing in the swamps of deep right field. Half of the time, I’d pay more attention to the dive-bombing dragonflies than to the game. Who can deny that three swings are worth the threat of malaria? We’d sully the national pastime for a few hours until someone noticed the

time. Yikes! What kind of budding neurotic wears a watch to day camp, anyway?

Swimming was next, so no one would complain. No one except me: I hated swimming. I still do. Let me correct that: I can’t swim. Let me be blunt: I’m afraid of the water. I fell in the deep end of a pool once and that was enough for me.

I’d hide anywhere to avoid swimming.

Inside bathroom stalls, under the boxing ring or up the weeping willow was where you could find me. Finally, I’d hear the squishing of soggy suits and sodden thongs and, presto, I would reappear in time for lunch. Who could resist hamburgers, franks and fried chicken?

I have to admit that Uncle Freddie put out a sumptuous spread. Lest I forget, Fred Nislow owned the camp. As per the whims of autocracy, he preferred the title of Uncle Fred. For some reason Uncle Fred wore his Bermuda shorts only in a downpour. Yet in heat that could stroke the maddest of Englishmen, he always wore long pants. Along with Uncle Fred was his wife, Mrs. Nislow or more casually, Uncle Fred’s wife. There was his sister, Dolly, who ran the concession stand.

Icy Cokes in real glass bottles sold for 20 cents. Aiding and abetting in this larceny was their mother, appropriately dubbed Granny.

Early afternoons were sort of ad lib.

I liked basketball but I was terrible. I detested tennis and I was terrible (notice the pattern to my athleticism). If one was truly cursed, you were scheduled for boating. We’d paddle endlessly around a tiny urban inlet of toxic waste. What could be better than to top off lunch with nausea?

Soon spirits would perk up as the counselor would shout “Get dressed for swimming!” Once again, a furtive search for cover would lead me to the camp’s nether regions. On a good day, Jeff and I would go off and play baseball. “Come on, I’ll

let you hit,” I’d offer. Helplessly, he’d fall prey to the sirens of the diamonds. I can still remember thinking that we’d always be friends. Best friends. We always kept in touch, even during the school year. It was always great to get a phone call when I was little. Now, when one comes in, I wave like the grounds crew at a SAC base to avoid the call.

“Wow, the phone is for me!” It was always Jeff checking to see if I’d be back.

“Of course! Are you?”

“Yep!” “Great! I’ll see you in July.”

We’d always request to be together.

Same group, same baseball team that always lost, and usually because of its pathetic right fielder avoiding dragonflies.

I remember camp picture day. Every year, each team took a picture along with their counselor and, of course, the almighty group leader. He was the commander of all groups within one age range.

What qualified these men to be entrusted with such power? That’s right—they were all relatives of Uncle Fred. There was Jerry for Chiefs (the oldest boys) and Mike for Junior Chiefs. If you did something wrong, he’d make you sit all day in the sun under the vent from the kitchen.

I knew nothing about the girls’ groups. If you did, obviously you spent one summer too many at Brooklyn Day Camp. Anyway, one year Jeff and I decided to take the picture while holding up cards of our favorite ballplayers. It would be our secret.

He held Willie Mays, I had The Mick.

I still have that photo. We’d sit on the swings underneath the tallest trees I’d ever seen. We laughed as we kicked higher and higher. I was so relieved that he wanted to be a doctor, too. We were going to open a practice together. We even knew how the office was going to look. You could smell the leather chairs and mahogany desks.

We’d be partners.

Every day was the same at Brooklyn Day Camp. Leading off was baseball, my passion. Every morning I’d check the skies. I can recall many a day after a deluge, playing in the swamps of deep right field. Half of the time, I’d pay more attention to the dive-bombing dragonflies than to the game.

Soon swimming was over and we could resurface. We’d return to our assigned lunch tables to get ice cream. Saturday brought the end of the camp week and with it came Awards Day. Each camper would get a button that read “Swimming Award” or “Baseball Award” or “Clean Table Award,” if the counselor happened to remember who dropped the lazy fly ball in deep right field.

At day’s end, everyone would line up for Flag Lowering. Standing at attention with baseball caps over our hearts, Old Glory would be lowered to a scratchy recording of “God Bless America.” Or, was it “The Star Spangled Banner”? As soon as the last note was sung, Jeff and I would run to our bus to get a good seat.

We always sat together. Yep, Jeff would be my best friend forever.

We were college freshmen when Jeff died. I guess sometimes that’s all forever lasts. Rare is the day without a reminder: a leather chair, a mahogany desk, a partnership offer. Each day I wonder: Am I the physician we wanted to be?

With day’s end, Bernie’s Bluebird would cruise past Uncle Freddie and his kin. We’d wave and they’d wave back.

We’d pass that elderly black woman on our way out of Queens. A few kids called her bad names but I never thought that was right. We’d wave and she’d wave back. Just people. With Brooklyn Day Camp fading behind us, everything in life was simple—except how to play deep n right field.

WITH LOWER DOSE

1

EFFICACY YOU EXPECT1

HalfLytely and Bisacodyl Tablet Bowel Prep Kit is a combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults.

Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. There have been reports of ischemic colitis in patients with use of HalfLytely and 10 mg or 20 mg Bisacodyl Tablets Bowel Prep Kit. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus.

Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reďŹ&#x201A;ex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use.

Please see brief summary of Prescribing Information on adjacent page.

50

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

Gastroenterology & Endoscopy News • JUNE 2012

FDA Issues Guidance on Approval Process for Medical Devices Agency Seeks To Provide ‘Common Framework’ for Device Manufacturers, FDA Reviewers

By George Ochoa In what the FDA described as a “firstof-a-kind guidance,” the agency published a document in March for medical device manufacturers explaining how FDA reviewers consider the benefits and risks of certain medical devices before an approval

decision is made.

“The guidance, for the first time, outlines the systematic approach device reviewers take in weighing the potential benefits and risks of a medical device,” said Peper Long, associate director for external relations in the FDA’s Center for Devices and Radiological Health (CDRH), in Silver Spring, Md.

Development of the guidance was prompted by problems in the past.

“The devices center identified several problems in our pre-market review programs, and started to address those problems to assure that they are predictable, consistent, transparent and efficient,” said Ms. Long.

The guidance primarily concerns pre-market approval (PMA) applications and de novo petitions. PMA

is the FDA review process to evaluate the safety and effectiveness of Class III medical devices—those that “support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential unreasonable risk of illness or injury,” according to an FDA press release.

Examples include coronary stents and anti–gastroesophageal reflux implants. The de novo process is for low- and moderate-risk devices that have been found to be not substantially equivalent to existing devices.

EFFICACY YOU EXPECT1

WITH LOWER DOSE1

• Lowest volume phosphate-free lavage1,2 • No oral sodium phosphate

References: 1. HalfLytely® and Bisacodyl Tablet Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2010. 2. See package inserts: GoLYTELY®(PEG-3350 and Electrolytes for Oral Solution), 2001; NuLYTELY® (PEG-3350, Sodium Chloride, Sodium Bicarbonate and Potassium Chloride for Oral Solution), 2008. Braintree, MA: Braintree Laboratories, Inc.; MoviPrep® (PEG-3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), 2006; Morrisville, NC: Salix Pharmaceuticals, Inc.

Brief Summary: Before prescribing, please see full Prescribing Information and Medication Guide for HalfLytely and Bisacodyl Tablet Bowel Prep Kit. INDICATIONS AND USAGE: Combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus. WARNINGS AND PRECAUTIONS: HalfLytely and Bisacodyl Tablet Bowel Prep Kit is a combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. There have been reports of ischemic colitis in patients with use of HalfLytely and 10 mg or 20 mg Bisacodyl Tablets Bowel Prep Kit. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 148 patients who took HalfLytely and 5 mg Bisacodyl Tablet Bowel Prep Kit in clinical trials, 42 (28%) were 65 years of age or older, while 10 (7%) were 75 years of age or older. The rates of success appear to be lower in patients 65 years and older. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of HalfLytely may not be absorbed completely. Do not take the bisacodyl delayed-release tablet within one hour of taking an antacid. ADVERSE REACTIONS: Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. Oral Administration: Take one 5 mg bisacodyl tablet with water. Do NOT chew or crush. Dissolve the HalfLytely powder in 2 liters of water. Wait for a bowel movement (or maximum of 6 hours) then drink all the HalfLytely solution at a rate of 8 ounces every 10 minutes. Consume only clear liquids until the colonoscopy. STORAGE: Store at 20-25°C (68-77°F).

Excursions permitted between 15-30°C (59-86°F). The reconstituted solution, may be refrigerated, use within 48 hours. Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit us at www.halflytely.com ©2011 Braintree Laboratories, Inc.

HL-12437T

January, 2011

The FDA developed the guidance to inform not only manufacturers but also reviewers. The intent, said Jeffrey Shuren, MD, director of CDRH, in a statement, is to allow “manufacturers and the FDA to use a common framework for benefit–risk determinations.”

Bob Laughner, MS, RAC, a regulatory science specialist at Cook Medical Urology & Women’s Health, in Bloomington, Ind., thought that the guidance has done “a pretty good job of clarifying the process that the FDA will use.” The guidance does not add new requirements or burdens, he said, but “lays out what the FDA is looking for in benefits and risks— what factors they’re looking for, how they’re weighing them.”

Another Cook employee, Chris Kilander, MS, RAC, CQE, regulatory affairs manager, said in an interview that there had been confusion in the past about how risk–benefit analyses fit in with safety and effectiveness in the FDA reviewing process.

In Cook’s response to the draft guidance, issued last year, “we were

Gastroenterology & Endoscopy News • JUNE 2012

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

51

US Endoscopy Announces Full Market Release of the Vasto™ Bite Block

trying to focus FDA reviewers on how risk–benefit fit within the context of safety,” he said.

Overall, said Mr. Laughner, “we were pleased at how the FDA addressed our comments.”

Other suggestions made by Cook and incorporated into the final guidance, according to Mr. Laughner, included mention of the Investigational Device Exemption, which permits investigational use of a device in a clinical study, and exclusion of the 510(k) process, through which substantial equivalence of devices is demonstrated.

The Vasto bite block offers wider side ports for easy mouth and suction access during upper gastrointestinal procedures.

Photo courtesy of US Endoscopy

On April 5, US Endoscopy announced the release of the Vasto™ bite block, the newest addition to the company’s family of bite blocks. The Vasto bite block offers wider side ports for easy mouth and suction access during upper gastrointestinal procedures. The device also features a 72FR opening and a larger faceplate for extra strength and comfort for patients.

“Customers performing more therapeutic procedures have requested a bite block to accommodate larger devices such as dilators,” said Gulam Khan, CEO, president, and co-chairman of US Endoscopy, in a statement. “The Vasto™ bite block is a simple solution to address their clinical needs.”

For more information, please visit the US Endoscopy Web site at www. usendoscopy.com.

—Based on a press release from US Endoscopy

Think of Enterography as a GPS for Crohn’s disease.

‘The guidance, for the first

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

time, outlines the systematic approach device reviewers take in weighing the potential benefits and risks of a medical device.’

—Peper Long

To illustrate its concepts, the FDA guidance includes case studies based on hypothetical and actual examples and a worksheet for benefit–risk determinations. According to Ms. Long, the result is to make “the process more explicit and systematic than it has been before, which benefits both FDA staff and industry.”

The guidance, entitled “Factors To Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications,” is available at www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ n UCM296379.pdf.

Ms. Long, Mr. Laughner and Mr. Kilander reported no relevant financial disclosures.

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery.

Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

52

BOO K R E V I E W S

Gastroenterology & Endoscopy News • JUNE 2012

Recommended Reads in Gastroenterology and Hepatology

By Nirmal S. Mann, MD, BSc, MS, PhD, DSc Clinical Professor of Medicine and Gastroenterology Senior Consultant in Gastroenterology–Hepatology UCDMC Sacramento Director of Gastroenterology–Hepatology UCDMC Folsom Folsom, California

Successful Training in Gastrointestinal Endoscopy

Diarrhea: Diagnostic and Therapeutic Advances Guandalini S, Vaziri H, eds. New York, N.Y.: Springer Science+Business Media; 2011: 500 pp.

Price: $219.00

Cohen J, eds. West Sussex, U.K.: WileyBlackwell; 2011: 396 pp. Price: $174.95

“Successful Training in Gastrointestinal Endoscopy” will provide gastroenterologists with the skills needed to perform endoscopy at a high level. Part I of the four-part volume deals with the evolution of the basic principles and practice of gastrointestinal endoscopy, providing an historical perspective on training in endoscopy as well as guidelines on how to become an excellent practitioner. Part II is devoted to training in major endoscopic procedures, including esophagogastroduodenoscopy, colonoscopy and endoscopic ultrasound. Part III addresses training in a variety of techniques, such as mucosal ablation, bariatric endoscopy and complicated polypectomy. The last section discusses the challenges for the future of the field.

Each chapter is authored by internationally recognized leaders in the field and provides clear and useful instruction on specific skill sets and procedures as well as hundreds of high-quality diagrams and pictures.

Chapter 7 on endoscopic retrograde cholangiopancreatogram and Chapter 9 on deep enteroscopy were particularly well done. One of the most useful features is the DVD, which includes 130 annotated teaching videos of both actual procedures and animal model simulations.

This book will help gastroenterologists develop, practice and perfect their endoscopic skills in the latest techniques and procedures.

The management of patients with acute and chronic diarrhea is discussed in the 27 comprehensive chapters of “Diarrhea: Diagnostic and Therapeutic Advances.” This volume incorporates new practical, clinically useful material for the busy clinician from respected gastroenterologists. Each chapter presents concise and comprehensive information on new advances in diagnostic and therapeutic technologies and ends with a thorough list of references for further reading. The chapters also discuss the costs of various diagnostic and therapeutic options to help the practitioner gauge the practicality of different methods.

Chapter 22, “Alcohol-Related Diarrhea,” is particularly well done. Chapter 12 on celiac disease is well written, but has two omissions: It does not mention the problem of small intestinal bacterial overgrowth in celiac sprue nor does it discuss insufficiency in some cases of severe sprue.

Illustrations and tables also are notable, emphasizing relevant information in an engaging and easy-to-read format. Tables 1.1 to 1.3 on clinical classification and differential diagnosis of diarrhea, for example, are particularly informative.

Overall, this book is recommended as a valuable reference for gastroenterologists, surgeons, internists and primary care physicians when treating pediatric or adult patients with acute or chronic diarrhea.

GI Motility Testing: A Laboratory and Office Handbook Parkman HP, McCallum RW, Rao S, eds. Thorofare, N.J.: Slack Inc.; 2011: 473 pp. Price: $83.95

This laboratory and office handbook offers a complete overview of how to perform procedures in gastrointestinal (GI) motility and interpret GI motility tests. The book explores GI motility disorders in the esophagus, stomach, small intestine, colon and anorectum.

It also discusses the most recent advances in technology and equipment as well as important information on billing and coding.

The impressive contributors carefully detail the procedures used to evaluate patients. Each chapter includes high-quality diagrams and

figures and is complemented with tables, which provide essential information in an easy-to-read form. The index also is comprehensive and user-friendly.

Chapter 13, “Ambulatory Capsule Tests for Assessment of GI Transit and Pressure,” was particularly notable, providing the latest data on this new diagnostic device. However, Chapters 15 and 16 included a glaring omission on breath testing; the chapters failed to mention the use of handheld portable hydrogen concentration determination devices. Additionally, in Chapter 16, the term lactose deficiency is used instead of lactase deficiency.

This is a useful handbook and is highly recommended for gastroenterologists, surgeons, GI fellows, internists, physician assistants, technicians, nurses and nurse practitioners.

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Acing the Hepatology Questions on the GI Board Exam: The Ultimate Crunch-Time Resource

Brennan Spiegel, MD, MSHS Slack, August 1, 2011 This book is truly the ultimate crunch-time resource for acing the often vexing liver section of the examination, taking recertifying examinations, looking good on clerkship rounds or for just challenging yourself with interesting and entertaining vignettes.

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Atlas of Endoscopic Ultrasonography Frank G. Gress; Thomas J. Savides

John Wiley/Blackwell Publishing, October 18, 2011 This atlas provides a large collection of excellent images obtained from both diagnostic and therapeutic procedures to give readers a preview of practice. It includes a CD-ROM with video clips and searchable database of images.

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Endosonography: Text with CD-ROM Robert H. Hawes, MD; Paul Fockens, MD, PhD

Elsevier/Saunders, May 16, 2006 Practical coverage on how to perform endoscopic ultrasound with written text describing the technique. The book’s two sections help you learn to manipulate the endoscope and interpret what you see and offers clear diagnostic guidance on each condition you may come across.

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Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

John Dibaise

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Gastroenterology Coding Manual, Third Edition

AGA Institute and the Professional Association of Healthcare Coding Specialists AGA Institute, May 1, 2011 Published jointly by the AGA Institute and PAHCS, this manual presents the essential elements of gastroenterology coding in a two-part, easyto-use format designed for both the experienced coder and the novice.

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Interventional Endoscopic Ultrasound, An Issue of Gastrointestinal Endoscopy Clinics

Kenneth Chang, MD, FACG, FASGE Elsevier/Saunders, April 28, 2012 The first section features articles dealing with the best practices of interventional EUS. Topics include FNA of solid pancreatic tumors, pancreatic cysts and diagnosis of SMTs. The second section addresses emerging technologies for intervention EUS. These articles discuss pancreatic cyst ablation, vascular access and therapy, anti-tumor agents, fiducial markers and brachytherapy, image enhancement, tumor ablation and anastomosis.

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Ulcerative Colitis: The Complete Guide to Medical Management

McGraw-Hill, April 20, 2012

Gary R. Lichtenstein MD, FACP, FACG, AGAF Slack, May 1, 2011

Gatroenterology and Hepatology Board Review: Pearls of Wisdom is a unique question-and-single-answer review for gastroenterology in-service and board exams. The book features about 3,500 questions with only the correct answer provided, reinforcing the answer students need to remember on exam day. Emphasis is placed on distilling key facts and clinical pearls essential for exam success.

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GEN0612

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

Gastroenterology & Endoscopy News • JUNE 2012

By George Ochoa The label for the hepatitis C virus (HCV) protease inhibitor (PI) boceprevir (Victrelis, Merck & Co., Inc.) has been revised to state that coadministration of the drug with certain ritonavir-boosted HIV PIs is not recommended, the FDA announced on April 26.

Ritonavir-boosted HIV PIs include atazanavir (Reyataz, Bristol-Myers Squibb), darunavir (Prezista, Janssen Therapeutics) and lopinavir (Kaletra, Abbott Laboratories). Another HCV PI, telaprevir (Incivek, Vertex Pharmaceuticals Inc.), already carries warnings about drug interactions with HIV PIs. The announcement follows a February safety alert in which the agency stated that drug interactions between boceprevir and ritonavir-boosted HIV PIs could reduce the effectiveness of the medications when used together.

The alert was based on a drug–drug interaction study that showed that receiving boceprevir while taking one of the three ritonavir-boosted HIV PIs could reduce levels of the medications in the blood.

The FDA also cited a small clinical

trial presented at the 19th Conference on Retroviruses and Opportunistic Infections from researchers at Merck (Sulkowski M et al, paper 47) that measured outcomes of HIV-HCV coinfected patients whose HCV was treated with either peginterferon/ ribavirin (n=34) or boceprevir plus peginterferon/ribavirin (n=64) and whose HIV infection was treated with ritonavir-boosted atazanavir, ritonavirboosted darunavir, lopinavir/ritonavir, or raltegravir (Isentress; Merck & Co., Inc.; see Gastroenterology & Endoscopy News, April 2012;63:44-45).

Kristen Marks, MD, assistant professor of medicine, Division of Infectious Diseases, Weill Cornell Medical College, New York City, and investigator, Cornell Clinical Trials, who was not an author of the study, commented by email that the trial “did not create any additional concerns about using [the drugs] together. There was no signal of either increased HIV or HCV breakthroughs.” Although the FDA wrote that it was revising the boceprevir label “in light of both the findings of the drug–drug interaction study and the clinical trial,” Dr. Marks thought the agency had just meant that it had revised the label “with the additional information gained.”

We’re in a

position

Photo courtesy of Merck

Boceprevir Label Revised: Do Not Coadminister With Ritonavir-Boosted HIV Protease Inhibitors

Dr. Marks said, “Given the drug interaction data, the updated FDA alert is appropriate. A larger AIDS Clinical Trials Group study (A5294) utilizing boceprevir in the treatment of HCV in HIV-coinfected subjects will provide additional important information about these combinations. It will look closely at the pharmacokinetic interactions for subjects on these drug combinations. It will also carefully monitor for breakthroughs in HIV suppression or lower response rates for HCV treatment.” Dr. Marks is on the A5294 study team and is the site

principal investigator for this study at Cornell Clinical Trials Unit.

The FDA recommended that patients do not discontinue their HCV or HIV medications without talking to their health care professionals, and that health care professionals who have started patients on boceprevir with one of the ritonavir-boosted HIV PIs should monitor patients for treatment response and virologic rebound.

n

Dr. Marks reported no relevant conflicts of interest.

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Gastroenterology & Endoscopy News • JUNE 2012

55

FDA Strengthens Monitoring of Post-Approval Drug Safety The FDA has revamped its postmarket drug safety program, tightening its oversight of drugs after they reach the public, according to a new report from the Center for Drug Evaluation and Research (CDER).

In this report “Advances in FDA’s Safety Program for Marketed Drugs,” released on April 21, the FDA describes how the CDER has enhanced the quality and accountability of its postmarket drug safety decisions.

“Our oversight of the safety of marketed drugs has changed significantly over the past few years,” said Janet Woodcock, MD, director of the CDER, in a statement, adding that the report shows the improvement in postmarket drug safety decisions and enhanced communication with the public.

Overall, the FDA has improved four main areas to monitor postmarket drug safety.

The initiative began in 2004, when the CDER introduced a comprehensive plan to strengthen drug safety.

The FDA Amendments Act (FDAAA) of 2007, which allowed the FDA to require postmarket studies of drug safety concerns and drug labeling changes, bolstered this plan.

The program appears to be effective. Since 2008, the FDA has required 65 safety-related labeling changes, in addition to those done

The following is a brief summary only; see full Prescribing Information for complete product information.

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.

voluntarily by drug manufacturers, and has compelled manufacturers to implement Risk Evaluation and Mitigation Strategies (REMS) to ensure that the benefits of a drug outweigh its risks.

Additionally, the FDA has doubled its staff in CDER’s Office of Surveillance and Epidemiology, has created a new division in the CDER’s Office of Biostatistics that focuses on postmarket drug safety, and has

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 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2.

(These include adverse events that may be attributable to the underlying disease).

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

Hepatic Encephalopathy

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

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

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

CONTRAINDICATIONS Hypersensitivity

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

WARNINGS AND PRECAUTIONS

1. Safety first: The FDA has established internal policies and procedures that give premarket drug safety review and postmarket safety monitoring an equal focus.

2. Safe use: The FDA has revved up its effort to ensure medicines are “used safely and appropriately” and to help users “avoid preventable medication errors.”

3. Strengthening drug safety science: By developing the Sentinel System, a national electronic system for monitoring FDA-approved medical products, as well as collaborating with other government agencies, the FDA has made strides in enhancing the science behind drug safety monitoring.

4. Drug safety communication: The FDA’s communications program provides important information to patients and physicians about new drug safety issues and does so earlier.

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

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

Clostridium difficile-Associated Diarrhea

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

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

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

Development of Drug Resistant Bacteria

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

Severe (Child-Pugh C) Hepatic Impairment

There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment.

The clinical trials were limited to patients with MELD scores <25.

Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

ADVERSE REACTIONS Clinical Studies Experience

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

Hepatic Encephalopathy

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

implemented the Mini-Sentinel pilot project, which allows the FDA to assess medical product safety issues using secure access to the electronic health care information of more than 125 million patients.

For information, visit www.fda. gov/Drugs/DrugSafety/ucm297389. htm. n

Number (%) of Patients

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

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

Postmarketing Experience

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

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

—Based on a press release from the FDA

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 Category C

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, rifaximin at the recommended dosing regimen is not

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. RIF 12/16

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS

75% of patients develop HE recurrences, even on lactulose.1 Protect your patients with Xifaxan 550 mg continuously from the moment they experience their first overt episode.

58% proven reduction in the risk of overt HE breakthrough2† 50% proven reduction in the risk of HE-related hospitalizations2‡§

Prescribe. Protect. Repeat.

*HE=hepatic encephalopathy. † Over a 6-month period; P<0.0001 vs placebo.2 ‡ Over a 6-month period; P=0.0129 vs placebo.2 § HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.2

IMPORTANT SAFETY INFORMATION 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. XIFAXAN has not been studied in patients with MELD 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. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

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.

Please see adjacent brief summary of Prescribing Information.

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

References: 1. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017. 2. Xifaxan [prescribing information].

Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16

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.

The most common adverse reactions occurring in >8% of patients in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), ascites (11%), muscle spasms (9%), pruritus (9%), and abdominal pain (9%).

Xifaxan550 is not available for sale outside the U.S. Xifaxan550 is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc.

www.Xifaxan550.com

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

Pancreatic Exocrine Insufficiency Part 2 of 2: Treatment and Therapeutic Considerations VIVEK KADIYALA, MD SHADEAH LAILA SULEIMAN DARWIN L. CONWELL, MD, MS Center for Pancreatic Disease Brigham and Womenâ&#x20AC;&#x2122;s Hospital Division of Gastroenterology, Hepatology, and Endoscopy Harvard Medical School Boston, Massachusetts

Update of Chronic Pancreatitis Etiology Data From Multicenter Study

I

n Part 2 of this 2-part review,

treatment approaches for patients

with pancreatic enzyme insufficiency

(PEI) are covered, including the proper use of currently FDA-approved pancrelipase preparations.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

As we have previously mentioned, the multicenter North American Pancreatitis Study 2 (NAPS2) consortium has recently provided valuable insights into the etiology of chronic pancreatitis. NAPS2 has reported that overall 45% of chronic pancreatitis cases (approximately 60% in males and 30% in females) seen in referral centers can be considered alcohol-induced.1 This represents a departure from previous estimates attributing more than 50%, and up to 80%, of chronic pancreatitis cases to excessive alcohol consumption.2 However, population level data from the United States is not currently available. NAPS2 data also have shown that although cigarette smoking is associated with heavy alcohol consumption, smoking is an independent, dose-dependent risk factor for chronic pancreatitis.3 Approximately 50% of chronic pancreatitis patients

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

1

reported 12 or more pack-years of smoking, and 26% reported more than 35 pack-years of smoking.3 Smoking and alcohol consumption combined appear to synergistically increase risk for chronic pancreatitis.

Treatment Approaches for Pancreatic Exocrine Insufficiency Treatment of diagnosed PEI is vital to maintaining nutritional status preventing exacerbation of cystic fibrosis (CF) and chronic pancreatitis (CP) related complications.4 For example, nutrition and lung health are closely linked; PEI exacerbates pulmonary disease and negatively impacts quality of life.4,5 Evidence indicates that maldigestion and malabsorption, secondary to CP and other pancreatic diseases, are associated with serious and potentially fatal complications, such as cardiovascular events associated with low plasma highdensity lipoprotein cholesterol, apolipoprotein A-I, and lipoprotein A.6 A prospective study of 23 patients recovering from acute pancreatitis and experiencing significant weight loss demonstrated that PEI developed in 86% of patients classified with severe pancreatitis as defined by preset criteria.7 In these patients pancreatic enzyme replacement therapy (PERT) may hasten recovery of pancreatic function.7 Patients who have been diagnosed with pancreatic cancer will require PERT for the remainder of their lives, regardless of concomitant therapies, to improve their level of nutrition and potentially reduce pain associated with high cholecystokinin levels.8-11 Clinical pancreatic malabsorption may remain despite the use of PERT and therefore requires individualized therapy and monitoring. In addition to PERT, treatment of PEI should also encompass dietary modifications and fat-soluble vitamin supplementation.

GOALS

OF

REPLACEMENT THERAPY

PERT is the standard therapy for PEI; 93% of patients in the US Cystic Fibrosis Registry are treated with pancreatic enzyme replacements.12 Clinical therapeutic goals of enzyme replacement include optimizing quality of life by correcting macronutrient and micronutrient malabsorption and reducing or eliminating abdominal symptoms associated with maldigestion.11 In adults, when optimal, PERT should prevent weight loss and wasting when accompanied by a normal diet.13 The pharmacokinetic objective of PERT is to optimize the nutritional value of each meal by achieving an adequate and timely concentration of active enzymes in the duodenal lumen for proper digestion.8,14-16 Despite the diverse armamentarium of available pancreatic enzyme replacement products (differing in enzyme content, dosage formulation, and coating) individual response to therapy is highly variable8,14-16 and limited, restoring fat absorption to only 80% to 85% of normal function.17

ENZYME OPTIONS Pancreatic enzyme replacement products were first

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I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

marketed as powders, tablets, and capsules. All were comprised of porcine pancreatic extracts containing lipase, amylase, and protease because of their similar composition to human pancreatic enzymes.18 The Unites States Pharmacopeia (USP) previously defined standards for 2 pancreatic enzyme preparationsâ&#x20AC;&#x201D;pancreatin and pancrelipaseâ&#x20AC;&#x201D;which are measured in units of lipase activity, as lipase is the lead enzyme.8 Pancreatin, a conventional preparation obtained from ox or swine pancreas, contained no less than 2 USP units of lipase activity and no less than 25 USP units of amylase and protease activity in each milligram.8 Pancrelipase, the newer preparation obtained from swine pancreas, contains no less than 24 USP units of lipase activity and no less than 100 USP units of amylase and protease activity per milligram.8 Because of the greater number of tablets required to achieve appropriate enzymatic concentration in the duodenum with pancreatin, the newer pancrelipase formulation has replaced the older preparation as the standard for PERT.8 Table 1 displays the commercially available, FDA approved, pancrelipase enzyme replacements. Previously, a wide array of unapproved products were available in 2 formulations: uncoated conventional immediate-release and enteric-coated microencapsulated enzymes.8 As of April 2010, only FDA approved pancreatic enzyme replacement products are commercially available in the United States; as of the date of this publication, there are 5 products that meet those requirements.19 There are no approved powdered formulations, nor are there any approved generic enzyme preparations. Creon is an appropriate first-line agent as it is approved for use in CP, pancreatectomy, and CF.19 Because of the acidic environment of the stomach, Viokace, the lone uncoated immediate-release preparation, is susceptible to inactivation before reaching the duodenum20,21; its efficacy has been established only when coadministered with proton pump inhibitors (PPI).

Enteric coating with acid-resistant film only allows the pancreatic enzyme replacements to be released from the microencapsulation when the pH exceeds 5.5, targeting release into the small intestine only.8 First introduced in the 1970s, one of the initial challenges with enteric-coated tablets was their inability to dissolve.18 The development of variably-sized, enteric-coated microspheres with small diameters (<2 mm) was an attempt to circumvent this issue by facilitating more even distribution within chime throughout gastric emptying.8 However, this theoretical advantage has never been evaluated.8 Taken correctly with food, enzymes last for approximately 1 hour following administration.22 When protected from acid degradation either by microencapsulation or by concomitant administration of acid suppressive therapy, pancrelipase preparations can survive transit through the stomach and effectively decrease steatorrhea.23 CF patients with PEI exhibit a marked

Table 1. FDA Approved Pancreatic Enzyme (pancrelipase) Preparations19 Product

Enzyme Content/Unit Dose, USP units Lipase

Amylase

Protease

Viokace 10,440

10,440

39,1550

39,150

Viokace 20,880

20,880

78,300

78,300

Immediate Release Capsule Non Enteric-Coated

Delayed Release Capsules Enteric-Coated Minimicrospheres Creon 6,000

6000

30,000

19,000

Creon 12,000

12,000

60,000

38,000

Creon 24,000

24,000

120,000

76,000

Ultresa 13,800

13,800

27,600

27,600

Ultresa 20,700

20,700

46,000

41,400

Ultresa 23,000

23,000

46,000

41,400

Zenpep 3,000

3,000

16,000

10,000

Zenpep 5,000

5,000

27,000

17,000

Zenpep 10,000

10,000

55,000

34,000

Zenpep 15,000

15,000

82,000

51,000

Zenpep 20,000

20,000

109,000

68,000

Zenpep 25,000

25,000

136,000

85,000

Enteric-Coated Minitablets

Enteric-Coated Beads

Enteric-Coated Microtablets Pancreaze 4,200

4,200

17,500

10,000

Pancreaze 10,500

10,500

43,750

25,000

Pancreaze 16,800

16,800

70,000

40,000

Pancreaze 21,000

21,000

61,000

37,000

decrease in the pancreatic secretion of bicarbonate needed to neutralize gastric acid. Suboptimal bicarbonate secretion results in increased acidity in the gastrointestinal tract, including the duodenum, which may prevent or slow the dissolution of enteric-coated microcapsules which dissolve over a variable period of time at a pH exceeding 5.5 to 6.0.9,24 The role of bicarbonate is to raise the duodenal pH to 8.5-9.0, potentially

allowing optimal lipase bioactivity and consequently decreased doses of PERT.25,26 These theoretical advantages require further clinical study and documentation before being recommended as standard initial therapy.

DOSING STRATEGIES

AND

GUIDELINES

PERT should be individualized to achieve a balance between minimizing steatorrhea and maximizing

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Pancreatic enzyme replacement therapy at initial recommended doses

Adequate response

Inadequate response • Steatorrhea • Poor weight gain in children or continued weight loss in adults

Check compliance

Adequate compliance

Address poor compliance

Increase dose by small increments • Avoid exceeding maximum recommended dose

Adequate response

Inadequate response

Adjunct therapy with acid-suppressing agent

Adequate response • Continue trial • Monitor regularly

Inadequate response

Recheck diagnosis • Stool check for Giardia lamblia • Celiac serology • Breath test for bacterial overgrowth • Liver diseases

If positive, treat with specific therapy

If negative, trial low-fat diet or substitute dietary fat by medium-chain triglycerides

Figure. Approach to pancreatic enzyme replacement therapy in patients with pancreatic exocrine insufficiency.68 Source: Australasian Pancreatic Club

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nutritional status.27 The Figure illustrates a reasonable approach to the management of PEI. Guidelines for the dosing of PERT have been issued by the Cystic Fibrosis Foundation (CFF). Weight-based dosing recommendations for PERT, promulgated by the CFF, require adjustment in relation to disease severity and clinical response to optimize fat absorption.27 Pancreatic lipase enzymes are susceptible to acidic deactivation; in order to restore nutrient digestion in patients with PEI, enzymes must be delivered into the duodenal lumen in sufficient quantities and synchronized with meals.27 In adults, intraluminal lipase activity requires a minimum of 40 to 60 IU lipase per minute in postprandial chime throughout the digestive period; corresponding to approximately 25,000 to 40,000 units of lipase needed for the digestion of a regular meal. Such doses should reduce steatorrhea to less than 15 g per day of fat.28,29 Unprotected immediate-release uncoated lipase is quickly rendered inactive in the low pH of the gastric environment; up to 10-fold more lipase must be given orally to reach the duodenum and correct steatorrhea.28 There are several preparations and methods for enzyme delivery designed to avoid gastric inactivation of enzymes. First, administering a higher-dose preparation may facilitate more active enzyme delivery to the duodenum. However, the benefits of prescribing higher dose pancreatic enzyme replacements must be weighed against potential adverse effects including bloating, diarrhea, flatulence, hyperuricosuria, and the development of colonic strictures.28,30-33 Second, the administration of acid-suppressing agents such as histamine-2 (H2) receptor blockers or PPIs enables an increase in the gastric pH (>4) to prevent acid-induced deactivation. This approach increases treatment costs and reported studies have not demonstrated a clear benefit associated with this strategy.29,34-36 Third, the introduction of enteric-coated preparations, which dissolve in a pH greater than 5.5, allows enzyme release to be targeted to the small intestine.8 The CFF consensus-based guideline for the nutritionrelated management adults with CF and PEI was readdressed in 2008.37 The recommended doses include 500 to 2,500 units lipase per kilogram of body weight per meal or less than 10,000 units lipase per kilogram of body weight per day, or less than 4,000 units lipase per gram of dietary fat per day.37 As lipase is the lead enzyme within individual preparations, it is the most important determinant of efficacy in the treatment of steatorrhea. Lipase enzymes possess specific biochemical properties including: 1) marked decrease in lipase synthesis compared with other enzymes in early pancreatic insufficiency fat malabsorption; 2) denaturation of lipase secondary to diminished pancreatic bicarbonate secretion; 3) minimal extra-pancreatic lipolysis; and 4) short intraluminal survival time of lipase compared with other enzymes.28,38 In most adults with CP, a minimum of 30,000 USP units of lipase per meal allows

adequate intraluminal digestion of fat and protein.28,38 The dose may need to be titrated to as much as 60,000 to 80,000 USP units lipase per meal because not all of the lipase may reach the proximal small intestine in the active form.28,38 Many CF patients will require numerous capsules of PERT daily—doses 15 to 25 capsules are common—but doses of lipase in excess of 75,000 units per meal are not recommended.28,38 The timing of PERT doses is subject to dietary and individual considerations. Enzymes may be taken before, during, and after the meal or snack. To maximize fat absorption, enzymes may be taken before and during, or during and after, the meal. A recent trial demonstrated that administration of enzymes was most effective when given during or after the meal.39 A nutritional consult from a registered dietician knowledgeable in CF care should be available for PEI patients and family members to assist with proper use and understanding of PERT.8 Several drinks and foods—items such as coffee/tea, lollipops, gum, jelly beans, and popsicles that contain simple carbohydrates and minimal nutritional value, as well as fruit and select fruit juices— do not require enzyme replacement.22 Usually, half the standard PERT dose is administered with snacks, and slightly higher doses may be appropriate when eating fried foods, pizza, or other high-fat foods.22 The total PERT daily dose should reflect 3 meals and 2 to 3 snacks.8,18,40 Recommended enzyme dose, based on lipase units per kilogram, is decreased for older patients as they weigh more and typically ingest less fat per kilogram of body weight.40 For patients who are unable to swallow capsules, they may be opened and the contents mixed with applesauce, rice cereal, bananas, or an alternate non-alkaline food to facilitate ingestion.17 Due to the risk of micro-coating disruption, the microcapsules cannot be crushed, chewed, or mixed with food for an extended period of time.17 Instead, the capsule beads are to be sprinkled on the food immediately prior to ingestion.

Pancreatic enzyme products are biologic extracts which contain, in addition to the active ingredients, protein and other substances which introduce the potential for enzyme activity to vary from batch to batch.13 Enzyme activity may also vary due to environmental factors and a decline in potency over time, especially with exposure to sunlight, heat, and humidity.13 Enzymes should be stored in a cool, dry environment and checked consistently for expiration dates.

ADVERSE EFFECTS PERT is generally well-tolerated at typical therapeutic doses. However, high PERT doses have been shown to induced nausea, vomiting, and diarrhea associated with transient intestinal upset, as well as hyperuricemia.8 In the past, the use of powdered preparations of PERT has caused hypersensitivity reactions in some patients.41

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Fibrosing colonopathy—a condition associated with ingestion of large quantities of PERT—can progress to colonic strictures at its most advanced stage. Highstrength microencapsulated products (>20,000 units of lipase) were first commercially available in 1991; 3 years later, the first colonic strictures were reported in CF patients, suggesting a temporal relation to the introduction of high-strength pancreatic enzyme replacement products. It has been hypothesized that the protease content of the pancreatic enzyme replacements at ultra-high doses may cause fibrosing inflammation in select predisposed patient populations.18 Recent studies have suggested that the intake of high doses of an included polymer, methacrylic acid copolymer, may be the cause of fibrosing colonopathy. Methacrylic acid copolymer is used as the acid-resistant coating on certain brands of microencapsulated enzymes. Until the cause of fibrosing colonopathy can further be ascertained, it is prudent to avoid excessive dose increases of microencapsulated products but instead attempt combination therapy of an uncoated tablet with a proton pump inhibitor or H2-receptor antagonist.27,30 Fibrosing colonopathy should be considered in patients receiving enzyme therapy who have evidence of obstruction, bloody diarrhea, or chylous ascites, as well as in patients with abdominal pain and persistent diarrhea, poor weight gain, or a combination thereof. The relative risk of developing this condition in the setting of high-dose pancreatic enzymes ranges from 10 to 200, increasing in a dose-dependent manner. Patients at high-risk for developing fibrosing colonopathy include individuals administered enzyme doses exceeding 6,000 lipase units per kilogram per meal for more than 6 months, or patients with a history of meconium ileus, distal intestinal obstruction syndrome, recent intestinal surgery, or inflammatory bowel disease.18,27,30-32 Overall, PERT is safe, well-tolerated, and produces few adverse effects if dosed and monitored based on a specific individual’s signs and symptoms.

VITAMIN REPLACEMENT THERAPY Comprehensive management of patients with PEI includes assessment of potential vitamin deficiencies and the use of over-the-counter (OTC) fat-soluble vitamin supplements.8 Steatorrhea is often associated with malabsorption of the fat-soluble vitamins A, D, E, and K. Vitamin deficiencies may develop as a consequence of fat maldigestion and malabsorption, for which both CF and CP patients are at risk. In fact, nearly half of all patients diagnosed with CF will have a deficiency of vitamins A, D, and/or E.42,43 In particular, vitamin D deficiency can lead to complications such as osteoporosis.

In fact, the odds ratio of fracture in CP has been shown to be comparable to that in other gastrointestinal disease recognized as having high fracture risk.44 Although all patients with severe PEI should receive a bone scan, it may be more practical to establish a baseline bone

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mineral density in menopausal patients with PEI, particularly if there is a family history of osteoporosis. Young adults, adolescents, and children with CF often have low levels of vitamin D despite taking daily supplements and consequently also are at high risk for metabolic bone disease.43,45 Although most vitamin deficiencies are not clinically observed, bone demineralization is commonly seen in CF and may also be a reflection of general malnutrition and corticosteroid treatment. Metabolic bone disease has been described in CP, but prospective studies are needed to accurately determine its incidence and prevalence. There is clinical consensus that a multivitamin and additional dietary supplementation of fat-soluble vitamins A, D, E, and K typically results in rapid normalization of serum markers of malnutrition (albumin) and vitamin deficiency.46

INCREASED CALORIC REQUIREMENT

AND

HIGH-FAT DIET

Patients with PEI should consume a high-calorie diet with unrestricted fat that is appropriate for age and clinical status.46 In fact, patients with CF may require anywhere from 20% to 50% more calories than a healthy individual.22 Additional calories are required for catchup growth, and nutritional assessment should accompany evaluation in all patients.46 The CFF recommends that nutritional status be appropriately managed to avoid unintentional weight loss in patients older than 20 years of age.37 In addition, as PEI in CF generally does not represent a risk factor for developing hyperlipidemia, the abundance of dietary fat—the highest density source of calories—is not particularly concerning.47 Meals can be complimented with store-bought nutritional supplements and homemade milkshakes, but these additions should not serve as primary sources of nutrition.22

Monitoring of Clinical Response to PERT Initial pancreatic enzyme replacement therapy should be adapted based on clinical response, measured in terms of energy utilization for growth and degree of steatorrhea.37 Follow-up and titration after initial PERT is vital to disease management and improved patient quality of life. Therapy should be initiated at the lowest possible dose and gradually increased until the desired control of steatorrhea is obtained. Achieving recommended normal weight and height ranges—assessed using age-appropriate ideal body weight (IBW) or body mass indices—is associated with better pulmonary function in CF patients.37 The CFF has established the following categories for objective growth measurements based on IBW: adequately nourished (>90% IBW); underweight (85%-89% IBW); mildly malnourished (80%-84% IBW); moderately malnourished (75%-79% IBW); or severely malnourished (<75% IBW). Malnourished patients also may be identified using measurements of triceps skinfold and midarm circumference.46 A list of useful considerations in patients experiencing

suboptimal response to PERT is outlined in Table 2.40 Poor response to therapy may be defined as continued abdominal complaints—such as bloating, flatus, abdominal pain, loose or frequent stools, or overt diarrhea—in conjunction with symptomatic steatorrhea and/or poor growth despite PERT. In patients with weight loss unrelated to caloric intake or malabsorption, or poor growth despite improved steatorrhea, alternative gastrointestinal disorders and diabetes mellitus should be considered in the differential diagnosis. Notably, abdominal pain alone does not indicate the need for increased PERT dosage.40,48 Clinical response may be measured objectively through a 72-hour stool fat quantification. A recent study performed in pancreatic duct–ligated mini-pigs demonstrated that the N-benzoyl-tryrosyl para-aminobenzoic acid (NBT-PABA) test can be used to monitor the efficacy and kinetics of treatment, particularly the extent of protein digestion and the effect of protease enzyme replacement therapy on digestion.49 In addition, clinical investigators have recently studied the use of the 13C-mixed triglyceride breath test to evaluate PERT efficacy in 20 patients with CP and malnutrition to target appropriate PERT.50 Despite an evaluated adequate clinical response to PERT, some individuals continued to have abnormal breath results.50 When therapy was titrated upward to normalize breath test results, patient nutritional status was also normalized, as measured by increase in body weight, serum concentrations of retinol binding protein, and prealbumin.50 Although the NBT-PABA and 13C-mixed triglyceride breath test are not currently available in the United States, evidence demonstrates the benefit of adjusted dosing to target appropriate PERT for PEI. If PEI is not adequately reduced by standard treatment with reported therapeutic compliance, a 2- to 3-fold enzyme dose increase may improve the clinical response.42 Changes in dose or product may require an adjustment period of several days before implementing further titration.42 If doses exceed 2,500 lipase units per kilogram per meal, further investigation is warranted prior to dose escalation; doses greater than 2,500 lipase units per kilogram per meal require caution.27,31,32 An alternative dietary strategy to improve clinical response is to distribute nutrient intake across 5 to 6 small meals.42 When assessing clinical progress, the great variation between individual response, enzyme products, and range in PERT dosage are important considerations. Enzyme doses are routinely adjusted by the prescriber, based on persistent signs and symptoms of malabsorption or adverse effects. Although the patients experiencing steatorrhea are often on lifelong PERT and therefore become familiar with the optimal dose required per meal, it is imperative to instruct patients not to adjust the dosage without the supervision of a healthcare practitioner.51,52 If symptoms persist, the PERT dose may be

Table 2. Treatment Strategies For Patients with Suboptimal Response to PERT40 Increase dosage Decrease fat intake to 50 to 75 g/day Check compliance (fecal chymotrypsin) Add proton pump inhibitor or H2-receptor antagonist Check expiration date of product Check storage environment of product Ensure patient is receiving enzyme dose with snacks or milk Look for evidence of concurrent gastrointestinal disorder PERT, pancreatic enzyme replacement therapy

inadequate or the preparation may not be appropriate for the individual. In most patients, enteric-coated microspheres are the most favorable therapeutic option as this formulation prevents release and degradation of the enzymes before reaching the duodenum. However, in patients with high gastric acidity, coated preparations that typically release enzymes when pH exceeds 5.5 may still fail to deliver enzymes to the duodenum. In other individuals, high acidity levels may deactivate the replacement enzyme and reduce efficacy, potentially requiring supplementation with a PPI or H2-receptor antagonist.27,53 Occasionally, employing other strategies may improve response. These alternatives include the use of non-enteric coated enzymes in combination with enteric-coated enzymes, the administration of only a portion of capsules halfway through a meal, concomitant administration of bicarbonate or gastric acid suppressive therapy, and prescribing a brand of enzyme with a different dissolution profile (eg, microspheres vs microtablets).17 The concurrent administration of PPIs or H2-receptor antagonists also may provide benefit when using immediate-release non-coated preparations.11

IMPACT

OF

COMORBIDITIES

Gastrointestinal comorbidities in PEI patients may cause persistent abdominal symptoms that will not respond to increases in PERT dosage. These diagnoses, listed in Table 3, may coexist with PEI as a result of CF and CP and should be considered in patients with inadequate response when treated with therapeutic doses.

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ADHERENCE

Table 3. Gastrointestinal Comorbidities in PEI27 Lactose intolerance Enteric bacterial infection Parasite, especially giardiasis Bacterial overgrowth of the small intestine Biliary disease, cholestasis Pseudomembranous colitis Celiac disease Short bowel syndrome Crohn’s disease PEI, pancreatic enzyme insufficiency

For example, patients with bacterial overgrowth following gastric and intestinal resection, intestinal infection, such as giardiasis, or other intestinal absorption disorders may have severely impaired absorption requiring surgical intervention.27

CONSIDERATIONS

IN

SPECIAL POPULATIONS

Special PEI populations require further consideration regarding PERT based on the etiology of PEI, past surgeries, or underlying disorders. For example, achlorhydric patients have been treated successfully with uncoated enzyme preparations.27 Patients who receive continuous acid suppressive therapy may also be able to use conventional nonenteric-coated pancrelipase formulations.28 Individuals who have undergone pancreatectomy should receive conventional enteric-coated enzyme preparations19; Creon 72,000 units lipase per meal and 36,000 per snack has been shown to be effective in PEI following pancreatic surgery.54 The use of PERT in patients receiving enteral feeding following gastrostomy is also of particular concern. Data concerning appropriate dosing and timing of pancreatic enzymes with different enteral nutritional supplementation is lacking; there is a need for further research to achieve evidence-based consensus on providing optimal enteral nutrition in conjunction with PERT.8,55 Although none of the currently approved enzyme preparations have been designed for delivery via gastrostomy, a recent study has demonstrated that the Creon spheres, mixed with baby food (pH <4.5), can effectively be delivered through 16Fr and 18Fr gastrostomy tubes without clogging or loss of lipase activity.55

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AND

SELF-MANAGEMENT

In addition to clinical considerations that may compromise response to PERT, patient adherence is another challenge to achieving and maintaining optimal therapeutic outcomes. In accordance with the 2004 CFF consensus guidelines, the primary objectives of the health care team are to ensure optimal care, facilitate access to pertinent medical resources, coordinate care among specialists and primary care practitioners, and support quality of life and independence for each patient.56 Counseling and management of patients receiving PERT generally takes place in the setting of the CF center clinic visit and is undertaken by a multidisciplinary care team that includes physicians, nurses, pharmacists, and dietitians. Additional patient resources are provided by the manufacturers of individual preparations. Family members are in a pivotal position to offer support, contribute to the development of strong lifemanagement skills, and serve as a positive influence on lifestyle choices.56 As PERT is required with every meal, PEI patients are confronted with an important daily commitment to manage their own health and prevent complications. The large quantity of capsules necessary for some patients may contribute to poor PERT adherence. Timing is also of concern as patients may take their medication before, but not during or after a meal, or may unintentionally forget to take the medication completely. To assist patients in adhering to demanding treatment regimens and dietary choices, the CFF has issued helpful educational tips that include “Grab ’N Go” ideas—ranging from high-fat deli meat and cheese roll-ups in an insulated cooler to trail mix and raisin bread that can be strategically stored—to cut down on preparation time when schedules are busy.57 Mini-meals can also be prepared in advance and then frozen or reheated when necessary. Adding color to meals in the form of various fruits and vegetables ensures antioxidants are incorporated into the high-calorie diet. Similarly, enzymes can also be stored in coat pockets or a book bag to facilitate access when consuming these meals or snacks.

Patients should be actively involved in monitoring their own progress and should be thoroughly educated regarding IBW ranges. Between regularly scheduled health care visits individuals can record their own weight using a scale at home and can be trained to report significant weight loss and seek immediate medical attention when necessary. Dietary factors may also result in inadequate response to therapy. In CF, excessive intake of fruit juice, observed most often in children, can cause loose stools due to carbohydrate malabsorption.58 PEI patients need to be aware of these complications and manage their diets accordingly. Another important counseling point pertains to the appropriate dosage of enzymes and dietary considerations; there is often lack of awareness that enzymes should be administered

with milk or small snacks in addition to regular meals.40 Communication between the patient and health care provider will help to optimize PEI management.

In contrast, deliberate misuse of and nonadherence to prescribed PERT can explain inadequate response and can be confirmed by measurement of fecal chymotrypsin; low activity is suggestive of insufficient enzyme intake. Poor adherence to PERT is more problematic in patients during adolescence and into young adulthood.59 Young women, in particular, may resist taking full doses due to fears of gaining weight or may have a distorted body image.40 Attention to special challenges confronting children and adolescents with CF, including rapid physical growth, can help facilitate the transition into adulthood and improve medication adherence.56 In addition, depression or inadequate coping mechanisms with new diagnoses may affect willingness to adhere to therapy and require medical attention to prevent interference with recommended therapy.40

PERT: Past and Future As a part of ongoing health care reform and national efforts to regulate available treatments, recent FDA mandates have been developed to establish and guarantee the safety and effectiveness of available PERT. Additionally, new therapeutic options are in development to provide more flexibility in managing PEI patients with various clinical needs.

FDA MANDATES Predating the 1938 Food, Drug, and Cosmetic Act, pancreatic enzyme replacements were not subject to the battery of dose-ranging, efficacy, and safety studies that are currently required for marketed products.60 Under the 1938 labeling of rules, enzyme products must contain at least 90% of the labeled amount. To meet this requirement, many capsules were overfilled by as much as 50% or more—based on lipase content— to account for deterioration over time and ensure that the preparations meet 90% of the labeled potency on their expiration date.61 Although most products listed in the USP have both a lower and upper limit regulation, this requirement was previously not applicable to pancreatic enzyme replacements listed in the USP prior to 2000.60 More recently, microencapsulated products had been marketed without formal FDA approval by claiming that they are covered by the 1938 regulations.62 Actions taken by manufacturers to meet labeling regulations may have compromised patient outcomes as higher doses of pancreatic enzyme replacements have been associated with fibrosing colonopathy in children with CF.18 In addition, variations between capsules, batches, and brands have resulted in an inconsistent absorption pattern among CF patients. This variability can be magnified with the use of H2-receptor blocking agents or PPIs to decrease gastric pH.61 A study of actual lipase activity demonstrated marked variability

in lipase activity, providing evidence that product labels frequently misrepresented efficacy and were inaccurate when labeled potency was compared with actual content.62 In 1985, the FDA reconsidered the Advisory Review Panel on OTC Miscellaneous Internal Drug Products stance that pancreatic enzyme replacements be considered safe, effective, and accurately branded.63 These data were reviewed, and written comments, objections, and requests for oral hearings on the proposed rule making were entertained.63 Based on the information received, the FDA launched an investigation of pancreatic replacement enzymes and found inconsistencies in the formulation, dosage, and manufacturing processes of enzymes that could compromise the safety and efficacy of the medication.64 The Federal Registry of 1991 reported that OTC products used to treat PEI were misbranded and could not be considered safe and effective because of bioavailability issues.63 In a 2008 review, the CFF addressed the use of generic rather than brand name PERT on the coefficient of fat absorption and on nutritional and growth status.37 The CFF concluded that there was insufficient evidence to support the efficacy of generic pancreatic enzyme preparations and highlighted the need for welldesigned studies of PERT preparations, dosing, and important clinical outcomes.37 Furthermore, the CFF stated that, due to a lack of evidence for generic products, they recommend the use of proprietary pancreatic enzyme preparations for PERT.37 In response to a number of complaints directed at the inconsistency among enzyme replacement products and the lack of scientific data of these agents, the FDA published a notice in the Federal Registry in 2004 stating that the manufacturers of all existing pancreatic enzyme replacements must submit New Drug Applications under FDA scrutiny, demonstrate adequate safety and efficacy of each product, and receive FDA approval by 2008 to remain on the market.63 This deadline was subsequently extended to April 2010 to enable the highly anticipated evidence of safety and tolerability to be properly collected. Five PERT preparations are currently FDA approved and commercially available.

EMERGING PERT OPTIONS There are currently several treatments and management strategies being evaluated to address the challenges in enzyme delivery and efficacy. In order to combat acid degradation of exogenous pancreatic enzymes and provide optimal duodenal pH, an enteric-coated high-buffered formulation of pancrelipase—which has the potential to increase duodenal pH and allow for optimal lipase bioactivity at lower PERT doses—has been explored in 2 trials.25,26 However individual responses to buffered PERT have been highly variable and the utility of these products requires further analysis. The current pancreatic

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enzyme preparations are porcine products; however, a microbial-derived preparation and human recombinant lipases may provide superior safety and resistance to acid and protease degradation. Microbial-derived liprotamase has been shown to be safe and effective in a Phase 3 trial of PEI in CF patients 7 years of age and older.65 Kiobrina, a recombinant human bile-salt stimulated lipase, is currently undergoing Phase 3 clinical trials in preterm (younger than 32 weeks) infants (ClinicalTrials.gov NCT01413581). Another approach under investigation is the engineering of functional dietary lipids that can be more effectively digested and absorbed by patients with PEI undergoing PERT. Modification of the substrate—specifically lipid droplet size, droplet surface composition, and fatty acid glycerol backbone esterification—may improve lipase function.66,67

Conclusion Loss of pancreatic function in CF, CP, and other patient populations is associated with digestive malabsorption and its clinical manifestations. Accurate diagnosis of PEI in at-risk individuals enables the initiation of PERT according to established recommendations for dosing and administration. Close and frequent monitoring of clinical response and adherence must be performed along with the implementation of treatment modifications, dietary management, and patient counseling to effectively reduce symptoms, maintain growth and nutrition, improve quality of life, and reduce complications and mortality.

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13. Durie P, Kalnins D, Ellis L. Uses and abuses of enzyme therapy in cystic fibrosis. J R Soc Med. 1998;91(suppl 34):2-13.

14. Holtmann G, Kelly DG, Sternby B, DiMagno EP. Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes. Am J Physiol. 1997;273:G553-G558.

15. Keller J, Runzi M, Goebell H, Layer P. Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal. Am J Physiol. 1997;272:G632-G637.

16. Layer P, von der Ohe MR, Holst JJ, et al. Altered postprandial motility in chronic pancreatitis: role of malabsorption.

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17. Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol.

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18. FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med. 1997;336:1283-1289.

19. Giuliano CA, Dehoorne-Smith ML, Kale-Pradhan PB. Pancreatic enzyme products: digesting the changes. Ann Pharmacother.

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20. Gow R, Bradbear R, Francis P, Shepherd R. Comparative study of varying regimens to improve steatorrhoea and creatorrhoea in cystic fibrosis: Effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet. 1981;2:1071-1074.

21. Ansaldi-Balocco N, Santini B, Sarchi C. Efficacy of pancreatic enzyme supplementation in children with cystic fibrosis: comparison of two preparations by random crossover study and a retrospective study of the same patients at two different ages.

J Pediatr Gastroenterol Nutr. 1988;7(suppl 1):S40-S45.

22. Maguiness K CS, Fulton J, Luder E, McKenna A, Hazle L. Nutrition: Pancreatic Enzyme Replacement In People with Cystic Fibrosis.

Volume 2012, 2006.

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AUTHOR DISCLOSURES—Ms. Suleiman and Drs. Conwell and Kadiyala have no conflicts of interest.

DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the author(s). Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright © 2012, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.

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