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The Independent Monthly Newspaper for Gastroenterologists

NATIONAL COLORECTAL CANCER AWARENESS MONTH ENDOSCOPY SUITE

ASGE Unveils New Training Facility BY BRIGID DUFFY

FOBT Shows ‘Striking’ Results for Long-Term Reduction in CRC Mortality BY MONICA J. SMITH

As the global home of endoscopy, the American Society for Gastrointestinal Endoscopy (ASGE) was long in need of a training facility worthy of its stellar reputation. After nine years of planning, see IT&T, page 26

WEO Provides Global Training In Endoscopy BY VICTORIA STERN Early last year, the World Endoscopy Organization (WEO) organized the first Program for Endoscopic Teachers (PET). The aim of the two-day program, held in Hyderabad, India, was to provide see PET, page 33

SAN DIEGO—A randomized controlled trial (RCT) of fecal occult blood test (FOBT) screening for colorectal cancer (CRC) has demonstrated dramatic reductions in mortality. The results are highly durable and persistent, and also support the role of polypectomy. Results of the Minnesota Colon Cancer Control Study, which included more than 46,000 participants, aged 50 to 80 years, who were randomized to receive annual or biennial CRC screening with FOBT, or no screening, showed a relative risk for CRC-related mortality of 0.68 in the annual screening arm and 0.78 in the biennial screening arm through 30 years of follow-up. This translated into risk reductions of 32% with annual screening and 22% with biennial screening. The Minnesota study confirms the findings of two RCTs of biennial CRC screening with FOBT carried out in the United Kingdom and Denmark see FOBT, page 18

OPINION

Colonoscopy— Facts The New York Times Omitted Farid Naffah, MD, MS Avamar Gastroenterology and Center for Endoscopy, Inc. Warren, Ohio If you happened to come across The New York Times article “The $2.7 Trillion Medical Bill: Colonoscopies Explain Why U.S. Leads The World in Health Expenditures” (by Elisabeth Rosenthal, June 2, 2013), you undoubtedly felt outraged by what you read, perhaps even betrayed. Outraged to

learn about the exorbitant cost of colonoscopy and the profit-mongering schemes of those who provide the service. Betrayed by the insight that the entire thing may have been a fraud: Your colonoscopy may not have even been medically necessary. On the other hand, if you were a patient at any one of the 5,300 physician-owned and operated ambulatory surgery centers (ASCs) across the country, you may have felt perplexed, even confused. You could not easily dismiss the

I N S I D E

EXPERT REVIEW Postoperative Pain Management In Anorectal Surgery By Gary H. Hoffman, MD and Stephen Yoo, MD .................................page 49

PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM PRINTER-FRIENDLY GASTROENDONEWS COM

CLINICAL REVIEW

Bowel Preparation For Colonoscopy Maximizing Efficacy, Minimizing Risk LAWRENCE B. COHEN, MD Clinical Professor of Medicine The Mount Sinai School of Medicine New York City

see insert after page 14

Disclosure—Dr. Cohen has served on the advisory board and speakers’ bureau of Salix Pharmaceuticals.

Bowel Preparation for Colonoscopy: Maximizing Efficacy, Minimizing Risks By Lawrence B. Cohen, MD

see Colonoscopy, page 6

he success of colonoscopy as a screening modality for colorectal cancer is highly dependent on the ability to

purge the colon of fecal material in order to provide an unobstructed view of the bowel wall. Inadequate cleansing of the colon, reported to occur in about 27% of all examinations, results in missed adenomas.1

Suboptimal bowel preparation leads to prolonged procedure times, lower rates of cecal intubation, reduced screening intervals, higher screening costs, and possibly an increased risk for procedure-related complications. Furthermore, recent studies demonstrate that colonoscopy is more effective in the prevention of leftsided than right-sided cancers.2-5 Possible reasons for this include suboptimal cleansing of the right side of the colon and increased difficulty in detecting right-sided lesions because they often are flat or sessile. The adoption of more effective methods of bowel cleansing and a greater emphasis on patient compliance with preparation instructions will improve the effectiveness and efficiency of colonoscopy, as well as minimize the risk for procedural complications.

Bowel Preparations The available purgatives for colonoscopy can be divided into 3 categories: osmotic agents, polyethylene glycol (PEG)–based solutions, and stimulants. Osmotic laxatives increase intraluminal water by promoting the passage of extracellular fluid across the bowel wall. Examples of osmotic preparations include sodium phosphate (NaP), magnesium citrate, and sodium sulphate. The PEG-based solutions consist of a high-molecularweight nonabsorbable polymer in a dilute electrolyte solution. PEG solutions are designed to be osmotically balanced, limiting the exchange of fluid and electrolytes across the colonic membrane. Stimulant laxatives work by increasing smooth muscle activity within the wall of the colon. Examples of stimulant purgatives include

G A S T R O E N T E R O LO GY & E N D O S CO P Y N E WS S P E C I A L E D I T I O N • M A R C H 2 0 1 4

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

PRODUCT ANNOUNCEMENT see page 55 for product information

FROM THE BENCH TO THE BEDSIDE see pages 10-11

Solesta for the Treatment of Fecal Incontinence Faculty Mitchell A. Bernstein, MD, FACS, FASCRS Associate Professor of Surgery Director, Division of Colon & Rectal Surgery NYU Langone Medical Center New York, New York

Indication

Medivators’ Jet Prep Flushing Device for cleansing of GI mucosa during endoscopic procedures

Solesta for the Treatment of Fecal Incontinence Mitchell A. Bernstein, MD, FACS, FASCRS

SOLESTA is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, fiber therapy, and anti-motility medications).

Important Safety Information about SOLESTA SOLESTA® (hyaluronic acid/dextranomer) is contraindicated in patients with active inflammatory bowel disease, immunodeficiency disorders or ongoing immunosuppressive therapy, previous radiation treatment to the pelvic area, significant mucosal or full thickness rectal prolapse, active anorectal conditions (including abscess, fissures, sepsis, bleeding, proctitis, or other infections), anorectal atresia, tumors, or malformation, rectocele, rectal varices, presence of existing implant (other than SOLESTA) in anorectal region, or allergy to hyaluronic acid-based products. SOLESTA must not be injected intravascularly as injection of SOLESTA into blood vessels may cause vascular occlusion. Injection in the midline of the anterior wall of the rectum should be avoided in men with an enlarged prostate. SOLESTA should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program on the SOLESTA injection procedure. The most common adverse reactions with SOLESTA (incidence >4%) in the clinical study were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. Please see complete Prescribing Information for SOLESTA at solestainfo.com.

Introduction Fecal incontinence (FI), loosely defined as the inability to defer the urge to pass stool until a socially acceptable time or place, affects about 19 million Americans.1 FI can be a devastating condition, leading to a decrease in activities of daily living (ADLs) and having an adverse influence on quality of life (QoL) for those who suffer with the condition.2,3 Unfortunately, stigma associated with FI often prevents patients from seeking treatment.4 FI has a broad range of causes with surgical and obstetrical trauma being the leading etiologies. In addition, a number of chronic diseases, including obesity, diabetes, and chronic obstructive pulmonary disease have been associated with higher rates of FI.5 Treatment options for patients with FI range from conservative, nonoperative therapies to invasive, surgical procedures. More recently, minimally invasive options have been introduced into the treatment paradigm for patients who have FI.

Burden of FI: Effect on QoL The devastating influence of FI on the well-being of affected patients is significant and closely correlates with the frequency and severity of episodes. In a study that took into account frequency of FI episodes, amount of stool lost, composition of stool lost, and fecal urgency, 82% of those with severe symptoms had a moderate to severe negative influence on one or more aspects of their QoL.6 The most profound effects may be psychological, with high rates of depression and anxiety reported in those with FI relative to the general population.7 FI also has been shown to affect the ability or willingness of individuals to participate in ADLs.2 In the largest existing assessment of US women with FI, 18.8% of participants (1,096 of 5,817) reported at least one episode of bowel leakage per year.8 Roughly 40% (368 of 938) of women with FI experienced a severe negative influence on QoL in one or more areas of their daily lives, with the most affected areas relating to frustration, and emotional well-being and participation in social activities. The study also found that despite the negative effect on QoL, less than one-third of women with the condition discussed it with their physician.2,8 FI imposes considerable social barriers on patients with the disorder.

Epidemiology Approximately 8% of noninstitutionalized adults in the United States report having experienced at least 1 episode of FI over the

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

past 30 days.9 Although FI rates are relatively higher in women,10 rates of FI increase with age regardless of gender.9 In women, childbirth by vaginal delivery may cause damage to the pelvic floor or other recto-genital structures causing FI soon after delivery, or manifesting several years later.

candidates for surgery. Recently, however, 2 relatively noninvasive treatments have been introduced into the armamentarium for these patients. Sacral nerve stimulation (SNS) and hyaluronic acid/dextranomer injections (Solesta, Salix Pharmaceuticals) have shown sustained benefit in multicenter trials.14,15

Evaluation of FI

Solesta: An Effective Treatment Option for FI

Evaluation of patients with FI begins with a thorough history, including surgical and obstetric history. The use of intake questionnaires such as the Cleveland Clinic Fecal Incontinence Score (CCFIS) or Fecal Incontinence Severity Index (FISI) are helpful in gauging the extent and severity of the condition.11 Following a history and physical examination, additional evaluation in a comprehensive anorectal physiology lab may be useful. Anorectal manometry, pudendal nerve testing, and endoanal sonography all provide additional information that may be useful in directing therapy.

Treatment Strategies Although treatment selection is dependent on many variables, conservative, noninvasive therapies are regarded as the first-line approach in most cases of FI.12 Conservative approaches include diet and medical therapies.10 Abstention from foods that increase colonic transit time, such as coffee, or increasing consumption of foods that increase bulk, such as fiber, should be an initial step in treatment.10,12 Additionally, the use of antidiarrheals may be appropriate for slowing transit time.10 In addition to these conservative therapies, pelvic floor exercises using biofeedback may be sufficient in improving bowel control. Although the efficacy of conservative approaches varies, surgical therapies may provide more definitive correction when anatomic defects are the primary cause of incontinence. A variety of surgical approaches have been described for specific anatomic defects; however, sphincteroplasty is the most common surgical repair used.10 The benefit from surgery is dependent on selection of the appropriate procedure performed by an experienced team. Even with appropriate patient and procedure selection, the results may not be durable.13

Minimally Invasive Treatment Options for FI Historically, patients with FI who did not respond to conservative therapies had surgical intervention as their only alternative option, and yet not all patients were

Solesta injections are a relatively noninvasive, office-based treatment. In 2011, it was approved by the FDA for the treatment of FI on the basis of a multicenter, doubleblind, sham-controlled trial.15 Solesta combines dextranomer microspheres with stabilized hyaluronic acid, which is injected into the submucosal layer of the anal canal and serves to augment tissue volume surrounding the sphincter. Four injections are typically performed without anesthesia in a quick, single in-office procedure. The safety and efficacy of Solesta was demonstrated in a registration trial of 206 adults with FI who had failed conservative therapy.15 Patients were randomized to receive either dextranomer or sham, and the end point was the percentage of patients with at least a 50% reduction in episodes of FI from baseline.15 After 6 months, 52% of those receiving dextranomer and 31% of those receiving the sham achieved this end point, producing an odds ratio of 2.36 (95% confidence interval, 1.24-4.47; P=0.0089; Figure).15,16 Treatment with Solesta was generally well tolerated by patients. The most common adverse events (>4%) were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. There were 2 cases of rectal abscess and 1 case of Escherichia colii bacteremia, and all were successfully resolved.16 The 47.2% reduction in the median number of FI episodes during 2 weeks of treatment with dextranomer and the 79.5% increase in the mean number of incontinence-free days at 12 months were statistically significant (P<0.0001 for both). Furthermore, significant improvements in QoL scores at 12 months were achieved by patients treated with Solesta for the 4 measured domains (lifestyle, coping and behavior, depression and self-perception, and embarrassment).15 Patients should be instructed to avoid physical activity for 24 hours after treatment with Solesta and to avoid sexual intercourse and strenuous physical activity for one week (eg, horseback riding, bicycling, and jogging). If a patient does not have an adequate

FROM THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Introducing ‘G&E Digest’ New Online Digest Offers Taste of Breaking Medical News Cynthia J. Gordon, PhD Managing Editor Gastroenterology & Endoscopy News Gastroenterology & Endoscopy News is proud to announce the debut of a new

column on our website: an online digest of current medical news and happenings in gastroenterology, endoscopy, hepatology and afield. The first edition appeared online on Feb. 10. For those of you who follow us on Twitter, you’re most likely already

aware of our daily goings-on and news coverage outside of our print issue. For those of you who don’t, this is a new option for you to keep up with Gastroenterology & Endoscopy News throughout the entire month: Visit our website, gastroendonews.com, where we will be

posting the online digest on a regular basis. Additionally, if you would like to be informed when new content is posted to our website, consider registering for our free e-Newsletter, if you haven’t done so already. The online digest will be included in the weekly e-Newsletters sent to registered users. Registration is quick and easy: Just visit www. gastroendonews.com/eSignUp.aspx, type in your email address and click “Submit”—that’s all it takes! Of course, we will continue to maintain our Twitter feed, where we currently tweet on a near-daily basis. If you are someone who likes to tweet and be tweeted, follow us at @gastroendonews. We are starting slowly, and during the coming weeks and months, we hope to increase steadily the content and frequency of our online digest. As we do so, we hope you will provide us with feedback on how we’re doing, and/or what you would like to see there. Comments can be posted online in the “Comments” section of each article, or simply send an email directly to me—I look forward to hearing from you! Contact the editor at cgordon@mcmahonmed.com.

Clarification In the January issue of Gastroenterology & Endoscopy News, a letter published in response to “Private Practice Is a Dinosaur and the ACA Is an Asteroid” (by Nicholas V. Costrini, MD, PhD, MBA. Gastroenterology & Endoscopy News August 2013;64:7) was missing the author’s name. The author of the letter “12 Reasons To Reject the Central Authority of Health Care” (Gastroenterology & Endoscopy Newss January 2014;65:10) was Ronald E. Feldman, MD.

FROM THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

A Sampling From Our New Column, ‘G&E Digest,’ Online Now at GastroEndoNews.com The first installments of ‘G&E Digest’ were posted online in February. Following is a sampling of what we covered. • First up: “Hot Topics in Crohn’s Disease 2014.” Reporters at MedPage Todayy asked inflammatory bowel disease experts Russell Cohen, MD, William Sandborn, MD, and Marla Dubinsky, MD: “What do you anticipate will be the most important clinical development in Crohn’s disease in 2014?” The three experts responded succinctly in a three-minute video interview. • “Does HRT Boost Pancreatitis Risk?” Researchers from the Karolinska Institute think it may. They reported a 57% increased risk for pancreatitis linked to use of hormone replacement therapy (HRT) based on a prospective study of 31,500 postmenopausal women in Sweden. The research was published online on Jan. 28, in CMAJ. J • A retrospective study of the U.S. Bariatric Outcomes Longitudinal Database revealed that laparoscopic sleeve gastrectomy did little to resolve

preoperative symptoms of gastroesophageal reflux disease (GERD), and actually led to the new onset of GERD symptoms in some patients. Authors of the study, published online on Feb. 5 in JAMA Surgery, “recommended evaluating all bariatric surgery candidates for the presence and severity of GERD.” • On Feb. 5, the American Society for Gastrointestinal Endoscopy (ASGE) issued a document “Guidelines for safety in the gastrointestinal endoscopy unit.” According to the ASGE, “the purpose of this new guideline is to present recommendations for endoscopy units in implementing and prioritizing safety efforts and to provide an endoscopy-specific guideline by which to evaluate endoscopy units.” The guideline highlights key safety strategies, including recommendations on staffing, infection control and sedation protocols, and is

published in the March issue of GIE: Gastrointestinal Endoscopy. • The American Medical Association (AMA) and other physician organizations recently highlighted the frustration that physicians are feeling with the federal electronic health record (EHR) meaningful use program. Among the chief complaints made by the organizations to a federal health information technology (IT) panel were “a lack of flexibility in the requirements to demonstrate meaningful use; shortcomings of EHR systems that make them less usable for physicians; and failure of health IT vendors to supply required product upgrades on time.” • Incidentally, on Feb. 7, the Centers for Disease Control and Prevention reported statistics on the numbers of U.S. office-based physicians using EHR systems: “From 2006 to 2013, the percentage of physicians using any EHR system increased 168%, from 29.2% to 78.4% in 2013.”

• News of a potential fix for Medicare’s flawed sustainable growth rate (SGR) formula made headlines in February. Congress is currently addressing legislation that seeks to repeal the SGR formula and is “now working against a March 31 deadline, at which point the SGR formula calls for a 24% cut to physician payments,” the AMA reported. The legislation includes “automatic positive payment updates of 0.5% for five years, a consolidated and restructured Medicare quality reporting program and transitions to alternative payment models.” The topic also was addressed by researchers from the Brookings Institution in an editorial published in the Feb. 19 issue of the Journal of the American Medical Association, “Medicare Physician Payment Reform: Will 2014 Be the Fix for SGR?” ■ Visit gastroendonews.com today to see our latest coverage and access links to more information on a variety of topics.

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Slow intestinal transit?

ACTIVIA helps with * occasional irregularity ACTIVIA® Improves Intestinal Transit Time in Healthy Volunteers. Total Colonic Transit Time in Healthy Adults Before and After Consumption of a Fermented Milk with B. lactis DN-173 010 or Control Product 50 p <0.05

Transit time (h)

33.0 ±16.1

30.1 26.2

±16.4

30.6 ±17.4

±14.7

20 10 0 B. lactis Group

Double-blind, parallel, placebo-controlled study in 72 adults consuming 3 containers (125g each) per day of ACTIVIA® or a control product. The improvement in total colonic transit time was statistically significant in both men (p<0.03) and in women (p<0.05), although the effect was more pronounced in women, particularly those with a slower baseline transit time (>40 hours).1

Control Group

Before ingestion of B. lactis or control product After ingestion of B. lactis product After ingestion of control product

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*Clinical studies show that ACTIVIA,® with Bifidus Regularis® (Bifidobacterium animalis lactis DN-173 010), helps with slow intestinal transit when enjoyed 3 times per day for two weeks as part of a balanced diet and healthy lifestyle. 1

Bouvier M, et al. “Effects of consumption of a milk fermented by the probiotic Bifidobacterium animalis DN-173 010 on colonic transit time in healthy humans.” Bioscience and Microflora, 2001; Vol 20(2):43-48.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Separation of Medicine and State Re: “Dear Professor Flexner: Medicine Is a Business, as Well as a Public Trust,” by Nicholas V. Costrini, MD, PhD, MBA. Gastroenterology & Endoscopy News January 2014;65:6. Once again, Dr. Costrini provided a well-written essay that was a pleasure to read regarding medicine being a business. Many years ago, one of our best medical residents went into private practice and took on a partner who was not a physician, but an MBA. At the time I thought this was rather unusual. He subsequently developed a very successful urgent care center. Although Web I agree with Comment Dr. Costrini

that health care is a business, I do not believe that medicine should be thought of as a business. I do agree that for some MDs, an added MBA would be very beneficial, as well as for the future of a well-managed health care system—but for most MDs, I believe this would be a disservice. Our purpose as physicians should be to make our patients feel well in an efficient health care delivery system. Gastroenterologists frequently have comforted our patients by freeing them of anxieties while performing endoscopies and communicating test results.

Colonoscopy continued from page 1

profusion of tales, quotes, figures and anecdotes carefully compiled by The New York Times. Yet you could not wrap your mind around the story, simply because the story did not reflect your own experience. Indeed, no one at the vast majority of ASCs ever sees the astronomical bills cited by The New York Times, and few, if any, of our patients perceive us as profligate moneymakers. So why the discrepancy? Could “all the news that’s fit to print” have omitted a few facts fundamental to the understanding of health care cost and delivery, but perhaps cumbersome to their message?

In fact, spending extra time talking to our patients may m accomplish the same thing g. What we need is a heallth care system that value es the time we spend witth our patients, and spendss less time focused on our business practices. The e business should be left to the MBAs, and perhaps the few among us with an MD and an MBA. William Erber, MD Gastroenterologist, Private practice Brooklyn, New York

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s 26 and Approach 27 to Hemorrh oids: A Primer for Gastroe nterologists By Harry Sarles Jr., MD

— Naffah’s article was originally Editor’s note—Dr. published online at www.avamargastro.com/PDF/ Colonoscopy-Facts_the_NY_Times_Omitted.pdf. It is reprinted here with his permission. Also see the related article, “The U.S. Trillion-Dollar Medical Bill: 99.6% Is Not Related to Colonoscopy,” by Victoria Stern. Gastroenterology & Endoscopy News December 2013;64:1,8,10,13-14,27,34.

and Medicaid) and private insurers alike. A consultation, for example, is valued by its “level of complexity,” a seemingly reasonable estimate of merit but in effect a ludicrous appraisal of worth. Complexity is measured by the amount of data gathering, no matter how irrelevant or unnecessary the time spent on the task. Neither diagnostic accuracy nor appropriateness of therapy even enters the picture. Our system derides efficiency and correctness in favor of verbosity. In fact, the pay-for-performance rules enacted in conjunction with the Affordable Care Act, and exalted as Ms. Rosenthal Opts for Sensationalism: a way to promote quality, do little to improve it. The soPrice Is Not a Reflection of Quality called “quality measures” are at best marginal to the manIn The New York Timess article, Ms. Rosenthal tells a agement of disease and their impact is insidious. Readily compelling story of four patients who were dismayed achieved, they create a collectivist standard of valuation, after undergoing a screenwhich sidesteps the essence of ing colonoscopy when they medical practice and makes a faced the whopping charges The so-called ‘quality measures’ mockery of clinical excellence. How are we then to expect they incurred, totaling $6,385, $7,563.56, $9,142.84 and are at best marginal to the that the price of colonoscopy $19,438, respectively. Although management of disease and would bear any relationship to they all enjoyed insurance covthe preeminence of care? their impact is insidious. erage and had no out-of-pocket Payments to Hospitals Far outlays, and although the actual Readily achieved, they create a Higher Than ASCs payment on each of those collectivist standard of valuation, charges was only on the order Commercial insurance carof $3,500, that amount is still which sidesteps the essence of riers compensate hospital outshocking. We agree. patient departments generously medical practice and makes a What Americans pay for for colonoscopy, as they do for mockery of clinical excellence. colonoscopy varies widely, and other services, with the tenas Ms. Rosenthal correctly dered sum frequently exceeding pointed out, the price is in no way a reflection of qual- $2,500. ASCs owned by hospitals and considered part ity. Indeed, variations in price should arouse suspicion in of the hospital outpatient department are paid a similar a society that has increasingly regarded medical services amount. Physician-owned ASCs, on the other hand, are as commodities. The very notion of quality has eluded a different entity altogether, but Ms. Rosenthal fails to our payors, government-funded programs (i.e., Medicare establish that distinction with clarity. Reimbursement to

ASCs for colonoscopies, as well as other procedures, is but a small fraction of what is paid to hospitals. According to a survey conducted by the Ohio Association of Ambulatory Surgery Centers, the average ASC reimbursement for a colonoscopy by commercial insurance carriers in 2012 was only $787. Medicare reimbursement is even lower. In our area, screening colonoscopy is reimbursed at $523, which includes the professional fee of $215.42 and the facility fee of $307.53. If anesthesia is used, which is optional, it generates an additional payment averaging $124, bringing the total to $646.95. With payments so modest, what is the explanation for the startling charges exposed by Ms. Rosenthal in her New York Timess article? The story remains untold, leaving the reader with indignation over the unconscionable abuses that have riddled our system. Well, perhaps portions of our system.

The Disparity Between Charges and Payments Charges that appear on a patient’s bill often seem excessive, but payments commonly amount to a thin slice of the charge. Medicare payments are fixed for physician-owned ASCs, whereas commercial insurance settles an amount predetermined by contractual agreement. Conversely, hospital compensation follows a different calculation. Medicare pays hospitals a base facility fee equal to 178% of the total fee paid to an ASC, and itemized charges follow, making for a bloated total. see Colonoscopy, page 8

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Colonoscopy continued from page 6

Commercial insurance payments to hospitals are even article suggests. In our area, for example, office-based The move away from office-based endoscopy was higher, but the payment formula is typically prearranged. screening colonoscopy is reimbursed by Medicare at primarily motivated by the desire for better service, Why then do hospitals and physicians maintain arti- $388.21, whereas the professional fee for the same proce- patient acceptance and safety concerns, particularly ficially high charges? Ms. dure performed at an ASC during a period that witnessed the largest proliferation Rosenthal states that they is only $215. Of course, an of malpractice lawsuits in the history of medicine. It is constitute a starting point Ms. Rosenthal describes the move ASC entails a facility fee of an aberration to recriminate gastroenterologists because for negotiations. Nego- from office endoscopy to ASCs as a $307.53, bringing the total they are hardworking. Working hard when you own a tiations between hospitals payment to $523. The dif- business, as when a physician owns his practice, is typical ‘lucrative migration for physicians,’ and insurance companies ference in cost between of any industry. It should be commended and rewarded. are impervious to public who started cashing in on the abundant screening colonoscopy at an Sadly, the inexorable escalation of regulations, coupled scrutiny. When it comes to new demand for the service—the office and an ASC is there- with declining reimbursement, is now forcing physicians physicians, however, reimfore only $135, an amount to trade their practices for hospital employment. It is an coronation of their lobbying efforts! bursement is mostly set by largely offset by the expense unfortunate trend, quickly leading to higher costs for the insurer, with minimal of maintaining, staffing and medical services, notwithstanding the erosion of access, bargaining room for the provider. Indeed, the offer to operating the facility, with the myriad of regulations that efficiency and quality. With the loss of their practices, join an insurer’s provider panel entails acceptance of govern it. We believe that safety alone, not to mention physicians also lose enthusiasm and dedication, and that insurer’s fee schedule. When a provider is excluded comfort and the other amenities, is well worth the small their productivity dwindles. from a certain panel because the insurance plan chooses price increase. Surely, those who indulge in spending to funnel patients to other providers, or when proposed billions on green energy to “save the environment” will Propofol: Benefit or Superfluous Expense? payments are unacceptably low, that provider may still warmly embrace that trifling surcharge, as they must Ms. Rosenthal takes issue with the use of propofol as bill the insurance plan on behalf of enrollees who seek cherish human life. a sedative for colonoscopy, contending that it increases his services, provided the plan includes out-of-network cost but is unnecessary. Propofol may result in respibenefits. Inflated charges then become pertinent because ASCs Provide 40% in Savings to Medicare, ratory depression, and most states mandate that it be payment is calculated as a percentage of the charge. 50% to Patients administered by anesthesia personnel to ensure experDepending on the market, that stance may eventuThe large majority of services performed at ASCs, tise in resuscitation techniques. Nurse anesthetists are ally pressure the insurance company to contract with including colonoscopy, are offered at a cost far lower than usually entreated with that task, rather than anesthesithe provider or the enrollee to change insurance plans. that at hospitals. Not only do ASCs produce approxi- ologists, whose charges may be considerably higher. In Although those instances are few and in no way typi- mately 40% in annual savings either case, however, Medical of the industry at large, the high charges are sure to to the Medicare program, care reimbursement is fixed raise eyebrows when the underlying dynamics are mis- but the savings translate to The difference in cost between for ASCs, with commercial construed. It is an unfortunate state of affairs that has an estimated 50% in out-ofinsurance generally paying screening colonoscopy at an office resulted from the inequity of insurance contracts. pocket costs for patients. As somewhat more. Nancy-Ann DeParle, former and an ASC is therefore only $135, The introduction of proRosenthal’s Attack on Physician-Owned administrator for the Centers an amount largely offset by the pofol as a sedative for coloASCs Unfounded for Medicare & Medicaid noscopy was initially met expense of maintaining, staffing and Colonoscopy was largely an office procedure, Ms. Services observed, physicians with resistance because of Rosenthal states, when it was approved by Congress as have no reason to apolo- operating the facility, with the myriad its added expense, but has a screening test for colon cancer. She suggests that the gize for their investments in of regulations that govern it. gradually gained acceptance anticipation of a substantial increase in the number of ASCs but instead should be and is now in great demand, colonoscopies spurred gastroenterologists’ interest in proud of the contribution attesting to the added value ASCs for financial gain. There is only one fee for an they have made in holding down the cost of ambulatory it brings. Its detractors continue to argue that it is an office procedure—the professional fee—but in an ASC, surgery; no other group would have come forward and extravagance fomented by anesthesiologists, with the gastroenterologists would benefit from a supplemental put up their own money to accomplish this. complicity of gastroenterologists, conspiring to gouge an facility fee. She describes the move from office endosunsuspecting public. Ironically, it turns out that propofol copy to ASCs as a “lucrative migration for physicians” No Evidence of Overutilization, was exactly what the public wanted. It provides restful who started cashing in on the abundant new demand According to OIG sleep and a refreshed feeling upon awakening. Patients for the service—the coronation of their lobbying efforts! In 2009, Ms. Rosenthal asserts, gastroenterologists familiar with it invariably prefer it to older sedatives, Not only is that characterization demeaning to physi- who bought into a surgery center performed 27% more which left them groggy, unsteady and confused. Endoscians, it is unfounded. In 1998, when colonoscopy was procedures. If the insinuation is that unnecessary proce- copists favor it for its capacity to provide deeper sedaapproved as a screening procedure, the vast majority dures were being performed, it is without substance. The tion at safe doses, without agitation, thus enhancing the (75%) of endoscopies were performed in hospitals, and Ambulatory Surgery Center Advocacy Committee has quality of the procedure as it relates to polyp detection ASCs already were growing in robust numbers. Office- examined similar claims and misconceptions. According and removal, particularly when the procedure is lengthy based endoscopy already had given way to ASCs, as to Andrew Hayek, chair of the committee, the increase and technically difficult. physicians, patients and regulators alike understood in the number of surgical procedures performed in Ms. Rosenthal argues that economies of scale should the many advantages. ASCs provide a safer environ- ASCs is due to a variety of positive factors, including have reduced the cost of colonoscopy, which is being ment, convenience and easy accessibility, as well as a the transition of procedures and services from outpatient performed in greater numbers. Indeed they have, at least high level of expertise provided by the availability of facilities to the less costly ASC setting, as well as patient with respect to ASCs. The facility fee has dropped by trained personnel. Other benefits include responsive, preference and cost savings. In the case of screening approximately 25% since 2008. Hospital reimbursement, nonbureaucratic environments tailored to patients’ colonoscopy, public awareness of the test continues to on the other hand, has not. needs, more convenient locations, ease in scheduling and grow, driving up the numbers, although screening rates shorter waiting times. According to a 2009 report from are still considerably lower than recommended. Regard- Ms. Rosenthal Confuses Screening and KNG Health Consulting, 70% of ASC volume growth ing overutilization, even the Office of Inspector Gen- Surveillance between 2000 and 2007 was due to migration from hos- eral, the federal agency charged with prosecuting fraud, Ms. Rosenthal seems to accuse physicians of tacking pitals to less costly ASCs. recognized the benefits of physician-owned ASCs: It on unneeded colonoscopies, presumably for the purpose Besides, the economic reality of office-based endos- stated that the risks for improper payment for referrals of enriching themselves. She tells the story of a patient copy compared with ASCs is not what Ms. Rosenthal’s were relatively low. see Colonoscopy, page 13

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Indication SOLESTA is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, fiber therapy, and anti-motility medications).

Important Safety Information about SOLESTA SOLESTAÂŽ (hyaluronic acid/dextranomer) is contraindicated in patients with active inflammatory bowel disease, immunodeficiency disorders or ongoing immunosuppressive therapy, previous radiation treatment to the pelvic area, significant mucosal or full thickness rectal prolapse, active anorectal conditions (including abscess, fissures, sepsis, bleeding, proctitis, or other infections), anorectal atresia, tumors, or malformation, rectocele, rectal varices, presence of existing implant (other than SOLESTA) in anorectal region, or allergy to hyaluronic acid-based products. SOLESTA must not be injected intravascularly as injection of SOLESTA into blood vessels may cause vascular occlusion. Injection in the midline of the anterior wall of the rectum should be avoided in men with an enlarged prostate. SOLESTA should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program on the SOLESTA injection procedure. The most common adverse reactions with SOLESTA (incidence >4%) in the clinical study were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. Please see complete Prescribing Information for SOLESTA at solestainfo.com.

Epidemiology Approximately 8% of noninstitutionalized adults in the United States report having experienced at least 1 episode of FI over the

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

Evaluation of FI

Solesta: An Effective Treatment Option for FI

14 12

57.4

54.4

52.2

54.4

52.2

44.1

50 40

8.6

7.2

6.5

30 20

4 10

2 0

Proportion of Responders, %

Median Number of Episodes/14 d

Supported by

Baseline

9 Months

Figure. Median number of FI episodes for Solesta group over 36 months. After 6 months, the end point (a 50% reduction in FI episodes from baseline) was reached in the Solesta group (n=136). FI, fecal incontinence From references 16 and 17.

FI is an underrecognized but common disorder that is a source of significant patient distress. Stigma may influence a patient’s decision not to seek treatment despite the significant burden of FI, poor QoL, and restricted ADLs. Although surgery may be an appropriate intervention in complex cases, minimally invasive approaches may provide adequate symptom control with a low risk for complications. Solesta, a quick, in-office procedure performed without the need for anesthesia, may be a viable solution for patients suffering from FI. Clinical data has shown that Solesta provides dependable results through 36 months, including a significant reduction in FI episodes in as few as 3 months, as well as meaningful improvements in QoL.

Contraindications Solesta is contraindicated in patients with the following conditions: active inflammatory bowel disease; immunodeficiency disorders or ongoing immunosuppressive therapy; previous radiation treatment to the pelvic area; significant mucosal or full- thickness rectal prolapse; active anorectal conditions including abscess, fissures, sepsis,

Please see Brief Summary of Prescribing Information on adjacent page.

References 1. Ditah I, Devaki P, Luma HN, et al. Prevalence, trends, and risk factors for fecal incontinence in United States adults, 2005-2010. Clin Gastroenterol Hepatol. 2013 Jul 29 [epub ahead of print]. 2. Dunivan GC, Heymen S, Palsson OS, et al. Fecal incontinence in primary care: prevalence, diagnosis, and health care utilization. Am J Obstet Gynecol. 2010;202(5):493 e1-e6. 3. Bharucha AE, Zinsmeister AR, Locke GR, et al. Symptoms and quality of life in community women with fecal incontinence. Clin Gastroenterol Hepatol. 2006;4(8):1004-1009. 4. Cheetham MJ, Brazzelli M, Norton CC, et al. Drug treatment for faecal incontinence in adults. Cochrane Database Syst Rev. 2009(3):1-39. 5. Varma MG, Brown JS, Creasman JM, et al. Fecal incontinence in females older than aged 40 years: who is at risk? Dis Colon Rectum. 2006;49(6):841-851. 6. Bharucha AE, Zinsmeister AR, Locke GR, et al. Prevalence and burden of fecal incontinence: a population-based study in women. Gastroenterology. 2005;129(1):42-44. 7. Edwards NI, Jones D. The prevalence of faecal incontinence in older people living at home. Age Ageing. 2001;30(6):503-507.

8. Brown HW, Wexner SD, Segall MM, et al. Quality of life impact in women with accidental bowel leakage. Int J Clin Pract. 2012;66(11):1109-1116. 9. Whitehead WE, Borrud L, Goode PS, et al. Fecal incontinence in US adults: epidemiology and risk factors. Gastroenterology. 2009;137(2):512-517. 10. National Digestive Diseases Information Clearinghouse. Fecal incontinence. http://digestive. niddk.nih.gov/ddiseases/pubs/fecalincontinence/. Accessed February 4, 2014. 11. Hayden DM, Weiss EG. Fecal incontinence: etiology, evaluation and treatment. Clin Colon Rectal Surg. 2011;24(1):64-70. 12. Tjandra JJ, Dykes SL, Kumar RR, et al. Practice parameters for the treatment of fecal incontinence. Dis Colon Rectum. 2007;50(10):1497-1507. 13. Glasgow SC, Lowry AC. Long-term outcomes of anal sphincter repair for fecal incontinence: a systematic review. Dis Colon Rectum. 2012;55(4):482-490. 14. Wexner SD, Coller JA, Devroede G, et al. Sacral nerve stimulation for fecal incontinence: results of a 120-patient prospective multicenter study. Ann Surg. 2010;251(3):441-449. 15. Graf W, Mellgren A, Matzel KE, et al. Efficacy of dextranomer in stabilised hyaluronic acid for treatment of faecal incontinence: a randomised, sham-controlled trial. Lancet. 2011;377(9770):997-1003.

SOL 13/86

Conclusion

bleeding, proctitis, or other infections; anorectal atresia, tumors, stenosis, or malformation; rectocele; rectal varices; presence of existing implant (other than Solesta) in the anorectal region; and allergy to hyaluronic acid–based products.

16. Solesta prescribing information. http://www. salix.com/assets/pdf/prescribe_info/solesta-pi. pdf. Accessed February 4, 2014. 17. Data on file. Salix Pharmaceuticals, Inc.

Disclosure: Dr. Bernstein reported that he is on the speaker’s bureau for Salix.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

BB1121

response to Solesta after the first injection, a re-injection with a maximum of 4 mL Solesta can be performed no sooner than 4 weeks after the first treatment.

Safety Data

Brief Summary Please consult Package Insert for full prescribing information.

Indication for Use Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (e.g., diet, ﬁber therapy, anti-motility medications).

Contraindications Solesta is contraindicated in patients with the following conditions: • Active inflammatory bowel disease • Immunodeficiency disorders or ongoing immunosuppressive therapy • Previous radiation treatment to the pelvic area • Significant mucosal or full thickness rectal prolapse • Active anorectal conditions including: abscess, fissures, sepsis, bleeding, proctitis, or other infections • Anorectal atresia, tumors, stenosis or malformation • Rectocele • Rectal varices • Presence of existing implant (other than Solesta) in anorectal region • Allergy to hyaluronic acid based products

Warnings • Do not inject Solesta intravascularly. Injection of Solesta into blood vessels may cause vascular occlusion. • Injection in the midline of the anterior wall of the rectum should be avoided in men with enlarged prostate.

Precautions General pprecautions • Solesta should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. • The safety and effectiveness of Solesta have not been investigated in patients with complete external sphincter disruption or significant chronic anorectal pain. • The safety and effectiveness of Solesta have not been investigated in patients with previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with rubber band within 3 months, anorectal implants and previous injection therapy, Stapled Transanal Rectal Resection (STARR) or stapled hemorrhoidectomy. • The safety and effectiveness of Solesta have not been studied in patients under the age of 18 years. • The safety and effectiveness of Solesta have not been studied in pregnant or breastfeeding women. • The durability of Solesta has not been studied past 12 months. • The safety and effectiveness of Solesta have been studied in patients who received one or two treatments. In the Pivotal study, the majority of patients received two treatments, four weeks apart. Patient related pprecautions • Patients with bleeding diathesis or patients using anticoagulant or antiplatelet agents, as with any injections, may experience increased bleeding at injection sites. • Patients should be counseled that a repeated Solesta injection procedure may be required to achieve a satisfactory level of improvement in incontinence. Procedure related pprecautions • Adequate bowel preparation of the rectum using enema is required prior to injection. The enema should be given immediately prior to the procedure to ensure evacuation of the anorectum. It is recommended that additional cleansing of the injection area with an antiseptic be performed prior to injection. Use of prophylactic antibiotics is recommended. • Solesta should be injected slowly to avoid undue stress on the Luer-lock connection which could cause leakage of the gel. • After injection of Solesta, hold the needle at the injection site for an additional 15-30 seconds to minimize leakage of Solesta. • Injections too close to the dentate line or too deep in the tissue might cause excessive pain. • Injection should be stopped if excessive bleeding or pain occurs. • One sterile needle should be used per syringe and injection. Device related pprecautions • The use of needles other than those supplied may impede injection of Solesta due to the properties of the gel and may cause device malfunction. • Solesta is supplied ready to use in a prefilled syringe with a Luer-lock fitting. Carefully examine the unit to verify that neither the contents nor the package has been damaged in shipment. Do not use if damaged. • Solesta is supplied sterile and is intended for single use only. Do not re-sterilize, as this may damage or alter the product. • In the event of accidental contamination of a needle, discard the needle. • Never mix Solesta with other products. • Solesta is to be stored at up to 25°C (77°F), and used prior to the expiration date printed on the label. Do not expose Solesta to either sunlight or freezing, as this may damage or alter the product. • Care should be taken when handling the glass syringes and disposing of broken glass to avoid laceration or other injury. • After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements. Adverse Events Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal fissure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back pain, constipation, C-reactive protein increased, chills, cold sweat, defecation urgency, dermatitis, diarrhea, device dislocation, dizziness, dyspareunia, escherichia bacteremia, fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal pain, genital discharge, genital prolapse, hematochezia, hematospermia, hemorrhoids, infection, injection site abscess, injection site discomfort, injection site hemorrhage, injection site hematoma, injection site inflammation, injection site irritation, injection site nodule, injection site pain, injection site pustule, injection site swelling, injection site ulcer, intestinal mass, malaise, mucosal inflammation, musculoskeletal pain, perineal abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, proctitis, pyrexia, rectal abscess, rectal discharge, rectal hemorrhage, rectal lesion, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum abscess, urinary retention, vaginal discharge, vulvovaginal pain. The adverse event profile of Solesta beyond 18 months is not known, but is under investigation in post-market studies.

The safety evaluation of Solesta in the treatment of fecal incontinence (FI) is based on the results from the Pivotal clinical study, and is supported by the Open-Label multicenter clinical study and one single site Proof-of-Concept study. The analysis of safety was based on the safety cohort of all 206 patients treated in the Pivotal study with either Solesta or Sham. Safety data for Solesta are available from 359 treatments in 197 total patients followed for up to 18 months post treatment (i.e., 136 subjects from the blinded phase and 61 subjects from the open phase). The primary safety data set includes data from 206 patients treated with either Solesta or Sham in the Pivotal study. The data show that a total of 232 treatment-related adverse events for either Solesta or Sham were reported up to 18 months after treatment. Three (3) adverse events assessed as related to Solesta, or 1.3% of the treatment-related adverse events, were deemed serious by the investigators. These three (3) serious adverse events occurred in three (3) patients, including one case of an E. coli bacteremia, and two (2) cases of rectal abscesses (one event per patient). All of these serious adverse events resolved following treatment without any sequelae within approximately 30 days of treatment. Overall, 96% of the 203 Solesta treatment-related adverse events in the Pivotal study were of mild to moderate intensity and 97% of the events required no intervention or required medical or simple non-invasive interventions, including application of local pressure, silicone ointment, water irrigation and warm baths. Seven (7) events required more invasive procedures including: perianal drainage of abscesses (4 events), one (1) case of rubber band ligation of an anal prolapse, one (1) case of lancing of a hemorrhoid, and one (1) case of a Kenalog injection in a pre-existing anal scar. The most frequent adverse events following Solesta treatment pertained to post-treatment proctalgia, minor anal or rectal bleeding, post-treatment fever, abdominal complaints (such as diarrhea and constipation), and events potentially related to peri-operative infection.

Patient Counseling Information The patient should be advised that Solesta treatment is not effective for all patients with fecal incontinence and that repeat treatment might be required for treatment effect. It should also be made clear to the patient that the available clinical study data are not sufﬁcient to predict in whom Solesta treatment will be effective. The patient should be informed about post-treatment care and potential adverse events. The patient should also be made aware that the implants might be detected during future anorectal examinations and radiographic imaging of the pelvis. Patients should be instructed to inform all future treating physicians about the presence of Solesta gel. If there should be a need for future surgery (e.g., hemorrhoidectomy) the Solesta implant can be resected.

Directions for Use Solesta should be administered by qualiﬁed physicians with experience in the treatment of anorectal conditions and who have successfully completed a comprehensive training and certiﬁcation program in the Solesta injection procedure. Solesta should only be used after a thorough physical evaluation of the patient to exclude treatable underlying disorders. Please consult Package Insert for full directions for use and method of administration.

Post-treatment care 1. The patient should be instructed to avoid taking hot baths during the first 24 hours post-treatment. 2. The patient should be informed of the risk of infections and bleeding. 3. The patient should be instructed to contact the clinic or physician’s office immediately if symptoms of rectal bleeding, bloody diarrhea, fever, tenesmus or problems with urinating occur. 4. Anti-diarrheal drugs should not be used for one week after treatment. 5. Stool softeners may be used until the first defecation occurs. 6. Analgesics other than Non-steroidal Anti-inflammatory Drugs (NSAIDs) may be prescribed, if needed. 7. The patient should be instructed to: – Avoid physical activity for 24 hours – Avoid sexual intercourse and strenuous physical activity for one week (e.g., horse back riding, bicycling and jogging, etc.) – Avoid anal manipulation for one month (e.g., insertion of suppositories or enemas and rectal temperature recording)

Re-treatment procedure 1. If the patient does not have an adequate response to Solesta after the ﬁrst injection, a re-injection with a maximum of 4 mL Solesta can be performed, no sooner than 4 weeks after the ﬁrst injection. 2. The re-treatment procedure and all pretreatment preparations are performed the same way as the initial treatment procedure. All pretreatment preparations and injection procedures should be performed as described in “Methods of Administration” above. However, the point of injection should be made in between the initial injections, shifted one-eighth of a turn (e.g., left posterolateral, left anterolateral, right anterolateral, and right posterolateral).

How Supplied Solesta is supplied in a glass syringe with a standard Luer-lock ﬁtting containing 1 mL gel. Each syringe is terminally moist heat sterilized in a pouch. Four pouches, each containing one syringe are packed in a carton together with ﬁve Sterican needles (21G x 4¾ inches, 0.80 mm x 120 mm), patient record labels and a package insert. The needles are sterilized by ethylene oxide.

Storage Store at a temperature up to 25°C (77°F) and protect from sunlight and freezing. To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is registered trademark of Galderma S.A.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

OPINION

Colonoscopy continued from page 8

who was advised by his physician to have a follow-up York Times sells for $5, whereas The Sunday Times and systems would quickly collapse. It is therefore remarkcolonoscopy 19 months after the finding of a polyp, then The Guardian are priced at 2.5 pounds (approximately able that our ASCs are able to provide screening cologoes on to denounce that physician because “medical $3.80) and the Sunday edition of Spain’s El País goes noscopy at a cost comparable to that of our European guidelines do not recommend such frequent screening.” for a mere €2.2 (approximately $2.86). Is it then fair to counterparts. Clearly, she does not understand the difference between say, using Ms. Rosenthal’s own words, that “that chasm Physician owners of ASCs favor price transparency, screening and surveillance. in price helps explain why the U.S. is far and away the but as Ms. Rosenthal points out, hospital charges often She quotes James Goodwin, MD, a geriatrician at world leader in spending” for news reporting? Have are shrouded. Sometimes, they are opaque to the point the University of Texas Medical Branch, Galveston, studies concluded that Americans get better news? that even physicians who refer their patients for certain who estimates that one-fourth of Medicare patients She refers to Cesare Hassan, MD, an Italian gas- procedures cannot get an accurate quote of their costs. undergo the screening troenterologist who is test more often than recchair of the Guidelines Ms. Rosenthal Hints Colonoscopy May Be ommended. However, Physician owners of ASCs favor price Committee of the Euro- Unnecessary Dr. Goodwin’s analysis pean Society of GastroWhat is most disturbing about The New York Times transparency, but as Ms. Rosenthal points assumes screening when intestinal Endoscopy. article, however, is that it seeks to cast doubt on colothat code is not actually out, hospital charges often are shrouded. According to Dr. Has- noscopy as the preferred screening method for colon used and underestimates Sometimes, they are opaque to the point san, studies in Europe cancer. It is a question that has been carefully examined poor cleansing as a reaestimated the cost of and thoroughly researched. Would Ms. Rosenthal opt for son for shorter exami- that even physicians who refer their patients colonoscopy to range fecal occult blood testing or flexible sigmoidoscopy for nation intervals. And for certain procedures cannot get an from $400 to $800. Does herself and members of her family? Is she perturbed by studies have shown that it follow that pricing in the fact that colonoscopy, as other procedures, is a source accurate quote of their costs. the rate of inadequate the United States should of income for private physicians? Or is her analysis meant cleansing during the be modeled accordingly? to serve as preparation for the rationing of medical serreferenced period may Any discussion of the vices anticipated under the new health care law? have been as high as 26%. Interestingly, Dr. Goodwin’s comparative cost of health care without discussion of That colonoscopy is superior to flexible sigmoidosanalysis found that extra colonoscopies were more likely its legal context and the bureaucracies that surround copy is not just a matter of intuitive sense, as Ms. Rosento occur in the office setting than in hospitals or ASCs. it is profoundly naive or fundamentally dishonest. thal suggests; it is a matter of common sense. No one Situations abound in clinical medicine where con- In Europe, malpractice lawsuits are few and rarely, if would think of doing mammography on a single breast! ventional guidelines and available resources fall short of ever, lead to the staggering awards that have become A town that harbors criminals must be patrolled in its individual expectations, but physicians usually are left well rooted in U.S. society. Sweden deals with dam- entirety. Keeping watch on the south side allows crime to bear the burden of that responsibility. We care for ages under a no-fault patient insurance scheme. Brit- to foster elsewhere. The argument that early lesions patients, not collectives. Although abuse admittedly ain, like most of Europe, has a loser-pay-all system: A may have been hard to detect in some parts of the colon occurs, as in any other trade, Medicare does not cover plaintiff who loses carries has led to the development screening colonoscopies unless performed at appropri- the burden of defraying all of better cleansing soluate intervals. costs, including those of That colonoscopy is superior to flexible tions, enhanced optics and the defense. By contrast, improved techniques. Colosigmoidoscopy is not just a matter Is Colonoscopy in the United States the perversion of our legal noscopy has made major Overpriced? system and its flagrant of intuitive sense, as Ms. Rosenthal strides since its inception. Ms. Rosenthal labels colonoscopy as the most expen- exploitation causes physi- suggests; it is a matter of common Negating technological sive screening test that healthy Americans undergo, but cians to fear the prospect advances retrenches it, as it even that is debatable. A screening colonoscopy is per- of bankruptcy every day sense. No one would think of doing would other inventions, to formed only every 10 years in average-risk individuals, of their lives. The fear of mammography on a single breast! its early stages of developgenerally costing less than $1,000 in an ASC, whereas lawsuits is indomitable and ment. Rather than embracmammography, with a price tag in excess of $270, is rec- has created an industry of ing its many advances, the ommended yearly. burdensome tasks and activities, suffused in litanies of critics of colonoscopy continue to disparage its early She concludes that colonoscopy, along with other senseless verbiage. They are costly, onerous and very limitations. By the same token, the Wright brothers medical procedures, accounts for the astronomical time-consuming. Regardless, malpractice insurance may have seen their efforts thwarted, and transatlantic cost of health care in the United States and illustrates premiums have continued to rise. flights would still be a fairy tale. More people should that point by way of comparison with other countries. Furthermore, our bureaucracy is shackling, and snow- be encouraged to undergo colonoscopy. It is lifesavDirect cost comparisons between countries are mis- balling regulations continue to create inefficiencies. If ing. Fifteen years ago, the case for screening colonosleading, in that different societal considerations apply the Brits, the Swedes and the Greeks had a mere cari- copy prevailed. Today, that victory would be even more to different markets. The Sunday edition of The New cature of our regulatory and legal environment, their resounding. ■

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Bowel Preparation For Colonoscopy Maximizing Efficacy, Minimizing Risk LAWRENCE B. COHEN, MD Clinical Professor of Medicine Icahn School of Medicine at Mount Sinai New York, New York Disclosure—Dr. Cohen has served on the advisory board and speakers’ bureau of Salix Pharmaceuticals.

he success of colonoscopy as a screening modality for colorectal cancer is highly dependent on the ability to

Bowel Preparations The available purgatives for colonoscopy can be divided into 3 categories: osmotic agents, polyethylene glycol (PEG)–based solutions, and stimulants. Osmotic laxatives increase intraluminal water by promoting the passage of extracellular fluid across the bowel wall. Examples of osmotic preparations include sodium phosphate (NaP), magnesium citrate, and sodium sulfate. The PEG-based solutions consist of a high-molecularweight nonabsorbable polymer in a dilute electrolyte solution. PEG solutions are designed to be osmotically balanced, limiting the exchange of fluid and electrolytes across the colonic membrane. Stimulant laxatives work by increasing smooth muscle activity within the wall of the colon. Examples of stimulant purgatives include

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS • M A R C H 2 0 1 4

senna, bisacodyl, and sodium picosulfate. Bisacodyl’s laxative effect is based on 2 mechanisms of action: stimulation of small intestinal secretion and increased motor activity within the colon. Dietary modification, consisting of a clear liquid or a low-fiber diet for 24 hours before the procedure, usually is combined with a purgative regimen. This section provides a brief overview of the available purgatives for bowel preparation (Table). Several comprehensive reviews on the comparative efficacy, safety, and tolerability of these agents recently have been published, and readers who want a more in-depth analysis of this subject are referred to these sources.6-8

POLYETHYLENEE GLYCOL A variety of PEG-based lavage regimens currently are available for bowel cleansing before colonoscopy. These preparations differ with respect to volume of lavage solution, electrolyte content, molecular weight of the polymer, requirement for an adjunctive laxative, and the presence of artificial sweeteners. FDAapproved PEG lavage solutions include the traditional 4-L preparations (GoLYTELY, Braintree; Colyte, Schwarz Pharma; NuLYTELY, Braintree; TriLyte, Schwarz Pharma), and low-volume 2-L regimens (HalfLytely, Braintree; MoviPrep, Salix). The recommended dosing of most PEG solutions is 240 mL (8 oz) every 10 minutes. A “split-dose” regimen—in which part of the laxative is taken the evening before and the remainder is taken the morning of the procedure—has been demonstrated to be more effective and better tolerated than a single dose taken the evening before the procedure.9 It is estimated that 5% to 38% of patients are unable to complete the 4-L PEG preparation because of volumerelated symptoms of abdominal fullness, nausea, and vomiting.8 Low-volume PEG preparations were developed in an effort to improve patient tolerance for the lavage regimen. Two reduced-volume PEG preparations are approved by the FDA for pre-colonoscopy bowel preparation. MoviPrep combines PEG-3350 with sodium sulfate and ascorbic acid, the latter 2 ingredients serving to enhance the bowel cleansing activity of PEG. At least 4 randomized controlled trials have demonstrated comparable, if not superior, bowel cleansing activity with MoviPrep compared with 4-L PEG.10-13 Furthermore, patient tolerability is generally reported to be better with MoviPrep than the conventional 4-L PEG preparations. HalfLytely, the other FDA-approved, low-volume PEG preparation, consists of oral bisacodyl (5 or 10 mg) to be ingested at noon the day before the procedure, followed by 2-L of PEG solution no more than 6 hours later. A study comparing MoviPrep with HalfLytely demonstrated improved bowel cleansing and higher rates of adenoma detection with MoviPrep.14 MiraLax (PEG-3350) is available as an over-thecounter (OTC) product for the treatment of mild constipation. It also has been used as a pre-colonoscopy bowel cleansing regimen. One often recommended

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regimen for MiraLax is for patients to consume 4 bisacodyl delayed-release tablets at approximately 1 PM the day before the procedure, followed by the ingestion of 238 mg of MiraLax (8.3-oz bottle) mixed with 64 oz of Gatorade. In some cases, 10 oz of magnesium citrate also is recommended. Unlike the FDA-approved 2- and 4-L PEG products that contain additional electrolytes in order to produce an osmotically balanced solution, thereby minimizing net absorption or secretion of fluid or electrolytes into the intestinal lumen, the MiraLax/Gatorade preparation is hypotonic. The safety and efficacy of MiraLax recently has been evaluated in several randomized, investigator-blinded single-site studies. Enestvedt14 and Hjelkrem15 independently observed that 4-L PEG solution with electrolytes was more effective than a solution of MiraLax in 64 oz of Gatorade. Split-dose preparations were used in both trials. However, Samarasena et al16 observed that MiraLax (238 g PEG)/64 oz Gatorade had comparable efficacy to 4-L PEG under conditions of either 1- or 2-day dose-splitting, and Gerard et al17 reported that a modified protocol of MiraLax (306 g PEG)/64 oz Gatorade taken at noon and between 5 and 9 PM the day before colonoscopy achieved efficacy and safety comparable to 4-L PEG. Anecdotal reports of severe hyponatremia resulting from MiraLax/Gatorade have been published, although the prevalence of this problem remains uncertain. Overall, the safety record with PEG-based preparations has been excellent. During the 6-year period ending in 2002, the FDA received 100 reports of adverse events (AEs) with PEG solutions, including 30 serious and 6 fatal events.8 Complications of PEG preparations include hypothermia, hyponatremia, intestinal perforation, aspiration, and Mallory-Weiss tear.18 The use of PEGbased bowel cleansing is contraindicated in patients with gastric outlet obstruction, high-grade small bowel obstruction, and suspected bowel perforation.

ORAL SODIUM M PHOSPHATE For many endoscopists, a new era in bowel cleansing for colonoscopy was ushered in on Dec. 11, 2008, when the FDA issued an alert about the safe use of oral sodium phosphate (OSP) products.19 The agency expressed its concern about the risks associated with the use of OSP at the higher doses typically used for bowel cleansing before colonoscopy, and it recommended that consumers not use the OTC OSP products designed specifically for bowel cleansing. The FDA said, however, that the available data continue to indicate the safety of OSP at the lower dose used for the laxative. In response to the FDA warning, CB Fleet immediately announced a voluntary recall of its OTC products, Fleet Phospho-soda and Fleet Phospho-soda EZ-Prep. The future of these products, either in the OTC or prescription market, is uncertain at this time. The FDA alert also indicated that the manufacturer of prescription NaP tablets (OsmoPrep, Salix) would be required to put a black box warning on its product labels. The warning highlights several key

Table. Commonly Used Purgatives for Colonoscopy Preparation Class Polyethylene glycol

Product

Recommended Usea

4-L PEG-ELS

GoLYTELY (Braintree)

240 mL (8 oz) every 10 min beginning at 5 to 6 PM the evening before colonoscopy (total, 3 L); remaining 1 L 10 to 12 h later (at least 3 h before procedure)

Colyte (Schwarz Pharma)

Same as above

NuLYTELY (Braintree)

Same as above

TriLyte (Schwarz Pharma)

Same as above

2-L PEG-ELS and bisacodyl delayed-release tablets

HalfLytely (Braintree)

2 bisacodyl delayed-release tablets at noon the day before colonoscopy; 240 mL (8 oz) every 10 min beginning at 5 to 6 PM (total, 1 L); repeat 240 mL (8 oz) every 10 min beginning 3 to 4 h before procedure (total, 1 L)

2-L PEG and bisacodyl delayed-release tablets

MiraLax (Schering-Plough)

Same as above

2-L PEG with ascorbate

MoviPrep (Salix)

240 mL (8 oz) every 15 min beginning at 5 to 6 PM the evening before colonoscopy (total, 1 L), followed by at least 16 oz of fluid; 240 mL (8 oz) every 15 min at least 3 to 4 h before procedure (total, 1 L), followed by 16 oz of fluid

OsmoPrep (Salix)

20 tablets (4 tablets every 15 min) at 5 to 6 PM the evening before colonoscopy; repeat with 12 tablets 10 to 12 h later (at least 3 h before procedure)

4-L SF-PEG

Sodium phosphate Tablet

Sodium picosulfate/magnesium citrate Prepopik (Ferring Pharmaceuticals, Inc.)

Step 1: Dissolve 1 packet in 5 oz of liquid and consume, followed by 5, 8-oz glasses of clear liquid at 4 to 6 PM Step 2: Repeat step 1, followed by 3, 8-oz glasses of clear liquid (later the same evening, or 4 to 6 h before the procedure)

Suprep (Braintree)

6-oz bottle diluted with 16 oz of water followed by 32 oz water over the next hour; take the evening before colonoscopy and repeat the morning of examination

Sodium sulfate

ELS, electrolyte lavage solution; PEG, polyethylene glycol; SF, sulfate-free a In some cases, these recommendations do not correspond with the FDA-approved dosage.

concepts related to the use of NaP laxatives for bowel cleansing, including the following: 1) acute phosphate nephropathy, sometimes resulting in permanent renal impairment, has been observed rarely following ingestion of OSP; 2) identifiable patient risk factors for acute phosphate nephropathy include increased age, hypovolemia, increased bowel transit time (such as bowel obstruction), active colitis, and baseline kidney disease; and 3) use of certain medications, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly nonsteroidal anti-inflammatory drugs, may increase the risk for kidney damage. Physicians, nurses, and other health care professionals who are involved in the process of advising patients about bowel cleansing for colonoscopy or other procedures should be thoroughly familiar with these cautions. The tablet formulation of NaP (Visicol, Salix) was approved by the FDA in 2000. The recommended dose of the initial formulation of Visicol was 48 to 60 g, or 32 to 40 tablets taken in 2 doses. Because of the

presence of insoluble microcrystalline cellulose—an insoluble excipient within the NaP tablet that obscured visualization of colonic mucosa in some instances—a residue-free NaP tablet (OsmoPrep, Salix) was developed. OsmoPrep is smaller and has a smooth waxy surface that facilitates swallowing. The recommended dosage is 32 tablets—20 tablets the evening before and 12 tablets 3 to 5 hours before the examination. Compared with Visicol, OsmoPrep induced smaller changes in electrolyte levels and fewer AEs, including abdominal distention, nausea, pain, and vomiting.20 At least 16 studies have compared the efficacy and tolerability of PEG with that of NaP.8 Overall, the trials demonstrated that NaP is as effective as either the 2- or 4-L PEG-based preparations. In most of the studies, patient tolerance and compliance with bowel preparation was improved with NaP compared with the PEG formulations. These conclusions are supported by the findings of 2 meta-analyses and an evidencebased position statement prepared by the Canadian Association of Gastroenterology.6-8

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The use of NaP often is associated with abnormalities in serum electrolytes, including hypernatremia, hypokalemia, hypocalcemia, and hyperphosphatemia. Although these electrolyte alterations usually are transient and patients are clinically asymptomatic, the FDA received 34 reports of AEs between 1997 and 2002, including 18 serious AEs and 8 fatalities related to the use of NaP preparations.8 A 2005 study reported 21 cases of acute phosphate nephropathy, all occurring in patients who recently had taken a NaP bowel preparation.21 Seventeen patients (81%) were female; the mean age of the patients was 64 years; 16 (76%) of the 21 patients had a history of hypertension; and 14 (67%) were taking an ACE inhibitor or an ARB. Although the exact incidence of this complication cannot be quantified accurately, the risk appears to be quite low considering the relatively small number of cases reported and the extraordinarily large number of exposures to NaP (estimated to be in excess of 5 million per year).22 On the basis of its overall safety and efficacy, NaP is an appropriate option for bowel preparation in healthy individuals without any of the contraindications previously discussed. One study suggests that in low-risk patients, hyperphosphatemia following standard NaP doses is related to body weight.23 Accordingly, it may be advisable to recommend a reduced dosage of NaP in low-weight individuals.

OTHER BOWEL PREPARATIONS Oral sodium sulfate (Suprep, Braintree) is a newly developed bowel cleansing preparation that contains sodium sulfate, magnesium sulfate, and potassium sulfate, plus flavoring agents in an aqueous form supplied in two 6-oz bottles. Each 6-oz bottle is diluted with water to 16 oz. Sulfate salts have long been used as osmotic laxatives, dating back to the 17th century. The traditional 4-L PEG preparation (GoLytely) includes sodium sulfate in order to improve bowel cleansing and to minimize fluid shifts and changes in serum electrolytes. Unlike OSP, sulfate salts do not produce renal tubular injury in animal models.26 The efficacy of oral sodium sulfate as a bowel cleansing preparation for colonoscopy has been established in 2 multicenter, randomized, single-blind studies.27,28 The sulfate preparation administered as a split-dose regimen produced better bowel cleansing than standard 4-L PEG and was comparable with MoviPrep. Patient tolerability and the safety profile were comparable for oral sodium sulfate and MoviPrep. The new drug application for Braintreeâ&#x20AC;&#x2122;s oral sodium sulfate was approved by the FDA in 2010. A dual-action bowel cleansing preparation, which exerts both stimulant and osmotic laxative effects, was recently approved in the United States for bowel preparation before colonoscopy. Prepopik (Ferring Pharmaceuticals, Inc.) contains sodium picosulfate and magnesium citrate. Magnesium citrate, which is formed during the dissolution of citric acid and magnesium oxide, acts as an osmotic agent to draw water into the lumen of the colon and flush it of debris. Sodium picosulfate undergoes

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bacterial cleavage in the colon, producing the laxative compound bis-(P-hydroxyphenyl)-pyridyl-2-methane, the active ingredient in bisacodyl, which stimulates peristalsis within the large bowel.27 Sodium picosulfate has gained significant popularity in Canada, Europe, and Australia as a bowel cleansing agent. A Phase III, randomized, multicenter, assessor-blinded study compared Prepopik and HalfLytely in a non-inferiority study.28 A total of 603 patients were randomized to receive either picosulfate/magnesium citrate or 2 L of PEG and two 5-mg bisacodyl tablets. Patients in both study groups completed bowel preparation on the day before colonoscopy. Based on the Ottawa scale, a validated instrument for assessing quality of bowel cleansing, overall bowel cleansing was comparable in the 2 groups, with successful preparation in 78.9% and 78% of patients receiving picosulfate/magensium citrate and HalfLytely, respectively. Similarly, cleansing within the ascending colon was successful in 83% and 79.7% in the picosulfate/magnesium citrate and HalfLytely arms, respectively. Patient tolerability differed between the 2 study arms; however, more patients in the picosulfate/magnesium citrate group were willing to repeat the bowel preparation than were patients in the HalfLytely group. Another newly approved bowel preparation combines oral sodium sulfate solution, the active ingredient in Suprep, with standard 2-L PEG with electrolyte lavage. The product (Suclear, Braintree) consists of 2 doses, which are taken at separate times, either the day before colonoscopy (1-day regimen) or as a split-dose regimen over 2 days. Anecdotal experience with this preparation suggests that it is effective in most patients, although head-to-head clinical studies comparing it with other formulations are not yet available.

Clinical Considerations An effective preparation for colonoscopy should consistently produce a high-quality bowel cleansing that is adequate for the detection of all adenomatous polyps. It also must be safe and, ideally, work quickly without producing gastrointestinal (GI) distress. None of the products currently marketed for colonoscopy preparation meet all of these criteria. Although most are effective when properly administered, they require 12 to 24 hours for adequate bowel cleansing, and a significant proportion of patients experience disturbing GI side effects. Consequently, the choice of purgative(s) and the regimen of administration vary considerably among endoscopists. This section examines strategies for colon cleansing and provides suggestions for improving the quality and safety of bowel preparation. Recommendations for colonoscopy preparation within special patient populations also are presented.

BOWEL PREPARATION N: ONE E SIZE E DOES S NOT T FIT T ALL Some endoscopists prefer to offer all patients a single method of bowel preparation. The benefits of such an approach include simplicity and economy of

time, eliminating the need to discuss with the patient more than 1 regimen of bowel cleansing. Among the disadvantages, however, is an inability to adjust for differences between patients. For example, individuals vary in their tolerance and reaction to purgatives.29 The same cathartic may be well tolerated by 1 patient but cause nausea, vomiting, and abdominal cramps in another. Individuals with chronic constipation may require a more rigorous regimen for adequate bowel cleansing. Differences such as these are best accommodated by offering several bowel preparations, so that each patient can be matched with the preparation that is most likely to be effective, safe, and well tolerated. When endoscopy is performed in an open-access setting, it is necessary to prescreen patients before selecting a purgative regimen. In our practice, a receptionist or medical assistant completes a brief medical questionnaire for each patient at the time of scheduling. Information obtained that pertains to the choice of purgative regimen includes the following: a list of current medications and drug/food allergies; a history of heart failure, kidney disease, ascites, or fluid/electrolyte abnormalities; and a history of chronic constipation or incomplete colonoscopy. Based on the responses, a bowel cleansing regimen (NaP vs PEG) is then suggested. When a PEG-based regimen is used, the 2-L PEG preparation is chosen, except for patients with chronic constipation. In this way, the method of bowel cleansing for colonoscopy is selected individually to maximize safety, efficacy, and patient satisfaction.

PATIENTT EDUCATION Some endoscopy centers use a patient education program when preparing patients for GI endoscopy. The topics to be covered include a description of the procedure, possible AEs and complications, and preparation instruction. The effect of bowel preparation on the success of colonoscopy and the importance of compliance with instructions should be emphasized. This message may be communicated through oneon-one sessions, group meetings, or self-instruction with either a videotape or a computer-based program. Communicating this information effectively to the patient helps to alleviate fear and anxiety related to the procedure. In a prospective study, an education program reduced the rate of failed preparations among ambulatory patients from 26% to 5%.30 A role for educational intervention in hospitalized patients has not yet been established.31

THEE ROLE

OF F

HYDRATION

Colon cleansing produces significant volume loss through the GI tract that can result in intravascular volume depletion. The fluid loss during bowel preparation may exceed 2 to 3 L, based on an assessment of hemodynamic parameters and indirect measures such as body weight, serum osmolality, and hematocrit.32 Significant

differences in fluid loss between NaP and PEG formulations have been reported in some studies.33-36 Decreases in systolic blood pressure (>10 mm Hg from baseline) and/or postural tachycardia (≥10 beats per minute from baseline) have been described in 10% to 35% of patients who completed a bowel cleansing regimen.33 Additionally, the use of NaP preparations often is associated with changes in serum electrolytes, including transient increases in phosphate and sodium and reductions in calcium and potassium. Despite these changes, serum electrolytes generally remain within the normal range, and patients are clinically asymptomatic. Serious electrolyte disturbances, however, have been reported with both NaP37 and PEG.38 Inadequate hydration is widely believed to play an important role in such complications. Therefore, adequate hydration during bowel preparation should be emphasized, particularly in highrisk individuals, such as the elderly, patients on diuretics or other medications that alter electrolyte levels, and patients with preexisting electrolyte abnormalities. Patients should be advised to consume at least 64 oz (approximately 2 L) of clear fluid the day before colonoscopy. The use of a carbohydrate-electrolyte solution (eg, Gatorade) has been reported to improve hydration, tolerance for the preparation, and the quality of bowel preparation.39 Patients also should be reminded to continue hydration after colonoscopy; we advise that they consume at least 32 oz (four 8-oz glasses) of clear fluid during the 8 hours after completion of the procedure.40

TIMING G IS EVERYTHING The quality of colon preparation—especially in the ascending colon—is closely related to the length of time between completion of preparation and the examination.35,41 Despite diet restriction for 24 hours, optimal cleansing of the colon requires that at least part of the preparation be ingested within 4 to 6 hours of the examination. When more than 6 hours has elapsed, ileal contents begin to fill the right colon, coating the ascending colon with a thin film of chyme that obscures mucosal detail. The American College of Gastroenterology (ACG) supports the concept of split-dosing as a method for enhancing the efficacy of commercial bowel cleansing preparations.42 Split-dose regimens improve the efficacy of both NaP and PEG preparations.9 In a study of 3-L PEG plus bisacodyl, a split-dose regimen (including 1 L on the day of the procedure) increased the proportion of satisfactory preparations (75% vs 66%) and patient compliance, with lower rates of discontinuation.43 Another study sought to determine whether the quality of bowel preparation was better with a 2-L PEG solution administered on the day of (6-8 hours before) versus the evening before (13-16 hours before) the procedure.44 Colon preparation was better (93% vs 72%) and more lesions were detected (2.8 vs 1.9) in the patients who received same-day bowel cleansing than in the patients who received cleansing the evening before the examination. A randomized trial compared 2 dosing regimens of

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NaP, one consisting of two, 45-mL doses taken the evening before (3 and 8 PM) the procedure and the other consisting of the same 2 doses with the second dose taken the morning of the procedure (8 PM and 6 AM).45 Patients who received part of their preparation on the same day had better scores for quality of cleansing compared with those who underwent preparation on the previous day (global rating of good/excellent, 80% vs 68%). These and other studies provide convincing evidence that a split-dose regimen, including a single dose of laxative within 6 to 8 hours before the examination, improves cleansing of the mucosa, especially within the right side of the colon, where flat polyps are encountered more often. When patients are prepared for colonoscopy, it is helpful to distinguish those scheduled for morning procedures from those scheduled for afternoon procedures. Patients undergoing a morning procedure should ingest the first dose of cathartic between 4 and 6 PM the night before and the remainder between 3 and 5 AM on the day of the procedure (depending on the time of the procedure and the laxative selected). Patients scheduled for afternoon procedures should take their first dose at 6 to 7 PM the night before and the second dose at 6 to 7 AM the day of the procedure. Some endoscopy units have modified their schedule, booking all colonoscopy procedures beginning at noon. This affords patients the convenience of taking the second dose of laxative at 6 to 7 AM, rather than at 3 to 5 AM. However, a study comparing the outcomes of morning versus afternoon colonoscopy reported significantly higher rates of incomplete procedures and lower rates of adequate bowel preparation in the afternoon.46 In our experience, many patients prefer to undergo colonoscopy in the morning, and most do not object to waking during the night to complete the cleansing regimen. In Japan, the concept of split-dosing has been taken a step further, with colon cleansing performed entirely on the morning of examination.47 Little or no diet modification is required the day before colonoscopy. Patients are instructed to begin the preparation at approximately 6 AM with 2 to 3 L of PEG. The preparation is complete when the rectal effluent is clear. A recent study from the United States compared the efficacy and tolerability of a 4-L PEG preparation administered either the evening before or the morning of the procedure in 136 patients undergoing afternoon colonoscopy. The overall quality of bowel cleansing was better in the morning group compared with the evening group (4.73 vs 7.10, respectively; P<0.01), based on the validated Ottawa scale (range 0-14, 0=best). However, there were no differences in polyp detection rates between the 2 treatment groups. Tolerability was better with the morning-only dosing regimen.48 In some instances, the timing of bowel preparation may require alteration in order to accommodate the fasting requirements related to procedural sedation. There are no universally accepted guidelines on pre-

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procedural fasting, and consequently the literature contains a variety of recommendations on this subject. Guidelines published by the American Society of Anesthesiology state that patients should fast for a minimum of 2 hours for clear liquids and 6 hours for light meals before sedation.49 On the other hand, an evidence-based review by the American College of Emergency Physicians50 states that “recent food intake is not a contraindication for administering procedural sedation and analgesia, but should be considered in choosing the timing and target level of sedation.” A position statement from the American Gastroenterological Association51 concluded that “there is inadequate evidence to permit the development of absolute requirements for pre-procedural fasting, and the clinician should be guided by the practice parameters provided by various professional societies.” A prospective study comparing residual gastric volume in patients receiving split-dose versus evening-before bowel preparation showed no significant difference between the 2 regimens (19.7 vs 20.2 mL, respectively; P=0.85). Based on the current available data, it is reasonable to recommend that patients undergoing colonoscopy with sedation fast for a minimum of 2 hours before the procedure.52

SPECIAL PATIENTT POPULATIONS Elderly Patients. Individuals aged 65 years and older comprise at least 20% of the patient population undergoing routine colonoscopy and are more likely to have an incomplete preparation.1,53 The reasons for this are multifactorial and include an increased likelihood of constipation, reduced mobility, and difficulty completing the preparation. Elderly patients using NaP also are more likely to manifest hyperphosphatemia as a result of impaired renal function, comorbid illness, and concomitant medications.36 The efficacy, safety, and tolerability of various purgatives in older individuals have been evaluated in several studies. A randomized controlled trial with octogenarians compared NaP with a 4-L PEG preparation.53 The quality of preparation was similar in the 2 groups, with a good or excellent rating in 77% to 81% of patients receiving NaP or PEG, respectively. As anticipated, PEG produced less change than NaP in the clinical parameters of dehydration and laboratory values. Fewer patients were unable to complete the NaP preparation than the PEG preparation, although the difference did not reach statistical significance. Overall, patients preferred NaP to PEG and were more willing to repeat this preparation in the future. A second study comparing NaP with PEG in elderly patients reported that the overall quality of colon cleansing was comparable for the 2 preparations.54 Furthermore, patients who received NaP tolerated the preparation better than those who received PEG, although the difference was not statistically significant. Patients With Inflammatory Bowel Disease. In general, patients with inflammatory bowel disease can prepare for

colonoscopy with any of the standard bowel purgatives. An exception is the patient with moderate to severe diarrhea (>6-8 bowel movements per day); for this patient, the dose of cathartic may be reduced or eliminated altogether. NaP preparations can produce aphthoid lesions in the colon, most prominently within the rectum and sigmoid. This endoscopic appearance is distinct and can be readily distinguished from the endoscopic appearances of Crohn’s disease and ulcerative colitis. Pediatric Patients. In children 12 years or older, an oral NaP solution at a dosage of 45 mL taken twice was probably the most widely used preparation.10 For children 6 to 11 years, the dosage often is reduced to 30 mL taken twice. NaP is not recommended for children aged 5 years and younger. A second method of preparation for children is a PEG-based formulation (MiraLax) administered at a dose of 1.25 to 1.5 g/kg daily for 4 days. In some instances, a laxative, such as bisacodyl, may be added to the regimen 1 day before colonoscopy. The least commonly used preparation is either a saline or a phosphate enema in combination with a senna laxative.10 In the pediatric population, there are inadequate data assessing efficacy and safety to recommend a particular regimen over another. The PEG-based preparations generally are effective but often are accompanied by abdominal bloating and vomiting.55 A modified PEG preparation that is administered over 4 days appears to be better tolerated but has the potential for disrupting a child’s ability to attend school and participate in other activities.56 Generally, children tolerate oral NaP better than PEG, although hyperphosphatemia often is observed. Practice recommendations for bowel preparation in children undergoing colonoscopy vary. A recent consensus statement prepared by a joint task force in the United States10 concluded that NaP, PEG, and phosphate enema/senna preparations all are “safe and will adequately prepare the child’s colon for colonoscopy.” The authors caution, however, that “in certain circumstances, such as bowel preparation in children, … it may be advisable to adhere to PEG-based solutions because of the risks for occult physiologic disturbances that may potentially contraindicate the use of NaP-based regimens.” Regardless of the regimen selected, it is important to provide children with adequate hydration during the process of bowel preparation. A carbohydrate-electrolyte solution designed specifically for children often is helpful for this purpose. Patients With Lower Gastrointestinal Bleeding. In most circumstances, patients undergoing colonoscopy for hematochezia must be prepared quickly.57 Colon transit is hastened by the presence of blood, and in most cases, bowel cleansing can be completed within 2 to 3 hours by using 0.5 to 2 L of PEG solution. Patients who are unresponsive or mechanically ventilated may receive the PEG solution through a nasogastric tube. Patients With a History of Inadequate Preparation or Chronic Constipation. There are no studies to provide the clinician with guidance for preparation of the patient with chronic constipation or a history of inadequate bowel

Key Points 1. The choice of bowel cleansing regimen for colonoscopy should be based on the patient’s age, health status, comorbid diseases, and personal preference. 2. A split-dose bowel cleansing regimen that includes one dose of laxative within 4 to 6 hours before the examination improves the quality of bowel cleansing, especially within the ascending colon. 3. NaP should be avoided in patients with impaired renal function, congestive heart failure, advanced liver disease, hypertension, or hypercalcemia. 4. All purgatives have been associated with serious AEs. The risk for complications can be minimized by selecting the most appropriate bowel cleansing regimen for each patient and highlighting the importance of adherence to preparation instructions. 5. The importance of adequate hydration during and after bowel preparation should be emphasized for all patients undergoing colonoscopy.

cleansing during a previous colonoscopy. Measures that have been recommended include the following: extending the period of diet modification from 24 to 48 hours; adding oral bisacodyl or senna to a PEG or a NaP regimen; and increasing the total volume of PEG from 4 to 6 L, with administration split over 48 hours (usually 1-2 L on day 1, and 3-4 L on day 2). Additionally, adequate hydration will help to improve the adequacy of cleansing.

REPORTING

THE E

QUALITY

OF F

BOWEL PREPARATION

The American Society for Gastrointestinal Endoscopy (ASGE)/ACG Task Force on Quality in Endoscopy has recommended that the quality of bowel cleansing be documented for every colonoscopy.58 The terms excellent, good, fair, and poorr often are used in clinical practice to characterize the quality of bowel cleansing, without reference to a standardized definition of these qualifiers. Preferably, clinicians should become familiar with one of the validated bowel preparation assessment scales and incorporate it into a structured endoscopy reporting system.59,60 The task force recommends that an examination be considered adequate if it enables the detection of colon polyps greater than 5 mm in size. An incomplete examination that results from poor bowel preparation will necessitate repeat examination.

Conclusion A substantial number of colonoscopy procedures are suboptimal because of inadequate bowel preparation. This figure ranges from 17% to 30% in randomized trials and is probably higher in clinical practice. Several patient characteristics have been associated with poor bowel preparation, including a history of constipation, inpatient status, use of antidepressants, and noncompliance with bowel preparation instructions.61,62 An awareness of these factors, combined with strategies designed to optimize the results of purgative regimens and an emphasis on patient education and compliance, will maximize the efficiency of colonoscopy and minimize its risks (Key Points).

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS • M A R C H 2 0 1 4

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32. Holte K, Nielsen KG, Madsen JL, Kehlet H. Dis Colon Rectum. 2004;47(8):1397-1402.

2. Brenner H, Hoffmeister M, Arndt V, Stegmaier C, Altenhofen L, Haug U. J Natl Cancer Inst. 2010;102(2):89-95.

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34. Cohen SM, Wexner SD, Binderow SR, et al. Dis Colon Rectum. 1994;37(7):689-696.

4. Baxter NN, Goldwasser MA, Paszat LF, Saskin R, Urbach DR, Rabeneck L. Ann Intern Med. 2009;150(1):1-8.

35. Mathus-Vliegen EM, Kemble UM. Aliment Pharmacol Ther. 2006;23(4):543-552.

5. Lakoff J, Paszat LF, Saskin R, Rabeneck L. Clin Gastroenterol Hepatol. 2008;6(10):1117-1121.

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6. Tan JJ, Tjandra JJ. Colorectal Dis. 2006;8(4):247-258.

37. Fine A, Patterson J. Am J Kidney Dis. 1997;29(1):103-105.

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38. Nagler J, Poppers D, Turetz M. J Clin Gastroenterol. 2006;40(6):558-559.

8. Barkun A, Chiba N, Enns R, et al. Can J Gastroenterol. 2006;20(11):699-710.

39. Barclay RL, Depew WT, Vanner SJ. Gastrointest Endosc. 2002;56(5):633-638.

9. Cohen LB. Gastrointest Endosc. 2010;72(2):406-412.

40. Lichtenstein GR, Cohen LB, Uribarri J. Aliment Pharmacol Ther. 2007;26(5):633-641.

10. Ell C, Fischbach W, Bronisch HJ, et al. Am J Gastroenterol. 2008;103(4):883-893.

41. Church JM. Dis Colon Rectum. 1998;41(10):1223-1225.

11. Marmo R, Rotondano G, Riccio G, et al. Gastrointest Endosc. 2010;72:313-320.

42. Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. Am J Gastroenterol. 2009;104(3):739-750.

12. Corporaal S, Kleibeuker JH, Koornstra JJ. Scand J Gastroenterol. 2010;45(11):1380-1386.

43. El Sayed AM, Kanafani ZA, Mourad FH, et al. Gastrointest Endosc. 2003;58(1):36-40.

13. Pontone S, Angelini R, Standoli M, et al. World J Gastroenterol. 2011;17(42):4689-4695.

44. Chiu HM, Lin JT, Wang HP, Lee YC, Wu MS. Am J Gastroenterol. 2006;101(12):2719-2725.

14. Cohen LB, Sanyal S, von Althann C, et al. Aliment Pharmacol Ther. 2010;32(5):637-644.

45. Parra-Blanco A, Nicolas-Perez D, Gimeno-Garcia A, et al. World J Gastroenterol. 2006;12(38):6161-6166.

15. Enestvedt BK, Fennerty MB, Eisen GM. Aliment Pharmacol Ther. 2011;33(1):33-40. 16. Hjelkrem M, Stengel J, Liu M, Jones DP, Harrison SA. Clin Gastroenterol Hepatol. 2011;9(4):326-332. 17. Samarasena JB, Muthusamy VR, Jamal MM. Am J Gastroenterol. 2012;107(7):1036-1042. 18. Gerard DP, Holden JL, Foster DB, Raiser MW. Clin Translational Gastroenterol. 2012;3:e16. 19. US Food and Drug Administration. Oral sodium phosphate (OSP) products for bowel cleansing (marketed as Visicol and OsmoPrep, and OSP products available without a prescription). www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103354.htm. 20. Rex DK, Schwartz H, Goldstein M, et al. Am J Gastroenterol. 2006;101(11):2594-2604. 21. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. J Am Soc Nephrol. 2005;16(11):3389-3396. 22. Rex DK, Balaban DH, Bond JH, et al. Oral sodium phosphate solution for bowel preparation: literature review and recommendations of an industry-sponsored advisory panel regarding safe and effective use. CB Fleet. 2006. 23. Casais MN, Rosa-Diez G, Pérez S, Mansilla EN, Bravo S, Bonofiglio FC. World J Gastroenterol. 2009;15(47):5960-5965. 24. Pelham RW, Russell RG, Padgett EL, Reno FE, Cleveland M. Int J Toxicol. 2009;28(2):99-112.

46. Sanaka MR, Shah N, Mullen KD, Ferguson DR, Thomas C, McCullough AJ. Am J Gastroenterol. 2006;101(12):2726-2730. 47. Parra-Blanco A, Quintero E, Jiménez A. Am J Gastroenterol. 2007;102(4):908-909. 48. Varughese S, Kumar AR, George A, Castro FJ. Am J Gastroenterol. 2010;105(11):2368-2374. 49. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: a report by the American Society of Anesthesiologists Task Force on Preoperative Fasting. Anesthesiology. 1999;90(3):896-905. 50. Godwin SA, Caro DA, Wolf SJ, et al, and the American College of Emergency Physicians. Ann Emerg Med. 2005;45(2):177-196. 51. Cohen LB, DeLegge MH, Aisenberg J, et al. Gastroenterology. 2007;133(2):675-701. 52. Huffman M, Unger RZ, Thatikonda C, Amstutz S, Rex DK. Gastrointest Endosc. 2010;72(3):516-522. 53. Seinelä L, Pehkonen E, Laasanen T, Ahvenainen J. Scand J Gastroenterol. 2003;38(2):216-220. 54. Thomson A, Naidoo P, Crotty B. J Gastroenterol Hepatol. 1996;11(2):103-107. 55. da Silva MM, Briars GL, Patrick MK, Cleghorn GJ, Shepherd RW. J Pediatr Gastroenterol Nutr. 1997;24(1):33-37. 56. Pashankar DS, Uc A, Bishop WP. J Pediatr. 2004;144(3):358-362.

25. Di Palma JA, Rodriguez R, McGowan J, Cleveland MB. Am J Gastroenterol. 2009;104(9):2275-2284.

57. Green BT, Rockey DC, Portwood G, et al. Am J Gastroenterol. 2005;100(11):2395-2402.

26. Rex DK, Di Palma JA, McGowan J, Cleveland MV. Am J Gastroenterol. 2009;104(suppl 3s):S180-S181. Abstract 479.

58. Rex DK, Petrini JL, Baron TH, et al. Am J Gastroenterol. 2006;101(4):873-885.

27. Hoy SM, Scott LJ, Wagstaff AJ. Drugs. 2009;69(1):123-136.

59. Romstom A, Jolicoeur E. Gastrointest Endosc. 2004;59(4):482-486;erratum: 2004;60(2):326.

28. Katz PO, Rex DK, Epstein M, et al. Am J Gastroenterol. 2013;108(3):401-409. 29. Keeffe EB. Gastrointest Endosc. 1996;43(5):524-528.

60. Lai EJ, Calderwood AH, Doros G, Fix OK, Jacobson BC. Gastrointest Endosc. 2009;69(3 Pt 2):620-625.

30. Abuksis G, Mor M, Segal N, et al. Am J Gastroenterol. 2001;96(6):1786-1790.

61. Ness RM, Manam R, Hoen H, Chalasani N. Am J Gastroenterol. 2001;96(6):1797-1802.

31. Chorev N, Chadad B, Segal N, et al. Dig Dis Sci. 2007;52(3):835-839.

62. Harewood GC, Sharma VK, de Garmo P. Gastrointest Endosc. 2003;58(1):76-79.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

NATIONAL COLORECTAL CANCER AWARENESS MONTH

Colorectal Cancer Prevention and Detection: Brief Reports From the 2014 ASCO GI Cancers Symposium BY CAROLINE HELWICK SAN FRANCISCO—At the 2014 American Society for Clinical Oncology Gastrointestinal Cancers Symposium, two research groups described how “missed” colorectal cancer (CRC) is different—including outcomes—from CRC detected by screening, ng, while other researchers found metformin to be protective against CRC and showed thatt repeat colonoscopies seem to raise an individual’s awareness of the need for additional health screenings. A brief summary of these studies follows.

Screen-Detected Versus Non–Screen-Detected CRC Investigators in Scotland compared th he characteristics of CRC detected by fecal occult blood test (FOBT) and colonoscopy—i.e., screendetected (SD) cancers—with non–screen-detected (NSD) cancers and identified several differences. Using data from the Scottish Bowel Screening Programme and a regional cancer audit database, they found that of more than 395,000 adults aged 50 to 74 years, invited to participate in CRC screening, approximately 204,000 (52%) responded. Of these, 6,085 (3%) had a positive FOBT result, 4,632 (76%) of whom underwent a colonoscopy. Of the patients undergoing colonoscopies, 420 were found to have CRC. This group was identified as the SD group. The researchers calculated the sensitivity of FOBT screening to be 77% and the specificity to be 97%. An additional 549 patients developed CRC, including 368 who did not undergo FOBT; 132 who had a negative FOBT result (i.e., interval cancer); and 49 who had a positive FOBT result and either underwent or did not undergo colonoscopy (i.e., missed cancers). This group was identified as the NSD group. The investigators found that patients in n the SD group were more likely to be men, too be less socioeconomically deprived, to have tumors with a lower Dukes stage and to have left-sided tumors (P<0.05 for all). These patients also were more likely to undergo surgery with curative intent, less likely to undergo an emergency procedure and less likely to die with hin 30 days of the procedure (P<0.001 for all). ) At a median follow-up of two years, SD patients had better cancer-specific survival rates (P<0.001), and this remained significant in a multivariate survival analysis (P<0.001). The unadjusted cancer-specific survival rate at three years was approximately 90% for SD patients compared with 60% for NSD patients. “Independent of established prognostic factors, SD patients have more favorable outcomes than those with NSD tumors,” study investigator David Mansouri, MD, of the University of Glasgow, said. “Therefore, further studies to improve both the response rate to a screening invitation and the sensitivity of the current screening test are warranted.” Thomas F. Imperiale, MD, professor of medicine at Indiana University School of Medicine, Indianapolis, who was not involved in the study, said, “The results of

this study are consistent with previous literature showing that screen-detected cancers have a more favorable stage distribution, and that FOBT is more sensitive for advanced distal neoplasia.” Uri Ladabaum, MD, director of the Gastrointestinal Cancer Prevention Program at Stanford University School of Medicine, in Palo Alto, Calif., agreed.

‘The results of this study are ‘T consistent with previous literature showing that screen-detected cancers have a more favorable stage distribution, and that FOBT is more sensitive for advanced distal neoplasia.’ —Thomas F. Imperiale, MD

‘One question raised by this study cal is whether there are biological s differences between cancers diagnosed in those who were not screened, versus those missed by FOBT, versus those missed by colonoscopy. While we await answers to these questions, the public health imperative must remain to in ening increase uptake of screening, which is proven to decrease colorectal cancer incidence and mortality.’ —Uri Ladabaum, MD

“Previous studies have shown a shift in CRC stage at diagnosis with screening,” he said. “One question raised by this study is whether there are biological differences between cancers diagnosed in those who were not screened, versus those missed by FOBT, versus those missed by colonoscopy. While we await answers to these questions, the public health imperative must remain to increase uptake of screening, which is proven to decrease CRC incidence and mortality,” he said.

‘Missed Cancers’ Anand Govindarajan, MD, and his colleagues at Mount Sinai Hospital, Toronto, Ontario, Canada, aimed to evaluate the outcomes of missed CRC compared with cancer detected by screening colonoscopy. They evaluated data from a population-based cohort study of all

patients diagnosed with CRC in Ontario, from 2003 to 2009, who had undergone colonoscopy within 36 months of diagnosis. The researchers identified 30,475 patients, of whom 2,804 had a “missed cancer.” Factors associated with missed cancers included location in the colon rather than the rectum, older age, female gender, rural residence and Charlson comorbidity score. Patients with missed CRC had several worse outcomes than patients whose cancers were detected at colonoscopy, including: • significantly lower five-year overall survival (60.8% vs. 68.3%; P<0.0001); • higher risk for death (22%; P<0.0001) in a multivariate analysis; • significantly greater likelihood of emergent presentation of obstruction, bleeding or perforation (odds ratio [OR], 2.86; P<0.001); and • significantly lower likelihood of surgical resection of cancer (OR, 0.61; P<0.001). Perioperative morbidity and mortality, however, were similar in both groups of patients. “Post-colonoscopy CRC is associated with significantly worse patient outcomes,” Dr. Govindarajan concluded. “Quality improvement in CRC screening is of critical importance.” screeni Dr. Imperiale said the findings D arre consistent with previously identified risk factors for interval cancers, including proximal location, female gender and older age. In some cases, the missed cancers may reflect a more aggressive tumor biology, he noted. Dr. Ladabaum said, “This sttudy adds to the literature on thee factors associated with CRCs missed d at colonoscopy. Although it is likely thatt both technical and biological ffactors are important, this study reminds us of the importance of attention to quality at the time of screening colonoscopy. We must strive to ensure thorough inspection and lesion detection and complete removal.”

Colonoscopy Associated With Other Good Health Practices Are patients who undergo colonoscopy more likely to undergo screening for other cancers? Researchers from Case Western Reserve University, Cleveland, addressed this question in a study of 717,334 Medicare patients who underwent colonoscopy at two time points—between 2004 and 2008 and between 2009 and 2010. Examining the rates of mammography and prostate-specific antigen (PSA) testing in the later period, the investigators found that individuals with more than one previous colonoscopy were five times more likely to undergo mammography and nearly three times more likely to undergo PSA testing, reported Gregory S. Cooper, MD, co-program leader for Cancer Prevention and Control, University Hospitals, Case Medical Center, also in Cleveland. Undergoing one colonoscopy examination raised the chances for undergoing mammography by two- to threefold and for PSA testing by about twofold. see ASCO GI, page 16

NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Cleveland Clinic Researchers Develop Online CRC Risk Predictor BY BEN GUARINO A new online calculator created by researchers at Cleveland Clinic is designed to help physicians determine a patient’s risk for colorectal cancer (CRC). Using age, weight, family history of colon cancer and other risk factor data, the calculator estimates the chance that a patient will develop CRC in the next 10 years.

Using a predictive tool such as this one is “much more effective” than relying on an age cutoff to assess whether or not a patient should receive a colonoscopy, said investigator Brian Wells, MD, PhD, a research associate at Cleveland Clinic’s Lerner Research Institute, in Ohio. “Not that the age 50 cutoff is arbitrary, but I think that’s a crude estimate of risk,” he said. Dr. Wells and his colleagues developed the new risk predictor, called the ColoRectal Cancer Predicted Risk Online (CRC-PRO) calculator, using data from the Multiethnic Cohort Study, which followed more than 180,000 participants in California and Hawaii for 11.5 years. They published the results in the January-February issue of the Journal of the American Board of Family Medicine (Wells BJ et al. 2014;27:42-55). Factors that were significantly associated with CRC risk included age, race, smoking status, alcohol intake, family history of colon cancer, diabetes and use

of multivitamins or nonsteroidal anti-inflammatory drugs. The Multiethnic Cohort Study did not assess whether patients had inflammatory bowel disease (IBD), a recognized risk factor for CRC; however, Dr. Wells believes the lack of this data should not greatly affect the calculator’s accuracy because of the expected rarity of IBD in such a large study population. Compared with other available CRC risk calculators, which use case–control data, Dr. Wells said the CRC-PRO tool is “less prone to bias than previous models, since the data was derived from a prospective cohort of patients.” However, patients who have a history of colon cancer or who have polyps should not rely on this calculator, he cautioned. Physicians may be reluctant to use risk calculators such as these, particularly if entering information becomes time-consuming. “If we can integrate calculators with electronic health records (EHRs), it will get past hurdles of trying to get physicians to use these tools,” Dr. Wells predicted. Mark H. Ebell, MD, MS, associate professor of epidemiology at the University of Georgia, in Athens, who was not involved with

developing the calculator, agreed. “Calculators like this, that help us determine the risk for cancer in an individual patient, especially when they can be integrated with EHRs, have the potential to help us individualize screening and prevention recommendations someday,” he said. About one in three Americans between the ages of 50 and 75 years have not been screened for CRC, according to a 2013 report from the Centers for Disease Control and Prevention. But if every American who is eligible to undergo a colonoscopy chose to do so, Dr. Wells said, there may not be enough physicians for the task. Cost, as well as the small but serious risk for bowel perforations or other complications, also may affect who undergoes a colonoscopy. “If we did a better job of identifying who needs [a colonoscopy],” Dr. Wells said, “maybe we could get better at allocating that resource.” The CRC-PRO calculator and other cancer prediction tools created by Cleveland Clinic are available for free online at http://rcalc. ccf.org. Drs. Wells and Ebell reported no relevant conflicts of interest.

ASCO GI continued from page 15

“These patterns may be due to physician practices and/or patient willingness to be screened,” Dr. Cooper said, predicting that “multiscreening interventions” could be efficacious. Dr. Imperiale said the studies may support “bundling” of CRC screening and other preventive interventions. “However, before creating and implementing interventions to enhance screening, we need to ensure that ‘screening’ was the indication for all testing [in this study] and need to understand more about how the findings distribute with respect to patients, providers and health systems.”

Metformin and CRC Risk Researchers from the University of Chicago found that individuals with diabetes who took metformin had a 12% to 15% reduced risk for developing CRC (P=0.007). P The finding came from a nested case–control study of 8,046 adults with diabetes, 38% of whom were taking metformin. The reduction was consistent regardless of

or coronary artery disease were associated with an The study adds to the increased risk for CRC. “Our study is unique ‘growing heterogeneous due to its relatively younger literature on metformin population, with a mean age p use and colorectal cancer off 57 years. We are not aware of any such study in the U.S. incidence, progression and populatiion,” said Amikar Sehdev, mortality.’ MD,, MPH. Dr. Imperiale noted that the study adds —Thomas F. Imperiale, MD to “the growing, heterogeneous literature on metformin use and CRC incidence, progresmetformin dose, duration of use or total exposure. sion and mortality. “It would help to understand the reasons for the difIn a multivariate analysis that adjusted for concomitant medicines and comorbidities, the investigators ferences among the studies, and to identify a clear, or at found that use of nonsteroidal anti-inflammatory drugs least putative, mechanism of metformin’s antineoplastic and having a low Charlson comorbidity index were pro- effect,” he said. ■ tective against CRC, whereas the use of insulin or sulfonylureas, and the presence of inflammatory bowel disease None of the researchers reported relevant conflicts of interest.

Lowest volume of active prep solution— only 10 oz.

Superior

cleansing *

…that

patients preferred †

in clinical trials

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

PATIENT PREFERENCE

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

reported in clinical trials†1-3

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

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

Colon segment

Prepopik

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

Overall

84%

74%

(n=256/304)

Ascending Mid (Transverse and Descending)

Rectosigmoid

90%

(n=272/304)

92%

(n=221/297)

79%

10%

86%

(n=255/297)

92%

87%

Completed preparation

DIFFERENCE

(n=234/297)

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

Patient perspective

(n=259/297)

Prepopik

99%

(n=304/305)

96%

Would ask for the prep again in the future

(n=290/302)

Was very easy or easy to take

(n=270/302)

89%

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

91%

(n=267/292)

55%

(n=162/296)

29%

(n=86/296)

SPLIT-DOSE OR DAY-BEFORE REGIMEN4

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

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

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

‡

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

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

NATIONAL COLORECTAL CANCER AWARENESS MONTH

FOBT continued from page 1

with more than 152,000 and 61,000 participants, respectively, showing that FOBT was associated with an 18% relative risk reduction in CRC-related mortality at 13 and 20 years of follow-up. For the Minnesota study, which was published in The New England Journal of Medicinee (Shaukat A et al. 2013;369:1106-1114) and presented at the 2013 Annual Scientific Meeting of the American College of Gastroenterology,

researchers used national death index data to update the vital status and cause of death of participants in the Minnesota Colon Cancer Control Study. â&#x20AC;&#x153;The aims of our study were to assess the long-term effect of screening for CRC on CRC mortality using FOBT, to assess the long-term effect of screening for CRC on all-cause mortality using FOBT and to evaluate the benefit of screening in age and gender subgroups,â&#x20AC;? said study author Aasma Shaukat, MD, MPH, chief of the GI Section at Minneapolis Veterans

Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHĂ&#x20AC;H[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ or aspiration should be observed during the administration of PREPOPIK. Use with caution in these patients. Not for Direct Ingestion Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances. INDICATIONS AND USAGE PREPOPIKÂŽ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, CONTRAINDICATIONS adverse reaction rates observed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: be directly compared to rates in clinical trials of another drug and may â&#x20AC;˘ Patients with severely reduced renal function (creatinine clearance QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG LQ SUDFWLFH less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and vomiting were the most common adverse reactions (>1%) â&#x20AC;˘ Gastrointestinal obstruction or ileus following PREPOPIK administration. The patients were not blinded to â&#x20AC;˘ Bowel perforation the study drug. Since abdominal bloating, distension, pain/cramping, â&#x20AC;˘ Toxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing â&#x20AC;˘ Gastric retention preparations, these effects were documented as adverse events in â&#x20AC;˘ An allergy to any of the ingredients in PREPOPIK the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adverse event), Serious Fluid and Serum Chemistry Abnormalities RU VKRZHG FOLQLFDOO\ VLJQLÂżFDQW ZRUVHQLQJ GXULQJ WKH VWXG\ WKDW ZDV Advise patients to hydrate adequately before, during, and after the not in the frame of the usual clinical course, as determined by the use of PREPOPIK. Use caution in patients with congestive heart investigator. IDLOXUH ZKHQ UHSODFLQJ Ă&#x20AC;XLGV ,I D SDWLHQW GHYHORSV VLJQLÂżFDQW YRPLWLQJ PREPOPIK was compared for colon cleansing effectiveness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters (2L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all lab tests (electrolytes, creatinine, and BUN) and treat accordingly. administered the day before the procedure. Table 1 displays the most Approximately 20% of patients in both arms (PREPOPIK, 2L of PEG common adverse reactions in Study 1 and Study 2 for the PREPOPIK + E plus two x 5-mg bisacodyl tablets) of clinical trials of PREPOPIK Split-Dose and Day-Before dosing regimens, respectively, each as had orthostatic changes (changes in blood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy. Table 1: Treatment-Emergent Adverse Reactions observed in at Fluid and electrolyte disturbances can lead to serious adverse events Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte abnormalities should be corrected before treatment with PREPOPIK. In addition, use caution when prescribing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who have conditions or who are using medications that Reaction LQFUHDVH WKH ULVN IRU Ă&#x20AC;XLG DQG HOHFWURO\WH GLVWXUEDQFHV RU WKDW PD\ PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adverse events of seizure, arrhythmia, and renal with 2 x (N=305) with 2 x 5-mg (N=296) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl bisacodyl tablets (N=302) n (% = n/N) Nausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) * 2L PEG + E = two liters polyethylene glycol plus electrolytes solution. **abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected tablets (N=298) n (% = n/N)

Seizures There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic DEQRUPDOLWLHV UHVROYHG ZLWK FRUUHFWLRQ RI Ă&#x20AC;XLG DQG HOHFWURO\WH abnormalities. Use caution when prescribing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or Electrolyte abnormalities In general, PREPOPIK was associated with numerically higher rates benzodiazepines, patients with known or suspected hyponatremia. of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two x 5-mg bisacodyl Use in Patients with Renal Impairment As in other magnesium containing bowel preparations, use caution tablets. These shifts were transient in nature and numerically similar when prescribing PREPOPIK for patients with impaired renal function between treatment arms at the Day 30 visit. or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, Postmarketing Experience DQJLRWHQVLQ UHFHSWRU EORFNHUV RU QRQ VWHURLGDO DQWL LQĂ&#x20AC;DPPDWRU\ 7KH IROORZLQJ IRUHLJQ VSRQWDQHRXV UHSRUWV KDYH EHHQ LGHQWLÂżHG GXULQJ drugs). These patients may be at increased risk for renal injury. Advise use of formulations similar to PREPOPIK. Because these events are these patients of the importance of adequate hydration before during reported voluntarily from a population of uncertain size, it is not always and after the use of PREPOPIK. Consider performing baseline and possible to reliably estimate their frequency or establish a causal post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) relationship to drug exposure. in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in Allergic reactions Cases of hypersensitivity reactions including rash, urticaria, and plasma may occur. purpura have been reported. Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with Electrolyte abnormalities the use of ionic osmotic laxative products for bowel preparation. Use There have been reports of hypokalemia, hyponatremia and caution when prescribing PREPOPIK for patients at increased risk of hypermagnesemia with the use of PREPOPIK for colon preparation arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled prior to colonoscopy. arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal ECGs should be considered in patients at increased risk of serious Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. There have been isolated reports of reversible Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has been reported with the use Osmotic laxatives may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. However, a and there have been reports of more serious cases of ischemic colitis causal relationship between these ischemic colitis cases and the use requiring hospitalization. Concurrent use of additional stimulant of PREPOPIK has not been established. laxatives with PREPOPIK may increase this risk. The potential for mucosal ulcerations should be considered when interpreting Neurologic FRORQRVFRS\ ÂżQGLQJV LQ SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG LQĂ&#x20AC;DPPDWRU\ There have been reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients. bowel disease. 8VH LQ 3DWLHQWV ZLWK 6LJQLĂ&#x20AC;FDQW *DVWURLQWHVWLQDO 'LVHDVH If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering PREPOPIK. Use with caution in patients with severe active ulcerative colitis.

DRUG INTERACTIONS

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

Affairs (VA) Health Care System, and associate professor of medicine at the University of Minnesota, Minneapolis VA Medical Center. Each of the three arms in the study included approximately 15,000 individuals, average age 62 years at randomization, with women making up slightly more than half of the participants. By 30 years of follow-up, 33,020 of the original participants had died, with 732 deaths attributable to CRC: 200 in the annual group, 237 in the biennial group and 295 in the control arm.

DUUK\WKPLDV DQG SURORQJHG 47 LQ WKH VHWWLQJ RI Ă&#x20AC;XLG DQG HOHFWURO\WH abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used LQ SDWLHQWV RQ QRQVWHURLGDO DQWL LQĂ&#x20AC;DPPDWRU\ GUXJV 16$,'6 RU drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate. Potential for Altered Drug Absorption Oral medication administered within one hour of the start of DGPLQLVWUDWLRQ RI 35(323,. VROXWLRQ PD\ EH Ă&#x20AC;XVKHG IURP WKH *, WUDFW and the medication may not be absorbed. 7HWUDF\FOLQH DQG Ă&#x20AC;XRURTXLQRORQH DQWLELRWLFV LURQ GLJR[LQ chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of PREPOPIK to avoid chelation with magnesium. Antibiotics Prior or concomitant use of antibiotics with PREPOPIK may reduce HIÂżFDF\ RI 35(323,. DV FRQYHUVLRQ RI VRGLXP SLFRVXOIDWH WR LWV active metabolite BHPM is mediated by colonic bacteria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with PREPOPIK have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to PREPOPIK. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREPOPIK should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PREPOPIK is administered to a nursing woman. Pediatric Use The safety and effectiveness of PREPOPIK in pediatric patients has not been established. Geriatric Use In controlled clinical trials of PREPOPIK, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatmentHPHUJHQW DGYHUVH HYHQWV ZDV VLPLODU DPRQJ SDWLHQWV Â&#x2022; \HDUV RII DJH DQG SDWLHQWV \HDUV RI DJH $PRQJ DOO SDWLHQWV Â&#x2022; years of age, the proportion of patients with successful colon cleansing was greater in the PREPOPIK group (81.1%) than in the comparator group (70.9%). 5HQDO ,QVXIĂ&#x20AC;FLHQF\ Patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor EORFNHUV RU QRQ VWHURLGDO DQWL LQĂ&#x20AC;DPPDWRU\ GUXJV PD\ EH DW increased risk for further renal injury. Advise these patients of the importance of adequate hydration before during and after the use of PREPOPIK. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. The signs and symptoms of hypermagnesemia may include, but are not OLPLWHG WR GLPLQLVKHG RU DEVHQW GHHS WHQGRQ UHĂ&#x20AC;H[HV VRPQROHQFH hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest. OVERDOSAGE The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications. Manufactured by: Ferring Pharmaceuticals (China) Co., Ltd. No. 6 HuiLing Lu (Ferring Road) National Health Technology Park Zhongshan City, Guangdong Province, CHINA Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, N.J. 07054

www.ferringusa.com 1-888-FERRING Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing PREPOPIK for patients with conditions ÂŠ2014 Ferring Pharmaceuticals Inc. RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW LQFUHDVH WKH ULVN IRU Ă&#x20AC;XLG DQG All rights reserved. Printed in USA. electrolyte disturbances or may increase the risk of seizure, PK/069/2014/US

â&#x20AC;&#x2DC;To summarize, screening for CRC using FOBT consistently reduces CRC mortality by 32% and this effect is sustained through 30 years of follow-up. The benefit appears to be larger for men than for women, and the benefit appears to begin for women after age 60.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Aasma Shaukat, MD, MPH

â&#x20AC;&#x153;Compared with the control group, the relative risk for CRC mortality in the annual group was 0.68, and 0.78 in the biennial group, translating into a relative risk reduction in CRC mortality of 32% and 22%, respectively,â&#x20AC;? Dr. Shaukat noted. â&#x20AC;&#x153;Over time, there is a fairly clear separation [on the KaplanMeyer curve] between the controls and the annual group, starting at about 13 years of follow-up and persisting through 30 years.â&#x20AC;? Despite the large number of deaths, the researchers did not see a difference in relative risk for all-cause mortality between the screened and unscreened cohorts. In a subgroup analysis based on age and gender, FOBT screening appeared to have a strong effect on CRC mortality

NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

first eight to 10 years. This sustained benefit suggests that these individuals underwent removal of polyps that would have turned into cancers resulting in death by 30 years.”

‘Striking’ Results Douglas Robertson, MD, MPH, associate professor of medicine, Geisel School of Medicine at Dartmouth in Hanover, and chief of gastroenterology at the VA Medical Center in White River Junction, both in Vermont, was impressed by the findings.

“The results are striking because the reduction in CRC mortality remains robust so many years after the initial screening intervention,” he said, noting that since the completion of the trial there has been ample opportunity for significant crossover. “You might think that after all this time, the initially screened and unscreened groups would start to look similar in terms of CRC mortality. However, the survival curves show no real loss of effect over the period of observation.” Dr. Robertson agrees with the authors’

Skills Training Assessment Reinforcement

assessment that the long-term gains observed in the screened group are likely due to the preventive benefits of polypectomy. “Although the study is limited in that it cannot provide direct data to support that claim, that is clearly the most likely explanation for the findings,” Dr. Robertson said. ■ Dr. Shaukat reported no relevant conflicts of interest. Dr. Robertson is on the advisory board of Given Imaging.

ASGE

STAR

ASGE EMR STAR Certiﬁcate Program An Assessment-Based Certiﬁcate

Certi Certificate Program EMR

Expand your endoscopic skills to meet the need for EMR in your practice Acquire the knowledge and skill you need to confidently perform this advanced technique Demonstrate your qualifications and proficiency in performing EMR Receive a transcript detailing the completed curriculum, earned CME and assessment of performance in EMR skills Offer better patient care Skills to be covered EMR has emerged as one of the most importan ant advancements in GI over the last 10 years. For established endosccopists, there have been no pathways to developing skills in this com mplex technique, until now.

‘The results are striking because the reduction in CRC mortality remains robust so many years after the initial screening intervention.’ —Douglas Robertson, MD, MPH

The ASGE EMR STAR Certificate Program prepares endoscopists to overcome challenges, gain confidence and demonstrate their “readiness” to perform EMR to medical colleagues. Endoscopic mucosal resection (EMR) is defined as the use of various snares, cautery and injection/lifting technique in the resection of large, complex or high risk colonic polyps.

LOWER GI EMR

UPPER GI EMR

★ ★ ★

★ ★

Lesion Recognition Submucosal Injection Techniques Piecemeal and Snare Resection Piecemeal Resection of Flat Lesions

★ ★

Polyp Retrieval Polypectomy Site Treatment Band Ligator and Cap Assisted Lesion Resection

★ ★

Tattooing Clipping /EMR Closure

The EMR STAR Certiﬁcate Program includes two modules: 1) Lower GI and an 2) Upper GI. The Lower GI Certiﬁcate is a prerequisite for participa ipation in the Upper GI module.

Perforation & Complication Management

★

Course and Assessment The EMR Program ram is designed to speciﬁcally teach core knowledge and motor skills in n EMR EM through case-based video sessions and intensive, standardized dh hands-on training. Immediately following the live components, all participan ipants will complete a post-test, as well as a one-on-one assessment of a standardized stand checklist of skills. CME credit can be earned for both online ne and live components. The ASGE EMR STAR Certiﬁcate of Completion is earned by completing several components sequentially over the course of three to six months per module.

Skills • Training • Assessment • Reinforcement

★

Perforation Management Communication Skills

in men aged 60 to 69 years. The group that was screened annually fared better in the older age groups for both men and women. “To summarize,” Dr. Shaukat said, “screening for CRC using FOBT consistently reduces CRC mortality by 32%, and this effect is sustained through 30 years of follow-up. The benefit appears to be larger for men than for women, and the benefit appears to begin for women after age 60.” She noted that adherence was very high, about 90%, and that of the 10% who had positive findings, 83% subsequently underwent colonoscopy. “This suggests the [beneficial] effect of polypectomy,” Dr. Shaukat noted. “With FOBT, which would detect early cancers, most of the benefit would be seen in the

★

★ ★ ★

2014 EMR STAR Certiﬁcate – Program Schedule Session Added! Module 1: Lower GI EMR

Online program opens

March 2014

Online program closes

June 2014

Course/Assessment

July 18-20, 2014

Module 2: Upper GI EMR (Completion of Module 1 prerequisite)

Online program opens

April 2014

Online program closes

October 2014

Course/Assessment

November 7-9, 2014

ASGE EMR STAR Certiﬁcate Program – Lower GI

ASGE has added a secon ond course for the Lower GI EMR STAR Certiﬁcate PProgram scheduled for July ly 2014 2 after the March 2014 course ccompletely sold out.

The American Society for Gastrointestinal Endoscopy certiﬁes that

John Doe, MD, FASGE Has successfully completed the training and assessment in Endoscopic Mucosal Resection (EMR): Lower GI as outlined in the ASGE EMR STAR Certiﬁcate Program The above-named participant has successfully demonstrated acquisition of knowledge and s kills in EMR: Lower GI including • Lesion Recognition • Submucosal Injection Techniques • Piecemeal and Snare Resection • Clipping /EMR Closure • Tattooing • Perforation Management • Communication Skills ASGE

STAR

Certi Certificate Program EMR

ASGE President The American Society for Gastrointestinal Endoscopy (ASGE) is dedicated to advancing patient care and digestive health by promoting excellence and innovation in gastrointestinal endoscopy. ASGE promotes the highest standards for endoscopic training and practice, fosters endoscopic research, recognizes distinguished contributions to endoscopy, and is the foremost resource for endoscopic education.

Your registration includes the opportunity to bring one nurse or one technician at no additional charge. Participation is limited to the ﬁrst 40 physician registrants. Register today to secure your spot! Visit www.asge.org/star for details.

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NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Patient Navigators a ‘No-Brainer’ for Improving Colonoscopy Screening Rates Navigators Increase Screening Rates, Reduce Costs BY CAROLINE HELWICK ORLANDO, FLA.—Rates of screening colonoscopy are typically much lower among underserved and minority populations compared with other groups, but the use of patient navigators can bring screening rates among these groups up to par, as well as reduce costs, according to two studies presented at the 2013 Digestive Disease Week meeting.

‘The adherence rate for screening colonoscopies was 83% or greater for all races, with less than a 5% difference between races.’ —Delia Calo, MD

‘Navigation was more effective and less costly, making it the “dominant” strategy.’

Adherence to Screening In one of the studies, researchers examined colonoscopy screening rates in a large urban hospital health care system in New York City. The investigators reviewed records from the New York City Department of Health and Mental Hygiene’s Navigator Program Network, which included 37,077 patients aged 50 years and older who were scheduled for screening colonoscopies at 10 New York City hospitals. The population comprised Hispanic (43%), black (29%) and white (9%) patients, with 19% being of unspecified race. Trained patient navigators provided education and information to patients, addressed barriers to colonoscopy, reviewed bowel preparation protocols, confirmed appointments, ensured that patients had an escort for their appointments and provided emotional support. As a result, the researchers found that 31,215 individuals attended their screening colonoscopies, with an adherence rate of 84.2%. The patient navigator program promoted the relative equivalence of adherence to screening colonoscopy among all racial groups, noted study author Delia Calo, MD, a fellow at Memorial Sloan-Kettering Cancer Center, New York City. “The adherence rate for screening colonoscopies was 83% or greater for all races, with less than a 5% difference between races,” Dr. Calo reported.

Cost-Effectiveness In another study, researchers from Stanford University in Palo Alto, Calif., and the Icahn School of Medicine at Mount Sinai in New York City, developed a model to demonstrate the cost-effectiveness of patient navigators in increasing screening colonoscopy rates. Investigators compared one-time navigation with no navigation (and no screening), using a time horizon through age 100 years, or death, for a cohort reflecting that of a typical New York City hospital. Patients in the model were Hispanic (49%), black (43%) or white (4%), or of other races (4%). Based on a previous micro-costing study performed at Mount Sinai Hospital, researchers assumed that screening uptake would be 40% without patient navigation and 65% with navigation; the cost would be $29 per colonoscopy completer, $21 per non-completer and $3 for an incomplete navigation. A diagnostic colonoscopy was calculated at $661, and a colonoscopy with intervention was $939. Study author Uri Ladabaum, MD, interim chief, Division of Gastroenterology and Hepatology, Stanford University Medical Center, and his colleagues estimated there would be 551 cases of colorectal cancer without

—Uri Ladabaum, MD

‘The significance of this study is that in emerging health care models that reward outcomes, payors should strongly consider covering the costs of patient navigation.’ —Uri Ladabaum, MD screening, 453 cases without navigation and 392 cases with navigation, resulting in the deaths of 216, 174 and 148 patients, respectively. “Navigation was more effective and less costly, making it the ‘dominant’ strategy,” Dr. Ladabaum reported. Clinical and economic benefits were greatest for patients aged between 50 and 59 years. In this age group, the mean quality-adjusted life-years gained per person was 0.015, at a mean savings of $91 per person. Gains in life expectancy and cost-effectiveness were seen in all racial and age groups. Cost savings were greatest in blacks, Dr. Ladabaum noted. Benefits could be even greater if there was widespread use of high-cost biologics for patients with advanced cancer, he said. “Patient navigation for one-time screening colonoscopy appears to increase life expectancy while saving costs,” Dr. Ladabaum said. “This reflects a favorable balance between the increase in screening uptake achieved by navigation and the costs required to provide navigation.” Patient navigation was cost-saving, and remained at least cost-neutral in various sensitivity analyses that Dr. Ladabaum presented. For example, navigation was costneutral if screening uptake increased by just 3%. “The significance of this study is that in emerging health care models that reward outcomes, payors should strongly consider covering the costs of patient navigation.”

Navigation a ‘No-Brainer’ A lively dialogue about the potential benefits of a patient navigation program ensued in the discussion following the presentation of the data. “So if I am the CEO of a coordinated care

organization, I should be rushing out to hire navigators?” asked David Lieberman, MD, professor of medicine and chief of gastroenterology and hepatology at Oregon Health & Science University in Portland. “Assuming you believe our results, I think the answer is yes,” Dr. Ladabaum replied. Steven Itzkowitz, MD, co-author of the Mount Sinai study, agreed. “Our patient navigator program actually turns a profit for the institution, mainly because we are increasing the volume of colonoscopies; our poor-prep rates are lower; and our completion rates are higher. The real benefit of navigation is getting the patient to show up at the procedure, prepped,” he said. Dr. Itzkowitz, who is professor of medicine, associate director of The Dr. Henry D. Janowitz Division of Gastroenterology and director of the GI fellowship program, added that, at Mount Sinai, the cost of navigating 1,000 patients for colonoscopy is 0.43 full-time equivalents. Assuming a salary of $40,000 per year for a health educator, which his program uses, “for $20,000 a year you can navigate 1,000 patients,” he said. “We have even shown that, if you really want to be cost-effective, you can train volunteers from the community whose only qualification to be a navigator is that they themselves have had a colonoscopy. They can be just as good as our health educators. It’s almost a nobrainer at this point.” ■ Dr. Ladabaum has served as a consultant for GE Healthcare and Given Imaging. Dr. Itzkowitz has consulted for Exact Sciences Corporation. Drs. Calo and Lieberman reported no conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

NATIONAL COLORECTAL CANCER AWARENESS MONTH

FIT Outreach Program Triples CRC Screening Rates in Underse erved BY CAROLINE HELWICK ORLANDO, FLA.—Among underserved patients who are not up to date with colorectal cancer (CRC) screening, a fecal immunochemical testing (FIT) outreach program tripled screening rates compared with usual care, according to a study originally presented at the 2013 Digestive Disease Week meeting and later published in JAMA Internal Medicine (Gupta S et al. 2013;173:1725-1732). “Organized outreach increased screening, compared with usual, office visitbased offers, and FIT was superior to colonoscopy for participation,” reported study author Samir Gupta, MD, of the San Diego Veterans Affairs Medical Center and the University of California, San Diego. CRC screening rates hover around 20% for uninsured individuals, and are lower than 50% for Hispanics. Strategies to boost screening among underserved populations are needed, Dr. Gupta said. In light of this, Dr. Gupta and his colleagues conducted a randomized controlled trial of CRC screening comprising three arms: • usual care: a primary care visit– based, opportunistic screening offer, which is the standard way screening is offered in the United States; • FIT outreach: a mailed invitation, telephone reminders, one sample FIT kit and a postage-paid return envelope; and • colonoscopy outreach: a mailed invitation with telephone reminders (two automated and two live), bowel preparation instructions and scheduling reminders. The study, which comprised 5,970 patients, revealed that FIT outreach tripled the screening rate, whereas colonoscopy outreach doubled it, compared with usual care. The findings were consistent across racial and ethnic groups. The study was conducted at John Peter

Smith Health System, a safety-net health system in Fort Worth, Texas, encompassing 12 primary care clinics, a public hospital and specialty care, in collaboration with the University of Texas Southwestern Medical Center, where Dr. Gupta was previously a faculty member. Patients included in the study were aged 54 to 64 years (white, 41%; Hispanic, 29%; black, 24%; “other,” 7%), and had had one or more health-system visits in the previous eight months. Patients were excluded from the study if they were current with CRC screening recommendations. The primary outcome was defined as participation with any CRC screening test within one year of randomization. Secondary outcomes were rates of adenoma and CRC detection. Screening participation was 40.7% with FIT, 24.6% with colonoscopy and 12.1% with usual care (P<0.001 for both comparisons vs. usual care). Screening participation was significantly higher for FIT compared with colonoscopy outreach, with an absolute difference of 16.1%. “Screening with FIT outreach was almost twice as high compared with colonoscopy outreach,” Dr. Gupta said. The researchers found that the highest screening rates (48.1%) occurred in the FIT outreach program among Hispanics, “a group that is traditionally hard to reach,” Dr. Gupta noted. Advanced adenomas or CRC were detected in 0.5% of patients in the usual care group, 1.5% of those in the colonoscopy outreach group and 1% of those in the FIT outreach group. FIT results were abnormal in 60 individuals, 49 (81.7%) of whom subsequently completed a colonoscopy. Two individuals underwent colonoscopy after the study ended. Reasons for noncompletion among the 11 patients who did not undergo colonoscopy included competing health concerns (n=5), nonresponse to phone calls and mailings (n=3), comorbidities precluding a colonoscopy (n=1), refusal to undergo colonoscopy (n=1) and

‘Organized outreach increased screening, compared with usual, office visit-based offers, and FIT was superior to colonoscopy for participation.’ —Samir Gupta, MD relocation out of state (n=1). The investigators calculated that the number needed to invite to achieve one additional CRC screening was 3.5 for FIT outreach and eight for colonoscopy outreach, compared with usual care. The study results were consistent with those of others showing that absolute screening rates among the underserved can be increased by 13% to 26% with the use of aggressive outreach programs involving stool testing or colonoscopy. “Based on our study and others, we believe that implementation of mailed outreach with telephone follow-up and/ or navigation should be considered for reducing racial/ethnic CRC screening disparities,” Dr. Gupta concluded. Walter Coyle, MD, head of Gastroenterology/Hepatology at Scripps Clinic, La Jolla, Calif., commented on the study for Gastroenterology & Endoscopy News. “CRC screening is in transition, with bundled care, resource allocation and so forth. FIT is a nice screening tool, although it has its false negatives and

false positives. But I think it fits nicely into a tiered, risk stratification approach,” he said. “A European study compared FIT testing and colonoscopy and showed them almost equal in detecting cancer, although the long-term data are lacking,” Dr. Coyle added. “We have data that guaiac testing does save lives, and we will soon have that data for FIT, which is a much better test. We are not there yet, but there could be a time when truly low-risk patients are screened with FIT and those at high risk get colonoscopy.” ■ This study was funded primarily by the Cancer Prevention and Research Institute of Texas (grant PP10039). Dr. Gupta has served as a consultant for Exact Sciences, and has received research support from Polymedco. Dr. Coyle has served as a consultant for CSA, and as a speaker/ teacher for Takeda Pharmaceutical Company Ltd.

Researchers Examine Validity of ADR, Withdrawal Time As Quality Indicators BY MONICA J. SMITH SAN DIEGO—An investigation of two national quality indicators for screening colonoscopy found that adenoma detection rate (ADR) and withdrawal time are variable measures, and that both can be improved with multiple interventions.

“The purpose of our study was to assess the variability of these two quality indicators over time for a large number of endoscopists, and also to see if these factors are modifiable,” said study author Aasma Shaukat, MD, MPH, chief of the GI Section at Minneapolis Veterans Affairs (VA) Health Care System, and associate professor of medicine at the University of Minnesota, Minneapolis VA Medical Center. She added, “If it is a valid

quality measure, how can we tell people to improve it?” To this end, Dr. Shaukat and her colleagues gathered data on colonoscopies performed by 51 board-certified gastroenterologists in Minnesota’s Twin Cities, between 2004 and 2009. “We had ADR data on every physician from the start, but withdrawal time was systematically captured after see Quality Indicators, page 25

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

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

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

see NAFLD, page 14

see Income, page 28

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

NAFLD Threatening Public Health BY KATE O’ROURKE

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

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

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Quality Indicators continued from page 23

2007,” noted Dr. Shaukat, who presented the findings at the 2013 Annual Scientific Meeting of the American College of Gastroenterology. The researchers plotted six- and threeyear trends in individual physicians’ ADRs and withdrawal times, while controlling for patient- and procedure-related factors. At the end of the study, 80,056 colonoscopies had been performed, with ADRs for the 51 endoscopists ranging from 13% to 45%. ADRs varied considerably over time, with a net change during the six-year period ranging from –2% to +28%. Similarly, withdrawal times varied considerably, ranging from 3.5 to 14 minutes, with the net change ranging from –0.5 to +3 minutes. The investigators also studied the effects of interventions to improve quality, which included the following: • education; • blinded and unblinded informal feedback; • meetings in which endoscopists were shown data on both their own and their peers’ quality performance; • the establishment of benchmarks to

NATIONAL COLORECTAL CANCER AWARENESS MONTH

which financial incentives and penalties eventually were added; • changes in bowel preparation; and • a shift in technology to high-definition endoscopes and widescreen monitors. “We discovered a few interesting things,” Dr. Shaukat said. “First of all, no one physician had a static rate of ADR or withdrawal time—rates vary from day to day, even with the same physician and

in response to interventions, but the changes did not occur immediately. “Initially there was some inertia, but over time—in two years—there was a sustained and significant improvement in these quality indicators,” Dr. Shaukat said. “This suggests that [ADR and withdrawal time] are valid quality indicators that can be measured over time and that can actually be modified with intervention,” she noted.

‘As physicians’ ADRs improved, their withdrawal times improved. It wasn’t quite a linear relationship, but it definitely suggested the two are interrelated. We are currently investigating which one is more important, and whether we can use one instead of both.’ —Aasma Shaukat, MD, MPH

a very similar patient population. This suggests that fluctuation captured over a short period of time may be erroneous, and that it may be better to measure such things over the long term and on a continuous basis for each physician.” The researchers also found that both ADRs and withdrawal times changed

Another finding that Dr. Shaukat and her colleagues observed is that ADR and withdrawal time appear to be linked. “They actually track very closely,” she said. “As physicians’ ADRs improved, their withdrawal times improved. It wasn’t quite a linear relationship, but it definitely suggested the two are

interrelated. We are currently investigating which one is more important, and whether we can use one instead of both.” Douglas Corley, MD, PhD, of Kaiser Permanente in Oakland, Calif., who has conducted a considerable amount of research on ADRs and interval cancers, identified the study as a powerful data source, evaluating ADR and withdrawal time within a large communitybased population over an extended period of time. “This suggests that multiple interventions may modify ADR and withdrawal time, although given that it was not a randomized trial, it is difficult to know for sure whether the trends of improved ADR over time are directly related to the interventions themselves or to other factors, such as improved endoscopes, improved bowel preparations, other changes in the endoscopy environment or increased knowledge about flat polyps,” he said. “Future studies will help to sharpen our knowledge regarding which interventions are the most effective and can be applied reliably in other settings,” Dr. Corley concluded. ■ Drs. Shaukat and Corley did not report any relevant conflicts of interest.

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ENDOSCOPY SUITE

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

This new column will zoom in on endoscopy, focusing on coverage of new research in endoscopic procedures, new devices and imaging tools, novel techniques used in clinical practice, trends in coding for procedures, the business of managing an endoscopy practice, a spotlight on practices throughou ut the country, a historical look at endoscopy through the ages and much more. We hope you enjoy this inaugural installment!

Endoscopy Center Examines Different Models of Propofol Administration for GI Endoscopy Procedures Propofol Delivery by CRNAs Found Safe, but Weakness of Study Design a Concern BY MONICA J. SMITH SAN DIEGO—Certified registered nurse anesthetists (CRNAs) can administer propofol in an ambulatory endoscopy setting with very few associated adverse events (AEs), according to the findings of a recent study. Furthermore, the presence of an anesthesiologist may not improve safety in any significant way, researchers found. The use of propofol in gastrointestinal endoscopy procedures has grown dramatically since the early 2000s, and studies have shown that its use results in greater patient satisfaction, with no difference in procedure time or AEs (Singh H et al. Cochrane Database Syst Rev

2008:CD006268). Propofol also has been found to be superior to opioids and benzodiazepines when delivered by endoscopists during endoscopic procedures (Rex DK et al. Gastroenterology 2009;137:1229-1237). “The elephant in the room is the package insert, which states that propofol should be administered only by persons trained in the administration of general anesthesia. This presented a big quandary when my endoscopy center was deciding to use propofol sedation back in 2008,” said the author of the current study, Murtaza Parekh, MD, MPH, of Digestive Healthcare, Raleigh, N.C., who presented the study at the 2013 Annual Scientific Meeting of the American College of Gastroenterology (ACG).

“We felt that we had three realistic options: an MD anesthesiologist in each room, a CRNA in each room with MD anesthesiologist supervising or a CRNA in each room with the gastroenterologist as the supervising physician.” Initially, Dr. Parekh’s endoscopy center used a CRNA with a supervising anesthesiologist (CRNA+a) during endoscopies. They later switched to using a CRNA alone. To see if there were any significant differences in AEs between the two models, they conducted a retrospective analysis of 106,919 endoscopic procedures performed by gastroenterologists from October 2008 through May 2013. see CRNAs, page 29

IT&T continued from page 1

fundraising and building, the organization’s concept for a state-of-the-art Institute for Training & Technology (IT&T) finally came to fruition in October, when the doors to the $20 million, 42,000-square-foot gastrointestinal (GI) endoscopy training facility were opened to ASGE members, donors and the local community of Downers Grove, Ill. The IT&T uses cutting-edge technologies to foster the development, training and adoption of new techniques in order to improve endoscopic skills and advance patient care.

Technology With a Global Reach The new facility, situated on a 3.5acre plot outside of downtown Chicago, is considered by many of ASGE’s 12,000 members to be a game-changer

in endoscopic care and interactive education. “The old facility in Oak Brook was essentially office space that we rented and pretty much set up folding tables in, so it was not very well set up for training,” ASGE President Kenneth K. Wang, MD, said. “Space was relatively tight and room sizes weren’t ideal for doing handson instruction.” The new center functions as both a live and virtual learning environment, equipped with 2,800-square-foot laboratory facilities that house hands-on training stations using endoscopy towers, simulators, fluoroscopy machines and other training equipment. “We can now house up to 16 groups of four people who all have the ability to see and hear our centralized teaching

station,” Dr. Wang said. “It has become a great way to ensure consistency in our teaching.” The IT&T also boasts a lecture hall that seats more than 100 and has the capability to broadcast and receive interactive training between the auditorium, meeting rooms and bio-skills lab. The auditorium streamlines long days of training, eliminating the need for participants to shuttle between the Oak Brook facility and conference rooms at the local hotel. But what truly gives the IT&T the capacity to function as a global home for endoscopists is its real-time, two-way broadcast capability via Internet2 and satellite. The state-of-the-art connections within its walls allow the center to see IT&T, page 28

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ENDOSCOPY SUITE

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

IT&T continued from page 26

broadcast and receive live transmissions and presentations nationally or internationally, thus making it possible for students around the world to attend an ASGE class. “It’s now possible to do a virtual course, where attendees can participate from England and interact with the faculty. We’ve already had some international students participate in lectures,” Dr. Wang said.

‘The old facility in Oak Brook was essentially office space that we rented and pretty much set up folding tables in, so it was not very well set up for training. Space was

ASGE’s Institute for Training & Technology (IT&T) boasts a lecture hall that seats more than 100 and has the capability to broadcast and receive interactive training between the auditorium, meeting rooms and bio-skills lab.

relatively tight and room sizes weren’t ideal for doing handson instruction.’ —Kenneth K. Wang, MD

Evolving Practices IT&T’s board members are the first to concede that even the most state-ofthe-art technology is futile without the guidance of top-tier gastroenterologists who stay on top of evolving practices. Looking throughout 2014 and beyond, ASGE courses will address new frontiers in endoscopy practices, including new methods for reaching the gallbladder in patients who have had bariatric surgery, new stitching devices for treatment of perforations in the GI tract and new mucosal dissection techniques for removing transmural tumors, among other areas. And as endoscopic procedures become more complex, a major component of the IT&T facility is team-based training within the lab. “You often can’t do a procedure by yourself anymore. It really requires a team effort,” Dr. Wang said. “Because of that, we always advise groups to come in and train.” ASGE encourages physicians to bring in their nurses and assistants so that they also can master the technical components of their roles in endoscopy.

‘People realized that a lot of the issues that the government has with medical care has to do with the quality of the care that patients are getting, and the training of physicians. The new $20 million, 42,000-square-foot, state-of-the-art IT&T is located in Downers Grove, Ill.

Everyone recognized the need for an education facility where we can ensure that everyone has the proper training and qualifications.’ —Kenneth K. Wang, MD

From Concept to Reality

Assessment of Skills Another component of evolving best practices is skills assessment. Until recently, there had been no formal pathways for established endoscopists

to develop new skills, such as endoscopic mucosal resection (EMR), until ASGE unveiled its STAR (Skills, Training, Assessment, Reinforcement) Certificate Program. “What we’ve found is that people really want to improve,” Dr. Wang said. “And now we’ve given them an opportunity to learn and receive critique.” With the ASGE’s first STAR Certificate Program in EMR, physicians may choose to pursue a Certificate of Completion in the Lower GI module only, or both the Lower and Upper GI modules. At the end of the program, participants receive a transcript of the activities they have completed and their performance results on the cognitive and skills assessment components of the program. Participants who pass the assessments components may use their transcripts to obtain privileges within their practice setting. When the new IT&T facility opened in October, the first STAR course, which was offered last month, was already sold out—a true testament to the eagerness of gastroenterologists to improve their skills and provide better patient care.

The new center is equipped with 2,800-square-foot laboratory facilities that house hands-on training stations using endoscopy towers, simulators, fluoroscopy machines and other training equipment.

When concepts for the IT&T were laid out nearly a decade ago, better patient care was at the heart of every discussion. “People realized that a lot of the issues that the government has with medical care has to do with the quality of the care that patients are getting and the training of physicians,” Dr. Wang said. “Everyone recognized the need for an education facility where we can ensure that everyone has the proper training and qualifications.” The initial hope was to break ground on the new facility in 2008. It was a year

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

ENDOSCOPY SUITE

Left: At the IT&T open house on Oct. 4, 2013. Front row: ASGE CEO, Patricia Blake, CAE; ASGE IT&T campaign co-chairs, John L. Petrini, MD, and Christopher J. Gostout, MD; ASGE past president, Thomas M. Deas Jr., MD, MMM. Back row: ASGE past presidents Gregory G. Ginsberg, MD, and M. Brian Fennerty, MD; ASGE Secretary, Kenneth R. McQuaid, MD; and ASGE president, Kenneth K. Wang, MD. Right: Colleen M. Schmitt, MD, MHS, ASGE president-elect, teaches a course in the bio-skills lab during the ASGE’s First Year Fellows Course.

when the economic situation changed drastically, and financing the project would have been extremely challenging, if not impossible. The ASGE IT&T Capital Campaign was the first fundraising effort of its kind in the organization’s 72-year history, and its goal was ambitious. But the support from ASGE

members and commercial sponsorship was nothing short of amazing. “Our members and partners came through like gangbusters and really exceeded expectations,” Dr. Wang said. The gastroenterology community and its partners recognized the urgency in supporting the campaign, and everyone

CRNAs continued from page 26

Dr. Parekh and his colleagues identified 70,436 patients who received propofol under the CRNA+a model, and 36,483 patients who received propofol with a CRNA alone. All patients were classified as the American Society of Anesthesiologists’ ASA status of 1, 2 or 3, and several patients were excluded from the analysis. Patient demographics were similar between the two groups. Outcomes were defined based on data from incident reports recorded during and immediately after the procedures, follow-up phone calls conducted within 24 hours of procedures, and reports of individual physicians regarding adverse outcomes they became aware of after the fact. Data were collected during the center’s quality assurance performance enhancement meetings, which occur on a quarterly basis. Documented AEs included aspiration, desaturation with intervention, laryngospasm, cardiac arrhythmias or hyper/hypotension, perforation and splenic injury. The investigators used a chi square analysis to compare the frequency of these events between the two groups. The investigators found no statistically significant difference between patients in the CRNA+a and CRNA only groups in terms of aspiration (0.020% and 0.027%, respectively), desaturation (0.075% and 0.078%), laryngospasm (0.024% and 0.041%) or cardiac issues (0.020% in both groups). “Perforation was down quite a bit in our CRNA

rose to action. “I could not have imagined better support,” he noted. A similar sentiment was shared by ASGE past presidents Thomas M. Deas Jr., MD, Gregory G. Ginsberg, MD, and M. Brian Fennerty, MD, and the many other board members, faculty and sponsors of other leading health

care organizations when the IT&T finally opened its doors to the community. Sheltered by a beautiful, high-tech, world-class facility, ASGE’s vision of leading the way to a better future for endoscopists and their patients was, at last, solidified. It was a proud moment of reflection for all involved. ■

group [0.003% compared with 0.011% in the CRNA+a School of Medicine at Mount Sinai, New York City. group], and there was one splenic injury, seen in the “It’s an interesting and provocative study that really CRNA group,” Dr. Parekh reported. helps to open a dialogue on CRNA administration of proOverall, there were no differences in adverse out- pofol without the assistance of an MD anesthesiologist. In comes between the two propofol delivery models, and that sense, I think it’s worthwhile,” Dr. Cohen said. the presence of an anestheOverall, however, he found siologist had no significant the study to be scientifically effect on safety outcomes in ‘It’s an interesting and provocative weak. this cohort. “The problem with a retrostudy that really helps to open a “These outcomes corspective, noncontemporanedialogue on CRNA administration relate with the Cochrane ous, nonrandomized study is database [evidence], and also of propofol without the assistance that other factors or knowledge with Rex et al and Vargo et of an MD anesthesiologist. In that gained over the years of the al showing that propofol sense, I think it’s worthwhile.’ study can influence outcomes,” sedation is as safe [as], if not he noted. “Also, the follow-up —Lawrence B. Cohen, MD for complications was generally safer than, conscious sedation,” Dr. Parekh concluded. only 24 hours, so this needs to He did note several limibe recognized as a study that tations of the study: Patients were not randomized; the looks at immediate complications.” procedures were not concurrent; and the average ASA Furthermore, the study may not be powered adestatus was not available for the cohort. quately to measure AEs for such a relatively safe proDespite these limitations, the researchers concluded cedure, he noted. that with a team approach that includes a gastroenterDr. Cohen predicted that over time, as reimburseologist, a CRNA and endoscopy nursing staff, and with ment becomes increasingly difficult, a variety of modadherence to careful patient selection criteria, propo- els and techniques for providing propofol sedation will fol sedation under the CRNA-alone model is safe and emerge. effective in an ambulatory endoscopy center setting. “I don’t believe that either gastroenterologists or The study garnered quite a bit of interest and discus- their patients will be willing to relinquish propofol,” sion at the ACG meeting, observed Lawrence B. Cohen, he said. “It’s a 21st-century drug for a 21st-century MD, associate clinical professor of medicine at the Icahn procedure.” ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

ENDOSCOPY SUITE

South Carolina Endoscopy Center Sets High Bar: 100% Colorectal Cancer Prevention Impressive Findings Revealed in Record-Setting Colonoscopy Initiative BY MONICA J. SMITH SAN DIEGO—Using standard colonoscopic equipment and adhering to a strict but reasonable protocol, a gastroenterology group in South Carolina was able to

achieve the greatest reduction in colorectal cancer (CRC) incidence and CRCrelated mortality ever documented in a community-based colonoscopy series. “The group believes that any CRC case is one too many, and that quality is the single most important endoscopy [variable],”

Sudha Xirasagar, MBBS, PhD, associate professor of Health Services Policy and Management at the University of South Carolina, Columbia, said during the 2013 Annual Scientific Meeting of the American College of Gastroenterology (ACG). With a goal of 100% CRC prevention,

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the South Carolina Medical Endoscopy Center practices the following measures: • Patients are contacted with bowel preparation instructions two days before the procedure. • Patients undergo propofol sedation administered by nurse anesthetists. • The procedure is done using a twoperson endoscopy technique, with a technician pushing the endoscope and providing torque, and the endoscopist managing the polyp searchand-removal process. • Adequate time is allowed for thorough examination of the colonic mucosa during both insertion and withdrawal, with polyps removed in all cases. • All personnel in the room view the video monitor and actively participate in the examination. • Large invasive or vascular polyps are referred to a surgeon for excision. To examine the effect of this protocol, the group commissioned an independent evaluation of their colonoscopy outcomes, in which academic researchers compared colonoscopy cohort data from October 2001 to December 2008 with data from the South Carolina Central Cancer Registry from 1996 to 2009. Investigators looked for cases of CRC, in addition to two control cancers, lung and brain; they also conducted a data merge with the state’s Vital Statistics Registry to identify deaths. Patients were excluded from the analysis if they had missing Social Security numbers, were younger than age 30 or older than age 90, had CRC before or discovered during the initial screening, had a prior or scheduled surgical resection of a colonic mass or lesion, had a polyp 3 cm or larger at the initial colonoscopy, or had an incomplete colonoscopy without a repeat procedure within three months. The final cohort consisted of 16,351 patients who were compared with the state’s general population and Surveillance Epidemiology, and End Results–18

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

‘The group believes that any CRC case is one too many, and that quality is the single most important endoscopy [variable].’ —Sudha Xirasagar, MBBS, PhD

population for CRC incidence and CRC-related mortality. The investigators found an adenoma detection rate of 31.4%, with an adenoma detection rate for advanced adenomas of 5.2% and an average follow-up of 4.8 years. Patients with adenomas were asked to return for surveillance according to the guidelines of the ACG/American Society for Gastrointestinal Endoscopy. Based on data from the state’s general population, researchers expected to find 104 new cases of CRC; however, the observed number was only 18. “This resulted in a standardized incidence ratio of 0.17 and a CRC incidence reduction of 83%,” Dr. Xirasagar noted. “To put this into perspective, the 18 cases in the study cohort are being compared with the [general population of ] South Carolina, which has significant background screening going on, about 32% over the study period for colonoscopy itself. So, the 104 expected cases would represent an underestimate of the expected cases in a screening-naive population.” The difference between expected and actual CRC-related mortality was equally impressive. “Thirty-six CRC deaths were expected, but there were only four observed deaths, for a standardized mortality ratio of 0.11 and a mortality reduction of 89%,” Dr. Xirasagar said. Of the 18 interval cancers that occurred, half were diagnosed at the follow-up surveillance colonoscopy, slightly less than half occurred in the left colon and three were diagnosed with distant metastases. Also worth noting, the researchers expected to find 149 lung cancers in the study cohort and observed 143, a reduction of virtually zero, illustrating “that our study cohort was no more or less healthy than the general population,” Dr. Xirasagar said. Also notable was the fact that even the patients who were excluded from study because of existing or probable cancer at the initial colonoscopy tended

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to fare much better compared with the general population. “The vast majority of the CRC cases in this study population were those who had cancer at the initial colonoscopy,” Dr. Xirasagar said. “Combining those cases with those who developed [CRC] among other excluded patients, 95 patients were alive and well by the end of the study period, and 24 had died, which is an extremely good ratio of mortality to incidence compared with the natural history in the general population.” With a CRC incidence reduction of

83% and a CRC-related mortality reduction of 89%, the researchers concluded that “excellent CRC prevention can be achieved by implementing a protocol that focuses primarily on quality and that CRC is a preventable disease for 80% to 90% of the U.S. population.”

The Importance of Being Careful Rami Abbass, MD, a partner with University Gastroenterology Associates, University Hospitals, in Cleveland, who was not involved in the study, agreed with the South Carolina group’s focus on quality.

For example, his group has found that calling patients two days ahead of their procedure rather than just one day before had a substantial effect on the quality of bowel preparation. “It gives patients time to make some small adjustments with their diet or with taking their prep,” Dr. Abbass said. “With one day’s notice, sometimes they can’t make some of those adjustments.” Dr. Abbass’ group also uses propofol sedation, which he thinks allows endoscopists to have a better focus on the see CRC Prevention, page 32

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

INTRODUCING

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

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

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

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

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CRC Prevention continued from page 31

procedure, as patients are less apt to move about. His team also keeps meticulous notes on withdrawal times as part of their involvement with the ACG’s GI Quality Improvement Consortium program. He feels that these efforts help create an atmosphere among nurses, technicians and physicians, where quality is of the highest importance. Dr. Abbass and his colleagues also agree with the South Carolina group’s protocol

of inspecting the mucosa on insertion and withdrawal. “Careful inspection on withdrawal is more commonly taught in training programs, but if you’re doing it on insertion too, you are giving yourself more time and may be able to see more,” Dr. Abbass said, noting that occasionally small adenomas seen on insertion are hard to relocate and remove on withdrawal. “What’s important is to spend an adequate amount of time inspecting the mucosa.” Dr. Abbass and his group encourage

nurses to watch the video screen during procedures, too, and the nurses occasionally see subtle lesions that gastroenterologists have missed. He also finds that gastroenterologists can detect subtle lesions by retroflexing in the ascending colon. Where Dr. Abbass questions the South Carolina group’s protocol, however, is in the use of a two-person technique during endoscope insertion. “I like to have full control of maneuvering the endoscope. If I’m able to torque the scope myself, I get better visualization

BRIEF SUMMARY

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

because I get a feel for every turn. If someone else was torquing for me, they’d have to be reading my mind,” he said. “I think the big highlight here is that there are things we can track that will improve outcomes,” Dr. Abbass said. “I’m not surprised that the more careful we are, the better we view the colon and the better the long-term outcomes are in preventing interval cancers.” ■ Drs. Xirasagar and Abbass reported no relevant conflicts of interest.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

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PET continued from page 1

a framework for endoscopy training programs around the globe. “The idea was to create a program on how to teach safe and high-quality endoscopy and improve the quality of endoscopic services, which could be brought to many institutions around the world, particularly the developing world,” said Douglas Faigel, MD, PET program director and professor of medicine at Mayo Clinic, Scottsdale, Ariz.

In 2009, Jerome D. Waye, MD, president of WEO, devised the idea for PET after recognizing a major flaw in endoscopy education. “There are no programs aimed at teaching endoscopists how to teach,” said Dr. Waye, clinical professor in the Department of Gastroenterology at Mount Sinai Medical Center, New York City. “When I first became president of WEO, I thought that I would like to have a special program to educate

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

endoscopists in the art of teaching endoscopy, and establish guidelines.” D. Nageshwar Reddy, MD, chairman and chief of gastroenterology, Asian Institute of Gastroenterology, in Hyderabad, volunteered to host the first meeting and invited the major trainers of endoscopy in India and from surrounding countries. Approximately 65 experts attended. The faculty included experienced instructors from the United States, India, China,

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

Chile, Egypt and Singapore, and guests were hand-selected based on their interest and willingness to teach endoscopic skills in their respective countries. Representatives from industry, including Olympus, Boston Scientific and Cook Medical, helped fund the program and were in attendance as well.

PET Design “The PET was designed to provide experienced endoscopists, working in countries that do not have an adequate number of trained endoscopists, with greater knowledge of the techniques and methods for teaching endoscopic skills,” said Lawrence Cohen, MD, gastroenterologist and clinical professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, who taught courses at the meeting.

‘The idea was to create a program on how to teach safe and high-quality endoscopy and improve the quality of endoscopic services, which could be brought to many institutions around the world, particularly the developing world.’ —Douglas Faigel, MD

To this end, the program delineated a set of strategies and rules on how to teach endoscopy using educational lectures, videos of mock training sessions and hands-on training with simulators. The lectures outlined criteria that make good teachers and students, and provided tactics for teaching technical and cognitive skills to trainees of all skill levels. For example, when teaching cognitive skills, instructors need to define a core curriculum in endoscopy and be able to tailor training to incorporate local practice and customs; risk management; pre- and postprocedure evaluation; and communication skills, as well as trainee assessment and mentoring. The trainer also should vary the educational format, supplementing textbook and lecturebased learning with videos and interactive approaches that include simulators and other training tools. In a session entitled “Teacher and Student,” presenter Ibrahim Mustafa, MD, see PET, page 34

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

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PET continued from page 33

from Egypt, said that a teacher must regularly monitor how well trainees are acquiring necessary skills by documenting their experience with procedures and determining how well they have met specific performance standards. The teacher should not only evaluate students, but also allow trainees to provide feedback and personalize the curriculum as needed. In the same session, Dr. Waye explained that when teaching technical skills, instructors should be patient and encouraging as students learn the ropes,

while also providing clear directions on what to do and how to do it. After a student has observed several procedures, possibly practiced on a simulator and aided a senior fellow during an actual procedure, the trainee should then handle the scope alone while the instructor watches closely and provides feedback throughout. Importantly, however, trainees should only be evaluated on their competence after completing a requisite number of procedures (Table). see PET, page 36

Table. Threshold Numbers of Endoscopic Procedures Before Competency Can Be Assessed by Direct Observation or Other Objective Measures, as Required in Different Countries or Regions Procedure

United Statesa

Australiab

Canada Poland

India

Europec

Colonoscopy

140

100 to cecum

150

500

120

150

EGD

130

200

150

500

190

200

ERCP

200

140

150

EUS

150

200

Sigmoidoscopy

150

EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography a

American Society for Gastrointestinal Endoscopy guideline.

Colonoscopy: cecal intubation in >90% of the last 50 logged procedures; ERCP: unassisted, with intact papilla, to include 80 sphincterotomies and 60 stent placements.

European Board of Gastroenterology: Colonoscopy numbers include polypectomy and assume competency in EGD.

An Organized Program for Global Training in Endoscopy Jerome D. Waye, MD Clinical Professor of Medicine Mount Sinai Medical Center Director of Endoscopic Education Mount Sinai Hospital New York, New York Past President, American Society for Gastrointestinal Endoscopy Past President, American College of Gastroenterology Past President, World Endoscopy Organization I have just stepped down from four years as president of the World Endoscopy Organization (WEO). This is an organization that oversees gastrointestinal endoscopy throughout the world. The major thrust is, of course, pointed at underserved areas where endoscopy is needed, but is a scarce commodity. During 2013, WEO organized a course called Program for Endoscopic Teachers, referred to as the PET program. When I began my presidency four years ago, I realized that this was a topic that had been completely overlooked by endoscopists throughout the world. There was no organized program for how endoscopy should be taught, who the instructors should be, what the curriculum should be for endoscopic teaching, what teaching material could be found on the Internet and how to best teach novices the techniques of the procedure. Additionally, there was no data to inform more advanced endoscopists how to perform more complex procedures. The first PET meeting was held in Hyderabad, India, under the direction of Douglas Faigel, MD, of Mayo Clinic, Scottsdale, Ariz., and hosted by Nageshwar Reddy, MD, who famously helped initiate natural orifice transluminal endoscopic surgery by passing an endoscope through the stomach into the abdominal cavity. The first meeting brought together a cadre of known experts in endoscopic teaching and 40 endoscopic teachers from throughout India and Asia. The meeting was a resounding success, and so far this year, three countries have requested that the PET program be brought to their areas because of the important material, which even now is in a state of rapid evolution. This is an exciting area and will undoubtedly affect the way endoscopy is taught.

D. Nageshwar Reddy, MD, chairman and chief of gastroenterology at the Asian Institute of Gastroenterology, in Hyderabad, India, volunteered to host the World Endoscopy Organizationâ&#x20AC;&#x2122;s first Program for Endoscopic Teachers (PET) meeting. The aim of the two-day PET program, held in January 2013, was to provide a framework for endoscopy training programs around the globe.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

PET continued from page 34

Reflections on PET Overall, Drs. Faigel and Waye agreed that the pilot program went well. “We had excellent attendance and interaction among experts and the feedback was very positive,” said Dr. Faigel. “We’re moving toward milestones and standardized training, and this program was a good first step to see how we could do so in India.”

Approximately 65 experts attended the first Program for Endoscopic Teachers (PET) meeting in Hyderabad, India. Faculty included experienced instructors from the United States, India, China, Chile, Egypt and Singapore, and guests were hand-selected based on their interest and willingness to teach endoscopic skills in their respective countries. Representatives from industry, including Olympus, Boston Scientific and Cook Medical, helped fund the program and were in attendance as well.

‘We have to be cognizant of local training facilities and local training venues for us to continue our success. We also want teachers to be able to adapt to different training situations and to be comfortable with using and teaching a variety of techniques and technologies.’ —Jerome D. Waye, MD

Reflecting on the success of the program, Dr. Cohen noted, “the attendees were enthusiastic and seemed committed to taking their experience back to their respective country and attempting to implement some of the techniques and concepts discussed at the course.” For instance, two attendees from Myanmar (formerly Burma) expressed their desire to use the PET educational model to train more endoscopists in their country, Dr. Cohen said. Myanmar currently has four endoscopists serving a population of more than 30 million. One attendee, C. Ganesh Pai, MD, professor and head of the Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, India, agreed that PET was a “successful and informative” program that “brought together expertise from different parts of the world and exposed trainers to what is happening elsewhere.” When asked how PET could be improved, Dr. Pai suggested “fewer lectures and more workshop-like situations, hands-on training and small-group interactive sessions, [that would involve] identifying problems in endoscopy training and solving them.” Dr. Faigel concurred and, in the next meeting, plans to incorporate more breakout sessions and subgroup discussions, as well as to create specific sessions tailored to local issues. As for increasing

hands-on training, Dr. Faigel noted that employing such features in local teaching facilities is expensive and may not be feasible everywhere, especially in parts of the world where resources and funds may be more limited. “We want a modular course so we can train with local faculty from all over the world and make implementation achievable for everyone involved.” To this point, Dr. Waye said that, “We have to be cognizant of local training facilities and local training venues for us to continue our success.” But, Dr. Waye added, “We also want teachers to be able to adapt to different training situations and to be comfortable with using and teaching a variety of techniques and technologies.” Going forward, the PET organizers plan to conduct at least one program a year and are currently planning other meetings. Three meetings are scheduled for 2014: July 11-12 in Moscow, Aug. 22-23 in Cairo and Dec. 5-6 in Rio. The PET meeting in Rio will be sponsored by Pentax, and the Moscow meeting will be sponsored by Boston Scientific. Planning is under way for a meeting in China in 2015. ■

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Combination of Virtual Chromoendoscopy and Hi-Def Endoscopy Provide Real-Time Prediction of Distal Polyp Histology BY CAROLINE HELWICK ORLANDO, FLA.—High-definition endoscopy in combination with virtual chromoendoscopy allows real-time prediction of polyp histology and is accurate enough to leave distal colorectal polyps in place without resection, according to German investigators. The histology of distal polyps was predicted with almost 92% accuracy with this technology, said study author Helmut Neumann, MD, of the University of Erlangen-Nuremberg, Erlangen, Germany. This exceeds the threshold of a more than 90% negative predictive value (NPV) proposed by the guidelines of the American Society for Gastrointestinal Endoscopy (ASGE).

‘To our knowledge, no prior prospective study has evaluated the feasibility of virtual chromoendoscopybased, real-time endoscopic prediction of polyp histology for the specific end point of leaving distal hyperplastic polyps in place.’ —Helmut Neumann, MD

“Colonoscopy is limited in detecting right-sided lesions beyond the right flexure using conventional surveillance techniques. These tend to be flat lesions and we miss many of them,” said Dr. Neumann. “To our knowledge, no prior prospective study has evaluated the feasibility of virtual chromoendoscopy-based, real-time endoscopic prediction of polyp histology for the specific end point of leaving distal hyperplastic polyps in place,” he said. Dr. Neumann’s study used iScan technology (Pentax, Japan), a post-processing light-filter technology that enhances different elements of the mucosa. It incorporates a variety of filters with increased pixel density to improve the digital image. “The iScan is digital chromoendoscopy that is less expensive than conventional chromoendoscopy and very easy to use,” said Dr. Neumann. iScan recently obtained FDA approval.

High Adenoma Detection Rate “With this approach, we proved we can detect more adenomas in the right colon,” Dr. Neumann explained. “Using

the iScan, we found significantly more polyps in the right colon, most of which were very small. But what surprised us was [that] these diminutive lesions were not only hyperplastic, but histologically, most small lesions in the right colon were adenomas. This is very important. We can detect more adenomas in the right colon.” The study, which was presented

at the 2013 Digestive Disease Week meeting, included 224 patients undergoing screening or surveillance colonoscopy. Investigators evaluated 121 distal colorectal polyps from 77 patients in real time using high-definition endoscopy and iScan. Before resection, the endoscopist described each polyp according to size, shape and surface characteristics

(including pit and vascular pattern, color and depression), and histology was predicted with a level of confidence (high or low). The procedure added less than three minutes to the total examination time. The histology was predicted with high confidence in 92% of polyps. The overall accuracy for adenomatous polyp histology was 90%, with a sensitivity of 92%,

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a specificity of 89%, a positive predictive value (PPV) of 89% and an NPV of 92%, according to Dr. Neumann. “When the prediction was made with high confidence, the accuracy increased to 96%,” he said. Corresponding sensitivity, specificity, PPV and NPV were, respectively, 98%, 95%, 95% and 98%. “We don’t only find more polyps, but we improve the ADR [adenoma detection rate] and that is important,” said Dr. Neumann. “We can safely leave small rectosigmoid polyps behind.”

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Technology Meets ASGE Criteria ASGE president-elect Colleen M. Schmitt, MD, commented: “It is essential that endoscopic research continues to address techniques that will enhance our identification of adenomatous polyps.” The ASGE Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) document on the real-time endoscopic assessment of the histology of diminutive colorectal polyps outlines clinical issues related to decision making for the management of polyps less than

5 mm in size. The committee concluded that in order for the technology to be used to guide the decision to leave diminutive rectosigmoid hyperplastic polyps in place without removal, the technology should have a 90% NPV for adenomatous histology. NPV describes the probability that a patient with a negative test (“this polyp is hyperplastic not adenomatous”) does not have the disease or characteristic of interest (in this case, a colon adenoma or worse, carcinoma), Dr. Schmitt explained. “Dr. Neumann and [his] colleagues

demonstrated that iScan technology could be one such method to not only improve detection of important adenomatous polyps for removal, but also may be an imaging tool that exceeds the PIVI threshold of 90% for diminutive colorectal polyps,” Dr. Schmitt said. “This technology could have a positive impact on patients and on cost savings; however, these results need to be translated from expert hands into the community to validate similar results among endoscopists in routine clinical practice.” ■

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New Balloon-Assisted Colonoscope Improves Polyp Adenoma Detection G-Eye Colonoscope Pending Approval in the United States BY MONICA J. SMITH SAN DIEGO—A novel balloon-assisted colonoscope appears to substantially improve polyp and adenoma detection rates (ADRs) by flattening out colonic folds and making it easier for the endoscopist to detect previously hidden polyps and adenomas. “As we all know, we miss up to 28% of polyps and anywhere from 12% to 24% of adenomas, and there are many reasons for this,” said investigator Seth Gross, MD, citing location behind proximal folds, lesions in the right colon, poor colonoscopic technique and subpar bowel preparations among the reasons. In recent years, industry has been hard at work to improve the detection of polyps and adenomas, especially on the back sides of colonic folds. Advances in endoscopic techniques have included the Third Eye Retroscope, FUSE Full Spectrum Endoscopy, OmniVision, the Endocuff, cap-assisted colonoscopy and the subject of the study by Dr. Gross and his colleagues, the balloon-assisted G-Eye colonoscope. Key features of the G-Eye colonoscope, which is approved for use in the European Union and is awaiting FDA approval in the United States, include “straightening of colonic folds, smoothing of colonic topography, preventing endoscopic slippage and centralizing optics. This allows you to visualize polyps right in front of you,” Dr. Gross explained. The platform consists of a regular video processor and colonoscope, which is fitted with a permanently integrated and reusable balloon, Dr. Gross said. The balloon is inflated after the endoscopist reaches the cecum, and remains inflated throughout the withdrawal portion of the procedure. Dr. Gross and his colleagues conducted a multicenter, tandem trial designed to compare G-Eye colonoscopy with standard colonoscopy. They randomized 106 patients to one of two groups: 54 patients in group A underwent standard colonoscopy followed by G-eye colonoscopy, and 52 patients in group B underwent the procedures in the opposite order. “Our study end points were polyp and adenoma detection, G-Eye additional polyp and adenoma detection rate, G-Eye polyp and adenoma miss rate, and other things such as insertion, withdrawal and total procedure times,” Dr. Gross said. Total procedure time with standard colonoscopy was 11 minutes, with insertion averaging 5.2 minutes and withdrawal averaging 4.8 minutes. With G-Eye colonoscopy, total procedure time was 13 minutes, with insertion taking 5.1 minutes and withdrawal 5.6 minutes. No adverse events occurred in either study group. In group A, when G-Eye colonoscopy followed standard colonoscopy, users of the balloon-assisted device detected twice the number of polyps. “Of note, eight new patients were found to have polyps,” Dr. Gross said. In group B, the initial colonoscopy conducted with G-Eye colonoscopy revealed 51 polyps in 28 patients, whereas the standard procedure found three polyps in

G-Eye endoscope Photo courtesy of Business Wire

‘In terms of [polyp] size, when standard colonoscopy went first, the G-Eye picked up larger polyps and standard colonoscopy missed polyps between 5 mm and 10 mm. When G-Eye went first, it did miss some polyps, but only smaller ones, less than 5 mm. There were no larger lesions missed.’ —Seth Gross, MD

two patients, suggesting a polyp miss rate of 5.6% for G-Eye colonoscopy. For adenoma detection, standard colonoscopy in group A identified 21 adenomas in 14 patients; the subsequent G-Eye procedure detected 17 additional adenomas in three new patients, for an additional ADR of 81%. In group B, G-Eye colonoscopy identified 37 adenomas in 21 patients, whereas standard colonoscopy found three adenomas in two patients, giving the G-Eye an adenoma miss rate of 7.5%. In the ascending colon, detection rates for polyps and adenomas with G-Eye colonoscopy were 35% and 41%, respectively, compared with 10% and 14%, respectively, for standard colonoscopy. G-Eye’s miss rate in the ascending colon was 5.6% for polyps and 7.5% for adenomas, compared with a miss rate of 50% and 44.7%, respectively, with standard colonoscopy. The finding of additional adenomas resulted in shorter surveillance intervals in patients whose adenomas were not detected by initial standard colonoscopy. “In terms of [polyp] size, when standard colonoscopy

went first, the G-Eye picked up larger polyps and standard colonoscopy missed polyps between 5 mm and 10 mm,” Dr. Gross said. “When G-Eye went first, it did miss some polyps, but only smaller ones, less than 5 mm. There were no larger lesions missed.” The researchers concluded that the use of G-Eye colonoscopy identified significantly more polyps and adenomas, and is associated with a much lower miss rate, compared with standard colonoscopy. A large randomized trial is being conducted. Amit Rastogi, MD, one of the moderators of the plenary session where Dr. Gross presented his study, noted that missed adenomas continues to be a major limitation of colonoscopy, and, aside from poor withdrawal technique, is largely due to the topography of the human colon. “Polyps can hide on the proximal aspect of the colonic folds and evade detection by even the most skilled colonoscopist,” said Dr. Rastogi, director of endoscopy at Kansas City Veterans Affairs Medical Center, in Missouri, and associate professor of medicine at the University of Kansas, Kansas City. “This study by Gross et al is encouraging and has shown that the balloon colonoscope misses fewer polyps and adenomas compared with standard colonoscopy by its ability to flatten the colonic folds. It appears to be a simple technique that will not require much training or experience to implement in practice,” he said. “However,” he added, “we need larger studies with multiple investigators to make definitive conclusions of its superiority, and before it can stake a claim to replace standard colonoscopy. Other issues, such as financial implications, also will need to be addressed.” ■ Drs. Gross and Rastogi reported no relevant conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014 42

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

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NBI Shows Potential for Prediction of Polyp Histology, Colonoscopy Surveillance Intervals Promising Results, but Proper Training Essential BY CAROLINE HELWICK ORLANDO, FLA.—Narrow band imaging (NBI) meets the established confidence thresholds for predicting the histology of diminutive polyps, thereby allowing them to be left in place or be resected and discarded without further assessment, according to the findings of an international multicenter study reported at the 2013 Digestive Disease Week meeting and later published in GIE: Gastrointestinal Endoscopyy (Repici A et al. 2013;78:106-114). “Before being incorporated into clinical practice, any new imaging technology for predicting polyp histology should meet specific criteria. According to our study, a high-confidence NBI characterization of polyps 5 mm or smaller is able to meet both of the thresholds for incorporating such technology into clinical practice,” said Alessandro Repici, MD, of the Istituto Clinico Humanitas, Milan. He presented the findings during the American Gastroenterological Association/American Society for Gastrointestinal Endoscopy (ASGE) Presidential Plenary Session.

The SHARP Trial In the multicenter, prospective study, known as the SHARP (Small Hyperplastic and Adenomatous Reliability Protocol) trial, the investigators evaluated whether endoscopists can use NBI to predict the histology of distal diminutive polyps and colonoscopy surveillance intervals according to criteria set forth by the ASGE. Endoscopists who participated in the study were trained with a Web-based module that included a library of small and diminutive polyps and corresponding histology derived from patients undergoing elective colonoscopy at five centers. They were required to pass a pre-study qualifying examination, in which the histology of polyps smaller than 10 mm was predicted with NBI and assigned a designation of high or low confidence. The accuracy of high-confidence NBI prediction of histology of polyps 5 mm or smaller in predicting colonoscopy surveillance intervals and the negative predictive value (NPV) for adenomatous histology in the rectosigmoid colon were compared with the ASGE thresholds of 90% agreement and 90% NPV. The study included 278 patients with 578 polyps smaller than 10 mm retrieved for histologic analysis. Nonadenomatous polyps were identified primarily by their “bland, featureless appearance,” “pattern of black dots surrounded by white” and “thin blood vessels coursing across the polyp surface and not surrounding pits.” Adenomas were detected mostly by their “tubular or oval pits,” “variable-size pits,” “overall brown color,” “short, thick blood vessels” and “straight blood vessels around pits, forming rectangles, pentagons and so forth.” The investigators found that NBI was highly accurate in predicting histology. The NPV of high-confidence NBI for adenomatous histology in rectosigmoid lesions 5 mm or smaller was 92%, which reached the NPV benchmark, Dr. Repici reported. “When simulating a ‘resect and discard’ strategy only for patients with polyps less than 5 mm, with an NBI

high-confidence level, endoscopic prediction of surveillance intervals was applicable to 76% of patients,” he said. Additionally, high-confidence characterization of polyps 5 mm or smaller predicted the correct surveillance interval in 92% of cases according to U.S. guidelines and in 99% according to European guidelines. A low level of confidence was the only independent predictor of an incorrect NBI characterization of polyp histology (odds ratio, 3.8; P<0.001). The researchers estimated that with NBI, the cost of pathologic examination could be reduced by 60%, and the cost of polypectomy by 33%.

Proper Training Critical to NBI’s Success

‘According to our study, a high-confidence NBI characterization of polyps 5 mm or smaller is able to meet both of the thresholds for incorporating such technology into clinical practice.’

In another presentation at the DDW meeting, Preetika Sinh, MD, a gastroenterologist at the University of Kansas School of Medicine, Kansas City, described the effect of an educational training session with active feedback on the performance of gastroenterology fellows. “NBI has been shown to be accurate in real-time histologic characterization of polyps by experts, but initial results from community gastroenterologists and nonexperts have not been promising,” Dr. Sinh explained. “[For NBI to] be successfully implemented in practice, teaching tools need to be developed and validated, and incorporated during fellowship.” Dr. Sinh’s study assessed the performance by gastroenterology fellows in characterizing the histology of diminutive polyps using NBI, after viewing a 20-minute computer-based teaching module followed by 80 short video clips of NBI without magnification, with active feedback by an expert. The study included nine fellows who had no previous NBI experience and had varying levels of colonoscopy experience. “The training session helped gastroenterology fellows achieve high accuracy in polyp histology characterization,” Dr. Sinh reported, citing an overall accuracy of 90.1%, with 80.4% of polyps diagnosed with high confidence. Sensitivity, specificity, accuracy and NPV generally increased over the training period, demonstrating the effectiveness of training. Review of at least 40 videos with active feedback was needed to attain an accuracy of at least 90%, Dr. Sinh said. “Whether this learning and performance translates to similar accuracies in real-time histologic characterization of diminutive polyps during colonoscopy is currently being evaluated,” she said. David Lieberman, MD, professor of medicine and chief of gastroenterology and hepatology, Oregon Health & Science University, Portland, and co-author of the ASGE guidelines for the real-time assessment of

—Alessandro Repici, MD diminutive polyps (www.asge.org/uploadedFiles/Publications_and_Products/Polyp_PIVI_Summary.pdf ) commented on the study for Gastroenterology & Endoscopy News. “The study suggests that for diminutive polyps 1 to 5 mm, with proper training using NBI, one can distinguish accurately between hyperplastic and neoplastic polyps. If you do that accurately, it’s feasible to remove those lesions and discard them without sending them for pathology assessment. In the guidelines, we set the sensitivity at 90%, and this study met that benchmark,” Dr. Lieberman said. He stressed that proper training is critical for the successful application of NBI. “Its efficacy hinges on training. The training piece will be critical,” he said. James Aisenberg, MD, clinical professor of medicine, Icahn School of Medicine at Mount Sinai, New York City, also commented on training. “One question I have regarding these kinds of studies is what is the durability of the training. It’s one thing to teach something, then grade the person on it, but then there is often a natural regression to the mean,” Dr. Aisenberg pointed out. Dr. Sinh said the durability of training is being evaluated in a second phase of her study, “to see if the training module will translate into real-time polyp histology characterization or not.” ■ Dr. Repici served on advisory committees or review panels for Almirall Prodesfarma and Boston Scientific Corporation; consulted for Cosmo Technologies, Ltd; received grant/ research support from Ferring Pharmaceuticals, Olympus Europe and US Endoscopy; and reported other relationships with Cook Inc. Drs. Sinh, Lieberman and Aisenberg reported no relevant conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Diagnosis of GERD Remains a Challenge Expert Proposes Diagnostic Algorithm To Aid Diagnosis of Difficult Cases BY TED BOSWORTH ORLANDO, FLA.—An algorithm for diagnostic testing for gastroesophageal reflux disease (GERD)—constructed on the basis that no test stands alone as a gold standard, particularly after an empiric trial of proton pump inhibitors

2014 ASGE Annual Postgraduate Course

Practice of Endoscopy in 2014:

Integration of Science, Art and Technology Monday, May 5, 2014 Arie Crown Theater McCormick Place Chicago, Illinois Held in conjunction with DDW® 2014

COURSE DIRECTORS

Betsy Rodriguez, MD The Oregon Clinic Portland, OR Prateek Sharma, MD University of Kansas Medical Center Kansas City, MO Louis-Michel Wong Kee Song, MD, FASGE Mayo Clinic Rochester, MN

(PPIs)—was presented by David Armstrong, MA, MB BChir, professor of medicine, McMaster University, Hamilton, Ontario, Canada, in a state-of-theart review at the 2013 Digestive Disease Week meeting. In a summary of data, where he repeatedly cited low to moderate sensitivities and specificities for current

diagnostic GERD tests, Dr. Armstrong said, “We still have a problem working out what we are dealing with” in any given individual. Physicians who follow an algorithm for diagnostic GERD testing should end up with a relatively small pool of candidates who are selected to undergo invasive testing, such as endoscopy with

Mark your calendar for ASGE’s Annual Postgraduate Course urse will as it returns to Chicago, Illinois for DDW® 2014. This cou feature didactic, interactive and video-based discussions from internationally renowned experts on the approach to com mmon clinical challenges and controversies related to gastrointe estinal endoscopy. ASGE will take endoscopy education to the next level by featuring state-of the-art lectures, panel discussions and live transmission of demonstrations of techniques, broadcast from the ASGE Institute for Training and Technology (IT&T) animate lab.

Early Registration Discounts End March 26

A variety of gastrointestinal conditions will be discussed, including Barrett’s esophagus, luminal neoplasia, gastro-intestinal bleeding, colon polyps, pancreaticobiliary dise eases and adverse events.

Course Objectives ◗ Discuss the state-of-the-art management of commonly encountered and challenging clinical scenarios related to o endoscopy ◗ Identify novel technologies that are ready for adoption iin endoscopic practice ◗ Apply new endoscopic techniques and tips from the masters of endoscopy ◗ Describe methods and solutions for the management off adverse events

Target Audience Practicing gastroenterologists, surgical endoscopists, ga astroenterology trainees, endoscopy nurses and technicians.

Highlight: Live transmission from ASGE IT&T

In particular, pH testing, once proposed as a gold standard, has now been moved far back in the algorithm and may be best interpreted in conjunction with impedance testing.

biopsy, pH monitoring, impedance testing or manometry. Because these tests alone do not yield a definitive diagnosis of GERD, they do not play a role in current algorithms until a series of other steps—particularly failure to respond to PPIs— first have provided more context.

PPI Test Optimization of PPI therapy, which Dr. Armstrong defined as at least 16 weeks of treatment with PPIs including a step up to a twice-daily regimen, is the first step in his algorithm, as it is in several guidelines, including those from the American Gastroenterological Association (AGA; Kahrilas PJ et al. Gastroenterologyy 2008;135:1383-1391) and the American College of Gastroenterology (ACG; Katz PO et al. Am J Gastroenteroll 2013;108:308-328). Dr. Armstrong noted that his algorithm closely follows the ACG guidelines. His algorithm also exhibits an evidence-based appreciation of the limitations of any individual step in the diagnostic process. For example, the PPI test, empiric PPI therapy or some variation of initiating patients with symptoms of GERD on PPI therapy has long been advocated as a simple and inexpensive step toward diagnosis; however, the limitations of this

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

The combination of pH and impedance monitoring is reserved for a relatively small subset of patients for whom no previous tests have led to a definitive course of action.

testing. With the exception of patients with achalasia or evidence of a motility disorder, for whom manometry might be an appropriate step, endoscopy and biopsy come first in patients with typical

GERD symptoms. Neither endoscopy, histology nor a combination of the two, however, are definitive diagnostic tests. And although a number of techniques, such as magnification, narrow band

imaging and image processing, have been proposed to improve the diagnostic yield of endoscopy, sensitivity and specificity rates, perhaps affected in part by intraobserver variability, remain unimpressive. The combination of pH and impedance monitoring is reserved for a relatively small subset of patients for whom no previous tests have led to a definitive course of action. In patients in whom the probability for GERD is low, Dr. Armstrong recommends performing this combination of tests off PPI therapy see GERD Testing, page 46

In Active, Mild to Moderate Ulcerative Colitis (UC)

POWER YOUR PATIENTS CAN HANDLE

• MMX® technology is designed to target delivery of budesonide throughout the full length of the colon1,2 • 3 times more patients taking UCERIS® achieved combined clinical and endoscopic remission compared with placebo3*

approach should be noted. The sensitivity and specificity of the PPI test are “less than stellar,” Dr. Armstrong said, whereas patient response or lack of response to empiric PPI therapy also is “not as good as we like to think.” Interpreting the meaning of response or lack of response to PPI therapy may be complicated by a lack of understanding of which symptoms are being controlled. Dr. Armstrong noted that although one previous consensus statement proposed that characteristic symptoms of GERD are sufficient to make a diagnosis, validated tools for symptom evaluation, such as the Reflux Disease Questionnaire, have “performed little better than chance” when considering sensitivity and specificity. The low negative and positive predictive values of empiric PPI therapy in patients with suspected GERD underscore the challenges of diagnosing an otherwise well-characterized disease.

Invasive GERD Tests Optimization of PPI therapy makes sense as a first step when considering the limitations in sensitivity and specificity of invasive GERD testing. In particular, pH testing, once proposed as a gold standard, is now situated far along in the algorithm and may be best interpreted in conjunction with impedance

• The rates of overall expected glucocorticoid-related side effects were similar for UCERIS and placebo at 8 weeks—10.2% vs 10.5%, respectively1* • Through the UCERIS savings program,† 90% of eligible patients with commercial insurance will pay only $253‡

INDICATION: UCERIS® (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Patients with moderate to severe liver disease should be monitored IMPORTANT SAFETY INFORMATION: UCERIS® (budesonide) extended release tablets are contraindicated in for increased signs and/or symptoms of hypercorticism. patients with hypersensitivity to budesonide or any of the ingredients Caution should be taken in patients with hypertension, diabetes of UCERIS. When glucocorticosteroids are used chronically, systemic mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a effects such as hypercorticism and adrenal suppression may occur. family history of diabetes or glaucoma, or with any other condition Since UCERIS extended release tablets are a glucocorticosteroid, where glucocorticosteroids may have unwanted effects. general warnings concerning glucocorticoids should be followed. Concomitant use of inhibitors of Cytochrome P450 3A4 (for example Care is needed in patients who are transferred from ketoconazole and erythromycin) should be avoided and patients glucocorticosteroid treatment with higher systemic effects to should be closely monitored for increased signs and/or symptoms glucocorticosteroids with lower systemic effects, such as UCERIS of hypercorticism. Avoid grapefruit juice, which is known to inhibit extended release tablets, since symptoms attributed to withdrawal CYP3A4, when taking UCERIS. of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Taper patients slowly In clinical studies, the most common adverse reactions (incidence ≥2%) were headache, nausea, decreased blood cortisol, upper from systemic corticosteroids if transferring to UCERIS extended abdominal pain, fatigue, flatulence, abdominal distension, acne, release tablets. urinary tract infection, arthralgia, and constipation. Patients who are on drugs that suppress the immune system Please see complete Prescribing Information for UCERIS are more susceptible to infection than healthy individuals. Glucocorticosteroids should be used with caution, if at all, in patients extended release tablets at www.UCERIS.com. CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical and endoscopic remission (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the Endoscopic Index [EI] score) after 8 weeks of treatment.1 *In a pooled analysis of 2 Phase III clinical trials.1,3 † Some restrictions apply. Please see the eVoucherRx™ and Instant Savings Card Program brochure for Terms and Conditions. Salix Pharmaceuticals, Inc. reserves the right to modify or cancel these offerings at any time. ‡ Source: RelayHealth, June 2013. References: 1. UCERIS Prescribing Information. Salix Pharmaceuticals, Inc. January 2013. 2. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. 3. Data on file. Salix Pharmaceuticals, Inc. UCERIS is a registered trademark of Salix Pharmaceuticals, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd. eVoucherRx™ is a trademark of RelayHealth.

Santarus, Inc. is a wholly owned subsidiary of Salix Pharmaceuticals, Inc.

www.UCERIS.com

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

GERD Testing continued from page 45

to increase the chance for detection of acid-related symptoms. In patients with a high probability for GERD, he recommended these studies be performed on PPI therapy to determine whether treatment has been effective.

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

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

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

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

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

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

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

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

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

increases the yield if invasive tests become necessary. The difficulty of isolating the cause of GERD-like symptoms perhaps is best illustrated by healing studies in patients with esophagitis. In these patients, it is common for rates of healing to exceed rates of symptom resolution. This disconnect may be illustrative of a pathologic entity that may be more than the sum of its parts, Dr. Armstrong suggested. Asked for his perspective, Philip O.

0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

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

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

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

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

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

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

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

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

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects:: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

â&#x20AC;&#x2DC;The combination of endoscopy and prolonged ambulatory pH monitoringâ&#x20AC;&#x201D;with or without impedance testingâ&#x20AC;&#x201D;optimally will allow the clinician to confidently make a diagnosis in most cases.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Philip O. Katz, MD Katz, MD, chair of the Division of Gastroenterology, Einstein Medical Center, Philadelphia, said that â&#x20AC;&#x153;Dr. Armstrong to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

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has put forth an excellent summary of the difficulties in making a diagnosis of GERD, especially in the patient in whom symptoms do not completely respond to a well-done therapeutic trial of antisecretory therapy.â&#x20AC;? First author of the ACG guidelines, Dr. Katz indicated that Dr. Armstrongâ&#x20AC;&#x2122;s summary and the ACG guidelines follow a similar path, designed to focus on the underlying problem in difficult cases. â&#x20AC;&#x153;Although the use of empiric antisecretory therapy is a pragmatic, relatively safe and a straightforward approach to patients suspected of having GERD, the combination of endoscopy and prolonged ambulatory pH monitoringâ&#x20AC;&#x201D;with or without impedance testingâ&#x20AC;&#x201D;optimally will allow the clinician to confidently make a diagnosis in most cases,â&#x20AC;? Dr. Katz said. â&#x2013; Dr. Armstrong reported financial relationships with Abbott, AstraZeneca, Axcan Pharma, ConMed Endoscopic Technologies, Cook Inc., Janssen, Merck & Co., NPS Pharmaceuticals, Nycomed, Olympus Canada, Pendopharm, Pentax Medical Company, Shire, Takeda Pharmaceutical Company and XenoPort, Inc. Dr. Katz reported financial relationships with Ferring Pharmaceuticals, Ironwood Pharmaceuticals Inc., Pfizer Consumer Healthcare and Takeda Pharmaceuticals.

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Experts Debate Value of Impedance Monitoring for Reflux BY TED BOSWORTH ORLANDO, FLA.—In patients with symptoms of gastroesophageal reflux disease (GERD) who do not respond to proton pump inhibitor (PPI) therapy, impedance monitoring as a stand-alone test is helpful only in limited circumstances, according to a state-of-the-art lecture delivered by Michael Vaezi, MS, MD, PhD, clinical director of the Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tenn., at the 2013 Digestive Disease Week meeting. Although impedance testing has been proposed as the key diagnostic tool for “refractory GERD,” Dr. Vaezi said “I personally do not believe in this term” as a meaningful description of pathology, particularly as some patients may not have GERD at all.

reflux as a sign of clinical pathology has gotten ahead of the data, Dr. Vaezi said. Tracing the history of upper gastrointestinal (GI) testing, Dr. Vaezi considered the trajectory that led from pH testing to bile acid and alkaline reflux testing, and finally to impedance monitoring. He cited studies in post-gastrectomy patients that suggest reflux of bile can produce symptoms of reflux, even if it did not produce esophageal injury, Dr. Vaezi remains unconvinced that non-acid reflux is a meaningful

clinical entity in the majority of patients. He said the test by itself should not be used to draw conclusions about persistent reflux in a symptomatic patient. Instead, it should be only part of the equation, along with endoscopic findings and pH findings off PPI therapy when applied within the context of the symptoms being treated. Symptomatic regurgitation is the exception, Dr. Vaezi noted. Regurgitation has been proposed as a marker of weakly acidic reflux, and Dr. Vaezi

characterized this assertion as “probably true.” Although impedance monitoring is likely to show reflux episodes, this confirmation may be redundant because the regurgitation “is already telling you about the reflux,” he said. However, in a patient with regurgitation, a positive impedance test in the context of other information, particularly physiologic testing for hiatal hernia, might support consideration of barrier strategies, see Impedance Monitoring, page 48

presents

The problem with obtaining evidence of an abnormal impedance test in most patients is ‘we do not know what to do with the data.’

Jack A. Di Palma, MD, FACG Professor and director, Division of Gastroenterology University of South Alabama College of Medicine M bil Alabama Mobile, Al b

—Michael Vaezi, MS, MD, PhD

Dr. Vaezi objects to the term because it implies that non-acid reflux is the underlying cause of an entity called “refractory GERD,” or alternatively a reflux disease that does not respond to PPIs. “In my book, that is not GERD,” said Dr. Vaezi, who indicated this term should be reserved for patients with objective evidence of injury or symptoms related to the reflux. Non-acid reflux can be detected with impedance monitoring, “but the big question is whether these reflux events are symptom-related, and we do not have an answer.” In patients with refractory symptoms despite undergoing PPI therapy and with abnormal impedance monitoring, Dr. Vaezi said, “I highly recommend that you do nothing,” adding that the “exception to that rule is in a patient with regurgitation,” for whom other findings, such as hiatal hernia, may define a role for surgery. The problem with obtaining evidence of an abnormal impedance test in most patients, he said, is “we do not know what to do with the data.” At this point, there are no controlled studies outlining the importance of abnormal impedance findings in patients who do not respond to PPI therapy. Ultimately, the concept of non-acid

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Early Referral to pH Monitoring Is Cost-Effective ‘Most patients are maintained on PPIs for periods that greatly After Failed PPI Therapy Trial surpass the cost-equivalence point with 24-hour esophageal BY TED BOSWORTH ORLANDO, FLA.—In patients with suspected gastroesophageal reflux disease (GERD) who fail an eight-week trial of proton pump inhibitors (PPIs), referral for esophageal pH monitoring is cost-effective, at least from the perspective of thirdparty payors, according to a cost model analysis. Using reasonable variables, the model predicted savings of between $2,000 and $6,000 per patient over 10 years if pH monitoring is performed promptly after failure of an eight-week PPI trial. “Most patients are maintained on PPIs for periods that greatly surpass the costequivalence point with 24-hour esophageal pH monitoring,” said study author David Kleiman, MD, of the Department of Surgery at Weill Cornell Medical College in New York City. “Early referral after a brief empiric PPI trial may result in substantial cost savings.” This course of action was considered relevant for patients presenting with esophageal or extra-esophageal GERD symptoms. The cost model was based on a retrospective analysis of data from a cohort of 100 patients who underwent pH monitoring at Weill Cornell Medical College. The low- and high-end costs of PPIs used for sensitivity analyses were determined based on the average wholesale unit prices of generic and brand-name drugs, ranging from conventional standard doses (e.g., omeprazole 20 mg) to standard double-doses (e.g., dexlansoprazole 30 mg, twice daily). The cost of

24-hour pH monitoring was obtained from 2012 Medicare fees for manometry, which is necessary for placing pH probes, as well as the monitoring itself. The cost attributed to pH monitoring was $690. The weekly cost of PPI therapy ranged from $29.07 to $107.70. PPI therapy reaches equivalence with pH monitoring in less than seven weeks when brand-name PPIs are given at double doses, or in approximately 24 weeks when generic PPIs are given in standard oncedaily doses. In the retrospective review of 100 patients, 32% of patients had a negative pH monitoring test result, indicating that PPIs were unnecessary, yet the median time on PPIs was 208 weeks in those with esophageal symptoms and 52 weeks in those with extra-esophageal symptoms. “If the sensitivity of pH monitoring was 96%, performing pH monitoring on all patients after an eight-week PPI trial would have saved between $1,197 and $6,304 per patient over 10 years. But the strategy remains cost-effective over a 10-year period, as long as the sensitivity of pH monitoring exceeds 35%,” Dr. Kleiman said. The cost savings were somewhat greater in patients with esophageal symptoms and substantially less in those with extraesophageal symptoms; the latter group already is being referred more quickly for pH monitoring. In these patients, cost savings from early referral for pH monitoring is dependent on pH monitoring sensitivity, particularly if generic PPIs in standard doses are used. However, at 96% sensitivity, projected cost savings ranged from $560 to $3,940.

Impedance Monitoring continued from page 47

such as as fundoplication, even though the value of an abnormal impedance test by itself would be limited. The issue is not whether impedance testing has been a valuable tool for better understanding the function of the lower esophageal sphincter; the question is whether it has any value as an isolated clinical tool when the finding is non-acid reflux. According to Dr. Vaezi, this information has no clinical value because there is no clear evidence that non-acid reflux is a source of pathology or a treatable condition in patients who remain symptomatic despite aggressive PPI therapy.

Reflux Semantics Asked for his perspective on this topic, Donald O. Castell, MD, director of the Esophageal Disorders Program at the Medical University of South Carolina, Charleston, drew a very different conclusion. In his experience, the combination of impedance and

pH monitoring. Early referral after a brief empiric PPI trial may result in substantial cost savings.’ —David Kleiman, MD

Many guidelines currently recommend an empiric i i eight-week i h k trial i l off PPIs PPI when h GERD is suspected, but there has been less of a consensus on the next step when PPIs fails to control symptoms. Although there are several potential advantages to conducting other studies if a PPI trial fails—including avoiding the risks associated with PPI therapy and ruling out acid-related causes of symptoms—this study indicates that early diagnosis is cost-effective, at least from the perspective of a third-party payor. Asked to comment, William C. Orr, PhD, clinical professor of medicine, Oklahoma University Health Sciences Center, Oklahoma City, could not speak specifically about the cost issues but did note that PPI treatment failure is both “a difficult and commonly encountered problem” which long trials of therapy are not likely to solve. For those with persistent symptoms, it makes sense to move toward a diagnosis rather than

pH monitoring has immediate value for understanding the underlying pathophysiology and for making treatment decisions. “When ambulatory impedance-pH monitoring is conducted in a patient well acid-suppressed on PPI therapy, evidence of reflux, whether acid or non-acid, can be objectively assessed,” Dr. Castell said. “If there is a meaningful positive symptom association, the patient is a candidate for appropriate therapy. If the test is clearly negative for symptomatic non-acid reflux, then at least this diagnosis is eliminated. “Impedance testing has taught us that PPIs stop the acid but they do not stop the reflux,” he continued. “Patients who have persistent symptoms in the absence of erosions, or after the erosions have healed, are still looking for relief, and we do have options. Although we still await the perfect [randomized controlled trial] for patients with good evidence of symptomatic nonacid reflux, there are impressive case–control reports of long-term success after fundoplication in these patients. A nationwide randomized comparison of such therapy

leaving symptomatic patients on PPIss i d fi i l indefinitely. “Information about reflux events in PPI-refractory patients can provide important data on whether or not the PPI is indeed providing adequate reflux suppression, and the addition of impedance monitoring can provide additional data as to whether nonacidic reflux may be playing a role in the generation of persistent symptoms,” Dr. Orr said, adding that these are appropriate steps in patient management, independent of cost. The results of the cost analysis were presented at the 2013 Digestive Disease Week meeting and published in the January issue of the Journal of Gastrointestinal Surgeryy (Kleiman DA et al. 2014;18:26-34). ■ Dr. Kleiman reported no conflicts of interest. Dr. Orr reported financial relationships with Reckitt Benckiser Healthcare and Takeda Pharmaceutical Company Ltd.

versus medical reflux inhibitors is under way in the VA [Veterans Affairs] system.” Recognizing that confusion may exist about the terms for reflux, particularly the use of “GERD” in connection with non–acid-related phenomena, Dr. Castell agreed with Dr. Vaezi that “refractory GERD” may be an unhelpful term. In patients with GERD-like symptoms unrelated to acid, Dr. Castell prefers “symptomatic non-acid reflux,” but he suggested terminology should not get in the way of using diagnostic tools to pinpoint the cause of symptoms. “Are we arguing about semantics or pathophysiology?” Dr. Castell asked. Although he called the lack of effective reflux inhibitors a “frustration” in patient care, he believes ambulatory impedance-pH monitoring does yield information that the clinician can use to direct care. ■ Dr. Vaezi reported a financial relationship with Takeda Pharmaceuticals. Dr. Castell reported financial relationships with Sandhill Scientific, Takeda and XenoPort.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

Postoperative Pain Management in Anorectal Surgery New Techniques: Antidotes or Anecdotes? Educating Patients

By Gary H. Hoffman, MD and Stephen Yoo, MD

Several areas of improvement can help to reduce postsurgical pain. A first line of defense involves managing patient expectations. Patient education goes far in this regard. Preoperatively, patients should be advised that their postoperative discomfort may occur along a spectrum of intensity and that their pain intensity

and frequency may change constantly until healing is final. Allowing patients to “prepare for the worst” actually helps with their expectations rather than hinders them. A frank discussion about postoperative pain management options reassures patients and helps them to understand that relief is available. With the advent of newer pain management

techniques, procedures are available that may allow foor sophisticated postoperaperative strategies to handle any discomfort. Transdermal patches, epidural injections and new oral pain medications are but a few strategies that will allow the patient see Pain Management, page 50

Los Angeles Colon and Rectal Surgical Associates Los Angeles, California

Anorectal surgery: often a painful cure; and worse, the performance of the curative operation is only 50% of the battle. Sleepless nights await both the patient and the surgeon once the cure has been inflicted. Postoperative pain relief represents the other 50% of the battle.

Effective pain control is essential for recovery, improved wound healing and reduced hospital admission

with the best-read gastroenterology publication.

rates.

Thirty-five million ambulatory surgical procedures are performed annually in the United States.1 Effective pain control is essential for recovery, improved wound healing and reduced hospital admission rates. In evaluating hospital admission data for 20,817 patients undergoing same-day surgery, 1.5% returned to the hospital in the postoperative period.2 Pain was the most common reason. There has been little progress in addressing this challenge.

Can We Do Better? Surveys from 1993, 2003 and 2012 have demonstrated that postsurgical pain is common and that a similar distribution of the quality of perceived pain has remained unchanged.3-5 Patient pain scores are now being used as metrics in measuring the adequacy of care. Surveys from the Hospital Consumer Assessment of Healthcare Providers and Systems during 2008 and 2009 confirmed the need for improving postoperative pain management. Mean pain management scores were 68 of 100 in 3,765 participating hospitals. The government and other third-party payors may use data of this type in determining reimbursement rates. Surgeons and hospitals alike are being pushed to demonstrate improvement.

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Pain Management continued from page 49

and the surgeon to sleep in the days and weeks following anorectal surgery. A preoperative consultation with a pain management specialist may be worth its weight in sleep. Initiating the use of stool softeners before the operation may help in easing the pain of the first postoperative bowel movement.

Educating the Operating Team Urinary retention is the bane of the anorectal surgeon. The discomfort of urinary retention adds to the pain from the operation. It is recommended that the operation be performed using a safe but limited volume of IV fluids. Should retention be encountered postoperatively, an attempt to void while sitting in a warm tub may be all that is necessary to achieve symptomatic relief. However, prolonged urinary retention may worsen matters and might indicate a more serious underlying problem. Patients should be instructed to contact their surgeon earlier rather than later in their course.

(NSAIDs) and acetaminophen (APAP) have been shown to help control postoperative pain. NSAIDs may be started before surgery and continued through the recovery period. Many studies have demonstrated a diminution in pain scores when up to 1,000 mg of APAP, 600 mg of ibuprofen or 30 mg of intravenous ketorolac were given immediately after surgery.7 NSAIDs aid in reducing and managing the inflammatory response. Cyclooxygenase-2 inhibitors, ketamine, clonidine and steroids also have demonstrated benefit. Many surgeons have patients begin taking NSAIDs preoperatively and continue taking the medication throughout the recovery period. As NSAIDs mayy be associated with postoperative bleeding, their use must be evaluated with a preoperrative assessment of various patient risk factors.

Any anesthetic agent that can inhibit the excitatory process in the nerve ending will block the perception of pain. The nerve membrane is a lipid and protein structure. The two key elements in pain control are anesthetic potency and duration of action.

Educating the Surgeon Another area of improvement has evolved through the efforts of surgeons and industry working together to develop less traumatic procedures. An example of this collaboration has been in the area of the hemorrhoidectomy. Procedure for prolapse and hemorrhoids (PPH) and transarterial hemorrhoidal dearterialization (THD) have been associated with diminishing, although not vanishing, postoperative pain. Procedures such as these are performed proximal to the dentate line and result in less pain because of the paucity of pain fibers in this region. These procedures require careful patient selection and are best suited for stage II/III hemorrhoids with prolapse and a limited external hemorrhoidal component. When PPH and THD are compared with the Milligan-Morgan technique for stage IV hemorrhoids, the duration and depth of pain after the excisional hemorrhoidectomy (MilliganMorgan technique) is typically longer and more severe. Although considered to be an advance in hemorrhoidal operations, the adoption of these newer techniques has been slow because special training is required. Traditionally, multimodality and multidisciplinary pharmacologic techniques have been used to help in the management of the patientâ&#x20AC;&#x2122;s recovery. Opioids have been a cornerstone in the management of postoperative pain. However, narcotics may be accompanied by numerous well-known adverse events (AEs) such as nausea, vomiting, constipation, respiratory depression, ileus, itching and dependence/tolerance. AEs related to opioids have been reported in 12% to 48% of patients.6 In the inpatient setting, opioid-related AEs account for a 3.3-day increase in hospital length of stay. Several options exist to help decrease the dependence on narcotics. Nonsteroidal anti-inflammatory drugs

Some institutioons are using gabapentin/pregabaalin in fast-track recoovery protocols for abdominal ominal surgery. Several studies have demonstrated that administering 1,200 mg of gabapentin or 300 mg of pregabalin preoperatively yields a decrease in adjunctive narcotic requirements.8 Some surgeons will administer the medication for up to two to three days postoperatively. Larger doses have been associated with sedation and dizziness. There are no established studies evaluating the use of these medications after anorectal surgery. Anecdotal reports abound, however, testifying to their effectiveness. This is an area ripe for larger, randomized trials.

Local Pain Control: The Basics Any anesthetic agent that can inhibit the excitatory process in the nerve ending will block the perception of pain. The nerve membrane is a lipid and protein structure. The two key elements in pain control are anesthetic potency and duration of action. These are related to the lipid and protein structure of the nerve membrane. Anesthetic potency is correlated with lipid solubility. Anesthetic duration is related to the degree of protein binding at the membrane level, with a longer duration of anesthesia being the result of a greater binding activity. Both pH and the type and size of the nerve fibers also play a role in the anesthetic effects of various agents.

Local anesthetics are more effective in more basic pH environments. Smaller nerves with lighter myelin coatings are more easily blocked than are larger, more heavily myelinated nerves. Pain is most commonly the first sensation to be blocked and the last to recover, followed by temperature sensation, touch and pressure. Anesthetic agents can be degraded by hydrolysis or by enzymatic activity. As bupivacaine is metabolized slowly, its anesthetic effects are longer lasting. Lidocaine is rapidly metabolized and is a short-acting agent. These two drugs are the most common local anesthetic agents used in anorectal procedures. Local anesthetics are used routinely and are extremely effective for completely blocking pain sensation intraoperatively. Administered in the form of a pudeendal block, coupled with direct injecttions into the operative sites beffore beginning the operation, loocal anesthetics also are effectiive in managing pain in the p postoperative setting. Their benefit, however, is limited d by their duration of eff ffectiveness. Bupivacainee and lidocaine have estaablished durations of action of less than 12 hoours, even with the usse of epinephrine. Because of this, there B have been attempts to im mprove the duration prrofile of local anestheetics. Elastomeric pain n pumps and catheter system ms have been shown to help p ameliorate the pain for severral days postoperatively. Ideallyy, the pumps should deliver a steady d dose of the anesthetic for one to seven days, depending on the size of the pump. However, there have been technical problems reported, including catheter dislodgement and infections.9 Epidural anesthesia is a reliable way to ensure a painfree postoperative recovery. The catheters can remain in place for up to five days after a procedure. Although most often used in the hospital setting, it is theoretically possible to use this type of system on an outpatient basis. Adoption of this technique has been hampered by the need for periodic infusion of the anesthetic, catheter dislodgement, various systemic side effects and the potential for a delay in the diagnosis of a possibly serious catheter-related infection. The topical application of local anesthetics is of marginal and unpredictable efficacy.

A Leap Forward? More Basics Liposomal depot formulations of bupivacaine have shown promise in the management of postoperative pain.10,11 Liposomes are laboratory-prepared, microscopic lipid bilayer membranes that encapsulate an aqueous core. A lipid bilayer is essentially a double-thickness layer of phospholipid molecules. Each of the two layers is one molecule in thickness. This dual-layer system is common in nature and serves to keep substances positioned

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

where they are needed, thus preventing these substances (proteins or ions) from diffusing away from their target area. Cell membranes are composed of lipid bilayers. The idea behind using a liposomal system is that the liposomes can be formulated into a multivesicular system, with the active anesthetic agent being held in each vesicle and slowly released to the target area over time. The anesthetic agent, bupivacaine, is not new; the delivery system is the apparent innovation. The anesthetic system is marketed under the name of Exparel (Pacira Pharmaceuticals). The microvesicular liposomal preparation theoretically results in a drug release pattern showing an increased stability and a prolonged duration of medication release. The pharmacokinetics result in a sevenfold increase in the Tmax, and a 9.8 times increase in the half-life of the medication. The manufacturer states that the medication has a duration of up to 72 hours of delivery and effectiveness. The onset of action is immediate, as there is free bupivacaine in the solution along with the microvesicular preparation.

total knee replacement demonstrated similar favorable results.13-17 It seems that the medication may be of benefit in many procedures requiring the use of local anesthesia.

Practical Considerations Liposomal bupivacaine comes in singleuse 20-cc vials containing 266 mg of bupivacaine that must be stored between 36 F

and 46 F. A temperature indicator will change from green to white if the medication has been exposed to excessively low or high temperatures. The medication may be stored at room temperature for up to 30 days. The liposomal structure may be altered if the preparation is exposed to lidocaine or other anesthetics and liposomal bupivacaine should not be mixed with other

preparations. Liposomal bupivacaine may used without dilution or may be mixed with up to 280 cc of preservative-free, sterile saline. It should not be diluted with water or any other hypotonic solution that might disrupt the delivery system. The profile of adverse events for liposomal bupivacaine is that of the parent drug, bupivacaine, and the surgeon see Pain Management, page 52

The Antidote? Recent FDA approval of the liposomal bupivacaine formulation has been granted for use in hemorrhoidectomies and bunionectomies. Gorfine et al performed a multicenter, double-blind, placebo-controlled study in patients undergoing hemorrhoidectomies.12 The use of 300 mg of the liposomal bupivacaine was compared with a saline placebo, and evaluated over a period of 72 hours. Pain intensity scores were significantly lower in the extended-release (ER) group versus the placebo group. At 12 hours, 59% of patients in the ER group were opioid-free compared with 14% in the placebo group. At 72 hours, 28% of patients in the ER group were opioid-free compared with 10% in the placebo group. In patients requiring opioids, median time to first use was 14.3 hours in the liposomal bupivacaine group compared with 1.2 hours for the placebo group. Ultimately, a 30% reduction in cumulative pain and a 45% reduction in opioid consumption were seen in the study. The safety profile of the formulation has been studied in dose le vels of 66 to 532 mg (with the FDA-approved dose at 266 mg), and cardiac safety has been demonstrated in supratherapeutic doses as high as 665 mg in healthy volunteers. Studies evaluating ER bupivacaine in the setting of open and laparoscopic colectomies, ileostomy reversal, breast augmentation, inguinal hernia repairs and

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Pain Management continued from page 51

must be familiar with the adverse-event profile and treatment of bupivacainerelated adverse events.

The Anecdote About the Antidote: Curbside Consultations and Operating Room Experience The use of liposomal bupivacaine has been the topic of many surgical lounge discussions and intraoffice surgical

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

debates. As Exparel is expensive, much thought has gone into the decision to purchase and use it clinically. We have discussed this topic with colleagues, drug representatives and the surgeons in our group. We decided to try liposomal bupivacaine in our own, unscientific trial. Our results have been impressive. Our protocol has been to administer the medication in the more dilute form using a pudendal block and a local infiltration in the perianal area and around the anal verge. The medication is typically diluted 2:1 and infiltrated just after

the surgical time-out is performed, with the patient under IV sedation. We have not experienced any anesthetic failures during the intraoperative period. At the conclusion of the procedure, a bolus of 30 mg ketorolac is given by IV route to those patients without any contraindications to its use. In the first three postoperative days, no oral or other adjunctive medications are used unless the patient feels the need for supplemental pain relief. After three days, patients are given ketorolac, 10 mg orally every six hours for 12 doses. To date, 100% of

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

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

Chair

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

Faculty

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

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

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

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

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

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

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

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

Designation of Credit Statement The Medical College of Wisconsin designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should only claim credit commensurate with the extent of their participation in the activity.

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

our patients have been almost pain-free for the entire six-day period. Opioid use has been minimal both during the six-day postoperative period and after the six-day period. In all of our cases, the operative anorectal procedures have been extensive. We have not used liposomal bupivacaine in procedures that we considered to be of a minor nature. Our patients have not experienced any adverse events.

The Tale of the Traveling Salesman Perhaps most interesting is one of our patients, a traveling salesman. He was due to leave town immediately after his office visit, for an important threeday sales trip. The pain from his acute thrombotic hemorrhoid had almost crippled him. Because of his impending trip, he was not amenable to surgical drainage or removal. He was desperate for pain relief and refused to consider canceling his trip. He was offered an injection of liposomal bupivacaine and he agreed to try it. The medication was diluted to 40 cc and the local injection was made through a 25-gauge needle around and deep to the thrombotic hemorrhoid. The injection of most local anesthetics in an awake patient is uncomfortable at best and the salesman’s expletives attested to this. Fortunately his office visit was at the end of the day when no other patients were nearby to hear his rather loud comments during the injection. Yet, he left the office without any pain. He returned three days later in a mood bordering on euphoria. He had had no pain since the initial injection. Unfortunately for him, he lost the sale. Because he had incorrectly accounted for the time zone change during his flight, he arrived an hour late for his presentation and was denied a chance to make his pitch. This time, however, his expletives were directed at himself rather than the injection of Exparel. Surgeons cannot fix everything.

Antidote or Anecdote? Judge for Yourself We have been happy with our results to date. Patients have been happy with their results to date. But our trial is only anecdotal. Although supported by clinical trials, our results may not be the same as those of other surgeons. Time and experience will be the final arbiter of clinical efficacy. But liposomal bupivacaine, although expensive, may be a useful medication in combating pain following anorectal operations. ■ The authors have no financial or other relationships with any of the maufacturers of any of the drugs mentioned in this review.

EXPERT REVIEW

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

References 1. Cullen KA, Hall MJ, Golosinkiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009;11:1-25. 2. Coley KC, Williams BA, DaPos SV, et al. Retrospective evaluation of unanticipated admissions and readmissions after same day surgery and associated costs. J Clin Anesth. 2002;14:349-353. 3. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology. 1995;83:1090-1094.

of depobupivacaine intraoperatively in patients undergoing inguinal herniorraphy: preliminary dose-ranging studies. Presented at: Annual Meeting of the International Anesthesia Research Society: March 14-17, 2009, San Diego, CA. 16.Langford RM, Chappell GM, Karrasch JA. A single administration of depobupivacaine intraoperatively results in prolonged detectable plasma bupivacaine and analgesia in patients undergoing inguinal hernia repair. Presented at: 62nd Postgraduate Assembly in Anesthesiology; December 12-16, 2008; New York, NY.

17.Bramlett KW, Jones RK, Pink M, et al. A single administration of depobupivacaine intraoperatively provides analgesia and reduction in use of rescue opiates compared with bupivacaine HCl in patients undergoing total knee arthroplasty [poster]. Presented at the XXXVI Biennial World Congress of the International College of Surgeons; December 3-6, 2008; Vienna, Austria.

Dr. Hoffman is attending surgeon in the Division of Colorectal Surgery at CedarsSinai Medical Center, and attending surgeon in the Division of General Surgery

and associate clinical professor of surgery at the David Geffen School of Medicine, University of California, Los Angeles. He is a senior member of Los Angeles Colon and Rectal Surgical Associates. Dr. Yoo is attending surgeon in the Division of Colorectal Surgery at Cedars-Sinai Medical Center and associate clinical professor of surgery at the David Geffen School of Medicine, University of California. He is a member of Los Angeles Colon and Rectal Surgical Associates. Visit Los Angeles Colon and Rectal Surgical Associates online at www.lacolon.com.

4. Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97:534-540. 5. Gan TJ, Habib AS, White W, et al. Postoperative pain continues to be undermanaged [abstract]. Presented at: Annual Fall Pain Meeting and Workshops of the American Society of Regional Anesthesia and Pain Medicine; November 15-18, 2012; Miami Beach, FL. 6. Oderda G, Gan T. Effect of opioid-related adverse events on outcomes in selected surgical patients. J Pain Palliat Care Pharmacother. 2012. 2013;27:62-70.

Advances in Probiotic Therapy For Diarrhea-Associated Illness

7. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21:185-211.

To participate in this FREE CME activity, log on to

8. Dauri M, Faria S, Gatti A, et al. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009;10:716-733. 9. Brown SL, Morrison AE. Local anesthetic infusion pump systems adverse events reported to the Food and Drug Administration. Anesthesiology. 2004;100:1035-1037. 10. Chahar P, Cummings KC. Liposomal bupivacaine: a view of a new bupivacaine formulation. J Pain Res. 2012;5:257-264. 11. Candiotti K. Liposomal bupivacaine: an innovative nonopioid local anesthetic for the management of postsurgical pain. Pharmacotherapy. 2012;32:19S-26S. 12. Gorfine SR, Onel E, Patou G, et al. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing a hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54:1552-1559. 13. Smoot JD, Bergese SD, Onel E, et al. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammoplasty: a randomized, doubleblind, active-control study. Aesthet Surg J. 2012;32:69-76. 14. Minkowitz HS, Onel E, Patronella CK, et al. A two-year observational study assessing the safety of DepoFoam bupivacaine after augmentation mammoplasty. Aesthet Surg JJ. 2012;32:186-193. 15. White PF, Schooley G, Ardeleanu M. Analgesia following a single administration

www.CMEZone.com

Release Date: February 10, 2014 Chair William D. Chey, MD Professor of Internal Medicine Director, Gastrointestinal Physiology Laboratory Co-Director, Michigan Bowel Control Program H. Marvin Pollard Institute Scholar Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Faculty Brooks Cash, MD

Statement of Need

Intended Audience

Probiotics can be powerful tools in managing a number of medical conditions. However, effi fficacy may be suboptimal if these agents are not used appropriately. As public interest in the benefi fits of probiotics increases, so does the need for clinical education. Many physicians and patients are unfamiliar with the nuances of probiotic pharmacology, or—with many probiotics available for over-the-counter purchase— may not be aware that their patients are selecting ineffective ff therapies. Thus, it is important for health care professionals to familiarize themselves with the latest research data on probiotic use.

Gastroenterologists, primary care physicians, nurse practitioners, nurses, physician assistants, pharmacists, and other health care professionals involved in the care of patients who may beneﬁt ﬁ from the use of probiotic therapy.

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

Goal

Shanti Eswaran, MD

Learning Objectives

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

Expiration Date: February 10, 2015

Th goal of this educational activity is to provide cliThe nicians with current evidence and strategies for effecff tive probiotic therapy in a variety of disease states. Upon completion of this activity, the participant will be better prepared to do the following: 1 Review key diff fferentiating characteristics of various probiotic therapies, including mechanism of action. 2 Describe the importance of strain specificity fi in the clinical applicability of probiotic therapies.

Estimated Time for Completion 1 hour

Course Format Monograph

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

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

3 Discuss the role of probiotic therapy in clinical digestive ailments. 4 Review strategies for appropriate patient selection and education in the use of probiotic therapies.

Jointly sponsored by AKH Inc. and Applied Clinical Education

Supported via an educational grant from Procter & Gamble

Distributed via CMEZone and Gastroenterology and Endoscopy News

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

FDA Warns Consumers About Risks of OTC Sodium Phosphate Laxatives The FDA issued a warning to consumers about the risks of over-the-counter (OTC) sodium phosphate laxatives in a Jan. 8 statement. The agency warned that these agents are potentially dangerous if labeling instructions are not followed properly, or when patients have certain coexisting health conditions. The label of sodium phosphate laxatives states they should be used as a single dose taken once a day, and the products should not be used for more than three days. Also, consumers who do not have a bowel movement after taking an oral or rectal dose should not take another dose of the product. Additionally, individuals with kidney disease, heart problems or dehydration are advised to ask a health care professional before using these products.

Who Is at Risk? In addition to highlighting the current labeling information, the FDA is now warning adults older than 55 years, as well as adults and children with certain health conditions, to consult a health

care professional before using sodium phosphate laxatives because they may be at increased risk for harmful side effects. These new warnings are not mentioned currently in the Drug Facts label, and apply to both adults and children under the following conditions: • those who are taking medications that affect kidney function, such as diuretics or fluid medicines; • those who are taking angiotensinconverting enzyme inhibitors, used to lower blood pressure; • those who are taking angiotensin receptor blockers, used to treat high blood pressure, or heart or kidney failure; • those who are taking nonsteroidal anti-inflammatory drugs, such as ibuprofen; and • those with inflammation of the colon. According to the FDA, there have been dozens of reports of serious side effects, including 13 deaths, associated with the use of sodium phosphate laxatives. Pediatric nephrologist Mona Khurana,

MD, who is a medical officer in the FDA’s Division of Nonprescription Regulation Development, noted the most serious harm occurred when consumers took a single dose that was higher than the recommended dose, or took more than one dose in one day because they did not respond to the first dose. “It is not possible to determine the precise rate of these events, as no one knows how many individuals who take these medications may experience side effects,” Dr. Khurana noted. “Not everybody who develops problems in association with sodium phosphate use reports to the FDA.” Additionally, these products should be used in young children with caution, as is outlined in the product labeling of sodium phosphate laxatives. “Caregivers should not give these products orally to children under age 5 years without first asking a health care professional. Both caregivers and health care professionals should avoid the rectal use of these drug products in children under age 2 years,” Dr. Khurana cautioned.

Image courtesy of the FDA

“These warnings against use in young children are listed on product labeling.”

What Are the Complications? In recent analyses, the FDA identified 54 cases of serious side effects associated with the use of oral or rectal OTC sodium phosphate products for the treatment of constipation in adults and children. Thirteen cases were fatal, including one child and 12 adults. The FDA is advising consumers taking OTC sodium phosphate laxatives see OTC Laxatives, page 55

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2014

NEW PRODUCT ANNOUNCEMENT

Medivators’ Jet Prep Flushing Device For Use in Suboptimal Bowel Preparation Procedures The Medivators’ Jet Prep Flushing Device provides an immediate solution for suboptimal bowel preparation, gastrointestinal (GI) bleeding and food impaction, eliminating the need to abort or reschedule procedures. The Jet Prep Flushing Device is used in conjunction with a standard flexible endoscope for cleansing GI mucosa during endoscopic procedures

through the use of high-powered irrigation and suction. This process quickly clears and removes stool, debris and fluids, resulting in considerably increased visualization during screening, diagnostic and therapeutic procedures. For more information, please see our ad on page 14.

The Jet Prep Flushing Device from Medivators Photo courtesy of Medivators

OTC Laxatives continued from page 54

to watch for certain warning signs. For example, a rectal dose that is retained and does not produce a bowel movement may cause dehydration and/or serious changes in blood electrolyte levels. Symptoms of dehydration include dry mouth, thirst, reduced urine output and lightheadedness, especially with changes in position. If a rectal dose is retained in the body longer than 30 minutes, a health care professional should be contacted right away, the FDA said. Symptoms of kidney injury include drowsiness, sluggishness, decreased amount of urine, and swelling of the ankles, feet and legs. The FDA advised individuals who experience any of these symptoms after use of sodium phosphate laxatives to seek medical attention immediately.

The Bottom Line Laxative products containing sodium phosphates are marketed under the brand name “Fleet,” and also are sold as store brands and generic products. These types of laxative help promote a bowel movement by drawing water into the bowel, which softens the stool and makes it easier to pass. All of them are potentially associated with the serious side effects of dehydration and/or abnormal levels of electrolytes in the blood that can lead to serious complications, such as kidney damage, and sometimes death. “The bottom line is that these products are safe for otherwise healthy adults and older children for whom dosing instructions are provided on the Drug Facts label, as long as they follow these dosing instructions and don’t take the product more often, or in greater amounts, than the label instructs,” Dr. Khurana said. For more information about this and other consumer warnings, visit the FDA Consumer Update at www.fda.gov/ ForConsumers/ConsumerUpdates. —Based on a press release from the FDA

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

Guidance Equivocal On HCV Screening Of Baby Boomers

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

see NAFLD, page 14

see Income, page 28

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients BY MONICA J. SMITH

tor

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

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8 Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

see Cost Sharing, page 32

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CLINICAL REVIEW

PRODUCT ANNOUNCEMENT

Ulcerative Colitis:

Optimizing Mesalamine Strategies

see insert between pages 20 and 21

ELLEN J. SCHERL, MD

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

Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

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

BRIAN BOSWORTH, MD

see page 63 for product information

he e greatest ch hallenge for clinicians who

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

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

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

2013

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

Bowel Preparations