February 2014 by McMahon Group

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 65, Number 2 • February 2014

HEPATOLOGY

I N

F O C U S

HCV Antivirals Race to Market BY KATE O’ROURKE BOSTON—Over the next five years, a whirlwind of new direct-acting antiviral agents (DAA) for hepatitis C are expected to get the green light from the FDA. The recent approval of simeprevir (Olysio, Janssen) and sofosbuvir (Sovaldi, Gilead)–containing regimens is only the tip of the iceberg. see DAAs, page 13

IFN/RBV-Free Combo for HCV BY KATE O’ROURKE WASHINGTON— —The combination of daclatasvir plus asunaprevir, both manufactured by Bristol-Myers Squibb (BMS), looks poised to gain approval in Japan for treating patients with hepatitis C virus (HCV) genotype 1b infection. Experts speculate that BMS will seek approval in the United States for this drug combination at a later date, but with the addition of a see IFN/Ribavirin-Free, page 20

Lacking Data, Physicians Attempt To Manage Non-Celiac Gluten Sensitivity BY TED BOSWORTH BERLIN—After ruling out a diagnosis of celiac disease, the evidence base for managing patients with gluten sensitivity is limited. A diagnosis of nonceliac gluten sensitivity (NCGS) is based on the observation of symptom relief associated with a gluten-free diet, a step that many patients with gluten sensitivity have already taken. Physicians who are asked to confirm and manage a diagnosis of NCGS, which is rising in prevalence, may be better guided by common sense than any available data. “There does appear to be a growing number of individuals who believe themselves to be gluten sensitive, but we are missing the data to tell us whether all of these patients need to be on a lifetime gluten-free diet,” reported David S. Sanders, MD, of Royal Hallamshire Hospital, University of Sheffield, United Kingdom. Delivering a state-of-the-art lecture on the subject at the 2013 United European Gastroenterology Week (UEGW) meeting, Dr. Sanders attempted to sort through the trends in NCGS and what it all means for physicians and their patients.

NCGS or Celiac Disease? NCGS is remarkably common. In a populationbased survey presented at the UEGW meeting by Imran Aziz, MD, also of Royal Hallamshire Hospital, the self-reported prevalence of gluten sensitivity was 13%. Of 1,002 individuals who were surveyed at a shopping mall, 3.7% said they were following a gluten-free diet but only 0.8% reported a diagnosis of celiac disease. This latter figure is consistent with National Heath and Nutrition Examination Survey see Gluten, page 26

I N S I D E

Surgeon Pits PPIs Against Anti-Reflux Surgery

HEPATOLOGY

I N

FOCUS

EXPERTS’ PICKS EXPERT Best of The Liver Meeting 2013..................................... page 10

BY MONICA J. SMITH BALTIMORE—Tasked with creating a lecture for the American Society of Gastrointestinal and Endoscopic Surgeons (SAGES) to fit the title, “PPIs Are Just as Good as Anti-reflux Surgery for GERD,” Christy M. Dunst, MD, needed to set aside her prosurgery bias. “It was a good opportunity to really review the literature with an

Kris Kowdley, MD

Suthat Liangpunsakul, MD, MPH

Raj Vuppalanchi, MD

see GERD Surgery, page 28 PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

CLINICAL REVIEW

First-Line Treatment Strategies for

Helicobacter pylori Infection RICHARD J. SAAD, MD, MS, AND WILLIAM D. CHEY, MD

see insert after page 46

First-Line Treatment Strategies for Helicobacter Pylorii Infection By Richard J. Saad, MD, MS, and William D. Chey, MD

Department of Internal Medicine Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan Dr. Saad has no relevant conflicts of interest. Dr. Chey has served as a consultant for AstraZeneca and Takeda Pharmaceuticals.

elicobacter pylori is a major cause of chronic gastritis and peptic ulcer disease (PUD); it is closely linked with gastric mucosa-associated lymphoid

tissue (MALT) lymphoma and gastric adenocarcinoma; and it is causally associated with unexplained iron-deficiency anemia, primary immune thrombocytopenia (formally termed idiopathic thrombocytopenic purpura), and vitamin B12 deficiency.

Given these known and potential complications of chronic H. pylorii infection, its identification mandates effective eradication (Table 1). Although it has been more than 3 decades since the discovery of H. pylori, no eradication therapy has been identified that guarantees a 100% cure rate. Moreover, there has been a tendency toward reduced efficacy of eradication regimens over time, largely because of the development of antibiotic resistance to H. pylori. In clinical practice, the initial course of eradication therapy generally offers the greatest likelihood for treatment success. Therefore, careful selection of firstline eradication therapy is essential. The most important factors to consider when choosing an initial course of eradication therapy are prior antibiotic exposure of the patient and, if available, the regional antibiotic-resistance profile of H. pylori.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • F E B R UA RY 2 0 1 4

OPTT IN

to receive your free monthly e-Newsletter at www.gastroendonews.com

Read the No. 1 publication in the

gastroenterology market,

anywhere, anytime!

Explore gastroendonews.com at your convenience, from your iPad, personal computer or smartphone.

gastroendonews.com Read all the articles from each monthâ&#x20AC;&#x2122;s issue online. Search the archive for articles from past issues that you may have missed. Post a comment about an article for your colleagues to see. Share articles you read online with your colleagues via email, Facebook, Twitter and other popular social networking sites. Follow our Twitter feed and keep up with us between monthly issues. View our Digital Edition, which includes articles in the same layout as our print edition.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Naloxegol Shows Efficacy Against Multiple Symptoms Of Opioid-Induced Constipation in Phase III Trials BY MONICA J. SMITH SAN DIEGO—Naloxegol, an oral, peripherally acting µ-opioid receptor antagonist, appears safe and effective in relieving opioid-induced constipation (OIC), according to data presented the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting. A new drug application for the agent was accepted for review by the FDA in November. OIC occurs in 40% to 60% of individuals taking opioids, and is a unique form of constipation, said William D. Chey, MD, who presented the findings of two identical, randomized controlled, Phase III trials of naloxegol at the ACG meeting. It can become so problematic that some patients choose to forego their pain medicine, leading to a significant negative effect on their quality of life. “The study objectives were to evaluate the safety and efficacy of naloxegol in two doses versus placebo in patients taking opioids for noncancer pain,” said

Dr. Chey, professor of medicine at the University of Michigan Health System in Ann Arbor. The primary outcome of the two trials—KODIAC-04 and KODIAC-05— was greater than three spontaneous bowel movements (SBMs) per week, with an increase of more than one SBM per week

“We tend to focus on stool frequency, but like constipation in general, OIC is associated with alterations in a variety of other symptoms, including straining, hard stools and a sense of incomplete evacuation.” The study population comprised patients aged 18 to 85 years with OIC

‘We tend to focus on stool frequency, but like constipation in general, OIC is associated with alterations in a variety of other symptoms, including straining, hard stools and a sense of incomplete evacuation.’ —William D. Chey, MD over baseline for at least nine of the 12 randomization weeks, and for at least three of the four final weeks. “In addition to this was the requirement of demonstrating symptom improvement for at least one of the following: straining, stool consistency and number of days with a complete spontaneous bowel movement,” Dr. Chey said.

who had been taking between 30 and 1,000 mg of oral morphine for noncancer pain for at least four weeks before the study period. About 65% of these patients had failed to respond to treatment with one or more laxatives before enrollment in the study. During a two-week screening period, patients were required to have active

Download the FREE

iPad App 3 Ways to Download: ➢ Go to the iTunes App Store on your iPad and search for Gastroenterology & Endoscopy News.

➢ Go to www.gastroendonews.com/apps and click on the "Available on the App Store" icon.

➢ Scan this QR code with your iPad and download the App from iTunes.

symptoms of OIC, defined as fewer than three SBMs per week and at least one symptom of hard lumpy stools; straining; or a sensation of incomplete evacuation more than 25% of the time. This was followed by a two-week confirmation period during which patients had to experience the symptoms previously described, documented by e-diary, to qualify for the trial. Roughly 700 patients completed the qualification and were enrolled in the two trials. The patients, who were similar in terms of demographics and constipationrelated symptoms, were randomized to receive 12 weeks of treatment with naloxegol at one of two doses, 12.5 or 25 mg, or placebo. The differences between the groups in each of the two studies were analyzed by the Cochran-MantelHaenszel comprehensive test stratified by response to laxatives at baseline. About 80% of the patients completed the trial. In both trials, the higher dose of the drug resulted in improvement in the primary end point compared with placebo, see Naloxegol, page 40

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

To Prevent Burnout, Be Proactive Re: “The Lowdown on Burnout in Medicine,” by Monica J. Smith. Gastroenterology & Endoscopy Newss January 2014;65:1,36-38.

ws.com

endone

gastro

logists

entero

Gastro per for

ndent

epe The Ind

ÊÓ

spa ly New

Month

n owdow

zz W CG Abu

oidin and Av g Stress The L itigatin nss for M ion Resolut

ith FM

ä£Î

m ews.co endon gastro edicine ut in M t in 2014 o rn u on B g Burnou

BY MONI

aration The prep —T nout IEGO— SAN D iding bur on avoid took for a talk alance ing bal and find logist Christero gastroen cz, MD, outawi tina Sur rt zone, comfort her e side r tim gave her own but it er ct on her to refle , whaatt she experience peers and her sees in eagues, collea younger doctor ors can and how selves and e help themestabli lish mor er g each oth rewardin ble and managea pattern ns. on fe work–li not an expert expeam have “I I cllearly ’t think t, but I ah I don burnou oug ou Dr. Sur Washingit, alth e,” said atitis C D WILD at rienced the tim versity of nts for hep d virothe Uni , who is based ed it att BY DAVI recogniz lty member at aine el treatme ttle facu everal nov to durable sust ndees of ne in Sea dicine, wicz, a Me atte IEGO—S lead D of n ter. ool ctio SAN ual ers told V) infe ton Sch dical Cen research olog y 2013 Ann view Me virus (HC onses (SVR), ated bor nter upd Har d troe logic resp College of Gas gators presente page 23 , an esti HCV Inv eric g. see Am ic Meetin Scientif

d at the D WILD presente 3 studies G) 201 swath of nterolog y (AC possible IEGO—A of Gastroe onstrated the splanSAN D tran an College Meeting dem robiota T Americ ic fecal mic mise for FM Scientif ons for pro Annual w cati (IBS) sho indi of data drome spectrum T). The new bowel syn also dem able (FM and irrit on in tati (IBD), nt of cedure disease treatme of the pro page 28 in the y bowel , efficacy ammator see FMT and infl the safety and ed trat ons

BY DAVI

V Drugscy ral HC New O sting Efﬁca La Show

ut’ ‘Burrno f ed Deefin

term The T was r out ” “buurn e by psy ned coin bert st Her to chologi berger Freudenb consethe t describe combinaoff a and quences ls h idea high ation of Dr. Sur stress, es in severe olleagu her col eriwicz told th Am the tion at logy a presenta Gastrooentero g. lege of i Meetin can Col Scientiffic ses who ual n 2013 Ann tors and nur up (ACG) often end of ple is doc e 36 cal exam es for others, and “A typi nout, pag selv see Bur ifice them may sacr I D E I N S ting: e 19 KS c Mee S’ PIC Scientiﬁ .............. pag EXPERT Annual ............ the ACG .................. ...... Best of ............ *>ÀÌÊÊÓÊ

proach ate’ Ap ff nvestig -and-I laims Pays O se lo c C ‘Dis ion that ractice e institut to of a larg usly, according B division To Malp rmo B T . The com terology benefited eno gastroen cy change s per Y

OSWORT

tribain con mai “The two orss were feel e uting fact I d didn’t hav ing that rol and that tro any any con t have I didn’t at work.” supporrt

SMITH CA J.

ms he the cost tice clai r the poli , FLA.—T malprac before and afte a reduction in in the time ORLANDO approach to n ms filed its of claims, and a reductio 40 number , page changed pared clai ms, Claims that com reduction in the defending clai practice a study a see Mal showed in total costs for parison n reductio claim, a Offers of Cancer s rogeneity nitie The Hete Opportu Therapy Targeted

in,

Frank

Kasm Franklin MD

G. Gres MD

CLINICAL

REVIEW

t between

pages 26

Sharma, Prateek MD

and 27

see inser

: orrhoids h to Hem ogists Approac roenterol for Gast A Primer By Harry

Correction

Thanks for this good burnout article. It is important to remember that burnout is present in an average of one in three physicians on any given office day, worldwide, regardless of specialty. That is a q quote from a Journal of the American Mediccal Association article by Shanafelt [20099;302:1338-1340], who is mentioned d repeatedly in this article. As someone who works one-onone h helping physicians recover from burnoout, I can tell you that in the vast majoority of cases burnout is multifactoorial and chiefly caused by the streesses of a particular job position. Evven the most burned-out doctors stiill enjoy the time they spend face too face with patients. To prevent burnout, it is key to be proactive and plan your pracb tice and your life regularly. Without this, your career becomes

the 800-pound Web gorilla that Comment dominates you and your family’s time and energy. Organizations have a huge role here if they choose. … Because most of the stress comes from the specifics of the job, and the “way we do things around here” is organizationspecific, I believe physician-leaders have a duty to do everything they can to create a physician-friendly workplace. Dike Drummond, MD Jan. 15, 2014

In the article, “Dear Professor Flexner: Medicine Is a Business, as Well as a Public Trust” (Costrini NV. Gastroenterology & Endoscopy News January 2014;65:6), an error was made in reference to Kenneth Ludmerer, MD. Dr. Ludmerer is a professor of medicine and history at Washington University in

Dr. Drummond is a Mayo-trained family practice physician who provides coaching to physicians with careerthreatening burnout. He offers speaking, training and consulting on a variety of physician wellness issues, and hosts a blog at TheHappyMD.com.

St. Louis; we mistakenly referred to him as Mr. Ludmerer. We regret the error.

MD Sarles Jr.,

s 8-9

see page

Vol. 65, No. 2

MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, BSC, MS, PHD, DSC

Farmington Hills, Michigan

FREDRIC DAUM, MD Mineola, New York

STEVEN M. FABER, MD Elizabeth City, North Carolina

RONNIE FASS, MD Cleveland, Ohio

BARBARA B. FRANK, MD Philadelphia, Pennsylvania

FRANK G. GRESS, MD New York, New York

EDITORIAL STAFF

SALES STAFF

CYNTHIA J. GORDON, PHD,

BRIAN J. HIGGINSON, Publication Director, bhigginson@mcmahonmed.com

Managing Editor, Sacramento, California

PETER R. MCNALLY, DO Fort Carson, Colorado

TARUN MULLICK, MD

cgordon@mcmahonmed.com DAVID BRONSTEIN, KEVIN HORTY, ADAM MARCUS, GABRIEL MILLER, DONALD M. PIZZI, SARAH TILYOU,

St. Charles, Illinois

Contributing Editors

JOEL E. RICHTER, MD

JAMES PRUDDEN,

Tampa, Florida

DAVID ROBBINS, MD

DONALD M. PIZZI,

ELLEN J. SCHERL, MD

Editorial Director

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

BRANDY WILSON, Circulation Coordinator

MATTHEW SPOTO, Senior Account Manager, mspoto@mcmahonmed.com

MCMAHON PUBLISHING

LAUREN SMITH, Classified Advertising Sales, lauren@mcmahonmed.com

VAN VELLE, President, Partner

RAYMOND E. MCMAHON, Publisher and CEO, Managing Partner

MATTHEW MCMAHON, General Manager, Partner LAUREN SMITH,

ART AND PRODUCTION STAFF

MICHAEL P. MCMAHON,

ROBIN B. WEISBERG,

MICHELE MCMAHON VELLE, Creative Director

Manager, Editorial Services

JEANETTE MOONEY, Senior Art Director

ELIZABETH ZHONG,

JAMES O’NEILL, Senior Systems Manager

New York, New York

PRATEEK SHARMA, MD

DAN RADEBAUGH, Director of Production and Technical Operations

Group Editorial Director

New York, New York

CHRISTOPHER JOLLEY, MD

February 2014

Associate Copy Chief

MICHELE MCMAHON VELLE, ROSANNE C. MCMAHON, Partners

Subscription to Gastroenterology & Endoscopy News Gastroenterology & Endoscopy Newss obtains its mailing list from the American Medical Association (AMA) and the American Osteopathic Association (AOA). You do not have be a member of the AMA or AOA to receive the publication, but you do need to be correctly listed on the appropriate organization’s file, with a designated specialty of “gastroenterology,” “hepatology” or “colon and rectal surgery.” All U.S. gastroenterologists, hepatologists and colorectal surgeons should receive Gastroenterology & Endoscopy News

free of charge. If you are a U.S. gastroenterologist, hepatologist or colorectal surgeon and you are not receiving Gastroenterology & Endoscopy News, or if you are changing your name, address or professional specialty, contact the AMA at (800) 262-3211 or the AOA at (800) 621-1773 and notify them of your name, address and professional specialty. If you are not a U.S. gastroenterologist, hepatologist or colorectal surgeon and would like to subscribe, please send a

McMahon Publishing is a 42-year-old family-owned medical publishing and medical education company. McMahon publishes monthly clinical newspapers, annual and semi-annual Special Editions, and continuing medical education and custom publishing pieces.

INFECTIOUS DISEASE SPECIAL EDITION

check payable to Gastroenterology & Endoscopy Newss to: Circulation Coordinator, Gastroenterology & Endoscopy News, 545 West 45th Street, 8th Floor, New York, NY 10036. Annual subscription: $70.00 (outside U.S.A., $90.00). Single copies: $7.00 (outside U.S.A., $10.00). Please allow 8-12 weeks for delivery of the first issue. Further questions may be addressed to the Circulation Coordinator at (212) 957-5300, ext. 362, or bwilson@mcmahonmed.com.

Educational & Commercial Reprints Reprints of articles appearing in Gastroenterology & Endoscopy Newss are available in minimum quantities of 500. Reprints can be ordered in black and white or four-color versions and are printed on 80-lb. glossy stock paper. Standard turnaround time is 4 weeks. For specific price quotes, contact Brian J. Higginson at (212) 957-5300, ext. 241, or bhigginson@mcmahonmed.com.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

65 (and Other Disturbing Statistics) Jon C. White, MD Professor of Surgery George Washington University Chief of Surgical Services VAMC Washington, DC I read a statistic the other day that I thought must surely be a misprint. It claimed that two-thirds (approximately 65%) of all people who have ever lived to the age of 65 are alive today. I did some research with the intent of exposing the obvious exaggeration, but instead came up with more disturbing statistics: The number of people who have ever lived on the earth since man first appeared 50,000 years ago can be estimated by mathematical modeling; the total is thought to be 106 billion. Currently, there are 7 billion people living, or about 7% of all who have ever drawn a breath. These extraordinary numbers are a consequence of the exponential nature of population growth. I also confirmed that an estimated 50% to 70% of people who have lived to age 65 are indeed alive today! The fact that 65% of the planet’s 65-year-olds are living now suggests that there is more than just the growth of the population at work: There is also a dramatic increase in life expectancy. In short, population growth is in a very sharp incline and these multitudes are living far beyond what they did in the past. There are sobering consequences to these numbers.

I manage to stay optimistic about the future of our planet, however, and the source of my optimism can be best explained by a computation done by the two-time Pulitzer prize-winning entomologist, E.O. Wilson. He estimated that if you take all 7 billion people in the world and stack them like logs they would form a cube one mile on each side. You could hide this cube in the Grand Canyon, which is one mile deep and 18 miles wide. If you

then look at earth from space the biomass representing all humanity becomes a vanishingly small speck that is all but invisible. The great swaths of green, representing plant life, and blue, which is the water, make up most of the surface of our planet. It seems improbable that this enormous globe with its considerable plant and water resources is not enough to sustain this microscopic speck of biomass hidden in the Grand Canyon. But if the exponential

see 65, page 44

GET RECOGNIZED IN GI! ASGE Recognized Industry Associate (ARIA) Program The American Society for Gastrointestinal Endoscopy supports industry’s efforts to have knowledgeable, GI-practice “ready” sales associates, and is pleased to announce the ASGE Recognized Industry Associate (ARIA) program, a new initiative dedicated to industry professionals.

Through a live course, the new ASGE ARIA program provides an overview of basic GI anatomy and physiology as well as common gastrointestinal diseases and their endoscopic findings through a lecture-based format. In addition, a hands-on experience introduces both basic and advanced endoscopic techniques. The ARIA program creates a common language and a shared understanding for improved communication between clinicians and industry representatives. Industry representatives who successfully complete the ARIA program are awarded the ASGE Certificate of Completion and receive a number of other prestigious recognition benefits and marketing tools

Food for Thought In the early 1800s, Thomas Malthus introduced the notion that the world’s increasing population would result in a food supply crisis. Fortunately, better agricultural techniques were introduced toward the end of the century and famine was averted. In the 1970s, another population scientist, Paul Ehrlich, opined that the disaster was not averted but only delayed until the 1980s. This time the “Green Revolution” intervened with improved farming techniques such as fertilizers based on petrochemicals and genetically engineered crops. The agricultural yields increased even further and, again, we avoided world food shortages and mass starvation. Both Malthus and Ehrlich are usually associated with global food supplies but their chief concern was more than food; it was overpopulation. They both understood that the population numbers are relentless and, although neither one had the dates right, it just seems to be a matter of time before we have a problem on our hands and again will need to be rescued by another scientific advance.

growth of the population is relentless, you may still postulate that this insignificant speck of humanity will eventually outgrow even the earth’s tremendous resources. I like to think not, so again I should explain the source of my optimism. It is estimated that by the year 2050, the earth’s population will be 9 billion and after that some estimates have it declining. At some point, the rate of growth, which

The results are in! The inaugural ARIA program last fall showed a signiﬁcant increase in participants’ basic GI knowledge. Avg score – pre-test: 52.1% Avg score – post-test: 90.7%

Upcoming ARIA GI Industry Training Courses ASGE will hold its next ARIA Program courses on: X X

Tuesday, April 8, 2014 Monday, November 3, 2014

All courses will be held at the ASGE Institute for Training and Technology (IT&T)

Physicians – Look for the “Seal” Knowledgeable and Dedicated GI Industry Reps For more information on the ARIA Program, including scheduling group training for your sales representatives, contact Linda kay Tyler, director of sales and business development at (630) 570-5601 or ltyler@asge.org.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

POEM: An Epic Step Forward or Esoteric Procedure for Achalasia? BY MONICA J. SMITH BALTIMORE—A dominant topic at the 2013 annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) was the emergence of per oral endoscopic myotomy (POEM), a technique that some consider emblematic of the society’s dedication to advancing endoscopic surgical approaches. Haruhiro Inoue, MD, the enthusiastic inventor of the new procedure, opened the session on POEM by describing his technique, and met independently with Gastroenterology & Endoscopy News to explain how it has revolutionized his institution’s treatment of patients with achalasia. “Before starting the POEM procedure for achalasia, I usually only had three new [surgical] cases of achalasia a year,” said Dr. Inoue, chief of Upper GI Endoscopy and Surgery, Digestive Disease Center, Showa University Northern Yokahama Hospital, Yokahama, Japan. “But in the last five years, at least in my hospital, that’s totally changed. Last year, we did 140 POEM procedures,” he said. To date, surgeons at Dr. Inoue’s hospital have performed almost 400 POEMs on patients who went there from around the world to get the scarless treatment. The cosmetic aspect seemed to be a large part of the appeal for patients, particularly young women, Dr. Inoue observed. But the patient who was largely responsible for publicizing the procedure and kicking off its surge in popularity was a 50-year-old schoolteacher whose achalasia resulted in dysphagia so severe that even drinking water was difficult. The patient kept a blog of his experiences and posted daily reports of his visits to the hospital, his exams, his treatment, and the days that followed. One day after his POEM procedure, the patient was able to drink water. On the second day, he was able to eat a soft meal, and progress continued. “Five days after surgery, he discharged from our hospital and went straight to a Chinese restaurant, ordered a full-course meal and ate it all,” Dr. Inoue recounted. “A lot of achalasia patients have access to his blog, and after that, patients from all over Japan came to our hospital.”

How It’s Done POEM requires an exacting set of surgical and nonsurgical skills, but the procedure itself is relatively straightforward. With the patient under general anesthesia, the surgeon introduces an endoscope into the esophagus, makes a small incision in the mucosa with an endo knife, tunnels through the submucosal space (an artificial space created by the surgery) to the defective gastroesophageal valve and performs a myotomy. Once the myotomy is complete, the surgeon retracts the endoscope and closes the mucosal incision with clips. “This is really endoscopicc surgery,” Dr. Inoue said. The goal of POEM is the same as that of a surgical myotomy: “We cut this tight band,” Dr. Inoue said. But with the alternative surgical procedure, the bulk of the procedure’s time is spent gaining access to the

esophageal surface: creating the pneumoperitoneum, retracting the liver, and dissecting the diaphragm and the esophageal ligament to expose the abdominal esophagus. “That is most of the surgical procedure,” Dr. Inoue said. “But when we approach from the inside, it’s not necessary to expose the esophagus. Outside, the esophageal structure is totally normal. We go directly, the shortest way, to the muscle. That is unique.” In addition to being virtually scarless, the POEM approach allows surgeons more control over the length of the myotomy. “With a surgical myotomy, at best we can get 8 to 10 cm; but in the POEM procedure, we can easily do a 20-cm myotomy because we approach from inside,” Dr. Inoue said. “It really is a paradigm shift from laparoscopic treatment to endoscopic treatment. So far, flexible endoscopy was mainly used by gastroenterologists, mainly for diagnostic purposes. But now, POEM is one of the typical examples of flexible endoscopic surgery.”

Pros and Cons In Dr. Inoue’s hands, a POEM takes about an hour. He has performed the procedure in patients as young as 3 years old, and has had overwhelmingly positive feedback from his patients. “Not only the high school teacher, but others have taken their experience to the Web,” he said. Most patients do well the day after the procedure; others feel a bit of irritation that is relieved with a mild painkiller. In the approximately 400 POEMs performed at his institution, Dr. Inoue and his colleagues have experienced no major complications. “Just minor, and those were easily controlled. We just extended the hospital stay a few days and all the patients are happy now,” he said. “Our success rate with the POEM procedure is more than 99%.” Since the report of Dr. Inoue’s first 17 cases was published in Endoscopy (2010;42:265-271), many surgeons have traveled to Japan to observe and learn the procedure. Dr. Inoue estimates that POEM now is being performed in about 30 centers in the United States. The University of California, San Diego (UCSD) Medical Center is one of them, where POEM is being performed by Santiago Horgan, MD, and championed by professor and chairman of the Department of Surgery, Mark Talamini, MD. At a SAGES Presidential Debate on the topic of whether POEM will render laparoscopic Heller myotomy obsolete, Dr. Talamini argued that POEM is surgical endoscopy and natural orifice translumenal endoscopic surgery (NOTES) at its best, that it is the type of disruptive progression toward improving surgical care that is at the core of SAGES’ philosophy, and that the early data support the safety and efficacy of the procedure. “When I was in medical school, this operation was done through a left thoracotomy. When I was a resident, it was being done as an abdominal operation. When I was a junior faculty member, thoracoscopy came in. Then it was done laparoscopically, then robotically in some instances,” Dr. Talamini said. “And

now, [it is done] completely through the mouth. That’s the full progression. “If you think of that dramatic transition for this disease, from Haruhiro Inoue, MD, inventor an open thoracotomy to of the POEM technique. operating through the mouth with an endoscope, it’s hard to imagine a more significant disruption,” he said. Dr. Talamini cited three published works—from Lee Swanstrom, MD’s group in Portland, Ore., from UCSD where the first POEM procedure was performed in the United States and from Dr. Inoue—and noted that with the inclusion of a group in China that has performed hundreds of POEMs, there have been about 1,000 procedures worldwide (as of spring 2013). “So this operation is now gaining traction and experience, and I believe it is here to stay,” Dr. Talamini said. Others were not so quick to embrace POEM. “I don’t do POEM, and you’ll see why,” said C. Daniel Smith, chair of the Department of Surgery, Mayo Clinic, Jacksonville, Fla. Arguing the anti-POEM side of the debate, first, he pointed out, it’s hard to improve on laparoscopic Heller myotomy, which takes about 90 minutes to perform, requires a one-day hospital stay and results in significant improvement of dysphagia in 90% to 95% of patients. “That’s what POEM’s got to deliver, something that takes less than 90 minutes in the operating room, less than one day in the hospital, an equivalent level of dysphagia, and perhaps [fewer] side effects, which gets us to the topic of reflux,” Dr. Smith said. An adequate Heller myotomy relieves patients’ dysphagia, but results in significant reflux. To avoid that consequence, surgeons can perform a fundoplication as part of the procedure. “You can’t do that with a POEM,” Dr. Smith said. The data point to a 20% reflux rate in 10 years’ follow-up on Heller myotomy patients, whereas the sixto 12-month follow-up available on POEM patients shows a reflux rate of 30% to 40%. “This new operation doesn’t seem to be an improvement in terms of outcomes, and might be worse in terms of reflux,” Dr. Smith said. Second, POEM requires a specific set of surgical and endoscopic skills, possibly new equipment, training, proctoring and a sufficient caseload to maintain proficiency. “Right now, there are 6,000 surgical achalasia patients in the country. There are 18,000 active general surgeons, and 7,000 active SAGES members,” Dr. Smith said. “There aren’t enough patients in the country to keep every surgeon who might want to do POEMs proficient. We need only about 150 to 180 surgeons in the entire country to meet the demand for surgical achalasia.” Dr. Smith’s third and final point was that, given the expense of training, POEM will inflate the cost of achalasia treatment without necessarily improving

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

outcomes. He suggested those health care dollars might be more wisely spent on disruptive innovation that would help larger numbers of patients, such as those who have gastroesophageal reflux disease or esophageal cancer. After Drs. Talamini and Smith offered their rebuttals, Jeffrey Ponsky, MD, Oliver H. Payne Professor and chair of the Department of Surgery, Case Western Reserve School of Medicine; and surgeon-in-chief, University Hospitals, Case Medical Center, both in Cleveland, offered his perspective. “This is difficult to do, and it is a beginning. The thing that makes me keep doing POEM is how well the patients do and how good we’re getting at it,” he said. “This is part of the future; it really works, although we will still need Heller myotomy for many patients. “This also distinguishes us from the gastroenterologists. They can’t do this. This is something we should own. It is the entrée to other things,” Dr. Ponsky continued. “So, we have to fight our anxiety and learn the technique. It’s not the end; it’s a beginning.”

Who Should Do POEM, and Why

maneuvers. POEM also requires a set of nonsurgical skills, such as diagnostic endoscopy, mucosotomy, creation of the submucosal tunnel, myotomy and closure of the mucosotomy. The endoscopic skills involve tools and techniques common to endoscopic submucosal dissection.

Time to Proficiency In the Oregon Clinic’s experience of the first 82 achalasia patients treated with POEM, proficiency— defined by shorter length of procedure, standardized variability in minutes per centimeter of myotomy and decrease in inadvertent mucosotomies—reached a plateau after an average of 20 cases (Kurian AA et al. Gastrointest Endosc 2013;77:719-725). “We saw both the minor complications and stress melt away by the 20th case,” Dr. Swanstrom said. “That was in a fellow-level surgeon with the fellowship being in complex endoscopy; they’re really the ideal learner situation.” When a surgeon or gastroenterologist seeks training off-site, some adjustments may need to be made once they return to their home operating room (OR). “Some ORs are not very familiar with flexible endoscopy, so there can be a cultural learning curve to get over as well,” Dr. Swanstrom said. “It’s a good idea to include both endoscopy and OR nurses in the learning phase, so that everyone knows their role.”

In fact, it appears gastroenterologists are performing POEMs. In data on a series of 37 POEMs presented at the annual meeting of the American College of Gastroenterology by Stavros Stavropoulos, MD, director of endoscopy in the Department of Gastroenterology, Hepatology and Nutrition, Winthrop University Hospital, Mineola, N.Y., all were done by ‘There is a group of physicians who are well gastroenterologists. Whether gastroenterologists will wantt to perform equipped to start doing it quite soon, after a POEM is a different issue. little bit of lab work, some didactic learning “There is a group of physicians who are well and proctoring—mostly surgeons who do equipped to start doing it quite soon, after a little bit of lab work, some didactic learning and proctoring— interventional endoscopy. Also, probably mostly surgeons who do interventional endoscopy,” some gastroenterologists who deeply said Lee Swanstrom, MD, chief, Division of GI and understand the anatomy and have MIS Surgery, The Oregon Clinic, in Portland. “Also, probably some gastroenterologists who deeply underadequate backup.’ stand the anatomy and have adequate backup in case —Lee Swanstrom, MD something bad happens, maybe in the context of a team situation with a surgeon close by and available.” A pioneer in NOTES and an early adopter of POEM, Dr. Swanstrom was able to practice the proPerhaps the best way physicians can shorten cedure on animal models and cadavers for about three the learning curve, he suggested, is to be procyears before POEM became a clinical reality. tored by someone with a lot of exxperience in “We were a little ahead of the learning curve because POEM. of that, and we had the benefit of going to Yokohama “Watch them do it so that you can observe and watching Dr. Inoue perform some procedures as their operating team. All of those details, such well, which was very helpful,” he said. n the operatas where you stand, how you position With this background, Dr. Swanstrom needed only ing table, where the assisting nurse puts her table, five or six cases before he became comfortable with are hard to convey in the laboratoryy setting, and POEM. But based on his experience watching other can really slow you down on your first cases if you surgeons gain proficiency in the technique, he esti- don’t have a map to go by.” mates many will need to perform about 20 cases before Patient Demand they feel confident. “In the early cases, it can be frustrating trying to get Again, achalasia is fairly rare, and d it may be difficult into the right plane,” he said. “There could be some for a substantial number of physiciaans to achieve prominor complications involved in that. Nothing terri- ficiency in a reasonable amount of time. bly serious, but time-consuming; if you get a mucosal “There are probably only about a dozen, maybe 20 perforation, you have to add a clip, and that’s certainly centers in the United States that treat more than 20 nerve-wracking on the part of the physician.” achalasia patients a year,” Dr. Swan nstrom said. “So,, if Even surgeons experienced in Heller myotomy will you did only three or four a year, your learning ng curve face a learning curve because the skill set differs signifi- will last forever.” cantly from laparoscopic myotomy. The necessary surgical For centers that have a high enou ugh volu lume to keep skills include strategy for identifying the lower esophageal the learning curve relatively brief, howev ever, being able sphincter, safe use of energy, surgical treatment of capno- to offer POEM may give them a marrketa table advantage. thorax/peritoneum and advanced endoscopic hemostasis “Achalasia is a chronic disease, so patien tients have the

luxury of shopping around,” Dr. Swanstrom said. Despite the obstacles to widespread acceptance of POEM, such as the need for advanced training, the relatively small number of patients indicated for such treatment, and the lack for now of long-term data, physicians who do become proficient in it may find themselves in high demand. “This is one of those things, like laparoscopic cholecystectomy [versus open], where patients perceive a massive difference between it and the laparoscopic approach,” Dr. Swanstrom said. So far, POEM has gotten a far different reaction from patients than NOTES cholecystectomy, which never really sparked patient interest. “They don’t see much difference between a transgastric or transvaginal cholecystectomy and a laparoscopic cholecystectomy,” Dr. Swanstrom said. “But for POEM, we see patients flying in from all over the country to have it done.” Dr. Swanstrom encourages surgeons and centers that want to offer POEM to secure institutional review board approval before doing so, not because it’s an experimental procedure, but because there is a need for people to publish their experiences. “We want to build a critical mass of data on this rare disease,” Dr. Swanstrom said. ■

COLORECTAL CANCER:

The “Right” Perspective

Adenocarcinoma Detection and Prevalence in the Proximal Colon

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

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

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

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

Flat lesion

Serrated lesion

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

Number of interval cancers†

35 33.6

30 25

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

25.5 22.1

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

15 10

‡ Proportion

2.4

5 0

<11%

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

of subjects in whom at least one polyp was identiﬁed.

≥20%

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

Screening colonoscopy: adenoma ﬁndings

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

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

>10 adenomas

Sessile adenomas removed piecemeal

Recommended timing of follow-up

5-10 years

3 years

<3 years; consider possibility of familial syndrome

2-6 months to verify complete removal

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

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

SU-13899

May, 2013

Brought to you as an educational service by

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Experts’ Picks:

Best of The Liver Meeting 2013 COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy Newss asked three hepatologists to share their insights on the annual meeting of the American Association for the Study of Liver Diseases/Liver Meeting 2013. Following are their selections of the top abstracts from the conference.

Kris Kowdley, MD Director of Research Director of the Liver Center of Excellence Digestive Disease Institute Virginia Mason Medical Center Seattle, Washington

LB-6.

Screening in Emergency Department Identifies a Large Cohort of Unrecognized Chronic HCV Infection among Baby Boomers (Galbraith JW et al) Both the Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force have encouraged hepatitis C virus (HCV) screening among baby boomers—those born between 1945 and 1965 (www.uspreventiveservicestaskforce.

org/uspstf/uspshepc.htm m). This study examined thee effect of an em mergency department (ED)–based HCV screeningg program m for patien nts in this age group. In this study, ED D patients at the University of Alabama at Birmingh ham meeting the specified criterion reeceived a questionnaire about prior testting for HCV and test results. Patients were given the option to participate in the screening program, and consentin ng patients underwent HCV antibodyy testing; assay-positive samples were con nfirmed by polymerase chain reaction (PCR) testing. Of 2,3363 baby boomers presenting to the ED during the first six weeks of the program, 1,721 completed the questionnaire: 1,287 were not aware of their HCV status, and of those, 86% ultimately underwent testing.

Dr. Kowdley: Because most patients with chronic HCV infection are unaware that they carry the virus, population-based “point-of-care” screening has the potential to identify a large proportion of those with chronic

‘This study confirms that the majority of patients with HCV are unaware that they have the disease, but also demonstrates that patients are willing to be tested for presence of the infection.’ —Kris Kowdley, MD

Results showed that 12% (118 of 984) of patients had positive antibody findings, and 72.5% (71 of 118) of those were confirmed as HCV positive by PCR testing. Statistical analyses revealed men were significantly more likely than women to have positive antibody assay results (16.5% vs. 7.7%; P<0.001) and PCR HCV RNA findings (80% vs. 57.6%; P=0.02). P

hepatitis C, while eliminating some of the barriers to screening, such as stigmatization. Given the dramatic advances in the treatment of HCV infection, identification of patients with hepatitis C may provide an opportunity to cure most patients and greatly reduce the health care burden associated with complications of liver disease, such as hepatocellular carcinoma

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY FEBRUARY 2014 2014

‘This study showed that increased iron in the reticuloendothelial cell system in the liver was an independent risk factor for the development of NASH and fibrosis in patients with NAFLD.’ —Kris Kowdley, MD

(HCC) and the need for liver transplantation. This study confirms that the majority of patients with HCV are unaware that they have the disease, but also demonstrates that patients are willing to be tested for presence of the infection.

644.

Reticuloendothelial Cell System Iron Staining is a Predictor of Progression to Borderline or Definite Steatohepatitis in Patients without Fibrosis (Kowdley KV et al) This study examined the utility of reticuloendothelial cell system (RES) iron staining for the prediction of nonalcoholic fatty liver disease (NAFLD), and progression to nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. This longitudinal analysis included 310 patients with NAFLD who had undergone at least two biopsies, the first of which included RES iron staining. The two biopsies were conducted at least one year apart, with a mean time between biopsies of 4.4 years. Patients were a mean 47 years of age; 65% were women; and most were white. Findings revealed that 47.2% (34 of 72) of patients who were nonfibrotic on initial biopsy had evidence of fibrosis (stage 1-3) at their second biopsy. Among those without fibrosis and without NASH at the first biopsy, 54.5% (24 of 44) had suspected or definite NASH at second biopsy. Multivariate logistic regression analysis revealed that those without fibrosis who had RES iron upon initial biopsy were nearly five times more likely than those without RES iron to develop fibrosis (odds ratio [OR], 4.89; 95% confidence interval [CI], 1.22-19.5; P P=0.024). Additionally, RES iron upon initial biopsy was associated with a 25-fold increased risk for subsequent NASH among those with no fibrosis at initial biopsy (OR, 25.2; 95% CI, 1.43-443; P=0.027). P Dr. Kowdley: NAFLD affects approximately 20% of individuals in the United States; a subset of these patients have NASH, a more serious form of the disease that may progress to cirrhosis and end-stage liver disease. NAFLD appears to be associated with

obesity, type 2 diabetes and other features of metabolic syndrome. One or more stressors, such as oxidative stress or mitochondrial dysfunction, in patients with NAFLD may lead to NASH and accelerated liver damage. We have been exploring the role of iron as a pro-oxidant in the pathogenesis of NASH, and this study showed that increased iron in the RES in the liver was an independent risk factor for the development of NASH and fibrosis in patients with NAFLD. Possible therapeutic implications may include the role of iron depletion in NASH and the role of dietary iron intake in this condition. Dr. Kowdley reported no relevant conflicts of interest.

Suthat Liangpunsakul, MD, MPH Associate Professor of Medicine Division of Gastroenterology and Hepatology Indiana University School of Medicine Indianapolis, Indiana

83.

Modest Alcohol Consumption Decreases the Risk of Having Nonalcoholic Fatty Liver Disease: A MetaAnalysis of 43,175 Individuals (Sookoian S et al) This study was conducted in light of prior epidemiologic findings showing that consumers of modest amounts of alcohol had a lower prevalence of NAFLD and less histologically severe disease compared with those who abstained from alcohol (Dunn W et al. Hepatology 2008;47:1947-1954). In the current study, researchers performed a meta-analysis of nine published case–control studies and also included unpublished case–control data they had amassed, including data on 414 Argentinean adults. The total patient population included 30,791 adults who abstained from alcohol and 12,384 who drank modestly.

The results revealed that moderate drinkers had a 31% lower risk for NAFLD compared with non-drinkers (OR, 0.684; 95% CI, 0.580-0.806; P<0.05). The protective effect of moderate alcohol consumption was more pronounced in women. Women who drank modestly had a 53% lower risk for NAFLD than nondrinkers, compared with a 30% lower risk among men who drank moderately (P<0.0002). Pooled liver histology data from 550 nondrinkers and 272 modest drinkers showed the latter group also had a 50% lower risk for developing NASH (OR, 0.501; 95% CI, 0.340-0.740; P<0.0005). Multivariate regression analysis showed the associations between modest alcohol consumption and NAFLD prevalence and NASH development were independent of body mass index (BMI). Dr. Liangpunsakul: It is generally recommended that patients with NAFLD not consume alcohol. However, because these patients are at increased risk for cardiovascular disease (CVD), and light to moderate alcohol consumption may have hepatic benefits in people with NAFLD or those at risk for NAFLD, this recommendation may be ill advised. This large meta-analysis found a protective effect of moderate alcohol consumption, which was associated with a 30% lower risk for developing NAFLD, after controlling for BMI. The protective effect seems to be greater in women.

174.

A Prospective, Double-Blind, Randomized PlaceboControlled Trial of Carvedilol for Early Primary Prophylaxis of Esophageal Varices in Cirrhosis (Bhardwaj A et al) Researchers set out to document the efficacy of carvedilol, a non–cardiac-selective vasodilating β-blocker, in the prevention of progression of esophageal varices. To this end, they enrolled 175 consecutive patients with cirrhosis and portal hypertension with esophageal varices less than 5 mm and that did not appear red during upper endoscopy. They randomized patients to receive either carvedilol (mean, 11.92±2.05 mg per day; n=88) or placebo (n=87) for 12 months. Patients underwent upper endoscopy at baseline, and then six and 12 months after treatment initiation. They also underwent transient elastography (FibroScan, Echosens) and hepatic venous pressure gradient (HVPG) measurements at baseline and after 12 months of treatment. Mean baseline HVPG in the drug and placebo groups was 15.3±3.9 and 16.06±5.7 mm Hg, respectively. Mean baseline ChildTurcotte Pugh and Model for End-Stage Liver Disease scores in the carvedilol group were 7.31±2.1 and 13.65±5.4, respectively, and 7.48±2.2 and 14.2±5.28, respectively, in the placebo group. Findings showed that 19% of carvedilol recipients and 20.1% of placebo patients developed large esophageal varices during

‘Although this is another piece of information showing the potential of light to moderate drinking to prevent NAFLD, until further data from rigorous prospective studies become available, individuals with NAFLD should avoid alcohol of any type or amount.’ —Suthat Liangpunsakul, MD, MPH

Although this is another piece of information showing the potential of light to moderate drinking to prevent NAFLD, until further data from rigorous prospective studies become available, individuals with NAFLD should avoid alcohol of any type or amount.

the 12-month period. Additionally, there were no significant differences in HVPG measurements between the two groups at 12 months. There was no correlation between changes in HVPG and transient elastography findings in carvedilol and placebo recipients after 12 months. see Best of AASLD, page 12

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Best of AASLD continued from page 11

Safety data revealed 7.9% of carvedilol patients experienced adverse events compared with 1.4% of placebo recipients (P=not P significant). No deaths related to variceal bleeding occurred in either group.

114.

improvement: At week 24, CK18 dropped an average of 134±376 U/L compared with a decrease of 19±387 U/L, respectively (P=0.09); at week 48, CK18 dropped an average of 194±467 U/L compared with a decrease of 45±350 U/L (P=0.004); and at week 96, CK18 dropped an average of 206±432 U/L compared with a decrease of 2±474 U/L (P<0.001). Similarly, changes in serum CK18 were significantly associated with resolution of NASH at week 96 (–202±465 U/L at baseline for those with NASH resolution vs. +16±474 U/L for those without; P<0.001). Multivariate analyses confirmed that serum CK18 changes were associated with changes in all NAFLD histologic components, as well as with the extent of fibrosis and alanine transaminase (ALT) levels.

Investigators set out to determine if serum keratin 18 fragment (CK18) levels, which are associated with NASH severity in children with NAFLD, also predict longitudinal changes in liver histology in these patients. To this end, they documented serum CK18 levels in 127 children with NAFLD enrolled in the

Dr. Vuppalanchi: Cross-sectional studies in children have shown that serum CK18 levels correlate with severity of NASH (Vos MB et al. J Pediatr Gastroenterol Nutr 2008;47:481485). It therefore holds the most promise of being a noninvasive biomarker for NASH. However, it is not known if serum CK18 levels can predict longitudinal changes in liver histology. The recently concluded TONIC trial provided investigators with the ideal platform to address this question. In the current study, changes in serum

‘This information, although intuitive, provides compelling evidence to identify and treat NASH patients with advanced fibrosis.’ —Raj Vuppalanchi, MD

Dr. Liangpunsakul: Esophageal variceal bleeding poses a significant risk for morbidity and mortality among patients with cirrhosis. Several attempts have been made to slow the progression of esophageal variceal from small to large varices. For example, previous research has shown the probability of developing large varices was significantly lower in patients treated with the nonselective β-blocker, nadolol (Merkel C et al. Gastroenterology 2004;127:476-484); however, there were no differences in survival or the incidence of variceal bleeding in the nadolol versus placebo groups. In the current study, Bhardwaj et al performed a randomized placebo-controlled trial of carvedilol for early primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. They found carvedilol was not effective in preventing the growth of small varices, and more importantly, this medication was not effective in reducing HVPG during the 12-month treatment period. Dr. Liangpunsakul reported no conflicts of interest.

Raj Vuppalanchi, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Indiana University School of Medicine Indianapolis, Indiana

LB-5.

Fibrosis Stage, But Not NAS, Is Predictive of Disease-Specific Mortality in NAFLD After 33 Years of Follow-Up (Ekstedt M et al) These investigators evaluated the risk for all-cause and disease-specific mortality in a cohort of 229 patients with biopsy-proven NAFLD compared with a group of 2,290 matched controls without NAFLD. NAFLD patients were a mean 47 years of age at the time of biopsy, and controls were age-matched. Causes of death among controls were determined

through national registry records. The researchers found a mortality rate of 41.9% (96 of 229) in NAFLD patients and 34.3% (786 of 2,290) among controls during the mean 26.4 years of followup. Statistical analyses revealed that NAFLD patients were 26% more likely than controls to die during the followup period (hazard ratio [HR], 1.26; 95% CI, 1.0-1.6; P P=0.034). Mortality among NAFLD patients was more likely to be due to CVD (HR, 1.5; 95% CI, 1.1-2.2; P=0.01), HCC (HR, 6.5; 95% CI, 2.1P 20; P P=0.001), cirrhosis (HR, 3.2; 95% CI, 1.0-9.8; P P=0.04) or infection (HR, 2.7; 95% CI, 1.0-7.3; P=0.046). P Patients with a NAFLD Activity Score (NAS) between 0 and 4 with a fibrosis stage of 0 to 2 at baseline did not have an increase in overall or disease-specific mortality. However, the combination of any NAS and stage 3 to 4 fibrosis increased the risk for all-cause mortality compared with controls (HR, 3.7; 95% CI, 2.4-5.7; P<0.001). Those with severe fibrosis also had the highest risk for death due to CVD, HCC, cirrhosis or infection. NAS greater than 4 did not independently increase the risk for all-cause mortality, but it did increase the risk for HCC-related death (HR, 15.7; 95% CI, 4.1-59.9; P<0.001). Dr. Vuppalanchi: Long-term outcomes of prior studies consistently have shown an increased overall mortality rate among patients with NAFLD and NASH compared with control populations. The most common causes of death are CVD, followed by cancer and liver-related death. Patients with NASH, but not NAFLD, have an increased risk for liver-related mortality (Rafiq N et al. Clin Gastroenterol Hepatol 2009;7:234-238). The current study confirms these prior findings in a large cohort of patients with biopsy-proven NAFLD over a long follow-up. Additionally, these adverse outcomes were related to advanced fibrosis (stage 3/4) and occurred independently of NAS. This information, although intuitive, provides compelling evidence to identify and treat NASH patients with advanced fibrosis.

Emerging modalities of fibrosis assessment—such as vibrationcontrolled transient elastography (FibroScan), magnetic resonance elastography, FIB-4 index, cytokeratin-18 or NAFLD fibrosis score—may allow us to identify these high-risk patients without a liver biopsy. Serum Keratin Fragment 18 (CK18) Levels Significantly Predict Changes in Liver Histology in Children and Adolescents With Nonalcoholic Fatty Liver Disease (NAFLD): Results From the TONIC Trial (Jain AK et al)

‘Changes in serum CK18 levels were strongly predictive of histologic response with fair accuracy, regardless of treatment assignment.’ —Raj Vuppalanchi, MD

TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial (Lavine JE et al. JAMA A 2011;305;16591668). That study examined the efficacy of 96 weeks of treatment with vitamin E, metformin or placebo. Serum CK18 levels were measured at baseline and then at weeks 24, 48 and 96, and liver biopsies were conducted at baseline and week 96. Investigators found that serum CK18 levels were similar in all three groups throughout the 96-week period. However, regardless of the type of treatment they received, children who experienced histologic improvements in NAFLD had greater decreases in serum CK18 compared with those without histologic

CK18 levels were strongly predictive of histologic response with fair accuracy (area under the receiver operating characteristic curve, 0.7-0.8), regardless of treatment assignment. An additional important finding from the current study is the ability to predict histologic response at an earlier time, based on a decrease in CK18 levels. There was a significant correlation between CK18 and ALT levels, and it would be interesting to know if changes in the combination of CK18 and ALT values would be more predictive of histologic change compared with changes in either of the values. ■ Dr. Vuppalanchi reported no relevant conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY FEBRUARY 2014 2014

HEPATOLOGY IN FOCUS

DAAs continued from page 1

“There are multiple, oral, interferon [IFN]-free DAA regimens in late-stage clinical trials with high SVR [sustained virologic response] rates,” said Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology and professor of medicine at the Johns Hopkins School of Medicine, in Baltimore. These include the Gilead-based regimen of sofosbuvir plus ledipasvir, with or without GS-9669; AbbVie’s ABT450/r plus ABT267 and ABT333; Boehringer Ingelheim’s faldaprevir plus deleobuvir, with or without PPI-668; Janssen’s simeprevir and

“We are now going to get into an era of using combinations of direct-acting antivirals,” said Luis Balart, MD, chief of gastroenterology and hepatology at Tulane University School of Medicine, in New Orleans. “There will be two drugs, three in some cases, attacking the virus at different sites. By attacking the virus at two or three different sites, you prevent the resistance to agents that may lead to failure or cause patients to relapse.”

Robust Pipeline At The Liver Meeting 2013, investigators presented data on numerous promising DAAs.

to follow-up), and the drugs were well tolerated. The ELECTRON trial examined SOF/LDV FDC in 110 patients with HCV genotype 1 and included five cohorts. Prior null responders with stage F4 fibrosis received SOF/LDV FDC or SOF/LDV FDC plus ribavirin for 12 weeks. Prior null responders with F3/ F4 disease received 12 weeks of SOF/ LDV FDC plus ribavirin, with or without GS-9669, an NS5B non-nucleoside inhibitor. In the fifth cohort, treatmentnaive patients without cirrhosis received SOF/LDV FDC plus ribavirin for six weeks. SVR rates at week 12 were 68%

‘There are multiple, oral, IFN-free DAA regimens in late-stage clinical trials with high SVR rates.’ —Mark Sulkowski, MD

samatasvir plus TMC647055/r; and Merck’s MK-8742 plus MK-5172. At press time, Bristol-Myers Squibb was in the process of submitting a regulatory filing for either daclatasvir plus asunaprevir, or this combination plus BMS 791325.

Three Mechanisms of Attack The new hepatitis C virus (HCV) DAAs can be classified into three groups: protease inhibitors, such as simeprevir, with drug names ending in “previr”; polymerase inhibitors, such as sofosbuvir, with names ending in “buvir”; and NS5A inhibitors, such as daclatasvir, with names ending in “asvir.” All of the new agents target specific processes of the HCV life cycle. Protease inhibitors prevent cleavage of HCV polypeptides into the mature viral proteins necessary for replication and tend to be genotype-specific. Polymerase inhibitors can be subclassified into nucleos(t)ide analogs and nonnucleos(t)ide analogs. Nucleos(t)ide analogs, which are pangenotypic, mimic the natural substrates of polymerase and inhibit the active site. Non-nucleos(t)ide inhibitors, aimed at HCV genotype 1, bind to several discrete sites outside of the polymerase active site, resulting in a conformational change, which in many cases, but not always, leads to loss of polymerase function. The NS5A inhibitors interfere with a membraneassociated phosphoprotein involved in HCV virion production. The treatment strategy involving these new agents is to include drugs that attack at least two different HCV targets in a single regimen.

variants, and the regimens were well tolerated. At press time, Gilead was finalizing regulatory filing for SOF/LDV FDC in HCV genotype 1 patients. The PEARL-I trial tested 12 weeks of treatment with ABT-450/r, an HCV protease inhibitor dosed with ritonavir, plus ABT-267, an HCV NS5A inhibitor, in HCV genotype 1b, treatment-naive patients (n=42) and prior null responders (n=40) with stage F1 to F3 fibrosis. Roughly 95% of treatment-naive patients and 90% of null responders achieved SVR at week 12. There were no treatment discontinuations due to adverse events, and only one drug interruption because of grade 3 alanine aminotransferase elevation. Researchers also presented results from a cohort of HCV genotype 1 patients treated in the AVIATOR trial with ABT450/r, ABT267 and ABT333 for 12 or 24 weeks, including 159 treatment-naive patients and 88 null responders. All 24 patients in the trial who required dose reductions achieved SVR at week 24. In the 223 patients who maintained full doses, 92.1% of treatment-naive patients and 94% of null responders achieved SVR at week 24. The SOUND-C3 trial tested faldaprevir and deleobuvir plus ribavirin for

‘We are now going to get into an era of using combinations of direct-acting antivirals. There will be two drugs, three in some cases, attacking the virus at different sites.’ —Luis Balart, MD The LONESTAR trial evaluated an oral, fixed-dose combination tablet containing sofosbuvir and ledipasvir (SOF/LDV FDC). In this trial, 60 non-cirrhotic, treatment-naive patients with HCV genotype 1 infection were randomized to receive treatment with either SOF/LDV FDC for eight weeks, SOF/LDV FDC plus ribavirin for eight weeks or SOF/LDV FDC for 12 weeks. Additionally, 40 patients who had not achieved SVR after previous treatment with an HCV protease inhibitor regimen were randomized to receive 12 weeks of treatment with SOF/LDV FDC or SOF/LDV FDC plus ribavirin; 55% of these patients had compensated cirrhosis. Only two patients in the entire study experienced relapse (one patient was lost

in treatment-naive patients and 70% in treatment-experienced patients with stage F4 fibrosis who received 12 weeks of SOF/LDV FDC. All other patients achieved SVR at week 12. The National Institute of Allergy and Infectious Diseases SYNERGY trial tested SOF/LDV FDC alone for 12 weeks or in combination with GS-9451 or GS-9669 for six weeks in HCV genotype 1–infected patients; nearly 90% of patients in the trial were black. SVR at week 12 was 100% in patients who received only the fixed-dose tablet. Among patients who received combination treatment, SVR at week 4 was 90% at the time the data were reported, with one relapse. Efficacy was not reduced in patients with baseline NS5A resistance

12 weeks in HCV genotype 1a (n=12) and 1b (n=20) patients. Although 10 of the 12 HCV genotype 1a patients failed therapy, 95% of patients with genotype 1b (19 of 20) achieved SVR at week 12. A Phase III trial in genotype 1b patients is under way. In another trial of faldaprevir and deleobuvir, 12 weeks of treatment including PPI-668, with or without ribavirin, is being tested in 37 patients with HCV genotype 1a. At press time, all 13 patients who were evaluable at week 4 had achieved SVR. Only one patient discontinued therapy due to gastrointestinal symptoms. The C-Worthy trial tested the NS5A inhibitor MK-5172 plus two doses of MK-8742, with (n=52) or without (n=13) ribavirin for 12 weeks. SVR rates at week see DAAs, page 14

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

DAAs continued from page 13

12 ranged from 89% to 100%. None of the patients discontinued treatment because of side effects. One patient who suffered a virologic relapse had HCV genotype 1a; he had an NS5A polymorphism in Y93N and a protease mutation in D168A/D, both of which were thought to play a role in the treatment failure.

“In general, when you look at an antiviral drug, you need think about its resistance profile, whether it’s pan-genotypic, how potent it is, the adverse-event profile and the drug–drug interaction profile,” Dr. Poordad said. For many of the new DAAs, clinicians will not be able to rely on traditional

was treated for eight weeks with sofosbuvir plus ledipasvir and then relapsed after treatment. At the time of relapse, the patient’s viral quasi-species included variants with mutations conferring decreased susceptibility to both sofosbuvir and ledipasvir. The key features of this patient’s case, Dr. Sulkowski said, were

Exciting Results, With Caveats

‘In general, when you look at

The list of DAA regimens in development outlined in this article is not even exhaustive. And although clinicians are enthusiastic about the new drugs, they also realize that increased options will bring challenges, especially because there are no clinical trials comparing one new DAA regimen with another. The activity of the new DAAs is being compared to historical data. “What we are seeing are new Phase III trials that are going to be producing approved drugs that have never been

an antiviral drug, you need think about its resistance profile, whether it’s pangenotypic, how potent it is, the adverse-event profile and the drug–drug interaction profile.’ —Fred Poordad, MD

the majority of studies, the new regimens are a homerun, according to Dr. Balart. Which combinations ultimately get used in clinical practice will be influenced by which drugs get to market first. “Whichever drugs are first to market always have an advantage, because physicians become familiar with them first,” Dr. Balart said. “However, given enough time, others will eventually catch up and become part of the available armamentarium, much like what has happened in the HIV treatment arena.” ■

‘By attacking the virus at two or three different sites, you prevent the resistance to agents that may lead to failure or cause patients to relapse.’ —Luis Balart, MD

compared with any other regimens,” said David Nelson, MD, vice president for research, University of Florida, Gainesville. “It is fantastic to move those drugs forward, but when we try to understand how those regimens will compare with each other in populations, it will be years before we have that type of data.” Dr. Nelson pointed out that there are many new regimens for HCV genotype 1 that have similar SVR rates. He believes that most clinicians will make decisions based on data from Phase II and Phase IV studies, the cohort and case–control studies using drugs in special populations. “We will have a lot of data like that and, of course, we will see a lot of case series and guidelines and opinions, based on a lower level of evidence. The highest standard of evidence will be limited, which will really challenge us to select the best regimen.” Fred Poordad, MD, vice president of academic and clinical affairs at The Texas Liver Institute, San Antonio, said clinicians will need to scrutinize the drug combinations.

feel like they have the flu every day. We have had patients who have been sick from something else, such as an appendectomy, that had nothing to do with DAAs, and they were able to continue therapy.” With the side-effect profile and the shortened treatment time, 12 weeks in

baseline predictors of response. “From AVIATOR, we learned that some of our previously learned baseline predictors do not hold true. Things such as subtype, high viral load, degree of fibrosis excluding cirrhosis and IL28B B [interleukin-28 B] status did not seem to affect the efficacy, even in this null-responder population,” Dr. Poordad noted. “I think the good news is that cirrhotics, even cirrhotic nulls, can achieve very high SVR rates with these oral agents. The caveat is the numbers are all small.” Dr. Nelson agreed: “We, unfortunately, still see very small numbers of cirrhotics in most registration trials, so we need to be careful about extrapolating data on limited patients to broad real-world representation.”

Redefining Treatment Failures According to Dr. Sulkowski, the new DAAs might change current notions about HCV resistance to these drugs. This concept is supported by a single patient in the LONESTAR trial who

the presence of the S282T T mutation, which has been rarely seen in patients treated to date, and what happened next with retreatment: When clinicians initiated a second round of treatment with the same drugs, sofosbuvir and ledipisvir, plus the addition of ribavirin, the patient had robust and rapid viral suppression, and following a longer course of therapy (24 weeks), achieved SVR. “Clearly, we need to learn more about retreatment of DAA failures, and that is one of our next challenges,” said Dr. Sulkowski. “This single case report may redefine how we think about treatment failures.”

DAAs a Homerun What will definitely be redefined is the patient experience. “The difference between these new DAA regimens and IFN and ribavirin is the difference between night and day,” said Dr. Balart. “The side-effect profile is so much better. These patients don’t get the systemic malaise, where they

Dr. Sulkowski has received consulting fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck & Co. and Vertex Pharmaceuticals. Dr. Balart has received research grant support from AbbVie, Bayer, Boehringer Ingelheim, Genentech, Genfit, GI Dynamics, Gilead, Janssen, Merck, Ocera, Salix Pharmaceuticals and Takeda Pharmaceutical; he has been involved with the advisory boards of AbbVie, Gilead, Janssen and Merck; and he has been on the speakers’ bureaus of Boehringer Ingelheim, Janssen, Merck and Salix. Dr. Poordad is a speaker for Gilead; he has received grant/research support from all of the companies mentioned in this article, except for AbbVie; and he is a consultant for Abbott, Achillion, Anadys, Inhibitex, Merck, Novartis, Pfizer, Pharmasset, Theravance and Tibotec. Dr. Nelson has received grant/research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech-Roche, Gilead, Merck and Vertex, and has served on the advisory committee/review panel for AbbVie, Gilead, Merck and Vertex.

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)

HEPATOLOGY IN FOCUS

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

The Rise of Sofosbuvir BY KATE Oâ&#x20AC;&#x2122;ROURKE BOSTONâ&#x20AC;&#x201D;Many clinicians are ecstatic about the recent approval of sofosbuvir (Sovaldi, Gilead Sciences) for patients with hepatitis C virus (HCV) infection. At The Liver Meeting 2013, several presentations provided new insight into just how sofosbuvir will perform in clinical practice. â&#x20AC;&#x153;I think sofosbuvir is the catâ&#x20AC;&#x2122;s meow,â&#x20AC;?

said Sammy Saab, MD, MPH, professor of medicine and surgery and head of outcomes research in hepatology at the David Geffen School of Medicine, University of California, Los Angeles. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s a drug that has no resistance or incremental adverse effects. It is very well tolerated, very safe, very efficacious and there are no significant drug interactions with it. I think it is going to revolutionize the way we treat hepatitis in this country and around the world.â&#x20AC;? Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHĂ&#x20AC;H[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ RU DVSLUDWLRQ VKRXOG EH REVHUYHG GXULQJ WKH DGPLQLVWUDWLRQ RI PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion (DFK SDFNHW PXVW EH GLVVROYHG LQ RXQFHV RI FROG ZDWHU DQG 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. LQJHVWLRQ RI WKH XQGLVVROYHG SRZGHU PD\ LQFUHDVH WKH ULVN RI QDXVHD YRPLWLQJ GHK\GUDWLRQ DQG HOHFWURO\WH GLVWXUEDQFHV INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV CONTRAINDICATIONS DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW PREPOPIK is contraindicated in the following conditions: EH GLUHFWO\ FRPSDUHG WR UDWHV LQ FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ Â&#x2021; 3DWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ FUHDWLQLQH FOHDUDQFH 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 DQG YRPLWLQJ ZHUH WKH PRVW FRPPRQ DGYHUVH UHDFWLRQV !

Â&#x2021; *DVWURLQWHVWLQDO REVWUXFWLRQ RU LOHXV IROORZLQJ 35(323,. DGPLQLVWUDWLRQ 7KH SDWLHQWV ZHUH QRW EOLQGHG WR Â&#x2021; %RZHO SHUIRUDWLRQ WKH VWXG\ GUXJ 6LQFH DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ Â&#x2021; 7R[LF FROLWLV RU WR[LF PHJDFRORQ and watery diarrhea are known to occur in response to colon cleansing Â&#x2021; *DVWULF UHWHQWLRQ SUHSDUDWLRQV WKHVH HIIHFWV ZHUH GRFXPHQWHG DV DGYHUVH HYHQWV LQ Â&#x2021; $Q DOOHUJ\ WR DQ\ RI WKH LQJUHGLHQWV LQ 35(323,. WKH FOLQLFDO WULDOV RQO\ LI WKH\ UHTXLUHG PHGLFDO LQWHUYHQWLRQ VXFK DV a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS GLDJQRVWLF SURFHGXUHV PHW WKH FULWHULD IRU D VHULRXV DGYHUVH HYHQW Serious Fluid and Serum Chemistry Abnormalities RU VKRZHG FOLQLFDOO\ VLJQLÂżFDQW ZRUVHQLQJ GXULQJ WKH VWXG\ WKDW ZDV $GYLVH SDWLHQWV WR K\GUDWH DGHTXDWHO\ EHIRUH GXULQJ DQG DIWHUU WKH QRW LQ WKH IUDPH RI WKH XVXDO FOLQLFDO FRXUVH DV GHWHUPLQHG E\ WKH XVH RI 35(323,. 8VH FDXWLRQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW LQYHVWLJDWRU IDLOXUH ZKHQ UHSODFLQJ Ă&#x20AC;XLGV ,I D SDWLHQW GHYHORSV VLJQLÂżFDQW YRPLWLQJ 35(323,. ZDV FRPSDUHG IRU FRORQ FOHDQVLQJ HIIHFWLYHQHVV ZLWK or signs of dehydration including signs of orthostatic hypotension D SUHSDUDWLRQ FRQWDLQLQJ WZR OLWHUV / RI SRO\HWK\OHQH JO\FRO SOXV after taking PREPOPIK, consider performing post-colonoscopy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compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were GRFXPHQWHG RXW WR VHYHQ GD\V SRVW FRORQRVFRS\ Table 1: Treatment-Emergent Adverse Reactions observed in at )OXLG DQG HOHFWURO\WH GLVWXUEDQFHV FDQ OHDG WR VHULRXV DGYHUVH HYHQWV Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** DQG HOHFWURO\WH DEQRUPDOLWLHV VKRXOG EH FRUUHFWHG EHIRUH WUHDWPHQW ZLWK 35(323,. ,Q DGGLWLRQ XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen IRU SDWLHQWV ZKR KDYH FRQGLWLRQV RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW Reaction LQFUHDVH WKH ULVN IRU Ă&#x20AC;XLG DQG HOHFWURO\WH GLVWXUEDQFHV RU WKDW PD\ PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* LQFUHDVH WKH ULVN RI DGYHUVH HYHQWV RI VHL]XUH DUUK\WKPLD DQG UHQDO (N=296) with 2 x (N=305) with 2 x 5-mg impairment. n (% = n/N) bisacodyl n (% = n/N) 5-mg Seizures 7KHUH KDYH EHHQ UHSRUWV RI JHQHUDOL]HG WRQLF FORQLF VHL]XUHV ZLWK WKH XVH RI ERZHO SUHSDUDWLRQ SURGXFWV LQ SDWLHQWV ZLWK QR SULRU KLVWRU\ RI VHL]XUHV 7KH VHL]XUH FDVHV ZHUH DVVRFLDWHG ZLWK HOHFWURO\WH DEQRUPDOLWLHV H J K\SRQDWUHPLD K\SRNDOHPLD K\SRFDOFHPLD DQG K\SRPDJQHVHPLD DQG ORZ VHUXP RVPRODOLW\ 7KH QHXURORJLF DEQRUPDOLWLHV UHVROYHG ZLWK FRUUHFWLRQ RI Ă&#x20AC;XLG DQG HOHFWURO\WH DEQRUPDOLWLHV 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK D 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 EHQ]RGLD]HSLQHV SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG K\SRQDWUHPLD Use in Patients with Renal Impairment $V LQ RWKHU PDJQHVLXP FRQWDLQLQJ ERZHO SUHSDUDWLRQV XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK LPSDLUHG UHQDO IXQFWLRQ or patients taking concomitant medications that may affect renal IXQFWLRQ VXFK DV GLXUHWLFV DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQJLRWHQVLQ UHFHSWRU EORFNHUV RU QRQ VWHURLGDO DQWL LQĂ&#x20AC;DPPDWRU\ GUXJV 7KHVH SDWLHQWV PD\ EH DW LQFUHDVHG ULVN IRU UHQDO LQMXU\ $GYLVH WKHVH SDWLHQWV RI WKH LPSRUWDQFH RI DGHTXDWH K\GUDWLRQ EHIRUH GXULQJ DQG DIWHU WKH XVH RI 35(323,. &RQVLGHU SHUIRUPLQJ EDVHOLQH DQG SRVW FRORQRVFRS\ ODERUDWRU\ WHVWV HOHFWURO\WHV FUHDWLQLQH DQG %81 LQ WKHVH SDWLHQWV ,Q SDWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

bisacodyl tablets (N=302) n (% = n/N) 1DXVHD 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) / 3(* ( WZR OLWHUV SRO\HWK\OHQH JO\FRO SOXV HOHFWURO\WHV VROXWLRQ DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ DQG ZDWHU\ GLDUUKHD QRW UHTXLULQJ DQ LQWHUYHQWLRQ ZHUH QRW FROOHFWHG tablets (N=298) n (% = n/N)

According to studies presented at The Liver Meeting, many factors traditionally thought to portend poor outcomes in HCV patients may not have an effect with sofosbuvir. One study was a retrospective analysis of 982 patients with HCV infection (genotypes 1-6) in four Phase III trials: FISSION, POSITRON, FUSION and NEUTRINO. Patients were treated with sofosbuvir plus ribavirin, with or without pegylated interferon

DUUK\WKPLDV DQG SURORQJHG 47 LQ WKH VHWWLQJ RI Ă&#x20AC;XLG DQG HOHFWURO\WH DEQRUPDOLWLHV 7KLV LQFOXGHV SDWLHQWV UHFHLYLQJ GUXJV ZKLFK PD\ EH 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 GUXJV NQRZQ WR LQGXFH $QWLGLXUHWLF +RUPRQH 6HFUHWLRQ 6,$'+ VXFK DV WULF\FOLF DQWLGHSUHVVDQWV VHOHFWLYH VHURWRQLQ UH XSWDNH LQKLELWRUV DQWLSV\FKRWLF GUXJV DQG FDUEDPD]HSLQH DV WKHVH GUXJV PD\ LQFUHDVH WKH ULVN RI ZDWHU UHWHQWLRQ DQG RU HOHFWURO\WH LPEDODQFH &RQVLGHU DGGLWLRQDO SDWLHQW HYDOXDWLRQV DV DSSURSULDWH 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 DQG WKH PHGLFDWLRQ PD\ QRW EH DEVRUEHG 7HWUDF\FOLQH DQG Ă&#x20AC;XRURTXLQRORQH DQWLELRWLFV LURQ GLJR[LQ FKORUSURPD]LQH DQG SHQLFLOODPLQH VKRXOG EH WDNHQ DW OHDVW KRXUV EHIRUH DQG QRW OHVV WKDQ KRXUV DIWHU DGPLQLVWUDWLRQ RI 35(323,. WR DYRLG FKHODWLRQ ZLWK PDJQHVLXP Antibiotics 3ULRU RU FRQFRPLWDQW XVH RI DQWLELRWLFV ZLWK 35(323,. PD\ UHGXFH HIÂżFDF\ RI 35(323,. DV FRQYHUVLRQ RI VRGLXP SLFRVXOIDWH WR LWV DFWLYH PHWDEROLWH %+30 LV PHGLDWHG E\ FRORQLF EDFWHULD USE IN SPECIFIC POPULATIONS Pregnancy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needed. Nursing Mothers ,W LV QRW NQRZQ ZKHWKHU WKLV GUXJ LV H[FUHWHG LQ KXPDQ PLON %HFDXVH PDQ\ GUXJV DUH H[FUHWHG LQ KXPDQ PLON FDXWLRQ VKRXOG EH H[HUFLVHG when PREPOPIK is administered to a nursing woman. Pediatric Use 7KH VDIHW\ DQG HIIHFWLYHQHVV RI 35(323,. LQ SHGLDWULF SDWLHQWV KDV QRW EHHQ HVWDEOLVKHG

Geriatric Use ,Q FRQWUROOHG FOLQLFDO WULDOV RI 35(323,. RI SDWLHQWV ZHUH \HDUV RI DJH RU ROGHU 7KH RYHUDOO LQFLGHQFH RI WUHDWPHQW HPHUJHQW DGYHUVH HYHQWV ZDV VLPLODU DPRQJ SDWLHQWV Â&#x2022; \HDUV RI DJH I DQG SDWLHQWV \HDUV RI DJH $PRQJ DOO SDWLHQWV Â&#x2022; years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities ZDV JUHDWHU LQ WKH 35(323,. JURXS WKDQ LQ WKH FRPSDUDWRU In general, PREPOPIK was associated with numerically higher rates JURXS RI DEQRUPDO HOHFWURO\WH VKLIWV RQ WKH GD\ RI FRORQRVFRS\ FRPSDUHG WR WKH SUHSDUDWLRQ FRQWDLQLQJ / RI 3(* ( SOXV WZR [ PJ ELVDFRG\O 5HQDO ,QVXIĂ&#x20AC;FLHQF\ WDEOHWV 7KHVH VKLIWV ZHUH WUDQVLHQW LQ QDWXUH DQG QXPHULFDOO\ VLPLODU Patients with impaired renal function or patients taking concomitant EHWZHHQ WUHDWPHQW DUPV DW WKH 'D\ YLVLW medications that may affect renal function (such as diuretics, DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQJLRWHQVLQ UHFHSWRU Postmarketing Experience EORFNHUV RU QRQ VWHURLGDO DQWL LQĂ&#x20AC;DPPDWRU\ GUXJV PD\ EH DW 7KH IROORZLQJ IRUHLJQ VSRQWDQHRXV UHSRUWV KDYH EHHQ LGHQWLÂżHG GXULQJ LQFUHDVHG ULVN IRU IXUWKHU UHQDO LQMXU\ $GYLVH WKHVH SDWLHQWV RI WKH XVH RI IRUPXODWLRQV VLPLODU WR 35(323,. %HFDXVH WKHVH HYHQWV DUH LPSRUWDQFH RI DGHTXDWH K\GUDWLRQ EHIRUH GXULQJ DQG DIWHU WKH XVH UHSRUWHG YROXQWDULO\ IURP D SRSXODWLRQ RI XQFHUWDLQ VL]H LW LV QRW DOZD\V RI 35(323,. &RQVLGHU SHUIRUPLQJ EDVHOLQH DQG SRVW FRORQRVFRS\ SRVVLEOH WR UHOLDEO\ HVWLPDWH WKHLU IUHTXHQF\ RU HVWDEOLVK D FDXVDO ODERUDWRU\ WHVWV HOHFWURO\WHV FUHDWLQLQH DQG %81 LQ WKHVH SDWLHQWV relationship to drug exposure. ,Q SDWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ FUHDWLQLQH FOHDUDQFH P/ PLQ DFFXPXODWLRQ RI PDJQHVLXP LQ SODVPD PD\ RFFXU 7KH Allergic reactions VLJQV DQG V\PSWRPV RI K\SHUPDJQHVHPLD PD\ LQFOXGH EXW DUH QRW &DVHV RI K\SHUVHQVLWLYLW\ UHDFWLRQV LQFOXGLQJ UDVK XUWLFDULD DQG OLPLWHG WR GLPLQLVKHG RU DEVHQW GHHS WHQGRQ UHĂ&#x20AC;H[HV VRPQROHQFH SXUSXUD KDYH EHHQ UHSRUWHG K\SRFDOFHPLD K\SRWHQVLRQ EUDG\FDUGLD PXVFOH UHVSLUDWRU\ SDUDO\VLV FRPSOHWH KHDUW EORFN DQG FDUGLDF DUUHVW Electrolyte abnormalities 7KHUH KDYH EHHQ UHSRUWV RI K\SRNDOHPLD K\SRQDWUHPLD DQG OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation 7KH SDWLHQW ZKR KDV WDNHQ DQ RYHUGRVH VKRXOG EH PRQLWRUHG FDUHIXOO\ prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias 7KHUH KDYH EHHQ UDUH UHSRUWV RI VHULRXV DUUK\WKPLDV DVVRFLDWHG ZLWK WKH XVH RI LRQLF RVPRWLF OD[DWLYH SURGXFWV IRU ERZHO SUHSDUDWLRQ 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV DW LQFUHDVHG ULVN RI DUUK\WKPLDV H J SDWLHQWV ZLWK D KLVWRU\ RI SURORQJHG 47 XQFRQWUROOHG DUUK\WKPLDV UHFHQW P\RFDUGLDO LQIDUFWLRQ XQVWDEOH DQJLQD FRQJHVWLYH heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal (&*V VKRXOG EH FRQVLGHUHG LQ SDWLHQWV DW LQFUHDVHG ULVN RI VHULRXV $EGRPLQDO SDLQ GLDUUKHD IHFDO LQFRQWLQHQFH DQG SURFWDOJLD KDYH EHHQ UHSRUWHG ZLWK WKH XVH RI 35(323,. IRU FRORQ SUHSDUDWLRQ cardiac arrhythmias. SULRU WR FRORQRVFRS\ 7KHUH KDYH EHHQ LVRODWHG UHSRUWV RI UHYHUVLEOH Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis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eurologic FRORQRVFRS\ ÂżQGLQJV LQ SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG LQĂ&#x20AC;DPPDWRU\ 7KHUH KDYH EHHQ UHSRUWV RI JHQHUDOL]HG WRQLF FORQLF VHL]XUHV associated with and without hyponatremia in epileptic patients. ERZHO GLVHDVH 8VH LQ 3DWLHQWV ZLWK 6LJQLĂ&#x20AC;FDQW *DVWURLQWHVWLQDO 'LVHDVH ,I JDVWURLQWHVWLQDO REVWUXFWLRQ RU SHUIRUDWLRQ LV VXVSHFWHG SHUIRUP DSSURSULDWH GLDJQRVWLF VWXGLHV WR UXOH RXW WKHVH FRQGLWLRQV EHIRUH I DGPLQLVWHULQJ 35(323,. 8VH ZLWK FDXWLRQ LQ SDWLHQWV ZLWK VHYHUH DFWLYH XOFHUDWLYH FROLWLV

Traditional Risk Factors Fade Away

DRUG INTERACTIONS

0DQXIDFWXUHG E\ Ferring Pharmaceuticals (China) Co., Ltd. 1R +XL/LQJ /X )HUULQJ 5RDG

1DWLRQDO +HDOWK 7HFKQRORJ\ 3DUN =KRQJVKDQ &LW\ *XDQJGRQJ 3URYLQFH &+,1$ 0DQXIDFWXUHG IRU Ferring Pharmaceuticals Inc. 3DUVLSSDQ\ 1 -

www.ferringusa.com )(55,1* Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Â&#x2039; )HUULQJ 3KDUPDFHXWLFDOV ,QF 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK FRQGLWLRQV $OO ULJKWV UHVHUYHG 3ULQWHG LQ 86$ RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW LQFUHDVH WKH ULVN IRU Ă&#x20AC;XLG DQG 35(3B%560B B HOHFWURO\WH GLVWXUEDQFHV RU PD\ LQFUHDVH WKH ULVN RI VHL]XUH

â&#x20AC;&#x2DC;I think sofosbuvir is the catâ&#x20AC;&#x2122;s meow. â&#x20AC;Ś I think it is going to revolutionize the way we treat hepatitis in this country and around the world.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Sammy Saab, MD, MPH (IFN). Sustained virologic response (SVR) rates were analyzed according to gender, age (<65 vs. â&#x2030;Ľ65 years), interleukin-28 B (IL28B) genotype, body mass index (<30 vs. â&#x2030;Ľ30 kg/m2), race (black vs. non-black), viral load (HCV RNA <107 vs. â&#x2030;Ľ107 copies/mL), opiate replacement status and cirrhosis. Of these factors, only male gender and the presence of cirrhosis were consistently predictive of worse outcomes; the difference between cirrhotics and noncirrhotics existed but was not large. In the NEUTRINO trial, for example, 80% of cirrhotics versus 92% of noncirrhotics achieved SVR at week 12. Also, IL28B genotype status was only predictive of SVR in the NEUTRINO trial.

HIV Coinfection Sofosbuvir in combination with ribavirin also works well and causes less toxicity than IFN-based regimens in HCV patients who are coinfected with HIV. In the PHOTON-1 trial, 182 treatmentnaive patients with HCV genotype 1, 2 or 3 and stable HIV disease, some of whom had cirrhosis, were evaluated. SVR rates at week 12 were 81% in HCV genotype 2 patients and 67% in HCV genotype 3 patients. Among the 19 patients not acheiving SVR at week 12, relapse was confirmed in 12 patients and data were missing for six patients. HCV genotype 1 patients received 24 weeks of treatment and had an SVR rate of 76%. Sofosbuvir was coadministered effectively with multiple HIV antiretroviral regimens, including inhibitors of HIV-1 protease, reverse transcriptase and integrase; it had

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY FEBRUARY 2014 2014

‘[Sofosbuvir] is a drug that has no resistance or incremental adverse effects. It is very well tolerated, very safe, very efficacious and there are no significant drug interactions with it.’ —Sammy Saab, MD, MPH `

no adverse effect on HIV status or antiretroviral therapy. “The IFN-free regimen of sofosbuvir plus ribavirin resulted in high SVR 12 rates in HCV treatment-naive, HIVinfected patients with HCV genotype 1, 2 or 3 coinfection,” said Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology, and professor of medicine at the Johns Hopkins School of Medicine, in Baltimore, who presented the study. “SVR 12 rates were similar to those observed in patients with HCV mono-infection.”

Null Responders Data from the COSMOS trial suggested that HCV genotype 1 null responders may be a lot easier to treat with the combination of sofosbuvir plus simeprevir (Olysio, Janssen) than with first-generation direct-acting antiviral agents. In this Phase II trial, investigators evaluated 167 patients in two cohorts. In cohort 1, patients with METAVIR scores of F0 to F2 who were prior null responders to IFN with ribavirin received 12 or 24 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. In an intent-to-treat (ITT) analysis of the data, these patients achieved SVR rates at week 12 of 79% to 96%. Cohort 2 included treatment-naive patients and prior null responders with METAVIR scores of F3 to F4; they received 12 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. These patients achieved SVR rates at

week 4 of 96% to 100%, based on an ITT analysis. The treatments were characterized as generally well tolerated. “The findings in this interim analysis suggest that the addition of ribavirin to simeprevir plus sofosbuvir may not be needed to achieve high rates of SVR in this patient population,” said Ira Jacobson, MD, chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medical College, New York City, who presented the data. “Anemia and bilirubin increases were predominantly limited to the ribavirin-containing treatment arms.”

Cirrhosis Results from the LONESTAR-2 trial echoed results of other trials showing the high efficacy of sofosbuvir in prior null responders and patients with cirrhosis. This trial tested 12 weeks of treatment with sofosbuvir plus pegylated IFN and ribavirin in treatment-experienced patients with HCV genotype 2 or 3 infection. HIV and HBV coinfected patients were excluded from the trial, but 50% of the study population had compensated cirrhosis. In patients with HCV genotype 2 (n=23), 93%

of cirrhotics and 100% of noncirrhotics achieved SVR at week 12. In HCV genotype 3 patients, the presence of cirrhosis did not affect outcomes, and 83% of patients achieved SVR at week 12. “Sofosbuvir plus pegylated IFN/ribavirin for 12 weeks demonstrated high efficacy in treatment-experienced genotype 2/3 patients who have historically low response rates and limited treatment options,” said Eric Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute and see Sofosbuvir, page 21

Download the Mira app, scan, and view the animation.

Her moment has arrived

NOW AVAILABLE

sovaldi.com/hcp

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

IFN/Ribavirin-Free continued from page 1

third drug, BMS-791325, and for an overall genotype 1 indication. Both the two- and three-drug combinations are highly efficacious, according to study results presented at The Liver Meeting 2013. A slurry of new direct-acting antiviral agents (DAAs) are currently in development, all of them targeting specific steps in the HCV life cycle. According to Vinod Rustgi, MD, clinical professor of medicine at Virginia Commonwealth University, Richmond, the strategy behind the new antiviral regimens, many of which exclude interferon (IFN), is to include drugs that attack HCV at least two of three targets: protease, polymerase and a replication step that uses the NS5A complex. The NS5A inhibitor daclatasvir has potent activity across all HCV genotypes, can be taken once a day and has no food restrictions. The NS3 inhibitor asunaprevir is active against HCV genotypes 1, 4, 5 and 6, and requires twice-daily dosing.

Two-Drug Regimen Kazuaki Chayama, MD, PhD, professor of medicine at Hiroshima University Hospital in Japan, presented results from a Phase III trial of daclatasvir and asunaprevir in patients with chronic HCV genotype 1b infection who were ineligible for or intolerant to IFN (n=135) or nonresponders to prior treatment with th IFN/ribavirin (n=87). In Japan, many HCV patients arre excluded from therapy because of the combined effecct of an aging Japanese population with chronic HCV an nd the poor tolerability of IFN/ribavirin–based therap py among the Japanese population. Patients in the trial were treated for 24 weeks, with a primary end poin nt of sustained virologic response (SVR) at week 24, including patients who discontinued therapy early. Roughly 10% of the study population had cirrhosis. SVR was achieved in 87.4% of the IFN–ineligible/intolerant group, and in 80.5% of patients who had previously not responded to therapy. “Both treatment groups showed a rapid virologic response,” Dr. Chayama said. “High rates of SVR were observed with concordance at weeks 12 and 24.” The regimen also was successful in all interleukin-28 B (IL28B) genotypes. Baseline factors, including male gender, advanced age, high baseline HCV RNA and cirrhosis, did not appear to affect response rates. Roughly 5% of patients discontinued therapy due to adverse events (AEs). Eight of 10 patients who had d received therapy ranging from four to 23 weeks and disiscontinued treatment because of elevations in liver function tests achieved SVR at week 24. The rate of virologic breakthrough and end-of-treatment detectable HCV RNA was 7.7%. The rate of relapse among patients with undectable RNA at the end of treatment was 8.3%. Common AEs included nasopharyngitis (30.2%), elevations in alanine aminotransferase (15.8%) and

aspartate aminotransferase (12.6%), headache (15.8%), diarrhea (9.9%) and pyrexia (12.2%). Grade 3/4 abnormalities included elevations in alanine aminotransferase (7.2%), aspartate aminotransferase (5.4%) and decreased hemoglobin levels (3.2%). “This all-oral, IFN-free, ribavirin-free regimen was well tolerated with low rates of discontinuation, representing a clinically meaningful improvement in both safety and efficacy compared with current standard of care,” said Dr. Chayama.

Table. Safety Outcomes in Patients Receiving Daclatasvir + Asunaprevir + BMS-791325 Most frequent on-treatment ment AEs

Patients, %

Headache

21.3

Diarrhea

15.0

Fatigue

15.0

Nausea

12.5

lities Grade 3/4 lab abnormalities Aspartate aminotransfera ase

1.3

Fasting serum glucose

1.3

AE, ad adverse event

At press time, A BMS had submitted a new drug application for approval of the combination regimen in Japan. “The combination of daclatasvir plus asunaprevir is very effective in genotype 1b, which is pretty much all you seee in Japan,” said Dr. Rustgi. “Japan is the second largest market es m in the world for hepatitis C drugs, after the United Unite Un nited States States. The Japanese have been looking for an interferon- and ribavirin-free combination because their patient population is about 10 years older, so they don’t tolerate interferon and ribavirin.”

Three-Drug Regimen A second study presented at The Liver Meeting tested daclatasvir plus asunaprevir in combination with

BMS-791325, an agent active against HCV genotypes 1, 3, 4, 5 and 6. BMS-791325 is a non-nucleoside HCV NS5B polymerase inhibitor that is dosed twice daily with no food restrictions. In this Phase IIb study, treatment-naive patients with HCV genotype 1 infection, some of whom had cirrhosis, received the three-drug regimen for 12 weeks. BMS791325, the least studied of the three drugs, was tested at two doses: 75 (n=80) and 150 mg (n=86). Patients were stratified based on HCV genotype 1a or 1b and the presence of biopsy-confirmed cirrhosis. Approximately 9% patients had cirrhosis, 38% had stage F3/F4 fibrosis and two-thirds had the difficult-totreat IL28B B genotype CT T or TT. T At week 12, SVR rates were similar for the 75- and 150-mg doses of BMS-791325, at 92.2% and 91.7%, respectively. Thirteen of 15 patients with cirrhosis achieved SVR at week 12. All of the virologic failures occurred in patients with HCV genotype 1a; no other predictive characteristics were identified. Seventeen w patients had NS3 or NS5A resistanceassociated variants at baseline, but 13 of those achieved SVR at week 12. A number of NS3, NS5A and NS5B resistanceassociated variants were identified in patients who did not achieve SVR. Just over 1% of patients exxperienced a serious AE. Side eeffects included headache, diarrhea and fattigue (Table). “This 12-w week, IFN- an nd ribavirin-free, all-oral, three DAA rregimen achievved SVR 12 in more than 90% of patien nts, despite a hiigh prevalence of genotype 1a, advanced fibrosis/cirrhosiis and IL28B B non-CC C genotypes,” said Greg G Everson, M MD, professor of medicine and director of the Section oof Hepatology, Division of Gastroenterology, University of Colorado, Aurora, who presented the study. BMS is going forward with Phase III trials to test this regimen further. Dr. Rustgi speculated that rrather than targeting a narrow HCV genotype 1b indicaation in the United States, BMS will wait to file approvval for the three-drug regimen for genotypes 1a and 1b. At press time, Carrie Fernandez, a BMS spokeswoman, said the company “iss continuing conversations with the FDA FDA, with an exp expectation of submitting a regulatory filing in the United States in the first part of 2014.” She would not provide any further specifics about the indication. ■ Drs. Everson and Chayama disclosed financial relationships with Bristol-Myers Squibb. Dr. Rustgi has received a clinical research grant from Bristol-Myers Squibb.

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY FEBRUARY 2014 2014

AASLD Unveils ‘Nimble and Responsive’ Online Treatment Guidance in Response to Flurry of New Hep C Drugs BY KATE O’ROURKE In the next two to five years, a slew of new direct-acting antiviral agents are expected to receive the FDA stamp of approval for hepatitis C. How will the physicians who author clinical guidelines for the management of hepatitis C virus (HCV) infection keep up to date with the whirlwind of new drugs? The answer is collaboratively and online. The American Association for the Study of Liver Diseases (AASLD), the Infectious Diseases Society of America (IDSA) and the International Antiviral Society (IAS)–USA have teamed up to create hepatitis C treatment guidance that will be updated and published promptly on the IAS-USA website with links on the AASLD and IDSA sites as well. “The pipeline for new therapies is robust,” said Donald Jensen, MD, one of the guidance chairs and director of the Center for Liver Disease at the University of Chicago Medical Center. “The online document has the ability to be quite nimble and responsive. As new studies and information become available, we have the ability to change a recommendation

rapidly. We think we can likely have a recommendation for a newly approved drug online within four to six weeks of FDA approval.” Five to 10 new HCV treatment regimens currently stand a good chance of being submitted for FDA approval in the next few years, he added.

writers who will serve a term of one to three years. The writers will work in small groups of roughly five to address new topics as they arise. The IAS-USA, with its long-standing history of quickly organizing and publishing clinical guidelines in the rapidly changing HIV field, will provide expertise in rapid guideline creation.

‘The online document has the ability to be quite nimble and responsive. As new studies and information become available, we have the ability to change a recommendation rapidly. We think we can likely have a recommendation for a newly approved drug online within four to six weeks of FDA approval.’ —Donald Jensen, MD

Five committee chairs—two from AASLD, two from IDSA and one from IAS-USA—are spearheading the treatment guidance effort. Each chair will serve for a term of three to five years, and at least one of the chairs from each society will have no conflicts of interest. Both the AASLD and IDSA recommended 10

“We are referring to our documents as a ‘treatment guidance’ rather than as a guideline,” Dr. Jensen noted. According to Dr. Jensen, technically, a guideline must fulfill certain criteria to be included in the guideline clearinghouse, mainly the use of a methodologist and the GRADE (Grading of

Sofosbuvir continued from page 17

clinical professor of medicine at the San Antonio University of Texas Health Science Center, who presented the study. “SVR rates were similar in patients with and without cirrhosis.”

Different Treatment Duration for Patients With HCV Genotypes 2 and 3 Although many of the traditional factors that predict treatment response in HCV patients do not seem to apply to sofosbuvir, there does seem to be a difference in response among HCV genotypes. In general, clinicians are accustomed to treating patients with HCV genotype 2 or 3 similarly, but these two groups respond differently to sofosbuvir. In Phase III trials, response rates have been higher in patients with HCV genotype 2 after 12 weeks of treatment with sofosbuvir plus ribavirin. The VALENCE trial originally set out to test 12 weeks of treatment with sofosbuvir plus ribavirin in patients with HCV genotype 2/3, but investigators amended the trial after recognizing that the two types of patients might respond to treatment differently; the 250 patients with HCV genotype 3 ultimately received 24 weeks of treatment. Among genotype 3 patients without cirrhosis, response rates were 94% in treatment-naive patients and 87% in treatment-experienced patients; genotype 3 patients with cirrhosis had response rates of 60%. More evidence that longer therapy is better for HCV genotype 3 patients came from data presented at a

Table. FDA Analysis of SVR Rates In Patients With HCV Genotype 3 Treated With Sofosbuvir and Ribavirin Cohort

Week 12

Week 24

Treatment-naive patients SVR rate, %

Relapse rate, %

Treatment-experienced patients SVR rate, %

Relapse rate, %

HCV, hepatitis C virus; SVR, sustained virologic response

meeting of the FDA Sofosbuvir Review team on Oct. 25. “The FDA did an elegant analysis of the effect of treatment duration with sofosbuvir–ribavirin in genotype 3–infected patients,” Dr. Sulkowski said. “[They] presented very convincing data that a 24-week duration of sofosbuvir–ribavirin should be the standard for all genotype 3–infected patients.” The FDA analysis combined data from the FISSION, POSITRON, FUSION and VALENCE trials.

Recommendations Assessment, Development and Evaluation) system for evidence rating. Although the guidance incorporates the evidence rating system used by many current guidelines, it will not use a methodologist because this would significantly slow the creation process. Most people will not notice a difference between the document and traditional guidelines, because the referenced literature will be recent and circumscribed, Dr. Jensen said. At press time, Dr. Jensen predicted that the first guidance statements would be published online by the end of January 2014 at HCVguidelines.org. “These are in the final stages of development, so we feel confident we will be on time. The first three will cover testing and linkage to care, initial HCV treatment and retreatment of HCV infection.” In addition to the online version, the guidance will be published annually in Hepatologyy orr Clinical Infectious Diseases. ■ Dr. Jensen reported no direct financial relationships but is an investigator on clinical trials with AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences and Janssen.

In both treatment-naive and treatment-experienced patients with HCV genotype 3, SVR rates dramatically rose and relapse rates fell when treatment was increased from 12 weeks to 24 weeks (Table). As a result, when the FDA approved sofosbuvir in December, the agency approved a 12-week treatment regimen in patients with HCV genotype 2 and a 24-week regimen in patients with genotype 3, both in combination with ribavirin. The FDA also approved a 12-week regimen of sofosbuvir in combination with ribavirin and IFN for patients with HCV genotypes 1 and 4. ■ Dr. Saab has served as a consultant and on the speakers’ bureaus for Boehringer Ingelheim, Genentech, Gilead Sciences, Janssen, Merck, and Vertex Pharmaceuticals. Dr. Sulkowski has received consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck and Vertex. Dr. Jacobson has received grants or research support and has served as a member of a speaker’s bureau or as a consultant/advisor for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix Pharmaceuticals, Janssen, Merck, Novartis, Roche/Genentech and Vertex. Dr. Lawitz has served on advisory committees or review panels for AbbVie, Achillion, BioCryst Pharmaceuticals, Biotica, Enanta, Idenix, Janssen, Merck, Novartis, Santaris, Theravance and Vertex; he has received grant and research support form AbbVie, Achillion, Boehringer Ingelheim, BristolMyers Squibb, Gilead, GlaxoSmithKline, Idenix, Intercept, Janssen, Merck, Novartis, Presidio, Roche, Santaris Pharma and Vertex.

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Sofosbuvir a ‘Potentially Lifesaving Therapy’ for Liver Transplant Patients With Hepatitis C BY KATE O’ROURKE WASHINGTON— —The outlook for patients with hepatitis C undergoing liver transplantation got a lot sunnier with the results of two studies presented at The Liver Meeting 2013. In one study, researchers showed the combination of sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin used in this patient population pre-transplantation prevented recurrence of the hepatitis C virus (HCV) infection in 64% of patients. Used after transplantation, the regimen achieved a sustained virologic response (SVR) rate of 77% four weeks after treatment completion. “These studies are both very dramatic,” said Adrian Di Bisceglie, MD, president elect of the American Association for the Study of Liver Diseases, who was not involved with the studies. “They signal a potential dramatic change in our practice of medicine related to hepatitis C and liver transplant.” Reinfection of a transplanted liver is inevitable in patients who have HCV RNA-positive serum at the time of transplantation. Recurrence of HCV infection is the most common cause of mortality and graft loss after liver transplantation. Between 10% and 50% of transplant patients with recurrent HCV infection progress to cirrhosis within five years, and once cirrhosis is established, 42% of patients have graft failure within 12 months. Current therapies to treat HCV infection before and after liver transplantation have limited efficacy and are poorly tolerated, causing severe adverse reactions and significant interactions with immunosuppression medications.

Post-Transplant Sofosbuvir Michael Charlton, MD, professor of medicine at Mayo Clinic, Rochester, Minn., presented a late-breaking abstract on the topic at The Liver Meeting. In this study, Dr. Charlton and his colleagues enrolled 40 patients with HCV infection who underwent liver transplantation between six and 150 months before study enrollment. Patients were given 24 weeks of treatment with ribavirin plus sofosbuvir, a nucleotide polymerase inhibitor with potent antiviral activity against HCV genotypes 1 to 6. Both treatment-naive and treatmentexperienced patients were included in the study; individuals with decompensated liver disease were excluded. The majority of patients had HCV genotype 1 (55%, 1a and 28%, 1b); the remainder had HCV genotype 3 (15%) or 4 (3%).

At the time of study analysis, 77% of patients had achieved SVR at four weeks after treatment completion, and 12 of 13 patients for whom data were available at week 12 still had SVR. Dr. Charlton reported that there were no interactions reported between sofosbuvir and any immunosuppressive agents, including cyclosporine and tacrolimus, and no deaths, graft losses or episodes of liver rejection. Adverse events (AEs) included fatigue (28%), headache (25%), arthralgia (23%), diarrhea (23%), cough (18%), nausea (18%) and anemia (15%). Grade 3/4 laboratory abnormalities occurred in 53% of patients and included decreased levels of lymphocytes (33%) and hemoglobin (20%), and hyperglycemia (10%). “In this difficult-to-treat population—enriched with a high prevalence of genotype 1, prior treatment experience, advanced fibrosis and receiving immunosuppression—77% of patients treated with 24 weeks of sofosbuvir plus ribavirin achieved SVR at week 4,” said Dr. Charlton.

Pre-Transplant Sofosbuvir Michael Curry, MD, medical director for liver transplantation at Beth Israel Deaconess Medical Center, Boston, presented an abstract on pre-transplantation treatment with sofosbuvir.

In this study, 61 patients with HCV infection were enrolled to receive sofosbuvir plus ribavirin until the time of liver transplantation, or up to 48 weeks. The patient population included those infected HCV genotypes 1a (39%), 1b (34%), 2 (13%), 3a (12%) and 4 (2%). At the time of analysis, 44 patients were scheduled to receive a liver transplant; of these, 41 were negative for HCV infection and three were positive. The remaining 17 patients stayed

on treatment, were post-treatment and awaiting a transplant, had discontinued treatment or had liver cancer progression. Of the 33 patients who received at least 12 weeks of treatment with sofosbuvir, 91% had HCV RNA levels below the lower limit of quantitation at the time of transplantation. Moreover, of the 44 patients who received any duration of treatment, 93% had undetectable HCV RNA at transplantation. Post-transplant see Liver Transplant, page 25

Transplant Pharmacists Help To Improve Organ Donation Rates BY BARRETT CROWTHER, PHARMD, BCPS There are more than 115,000 individuals in the United States awaiting a potentially lifesaving liver, pancreas, intestine, kidney, heart and/or lung transplant. This number greatly overshadows the 28,052 solid organ transplants completed in 2012 (optn.transplant.hrsa. gov). Pharmacists are helping to make a difference in closing this disparity. Transplant pharmacists are actively involved in efforts by transplant centers to increase and efficiently use the potential organ pool. Many transplant pharmacists assist with living donor programs. Living donation is most common with kidney transplantation, although living donation is also available with livers and lungs (www.transplantliving.org/living-donation/). Transplant pharmacists are involved in education and management of both the donor and the recipient. Additionally, many transplant centers participate in paired organ exchange programs, in which incompatible blood type donor and recipient pairs are matched with others who are compatible. Transplant pharmacists are involved in evaluating patients, helping to make decisions for matching and post-transplant care. Transplant

pharmacists also can be key decision makers in their transplant center’s desensitization program. Desensitization typically involves plasmapheresis and/or a combination of medications, such as IV immunoglobulin and rituximab, to reduce the amount and strength of circulating antibodies in the potential recipient to make a previously incompatible donor and recipient pair compatible. Alloway et al have outlined the roles and responsibilities of the transplant pharmacist ((Am J Transplantt 2011;11:1576-1583).

The Organ Donation Awareness Challenge Beyond routine work duties, many transplant pharmacists have helped to educate the community about organ donor awareness. Pharmacy students have embraced these organ donation awareness projects/ events as well, working closely with the transplant pharmacy community. These collaborations have allowed pharmacy students to learn more about the field of transplant pharmacy. For the past four years, the American Society of Transplantation (AST) Transplant Pharmacy Community of Practice (CoP) has supported an annual Organ Donation Awareness Challenge. The Challenge see Organ Donation, page 24

Compliance comes quicker when you have the right partner on board. Miraca offers tailored technology solutions to help your practice with workflow efficiency, adherence to new regulatory measures, and more. All while minimizing disruptions and keeping you focused on your patients’ well-being. To learn more about our custom technology services–and how we can help you maximize government-supported incentives along the way–visit MiracaLifeSciences.com.

HEPATOLOGY IN FOCUS

Organ Donation continued from page 22

highlights partnerships with U.S. schools of pharmacy to increase donor awareness. Past projects have included holding organ donation drives and helping community members sign up on state online registries. One particularly creative example included the development of a special ice cream flavor to celebrate Donate Life Month in April. Past winners of the Challenge have

received recognition at the annual American Transplant Congress with the presentation of an engraved plaque from AST recognizing their school. The Challenge has been well received by pharmacy students. Jillian Descourouez, PharmD, BCPS, a clinical pharmacist in solid organ transplant at the University of Wisconsin Hospital and Clinics, in Madison, explained, “What amazes me most about the Challenge is the fact that so many students are

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

willing to put in a vast amount of time and energy in developing and implementing such a wide variety of events, with little more incentive than increasing organ donation awareness and a small donation from the American Society of Transplantation for the winning team. While some people may think that pharmacy students have too many things going on with school, work, clubs and their personal lives to dedicate much time to volunteerism, the students who have participated in the Challenge prove

Read the No. 1 publication in the

gastroenterology market,

anywhere, anytime!

Explore gastroendonews.com at your convenience, from your iPad, personal computer or smartphone.

gastroendonews.com Read all the articles from each month’s issue online. Search the archive for articles from past issues that you may have missed. Post a comment about an article for your colleagues to see. Share articles you read online with your colleagues via email, Facebook, Twitter and other popular social networking sites. Follow our Twitter feed and keep up with us between monthly issues. View our Digital Edition, which includes articles in the same layout as our print edition.

this notion wrong.” Participation in the Challenge has risen steeply in four short years, with only a few schools of pharmacy participating in 2009 to 13 schools participating this past year. The winner of the 2012-2013 Challenge, University of Arkansas for Medical Sciences (UAMS) College of Pharmacy, recently was recognized at the 2013 American Transplant Congress. UAMS pharmacy students educated nearly 300 high school students at four different high schools on organ donation. One of the education sessions was recorded and broadcast by a local news station with an interview of one of the group’s members. Also, Seth Heldenbrand, PharmD, a clinical specialist of solid organ transplant and an associate professor at UAMS College of Pharmacy, participated in a different live local NBC news interview discussing the common myths regarding organ donation. UAMS students educated approximately 200 adults in person and collected more than 200 organ donation pledge forms, many from high school students. Additionally, UAMS students raised $1,000 for their local organ procurement organization by selling Donate Life Month shirts that they designed. New groups are participating in the Challenge each year. Karen Hardinger, PharmD, BCPS, a clinical associate professor of pharmacy practice at the University of MissouriKansas City (UMKC) School of Pharmacy, said that UMKC participated in the initiative for the first time last year. “The students raised donor awareness through health fairs and created a manual that instructs students on how to educate potential donors,” Dr. Hardinger said. The students were able to reach numerous potential donors through their efforts and educated many people. I would encourage all schools to participate in this very beneficial competition.”

Rewards of Giving Pharmacy students and the community benefit from participation in the Challenge. Dr. Descourouez said, “The Challenge helps students realize there is a bigger picture than completing pharmacy school. It helps to keep their education in perspective as they realize the impact they can have on health care across the United States. By responding to the call for organ donation awareness and increasing the number of registered donors, the pharmacy

HEPATOLOGY IN FOCUS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY FEBRUARY 2014 2014

Liver Transplant continued from page 22

virologic response (pTVR) rate at 12 weeks was 64%. The number of consecutive days with undetectable HCV RNA before transplantation was the strongest predictor of pTVR (P<0.0001). On-treatment HCV RNA suppression was rapid. Dr. Curry characterized the treatment as safe and well tolerated. Although 18% of patients experienced a serious AE, none of the AEs were deemed related to sofosbuvir: Laboratory abnormalities and

students participating in the Challenge are increasing the odds that someone waiting will receive a lifesaving organ.” Pharmacist participants of the Challenge have noted a sense of fulfillment with conducting organ donation awareness projects. “Getting involved with our students and community to promote organ donation awareness was one of the most rewarding things I have done in my career as a transplant pharmacist,” said Dr. Heldenbrand. For 2014, the AST Transplant Pharmacy CoP is supporting the fifth annual Organ Donation Awareness Challenge. The ultimate goal for the project is to have all U.S. schools of pharmacy participating in at least one organ donation awareness activity each year. Each school of pharmacy has been assigned a transplant pharmacist point-ofcontact/liaison for assistance with projects. To submit projects for the Challenge, applicants must have a collaborator who is a current member of the AST Transplant Pharmacy CoP. Applicants should submit a twopage, typed summary of activities in paragraph form via email to Barrett Crowther at barrett.crowther@uhssa.com. The submission deadline for the 2013-2014 academic year is May 19, 2014. Those interested in more information regarding the annual AST Transplant Pharmacy CoP Organ Donation Challenge and a copy of the Organ Donation Challenge manual, which lists potential transplant pharmacist liaisons for the Challenge, may email Dr. Crowther at Barrett.Crowther@ uhs-sa.com. Dr. Crowther is a clinical pharmacist in the Department of Pediatrics & Solid Organ Transplant, University Health System, San Antonio, Texas. He reported no relevant financial conflicts of interest.

AEs observed pre-transplantation were similar to those seen in the post-treatment study. Only 3% of patients discontinued treatment because of side effects.

‘Potentially Lifesaving’ Implications According to Dr. Di Bisceglie, the studies will have an immediate effect on clinical practice. “Sofosbuvir has been available on a compassionate use basis after transplantation for a little while, so probably a couple dozen patients around the country

have already seen some benefit,” he said. Sofosbuvir was approved for the treatment of HCV infection in December 2013, including patients with hepatocellular carcinoma awaiting liver transplantation to prevent HCV recurrence. “Its availability, combined with these data, will probably mean we are going to start treating patients after liver transplantation very quickly. This is a potentially lifesaving therapy, and I’m sure physicians will not want to wait until it is approved for this indication,” Dr. Di Bisceglie said.

He called the pre-transplant data “dramatic,” but thinks clinicians will be more likely to use the medications after transplantation at first. Until sofosbuvir’s label includes a transplant indication, he noted, clinicians “might meet resistance from third-party payors.” ■ Dr. Curry disclosed having a financial relationship with Gilead Sciences. Drs. Charlton and Di Bisceglie have received support from and have served as consultants for Gilead.

NEW from Amneal Pharmaceuticals

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

INTRODUCING

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

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

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

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

Gluten continued from page 1

(NHANES) data from the United States, where the prevalence of celiac disease is estimated at 0.71% (Rubio-Tapia et al. Am J Gastroenteroll 2012;107:1538-1544). With gluten sensitivity often selfdiagnosed, presumably confirmed with an observation of diminished symptoms after starting a gluten-free diet, many patients consult physicians for help with their condition rather than a diagnosis. However, Dr. Sanders recommended

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

that clinicians start at the beginning, by first testing for unrecognized celiac disease and then confirming that symptoms are related to gluten exposure. “We need to reassure the patient and ourselves that celiac disease, which poses a greater risk for serious complications than non-celiac gluten sensitivity, is not the underlying issue,” Dr. Sanders said. “Because so many individuals are now taking gluten-free diets, it is essential that clinicians verify that patients are back on a normal diet before conducting the diagnostic studies.”

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.

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 • FEBRUARY 2014

‘There does appear to be a growing number of individuals who believe themselves to be gluten sensitive, but we are missing the data to tell us whether all of these patients need to be on a lifetime gluten-free diet.’ —David S. Sanders, MD

Show Me the Data If celiac disease is ruled out, then NCGS is the default diagnosis for those with a positive correlation between gluten exposure and symptoms. But the mechanism behind gluten sensitivity in these individuals remains unclear. An immune-mediated response to wheat proteins is a logical assumption, but the correlation between a gluten-free diet and symptom control is often imperfect. Many patients are seeking more information, but there is little. “We should explain [to patients] that

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,

we, as doctors, are still in the middle of the learning curve. Gluten-free diet makes sense when it provides symptom relief, but the diets can be restrictive and the foods often cost more,” Dr. Sanders said. “At some later date, patients may want to gradually increase their gluten intake to confirm that the sensitivity persists.” The growth in prevalence of NCGS appears to parallel an increase in the availability of gluten-free foods, raising concerns that advertising of these products has created a market independent of

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

a health benefit; however, data dispelling the correlation is lacking. Noteworthy in the U.K. survey findings is that gluten sensitivity was highly correlated with symptoms of irritable bowel syndrome (20% vs. 3.89% in individuals without gluten sensitivity; odds ratio, 6.23; P<0.0001). According to Dr. Sanders, who noted that wheat has only been part of the human diet for about 4,000 years, there have been reports of growing rates of NCGS in many parts of the world where wheat is not a major diet staple, such as India and China. Still, the mechanism behind NCGS is elusive and deserves further study. Joseph A. Murray, MD, professor of medicine in the Division of Gastroenterology at Mayo Clinic, Rochester, Minn., said that the data from the United States indicate a much lower penetration for gluten-free diets. However, Dr. Murray agreed that only small fraction of U.S. individuals, as those in the United Kingdom, are eliminating gluten because of diagnosed celiac disease. Nevertheless, in patients who report that they are avoiding gluten, he, like Dr. Sanders, first rules out celiac disease. “There are several strategies,” Dr. Murray said. “One is gluten challenge and then testing for antibodies for celiac disease. The second is to check for genetic susceptibility for celiac disease. If the genes are absent then celiac disease is extremely unlikely.”

FODMAPs For the large proportion of patients who report a reduction in gastrointestinal symptoms with a gluten-free diet but who do not have celiac disease, Dr. Murray suggested that it may be useful to test for other diet-related causes, for example, by following an elimination scheme such as the low-FODMAP (fermentable oligo-, di- and monosaccharides and polyols) diet. He suggested it is reasonable to test alternative causes while the patient is following a gluten-free diet, and to rechallenge with gluten if an alternative cause is identified. ■ Drs. Sanders and Aziz reported no conflicts of interest. Dr. Murray has consulted for or received financial support from ActioGenix, Alba Therapeutics, Alvine Pharmaceuticals, Inc., Bayer, Ferring Pharmaceuticals, Flamentera, Ironwood Pharmaceuticals, Nexpep and Shire Pharmaceuticals.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

GERD Surgery continued from page 1

antisurgical point of view,” said Dr. Dunst, an esophageal surgeon with the Oregon Clinic, Portland, and director of research and education at the clinic’s Division of Gastrointestinal Minimally Invasive Surgery.

with one, but according to the current American College of Gastroenterology (ACG) guidelines for management of refractory GERD, the first step for these patients is to give them more medicine. Extrapolating from studies looking at the composition PPI Responders of reflux, more than half of dissatisfied PPI users have a “Overall, I do agree that medical management is an non-acid component of reflux. effective treatment for garden-variety reflux disease for “You can add more medicine if you want, but it’s patients who respond well unlikely to do anything for to it,” Dr. Dunst said. “But this group of patients,” Dr. for the patients who don’t ‘Overall, I do agree that medical Dunst said. “PPI therapy respond, we need to do a does not change the number management is an effective treatment of reflux episodes; it just neubetter job.” An estimated 19 million for garden-variety reflux disease for tralizes the acid.” Americans suffer from gasSurgery, in contrast, does troesophageal reflux disease patients who respond well to it. But appear to help these patients. (GERD), which is the most for the patients who don’t respond, A recent study of patients common gastrointestinal with refractory GERD— we need to do a better job.’ diagnosis leading to a docthose with persistent regurgi—Christy M. Dunst, MD tation or heartburn, a positive tor visit. In 2010, more than 53 million prescriptions for symptom score, abnormal pH omeprazole were filled and or abnormal impedance while $6.3 billion was spent on Nexium alone. Despite the taking a PPI—showed satisfactory results with laparoscope of the problem, however, only 1% of sufferers scopic Nissen. At three years postsurgery, 89% of the 38 receive surgical treatment. patients were in complete remission (Frazzoni M et al. Why is that? The prevailing attitude is that proton Surg Endosc 2013;27:2940-2946). pump inhibitors (PPIs) are just as good as surgery but However, the ACG pointed out that this was an with fewer side effects, as demonstrated by the findings uncontrolled trial and that it included only carefully of the LOTUS (Long-Term Usage of Esomeprazole vs selected participants; the ACG does not recommend Surgery for Treatment of Chronic GERD) trial, funded this approach “except in highly individual circumstances” by AstraZeneca, in which 554 reflux patients were ran- (Katz PO et al. Am J Gastroenteroll 2013;108:308-328). domized to receive laparoscopic Nissen fundoplication Dr. Dunst agrees with the ACG that the little data availor medical therapy with ezomeprazole (Galmiche JP et able covers only carefully selected patients. al. JAMA A 2011;305:1969-1977). “Nonresponders are a heterogeneous group and defi“Both groups had excellent control of heartburn,” nitely demand a comprehensive workup to determine if Dr. Dunst said. “Overall, remission rates of GERD for rebuilding their antireflux barrier is going to work,” she both groups were excellent, and it approaches signifi- said. “But they shouldn’t be tossed aside just because medcance favoring PPIs at five years.” ical management doesn’t work for them.” The catch is that all 554 participants in the LOTUS trial were complete responders to PPIs to begin with. Alternatives to PPIs So what happens to the estimated 30% to 60% of PPI The question, she said, really comes down to whether users who do not achieve remission of symptoms with these patients are unhappy enough for antireflux surgery. medication? Fundoplication has well-documented side effects: flatulence, bloating, dysphagia and so on. But PPIs are not PPI Nonresponders without risk either: Clostridium difficilee infection, comOne study found that 28% of the patients seek- munity-acquired pneumonia, vitamin B12 deficiency, hip ing alternative treatment for GERD technically fracture and so forth. did not have reflux (Oh DS et al. J Gastrointest Surg Of course, obtaining a surgical solution requires know2006;10:787-796). ing that such surgery exists. “They have normal bile exposure, normal acid expo“It’s well documented now that 45% to 50% of sure and normal EGD [esophagogastroduodenos- patients have significant symptoms despite their PPI, copy],” Dr. Dunst said. “If you apply that number to but the vast majority of patients never get told that [previous data], we can estimate about 12% of dissatis- there are alternatives to medication; their primary fied GERD patients don’t have GERD. But that leaves care doctor doesn’t tell them, their gastroenterologist 33% of 19 million patients unhappy. Why aren’t they doesn’t tell them,” said Jeffrey Peters, MD, professor of responding?” surgery and chair, Department of Surgery, University The literature reveals a number of reasons, the of Rochester Medical Center, Rochester, N.Y. biggest being lack of compliance or inadequate “This is likely a history of how antireflux treatment suppression. evolved and various schools of thought. Primary care doc“But the more likely reason is that refractory patients tors may never have been educated about the potential for have more severe or complicated disease such as longer reflux surgery, and gastroenterologists may have more of a duration of symptoms, persistent regurgitation, hiatal resistance to it than is appropriate or necessary,” Dr. Peters hernia, obesity, motility disorders (esophageal or gas- said. “So there is a huge gap in patient information and tric) or atypical symptoms,” Dr. Dunst said. understanding. Not that surgery should be used [heedSurgical treatment is an option for patients who don’t lessly], but it probably is underutilized.” take their PPI or who can’t gain control of their symptoms Increasingly, however, patients who aren’t getting

satisfactory answers from their doctors are turning to the Internet for solutions. Over the past couple of years, Dr. Dunst has noticed an increase in the number of self-referrals who arrive at her clinic, informed by online sources such as RefluxMD.com. “Patients are getting frustrated, and they’re going to the Internet where there is increasingly more information being posted these days,” she said. “With the increased online presence of nonmedical options, the patients are learning, and I think that’s the way to go.” Dr. Peters suggested the solution to better care for these patients boils down to increasing recognition among primary care doctors and gastroenterologists that PPIs are not the cure they once were considered to be, and the presence of better options. “We need a good alternative that’s relatively straightforward and easy to produce; traditional antireflux [surgery] is not, which is one of the reasons it hasn’t evolved to larger numbers,” he said. Although it’s too soon to tell, the LINX (Torax Medical, Inc.) system may open an avenue.

A “credible” alternative: The LINX system is designed to keep the lower esophageal sphincter closed. The system expands temporarily to allow food and liquid to pass.

“The LINX is a credible alternative slowly percolating into the marketplace,” Dr. Peters said. “I wouldn’t say it’s experimental because there’s pretty good data that it works. The clinical information is just emerging as to the right patient population to use it in.” ■

ACT NOW! Renew your free subscription to

today at GastroEndoNews.com/Renew

best-read

♦

high readers

♦

average issue readers

♦

total readers

♦

high readers (% total readers)

♦

average page exposures Based on data from Kantar Media, June 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Prospective Trial Provides Positive Evidence For Weight Loss in Treating GERD BY TED BOSWORTH ORLANDO, FLA.—Weight — loss is an effective treatment for gastroesophageal reflux disease (GERD) in obese patients, according to the first prospective trial of this topic. Although multiple studies have demonstrated a correlation between

obesity and an increased risk for GERD, this is the first trial conducted in a prospective manner to confirm that weight loss can control symptoms. “There is a dynamic relationship between weight and GERD in patients with obesity,” said Preetika Sinh, MD, a fellow in gastroenterology at the University of Kansas School of Medicine, in Kansas City, Kan.

“We were able to demonstrate that weight loss leads to a significant improvement in symptoms, but we also saw that symptoms return even when a relatively small amount of weight is regained,” said Dr. Sinh, who presented the data at 2013 Digestive Disease Week (DDW) meeting. The weight loss trial was part of a study of a structured weight loss program

‘We were able to demonstrate that weight loss leads to a

OPT IN to receive the free monthly e-newsletter at

Be the ﬁrst to see the top news stories from Gastroenterology & Endoscopy News’ print edition and pass them on to your colleagues. Register online to receive your free monthly e-newsletter with the most recent and important news stories and online links.

significant improvement in symptoms, but we also saw that symptoms return even when a relatively small amount of weight is regained.’ —Preetika Sinh, MD

conducted at a tertiary referral center with 213 obese patients (average age, 46 years; 67% women). The investigators recorded body weight and symptoms of GERD at baseline, over the six-month duration of the weight loss program and over an additional six months. Physical activity also was monitored. Of the 213 participants, 38% had GERD at baseline. At the end of the six-month weight loss program, all 213 participants had lost weight, with a mean loss of 14.8 kg (P<0.01 vs. baseline). The proportion of patients with GERD fell to 16%, and there was a significant reduction in mean GERD symptom score (P<0.01). Over the next six months, 172 participants (81%) regained weight; the remainder of patients maintained or further reduced their weight. In those who gained weight, mean weight gain was 5.3 kg. Although this was less than half of the mean weight loss, the proportion of those with GERD increased to 22%, and the mean GERD symptom scores increased significantly (P<0.01). When participants were stratified based on weight gain of less than 5% or greater than 5%, the investigators found that a greater increase in weight was associated with a greater increase in GERD symptoms: Notably, symptoms were significantly increased even in patients with only modest weight gain. Those who continued to lose weight continued to experience relief of GERD symptoms.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

what is ‘I definitely advocate weight loss to the obese patients in my clinical practice. I believe this study and our study [NessJensen E et al] clearly demonstrate a benefit.’ —Eivind Ness-Jensen, MD

change clinical practice, according to Eivind Ness-Jensen, MD, of the Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. “I definitely advocate weight loss to

In women, a multivariate regression analysis revealed that increased physical activity was a significant negative predictor of GERD symptoms at six months relative to baseline. This result was observed independently of weight change, dietary intake or age. The same relationship was not seen in men. The findings, some of which were published before the DDW meeting (Singh M et al. Obesity 2013;21:284290), provide prospective evidence of a benefit from weight loss in obese patients with GERD. Control of GERD may not be the most important reason to suggest weight loss in obese patients, but it could be an additional motivational factor. The evidence is strong enough to

the obese patients in my clinical practice. I believe this study and our study [Ness-Jensen E et al. Am J Gastroenterol 2013;108:376-382] clearly demonstrate a benefit,” Dr. Ness-Jensen said. “In addition, we have shown that those who lose weight have increased treatment success with antireflux medication, but hopefully some might be able to stop all medication for GERD with weight loss.” ■ Drs. Sinh and Ness-Jensen reported no relevant conflicts of interest.

your opinion? Gastroenterology & Endoscopy News is now accepting opinion pieces. Send your thoughts to

the editor at: mail: 545 West 45th Street, 8th Flr., New York, NY 10036 fax: 212.957.7230 email: cgordon@mcmahonmed.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Controversial Data Show RFA Beneficial for LGD In Barrett’s, but Accurate Diagnosis Is Key

‘The data suggest that if you can confirm

BY TED BOSWORTH ORLANDO, FLA.—Radiofrequency ablation (RFA) in Barrett’s esophagus (BE) patients with low-grade dysplasia (LGD) provides significant protection against progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma,

according to the findings of a multicenter, randomized trial presented at the 2013 Digestive Disease Week (DDW) meeting. In fact, the benefit of RFA relative to surveillance alone was so great, that the trial’s safety monitoring committee recommended terminating the trial after an interim analysis. The demonstration that RFA can

reduce the risk for progression in patients with LGD has immediate relevance to clinical practice, said the senior author of the study, Jacques J. Bergman, MD, PhD, of the University of Amsterdam, The Netherlands. “The data suggest that if you can confirm LGD, the risk for progression does not appear to be much different than it

LGD, the risk for progression does not appear to be much different than it is for patients with HGD.’ —Jacques J. Bergman, MD, PhD

is for patients with HGD. We are now working to change the Dutch guidelines,” Dr. Bergman said.

LGD: Overdiagnosed and Underestimated An important implication of the study was the need for rigorous confirmation of LGD by expert pathologists: An accurate diagnosis of LGD is essential for the benefits of RFA to be observed. In this study, LGD was “frequently overdiagnosed,” said co-author K. Nadine Phoa, MD, of Academic Medical Center, Amsterdam. A diagnosis of LGD was confirmed in less than half of the patients who were evaluated for entry into the study. The study was conducted at nine European centers, where 136 patients were randomized into two equal groups to receive surveillance or RFA. After two years of the planned three-year study, 17 of 68 patients (25%) who were randomized to undergo surveillance progressed to HGD or esophageal adenocarcinoma compared with only one patient in the RFA group who progressed to cancer (P<0.01). Six of the 17 patients in the surveillance group who had progression developed cancer. The single progression to cancer in the RFA treatment arm was a cancer that developed early; at the time of presentation of the data, that patient was

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

cancer-free after undergoing an endoscopic resection. A second analysis of the data showed high rates of progression when LGD is confirmed by an expert panel. Both of these studies validate the need for expert pathologic confirmation of LGD in patients with BE, which is part of a national program that has been in place in the Netherlands for more than a decade. The Barrett’s Advisory Committee (BAC), formed in the Netherlands in 1998, provides an expert review of all LGD pathology specimens from any community hospital in the country. The committee was formed because of an observed large divergence in reports of progression after diagnoses of LGD, which suggested a disparity in the quality of diagnoses. Follow-up data collected by the BAC on 466 patients diagnosed with LGD support this premise. After an expert pathology review by the BAC, 71% of LGD diagnoses were downstaged either to nondysplastic BE or indefinite for dysplasia. LGD was confirmed in the remainder of patients, with the exception of 2% of specimens that were upstaged to HGD. A median 51-month follow-up showed the rate of progression was 10% annually in the group with confirmed LGD versus 1% in the group that was downstaged. “The estimated cumulative risk for progression over five years in [patients] with LGD was 40%, as opposed to 5% for patients downstaged to non- or indefinite dysplasia,” said Lucas C. Duits, MD, a research fellow in the Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, and co-author of the study. The median time to progression was 35 months. In a 2010 study by Dr. Bergman’s group, 85% of cases initially identified as LGD were downstaged after an expert review (Curvers WL et al. Am J Gastroenterol 2010;105:1523-1530). The incidence rate of HGD or cancer in this study was 13.4% per patient per year in those whose LGD diagnosis was confirmed versus 0.49% in those who were downstaged to nondysplastic BE. In the Netherlands, digitized biopsies are streamlining the review process between community hospitals and the BAC, but Drs. Phoa and Bergman believe that biomarkers eventually will replace histopathologic reviews of biopsies for staging BE. Nevertheless, these data immediately challenge clinical practice by suggesting that RFA is justified for LGD, if LGD can be confirmed by experts.

moderators of the DDW session where the data were presented expressed some skepticism. “This is not an average LGD population,” remarked Pradeep Bhandari, MBBS, MD, professor at Spire Portsmouth Hospital, Portsmouth, United Kingdom, noting that the progression rate in this population of patients with LGD was about the same as progression rates previously reported in HGD cohorts. By eliminating nearly 75% of the LGD patients considered for entry into the study, Dr. Bhandari said, the

trial center may have recruited a highrisk subset of patients with LGD. Nicholas J. Shaheen, MD, MPH, professor of medicine and epidemiology and director of the Center for Esophageal Diseases & Swallowing, University of North Carolina School of Medicine, Chapel Hill, said that the study “fills an important gap.” Although the value of RFA in patients with HGD is well established, the controversial benefit for LGD has been “a reflection of the heterogeneity in outcomes” in this population. These data suggest that heterogeneity

Get recognized for promoting Quality and Safety in your endoscopy unit

arises from a failure to adequately document LGD, Dr. Shaheen said. ■ Dr. Bergman has received consulting fees and research support from Boston Scientific, C2 Medical, Cook Inc., Covidien, Olympus and Spectra Science. Dr. Shaheen has received consulting fees and research support from AstraZeneca, BARRX Medical, CSA Medical Inc., NeoGenomics, Oncoscope Inc., Procter & Gamble Pharmaceuticals, Shire Pharmaceuticals and Takeda Pharmaceuticals. Drs. Phoa, Duits and Bhandari reported no conflicts of interest.

ASGE Endoscopy Unit Recognition Program ASGE’s Endoscopy Unit Recognition Program honors endoscopy units committed to the highest standards of quality and safety. It is the only national program recognizing quality and safety in the practice of endoscopy. > Gain recognition among healthcare professionals, public and private regulatoryy bodies, and patients as a unit dedicated to quality care > Prepare to meet the changing expectations of public and private regulatory bodies > Promote improvement and create uniformity in your practice > Access marketing tools to promote your recognition Program eligibility criteria includes completion of the ASGE Quality Course, “Improving Quality and Safety in your Endoscopy Unit,”” by a representative of your unit within one year of program application. ASGE offers mu ultiple courses throughout the year. The upcoming cou urses are as follows: ay 2, 2014 – Nashville, TN • Ma egas, NV at EndoFest® 2014 • eptember 18 2014 – Las Ve Dec cember 11, 2014 – ASGE IT&T, Downers Grove, IL Receiv the ASGE Certifi Receive ficate of Recognition to proudly display in your endoscopy unit’s office fi

For program details, including eligibility criteria, and to download an application, visit www.asge.org or call 630.573.0600.

Not Your Average LGD Due to the stark divergence of these results from past evidence, one of the

BECAUSE QUALITY IN ENDOSCOPY MATTERS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Amitriptyline ‘Arguably’ Effective for Functional Dyspepsia Data on Other Antidepressants Questionable BY TED BOSWORTH ORLANDO, FLA.—At long last there is good evidence that amitriptyline is effective for the treatment of functional dyspepsia. The data was generated by a multicenter study funded by the National Institutes of Health. “We believe, based on these results, that amitriptyline arguably appears to be efficacious for functional dyspepsia,” reported study author, Nicholas Talley, MD, of the Faculty of Health, University of Newcastle, Callaghan, Australia. The study was completed only weeks before the 2013 Digestive Disease Week (DDW) meeting, where Dr. Talley presented “just the top-line results.” The benefit of amitriptyline in this study was modest but statistically significant relative to placebo, and validates a clinical practice that has been widely used but was until now poorly supported by level 1 evidence. Amitriptyline, a tricyclic antidepressant that is believed to work as a neuromodulator, beat out placebo in the study’s primary end point, unlike the selective serotonin reuptake inhibitor (SSRI) escitalopram, which was used in a third treatment arm of the study. Case reports and small studies previously suggested that amitriptyline may

benefit patients with functional dyspepsia. However, Dr. Talley indicated that no prior study has been conducted on this scale or with the strict intention-to-treat analysis that was applied in the current study.

‘We believe, based on these results, that amitriptyline arguably appears to be efficacious for functional dyspepsia.’

—Nicholas Talley, MD

Amitriptyline Patients who were eligible for the study included those with any symptoms of functional dyspepsia consistent with Rome II criteria. (Rome III criteria were not available at the time of study enrollment.) The study, which was conducted at eight U.S. centers, included 292 patients with dysmotility-like and ulcer-like symptoms. Individuals with depression or a history of depression were excluded from the trial. Treatment efficacy was defined as adequate relief of functional dyspepsia (defined on a yes or no basis) for at least half of the 12 weeks of study evaluation. Dr. Talley and his colleagues found that efficacy was reported by 53% of patients taking amitriptyline 50 mg, 40% of those on placebo and 38% of those taking escitalopram 10 mg. The 13% gain in efficacy for amitriptyline users compared with the placebo group was close enough to the conventional definition of statistical significance that the result was considered positive (P=0.05). A stratification of baseline

measures of patients revealed that ulcerlike symptoms of dyspepsia predicted a greater response to treatment, whereas delayed gastric emptying predicted a poorer response compared with nondelayed gastric emptying. Rates of adverse events in all three arms of the study were low.

Discontinuation rates also did not differ between the three arms.

Nortriptyline Also at the DDW meeting, a study of nortriptyline, another tricyclic antidepressant, for the treatment of patients see Amitriptyline, page 40

Potentially Practice-Changing Results for Amitriptyline in Functional Dyspepsia BY CAROLINE HELWICK ORLANDO, FLA.—A study of the tricyclic antidepressant amitriptyline revealed it to be an efficacious, and potentially practice-changing, treatment for functional dyspepsia, based on top-line results from the Functional Dyspepsia Treatment Trial. “Antidepressant neuromodulating agents are frequently used to treat functional dyspepsia but their true efficacy in this disorder—particularly in the absence of depression—remains unclear,” said study author Nicholas J. Talley, MD, professor of medicine and epidemiology at Mayo Clinic, Rochester, Minn., who presented the findings at the 2013 Digestive Disease Week meeting. With nearly 300 patients, “this National Institutes of Health–funded trial is the largest study in the world on this topic, and the most important so far,” Dr. Talley said (see above, “Amitriptyline Arguably Effective for Functional Dyspepsia”). Dr. Talley noted that amitriptyline took effect promptly—within four days—unlike its action in the treatment of depression, which is often delayed.

“We don’t yet know the duration of response, and there is no guidance in the literature as to when to stop therapy,” he noted. “With our sixmonth follow-up, we will be able to observe relapses and look for clinical predictors, which should help us determine how long we should treat these patients.”

TCAs Versus SSRIs In his own practice, Dr. Talley treats patients for three to six months, then stops the drug and assesses the situation. Also, he said, he uses low-dose amitriptyline as his preferred treatment because he finds selective serotonin reuptake inhibitors (SSRIs), like escitalopram, which was used in his study, ineffective. “The study results fit my bias,” he noted. The investigators have not formally assessed adverse events yet, but Dr. Talley’s impression is that side effects were not as high as anticipated. “We did not see cholinergic effects or drowsiness,” he said. Braden Kuo, MD, director of the Gastrointestinal Motility Lab at Massachusetts General Hospital, in Boston, commented on the findings.

“I think the tricyclics are potentially a great class of medications to consider for functional dyspepsia, and I do use them. I also have been using SSRIs, but these data will make me think twice about this,” he said. “The study provides convincing data, and more or less reinforces the use of tricyclics while putting a damper on my enthusiasm for SSRIs—although I think the bar for positive symptomatic response in functional dyspepsia clinical trials can be set very high. Also, I was intrigued to find the side effects to be surprisingly low,” Dr. Kuo noted. “The fact that the drug works best in patients with normal gastric emptying is also provocative and could have implications for selecting functional dyspepsia patients for this treatment,” he added. Dr. Talley has served as a consultant for ARYx Therapeutics, AstraZeneca, Boehringer Ingelheim, Falk Pharma, Focus Medical Communications, Forest Laboratories, Ironwood Pharmaceuticals, Janssen-Cilag, MD Evidence, Meritage Pharmaceuticals, Procter & Gamble Pharmaceuticals and Zeria Pharmaceutical. Dr. Kuo has served as a consultant for Given Imaging and has received research support from GlaxoSmithKline.

The procedure isn’t a success

if the clip fails.

With more than 4 million clips placed, more than 220 clinical articles published, and almost a decade of proven clinical efﬁcacy, why would you trust anything else?*

Resolution™ Clip Leave nothing to chance™

For more information, contact your local representative, visit www.bostonscientifi c.com/endo-resources ©2013 Boston Scientific Corporation or its affiliates. All rights reserved. ENDO-000000-XX September or call 1.888.272.1001. 2013

*Data on file Resolution is a registered or unregistered trademark of Boston Scientific Corporation or its affiliates. ©2013 Boston Scientific Corporation or its affiliates. All rights reserved. ENDO-187606-AA September 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Two New Agents Evaluated for Two Types of Constipation BY TED BOSWORTH ORLANDO, FLA.—Two agents designed to treat two different forms of constipation performed well enough in recent studies to encourage regulatory approval. Plecanatide was tested in a trial of patients with chronic idiopathic constipation (CIC), and naloxegol was tested for opioid-induced constipation (OIC). Both drugs exert most of their effects in the bowel wall, thus potentially avoiding systemic adverse events (AEs); study data showed that both drugs met their primary end points, and both were described as “safe and well tolerated.” Findings from both trials were presented at the 2013 Digestive Disease Week (DDW) meeting.

Both drugs met their primary end points, and both were described as ‘safe and well tolerated.’

Oklahoma City, characterized the activity of plecanatide as physiologic. He suggested that the improvements in stool consistency observed with plecanatide support the theory of triggering molecular pathways of fluid transport as a therapy for constipation. However, diarrhea can result from treatment with drugs with this mechanism of action: In this study, “bothersome” diarrhea was reported by 5.5% of patients on the lowest dose

Plecanatide, an agonist of the guanylate cyclase-C receptor on epithelial cells, induces spontaneous bowel movements by increasing fluid secretion into the gastrointestinal tract.

of plecanatide and by 9.7% of patients on the highest dose compared with 1.3% of patients in the placebo group.

Discontinuation in the study because of diarrhea occurred in 0.8%, 3.4% and 3% of participants taking the 0.3-, 1- and

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

Plecanatide Plecanatide, an agonist of the guanylate cyclase-C receptor on epithelial cells, induces spontaneous bowel movements (SBMs) by increasing fluid secretion into the gastrointestinal tract. In the multicenter, double-blind, placebo-controlled trial of plecanatide, 946 patients with CIC as defined by Rome III criteria were evaluated. Patients were randomized to receive 0.3, 1 or 3 mg of plecanatide once-daily, or placebo. The primary end point of the 12-week study was more than three complete SBMs per week (including an increase in one SBM over baseline) for nine of the 12 weeks (including three of the four final weeks of the study). The primary end point was reached by significantly more patients in the 0.3-, 1- and 3-mg plecanatide treatment arms (19%, 17.2% and 21.5%, respectively) than in patients in the placebo group (11.5%; P<0.01 for 3 mg and P<0.05 for 0.3 and 1 mg vs. placebo). Additionally, a dose-response effect was seen across most of the secondary end points, which included degree of straining, need for rescue medication, time to effect and patient-reported satisfaction with therapy. Noting that plecanatide mimics the effects of the natriuretic peptide uroguanylin, the lead author of the study, Philip B. Miner, MD, of the Oklahoma Foundation for Digestive Research, in

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

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

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

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

3-mg doses of plecanatide, respectively. Other AEs, including serious AEs, were not remarkably higher in patients taking plecanatide.

Naloxegol In a separate study, investigators evaluated the effect of naloxegol in patients with OIC. Naloxegol acts by competitively binding to the µ-opioid receptor to block opioid-induced inhibition of bowel function. In this Phase III trial of naloxegol, data were drawn from two identical 12-week,

Naloxegol acts by competitively binding to the µ-opioid receptor to block opioid-induced inhibition of bowel function.

multicenter, randomized, double-blind, placebo-controlled trials. Eligibility required OIC, defined as less than three SBMs per week, involving hard or lumpy stools, straining or sensation of incomplete evacuation. All patients were taking morphine and remained on the drug during the treatment phase of the study, or were taking an equivalent opioid for noncancer

pain. Patients in these trials were randomized to receive 12.5 or 25 mg of naloxegol, or placebo. Similar to the plecanatide trial, the primary end point of the trial was more than three SBMs per week (including an increase in one SBM over baseline) for nine of the 12 weeks (including three of the four final weeks of the study).

Through the UCERIS Savings Program

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

ulary New Forme and g Covera avings S Expanded ram Prog

UCERIS : ®

A POWERFUL, LOCALLY ACTING STEROID1-3 •

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

•

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

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

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

www.UCERIS.com

Relative to a 29% response rate in the placebo arms of both studies, there was some variability in the active treatment arms between the two trials. In the 25-mg naloxegol arms of both studies, the 44% and 40% response rates were significant (P=0.001 and P=0.021, respectively). However, the 12.5-mg dose of naloxegol resulted in a statistically significant response rate in one study (41%; P=0.015) but not in the other (35%; P=0.202). P Similar to the plecanatide trial, the see Constipation, page 38

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

Constipation continued from page 37

efficacy and the risk for diarrhea with naloxegol were dose-dependent. However, there were also dose-related reports of abdominal pain, nausea, flatulence and vomiting. Discontinuation rates due to AEs were approximately 5% in both of the naloxegol studies for patients on the 12.5-mg dose of naloxegol and those in the placebo group, but climbed to 10% in both 25-mg naloxegol groups. The rates of serious AEs in the naloxegol and 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)

placebo groups did not differ markedly. Therapeutic options for OIC, which is common in patients on narcotic analgesics, remain limited. According to William D. Chey, MD, professor of internal medicine, University of Michigan Health System, in Ann Arbor, who presented the naloxegol results at the DDW meeting, the sustained activity of naloxegol throughout the course of the study was promising. Although naloxegol was not without AEs, 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

all were gastrointestinal-related, as a result of its localized mechanism of action.

â&#x20AC;&#x2DC;Menuâ&#x20AC;&#x2122; of Therapeutic Options Michael Camilleri, MD, professor of medicine and physiology at Mayo Clinic, Rochester, Minn., and co-investigator on the Phase III study of plecanatide, noted that there is a â&#x20AC;&#x153;relatively large number of medications available or being developed for CIC. to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

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

1-UCE13033 V1

â&#x20AC;&#x153;Plecanatide may provide an additional option for patients with this chronic constipation,â&#x20AC;? he said, but the order in which medications are selected for this indication may evolve as clinical data on plecanatide, and other treatment options, emerge. Dr. Camilleri also noted that there are very few trials that compare new medications for CIC with approved or overthe-counter remedies. Thus, clinicians will have a â&#x20AC;&#x153;menuâ&#x20AC;? of medications to try for the optimal management of patientsâ&#x20AC;&#x2122; symptoms. With naloxegol, there is a growing appreciation among gastroenterologists, physicians who treat chronic pain and oncologists that OIC may not respond to first-line laxative treatments. Based on the Phase III data of naloxegol, Dr. Camilleri said the drug â&#x20AC;&#x153;would likely expand therapeutic options for this challenging condition.â&#x20AC;? â&#x2013; Dr. Miner reported no relevant conflicts of interest. Dr. Chey reported relationships with AstraZeneca, Forest Laboratories, Ironwood Pharmaceuticals Inc., Nestle Nutrition, Procter & Gamble Pharmaceuticals, Prometheus Laboratories Inc., Salix Pharmaceuticals Inc., SK Pharmaceuticals and Takeda Pharmaceuticals. Dr. Camilleri reported relationships with Albireo, Alkermes, ARYx Therapeutics, Astellas Pharma, AstraZeneca, BioKier, EnteroMedics Inc., Ferring Pharmaceuticals, Ikaria, Ironwood Pharmaceuticals, NPS Pharmaceuticals, Ocera Therapeutics, Rose Pharma, RHYTHM, Salix Pharmaceuticals, Shire Pharmaceuticals, SK Pharmaceuticals, SmartPill Corporation, Synergy Pharmaceuticals, Takeda Pharmaceutical Company, Theravance Inc., Tranzyme Pharmaceuticals and Tsumura & Co.

Comment on this article at gastroendonews.com Do you treat patients with constipation? Comments on these and other articles can be posted and viewed online at www.gastroendonews. com. Access the article web page online, scroll down to the end of the article and look for the â&#x20AC;&#x153;Comment on This Articleâ&#x20AC;? section. Or, send your comments to the editor at cgordon@mcmahonmed.com. Comments may be published in a future issue of Gastroenterology & Endoscopy News.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Study Highlights Gaps in Knowledge About Opioid-Induced Constipation BY BEN GUARINO More than 3% of all Americans use opioids for chronic pain relief, and many experience constipation as a side effect. When opioids interact with the gastrointestinal tract, the drugs can trigger opioid-induced constipation (OIC), which poses a serious obstacle to effective pain management. However, data from a recent study showed that about half of physicians who prescribe opioids for long-term use do not prescribe prophylaxis for OIC.

determine if patients are suffering from OIC, Dr. Hwang said—and not all clinicians take that step. “The first step is making everyone aware this is a big issue,” said Gyanprakash Ketwaroo, MD, a gastroenterologist at Beth Israel Deaconess Medical Center in Boston. “There are multiple approaches, but no real comparison studies yet.”

Prophylaxis Pays Off One approach to managing OIC is under way at Abington Memorial Hospital, near Philadelphia, where Maria Foy, PharmD, a clinical specialist in pain management, has enacted a prophylactic bowel regimen in the palliative care unit. Over two yearlong trials, from November 2011 to February 2012 and April 2012

to March 2013, clinicians carried out the regimen, aimed at reducing the effects of OIC. In the first year of the trial, 29 palliative care patients were eligible for the initiative; of these, 25 (86%) had bowel movements within 72 hours after treatment (PAINWeek 2013, abstract 33). The second trial demonstrated similar see OIC, page 40

‘Among surveyed clinicians, there was a lot of varied understanding of opioidinduced constipation.’ —Sharon Hwang, MD

“Constipation is a top side effect” of opioid use, said study author Sharon Hwang, MD, MPH, medical director of CE Outcomes, a health care research firm in Birmingham, Ala. “Among surveyed clinicians, there was a lot of varied understanding of OIC,” she said, specifically citing differences in knowledge of the condition between nurse practitioners, primary care physicians and pain specialists. The results of these surveys were presented at the 2013 PAINWeek meeting (abstract 54). With support from Takeda Pharmaceuticals, Inc., Dr. Hwang posed a series of questions to clinicians to ascertain their perceptions of OIC. Based on responses of more than 300 health care professionals, Dr. Hwang and her colleagues observed “many gaps in the care of patients with chronic pain and OIC.” For example, they found that only half of primary care physicians and pain specialists regularly prescribe a prophylaxis regimen for opioid users. Alternatively, about three-fourths of nurse practitioners prescribe prophylactic medication to long-term opioid users more than 40% of the time. Dr. Hwang noted that some survey respondents had not considered OIC as a side effect of treatment with opioids. She believes that nurse practitioners, by virtue of the increased time they spend with patients, are the most likely to recognize OIC and prescribe prophylactics accordingly. “You have to ask the right question,” to

WE’RE

NG ORM

FOR PATIENTS WITH CROHN’S DISEASE After Crohn’s surgery, it is common for the disease to return within a few months despite anti-inﬂammatory medicine. At UPMC, our multidisciplinary team developed a new post-op treatment approach that has reduced the recurrence of Crohn’s disease by nearly two thirds. And now many other hospitals are adopting this novel approach. Because when you make patients feel better, it’s normal to want them to stay that way. Learn more at UPMCPhysicianResources.com/Crohns.

UPMC is afﬁliated with the University of Pittsburgh School of Medicine.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Naloxegol continued from page 3

even after symptoms beyond stool frequency were incorporated into the response. Additionally, in both trials, the higher dose was associated with statistically significant therapeutic gains of 10% to 15% in other symptoms of OIC (e.g., straining) compared with placebo. In the KODIAC-04 trial, the lower dose was associated with a statistically significant benefit over placebo in terms of meeting the primary end point; this was not seen in the KODIAC-05 trial. Serious adverse events (AEs) and AEs were rare and were observed equally at both dose levels of naloxegol. The more commonly reported AEs, abdominal pain and diarrhea, were dose-dependent. Discontinuation of treatment occurred more often in the 25-mg group.

OIC continued from page 39

results, with 24 of 31 patients achieving laxation within 72 hours. Once a regimen is recommended, clinicians at Abington Memorial Hospital rely on several techniques for treating OIC. A typical regimen begins with the use of a stimulant and stool softener combination. Depending on the patient, Dr. Foy said, she might titrate up to nine tablets of senna per day—three tablets, three times daily. “Most people wouldn’t think of going that high,” Dr. Foy said, but she maintains that it is a safe and effective way to manage constipation. If laxatives are insufficient, next steps include tap water enemas and suppositories. After 72 to 96 hours of constipation and failure of rectal treatments, clinicians may administer methylnaltrexone. For example, when she encounters a patient who hasn’t had a bowel movement in about 10 days, Dr. Foy said, “I will use Relistor [methylnaltrexone] right off the bat.” Although effective, methylnaltrexone is a restricted-use drug at Abington Memorial Hospital because of its cost. The average price for a single-use vial of methylnaltrexone is $48, and a seven-dose kit is $336 (Crownover B et al. Am Fam Physician 2010;82:678-681). The high cost of laxatives isn’t the only way that OIC can put a squeeze on budgets. Based on a retrospective review of Medicare and commercial claims data from more than 16,000 chronic opioid users, researchers at Pharmerit International in Bethesda, Md., and Takeda Pharmaceuticals found that patients who developed OIC had higher than average health care costs compared with patients without constipation. The average annual cost of health care (including inpatient and outpatient care) for a

‘Naloxegol has the potential to increase bowel movement frequency in OIC, [and] also to improve the associated symptoms that patients find so distressing.’ —Brooks D. Cash, MD

“To conclude, naloxegol was efficacious over 12 weeks of treatment for noncancer pain patients with OIC; efficacy was demonstrated with the 25-mg dose in both of these large, randomized Phase III studies,” Dr. Chey said. The results presented by Dr. Chey and his colleagues are especially important “because they indicate not

nonelderly patient with OIC was more than $23,000, significantly higher than the $13,000 average annual cost for a patient without OIC (P<0.001; PAINWeek, abstract 133). The same study revealed that clinicians prescribed laxatives to significantly more patients with OIC than to non-OIC patients (8.8% vs. 0.8%, respectively; P<0.001). Additionally, the Pharmerit and Takeda researchers found that the incidence of OIC among chronic opioid users without cancer ranges from 2.9% among nonelderly patients to 6.6% among elderly patients, and up to 15% in long-term care noncancer patients.

Eye-Opening Data Dr. Ketwaroo described the prevalence of OIC as “somewhat eye-opening.” Clinicians should try to do more, he said, to increase awareness about OIC. As a gastroenterology fellow, he receives a “fair amount” of tertiary care referrals for OIC, but practitioners in community care may not be as cognizant of the side effect, he said. “Everything has its own side effects,” Dr. Ketwaroo said. “Can we minimize the number of opioids we are prescribing? I think that’s a fair question to ask.” Half of the clinicians who spoke with Dr. Hwang voiced concern that constipation or sedation, as side effects of treatment with opioids, would result in poor adherence or discontinuation of the drugs for long-term pain management. Relieving OIC, then, becomes vital for effective pain management. “If we can control constipation in clinical opioid use,” Dr. Hwang said, “we can optimize patient adherence.” ■ Drs. Ketwaroo and Foy reported no relevant financial conflicts of interest. Dr. Hwang, as an employee of CE Outcomes, received support from Takeda Pharmaceuticals.

only that naloxegol has the potential to increase bowel movement frequency in OIC, but also to improve the associated symptoms that patients find so distressing,” said Brooks D. Cash, MD, professor of medicine at the University of South Alabama, in Mobile. Dr. Cash said that if approved, naloxegol would join lubiprostone, a type 2 chloride channel activator, as the only oral medications specifically approved for OIC. Furthermore, he said, “naloxegol would be the only oral [peripherally acting µ-opioid receptor antagonist] approved for noncancer related OIC.” ■ The KODIAC-04 and KODIAC-05 trials were supported by AstraZeneca.

Amitriptyline continued from page 34

with gastroparesis was presented. In this multicenter, randomized doubleblind study, the primary outcome was at least a 50% decrease from baseline scores on the Gastroparesis Cardinal Symptom Index on two consecutive assessments conducted over the course of the 15-week study. This criterion was met by only 15 of 65 patients (23%) randomized to receive nortriptyline compared with 14 of 65 patients (21.5%) who received placebo. Calling this the “first adequately powered, randomized clinical trial of a neuromodulator in idiopathic gastroparesis,” Henry P. Parkman, MD, of Temple University School of Medicine, Philadelphia, noted that the results do not support the use of nortriptyline for this indication. Some concern was expressed about the dose of nortriptyline used in this study, which was increased from an initial 10 mg to 75 mg by the end of the study. Earlier in the study, when the dose of nortriptyline was low, abdominal pain and nausea were both significantly less common in patients on active treatment compared with placebo; however, by the end of the study, the discontinuation rate was significantly higher in patients taking nortriptyline compared with placebo (29% vs. 14%; P=0.007). P

Antidepressants in Perspective Regarding other antidepressants with potential neuromodulatory activity, Dr. Talley used the data from the escitalopram arm of his study to question the value of the use of SSRIs for the treatment of any form of functional dyspepsia. Citing a negative study of venlafaxine, a serotoninnorepinephrine reuptake inhibitor, Dr.

Talley said that although he has used SSRIs on an empirical basis in the past to treat patients with functional dyspepsia, he would not be doing so in the future. Baha Moshiree, MD, associate professor of medicine and director of motility at the University of Miami Leonard H. Miller School of Medicine, in Florida, said that the results “highlight the importance of subtyping patients in randomized clinical trials of functional dyspepsia based on their predominant symptoms of early satiation, abdominal fullness, epigastric pain and burning, especially given the lack of a distinct pathophysiologic mechanism for the syndrome.” Ultimately, the results indicate that the benefit of amitriptyline is limited to visceral neuropathic symptoms, with less or no benefit on altered gastric accommodation or delayed transit, as with gastroparesis. “This was a limitation of prior studies done with nortriptyline and venlafaxine and is now less vague based on this well-designed study,” she said. ■ Dr. Talley has served as a consultant for ARYx Therapeutics, AstraZeneca, Boehringer Ingelheim, Falk Pharma, Focus Medical Communications, Forest Laboratories, Ironwood Pharmaceuticals, Janssen-Cilag, MD Evidence, Meritage Pharmaceuticals, Procter & Gamble Pharmaceuticals and Zeria Pharmaceutical. Dr. Parkman has served as a consultant for Evoke Pharma, GlaxoSmithKline, ProStrakan, Rhythm Pharmaceuticals, Inc., SmartPill Corporation and Tranzyme Pharmaceuticals. Dr. Moshiree reported relationships with Amgen, AstraZeneca, Celgene, Millennium Pharmaceuticals, Pfizer, Sanofi and Takeda Pharmaceuticals; she has served on the advisory board for Prometheus.

RetroView Gives You The Power To See It. ™

One look and you’ll see how this revolutionary new colonoscope can help you find more disease, remove more polyps and increase efficiency more effectively than ever before. With its remarkably small retroflex radius wide angulation capacity, EC-3490TLi Video Colonoscope (RetroView ™ ) allows for greater visualization and access to the proximal side of colon folds and flexures. Even in the most challenging situations, you have the potential to improve your cecal intubation and adenoma detection rates in colonoscopy. To learn more about how RetroView™ gives you the power to see and do more visit RetroViewSeeks.com

Polyps Hide. RetroView™ Seeks.

The latest innovation from the best-in-class colonoscopy solutions provider. ©2013 PENTAX America, Inc. All Rights Reserved. All company and product names and marks contained within are federally registered trademarks, trademarks or service marks of PENTAX of America, Inc. MK-440 Rev: B

FDA UPDATE & PRODUCT NEWS

Will Opioid Scrutiny Spur NSAID Overuse? BY BEN GUARINO In the wake of FDA changes to labels for extended-release/long-acting opioid pain relievers, clinicians and patients may be looking elsewhere for ways to manage moderate pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) offer a potential alternative, but some clinicians are urging that a possible increase in NSAID consumption should be met with caution.

“We hope the impact will not be great,” said Daniel Brzusek, DO, vice chair of the Alliance for Rational Use of NSAIDs. “But we think that not only physicians, but the lay public will rely on NSAIDs.” Michael Carome, MD, director of Public Citizen’s Health Research Group, said it’s “hard to say” if the new FDA labeling will influence NSAID use. He cited the variety of pain relief options that could be used in lieu of

opioids or NSAIDs. “Non-NSAIDs, like Tylenol, may be reasonable for some patients,” Dr. Carome said. “And frequently, these are underutilized.” Both Drs. Carome and Brzusek noted that there are ways to relieve pain that do not rely on pharmaceuticals, such as exercise and behavioral therapy. Dr. Brzusek also cited acupuncture as “a safer, zero-risk alternative” to NSAIDs. In the United States, an estimated 23 million people use NSAIDs for

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

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

daily pain relief. Although considered safe when used properly, these drugs may result in adverse effects, such as cardiovascular events and gastrointestinal (GI) bleeding. A recent meta-analysis of the adverse effects of NSAIDs found that, compared with placebo, for every 1,000 patients per year receiving a coxib or diclofenac, there would be three additional vascular events, of which one would be fatal. The meta-analysis also reported an increase in upper GI complications compared with placebo—most frequently, bleeding—at relative risks of 1.81 for coxibs ((P=0.0070), 1.89 for diclofenac ((P=0.0106), 3.97 for ibuprofen (P ( <0.0001) and 4.22 for naproxen ( <0.0001; Lancett 2013;382:769-779). (P Patients who use NSAIDs should take the “least dose possible for the shortest period of time,” Dr. Brzusek said. “That’s a maximum of 10 days.” Dr. Brzusek begins with a minimal dose—for example, 200 mg of ibuprofen three times daily, 75 mg of diclofenac daily or 250 mg of naproxen twice daily—and titrates up the dosage every three days until there is no additional positive response. How big a problem NSAIDs pose is a matter of debate. Lynn Webster, MD, president of the American Academy of Pain Medicine, has said that deaths from GI bleeding linked to NSAIDs “rival deaths from opioids, according to some estimates.” This statement provoked a strong response from Andrew Kolodny, MD, president of Physicians for Responsible Opioid Prescribing, who wrote on Twitter that Dr. Webster’s remark was “false” and should be corrected. Estimates of deaths from GI bleeding range from a high of 16,500 (Singh G, Triadafilopoulos G. J Rheumatol Suppl 1999;56:18-24) to a more conservative 2008 report from the Centers for Disease Control and Prevention, which cited 3,400 deaths. In contrast, the agency recorded 14,800 deaths from opioids in 2008. When asked about the number of deaths from NSAIDs compared with the number of opioid-related deaths, Dr. Brzusek said he did not believe deaths from NSAIDs are quite so high. “There are definitely a lot of deaths from bleeding,” he said, “but hospitalizations are more common.” According to the Alliance for the Rational Use of NSAIDs, NSAIDs contribute to at least 100,000 hospitalizations per year. Dr. Carome emphasized that he is not opposed to the reasonable administration of NSAIDs. “All drugs have problems,” he said. “Patients need to be made aware of that.” ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

FDA UPDATE & PRODUCT NEWS

New Low-Dose NSAID Developed To Address GI-Related Adverse Events Iroko Pharmaceuticals, LLC, has announced the availability of Zorvolex (diclofenac) capsules in 18and 35-mg strengths at pharmacies nationwide. Zorvolex, a novel lowdose nonsteroidal anti-inflammatory drug (NSAID), was approved by the FDA in October for the treatment of mild to moderate acute pain. Zorvolex is the first and only FDAapproved NSAID developed using proprietary SoluMatrix Fine Particle Technology. It contains diclofenac in submicron particles that are approximately 20 times smaller than their original size. The reduction in particle size translates to an increased surface area, leading to faster dissolution of the drug. “Zorvolex is approved by the FDA at dosage strengths that are 20% lower than other currently available diclofenac products, filling an important market need,” said John Vavricka, president and CEO of Iroko Pharmaceuticals. Iroko cited data showing that serious NSAID-related adverse events, including gastrointestinal ulcers and bleeding, are dose related (Rahme E et al. Br J Clin Pharmacol 2001;52:185-192; Risser A et al. Am Fam Physician 2009;80:1371-1378). As such, Zorvolex was developed to address recommendations from the FDA and other professional medical organizations, including the American Gastroenterological Association, that NSAIDs be used at the lowest effective dose for the shortest possible duration of time consistent with individual patient treatment goals. For more information about Zorvolex, visit www.zorvolex.com. —Based on a press release from Iroko Pharmaceuticals, LLC

Zorvolex (diclofenac) capsules are available in 18- and 35-mg strengths.

Your Go-to Resource for Endoscopy Self-Assessment The ASGE Gastrointestinal Endoscopy Self-Assessment Program VII (G GESAP GESAP SAP VII) VI is the premier V resource for assessing knowledge, preparing for certification exams ms and earning points for ABIM Maintenance of Certification (MOC). With more than 300 peer-re peer-reviewed questions, GESAP VII offers 100 study modules by topic area and a comprehensive com self-test module that includes the same 300+ questions in random order for a true self-assessment experience.

Online format – earn up to 90 MOC points! Participants may purchase the online version of GESAP VIII as individual modules, MOC packages, or the comprehensive suite that includes all modules at a signiﬁcant g discount! All nine modules qualify for ABIM MOC points – that’s up to 90 MOC points with one resource!

“What a phenomenal program! I am already looking forward to GESAP VIII!” – Comments from GESAP VII purchasers

Track your progress and return at any time See how your answers compare to your peers Earn CME and print certificates from your account Earn up to 90 MOC p points and submit them directly to ABIM • Comprehensive Suite — The ultimate study and self-test package. Ideal for those looking for a complete self-study resource. *Best Value* • Individual Modules — Choose and purchase individual modules. Ideal for those looking to study speciﬁc topics.

GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,500 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2013). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2014 by McMahon Publishing.

“This is a superb, magnificent, well done, detailed assessment. I can’t think of anything done like this before. It is easy to tell that the authors spent lots of time and energy putting this together.”

• MOC Packages — Purchase modules available for MOC only. Ideal for those looking to earn ABIM MOC points. Visit www.ASGE.org to purchase the online version of GESAP VII.

Topics covered: • Biliary • Colorectal • Esophagus • Nutrition • Pancreas • Patient Preparation, Monitoring and Sedation • Pediatrics • Stomach • Small Intestine • GIE Focal Points

GESAP VII Features DVD Format – a “true” self-test DVD — The self-test module of 300+ questions in random order is available on DVD through the ASGE Store. Ideal for studying oﬀ-line providing a true self-assessment experience. MOC points are not available through the DVD version.

• All questions and critiques developed and peer-reviewed by ASGE member endoscopists • Includes real-life scenarios, a rationale for each correct answer and references • Fully interactive format with images and videos throughout the program to clarify important topics • Earn up to 90 ABIM MOC points with the online version • Earn up to 40 AMA PRA Category 1 Credits™

Order GESAP VII today at www.asge.org

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

65 continued from page 5

has been slowing, will go to zero and will then start to reverse. When the earth’s fertility rate, which has been continuously decreasing, falls below 2.33 children per family, the population will start to shrink and we will stay forever small enough to be hidden in the Grand Canyon. So, I am confident that a combination of decreased fertility rates and our scientific ingenuity can and will prevent the earth from running out of resources to support

its multitudes, but how about our own microcosm, the United States of America? I’m afraid that our national populationrelated problems will be more difficult to solve than those of global resources. The gre atest threat for us is not our food supply but our health care system.

U.S. Health Care There are many problems that will be caused by our expanding and aging

population, but none is as severee or as imminent as its effect on our already over-burdened healtth care system. Of course the sheeer numbers are daunting. Both th he population and the percentage of people who are older and requ uire more expensive care are grow wing at alarming rates. We recently have closed a few more gaps in the safety net, which should add about 30

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere. 1978 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

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

Guidance Equivocal On HCV Screening Of Baby Boomers

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

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

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

see NAFLD, page 14

see Income, page 28

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

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

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

BY MONICA J. SMITH

tor

Ma Vis it y DD 19-2 us W bo 1, 20 oth 13 15 31

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

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

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

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

CLINICAL REVIEW see insert between pages 20 and 21

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

PRODUCT ANNOUNCEMENT

Ulcerative Colitis:

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

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

BRIAN BOSWORTH, MD

see page 63 for product information

he e greatest ch hallenge for cllinicians who

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

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

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

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

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

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

million to the rolls of people with health care coverage. The financial effect of this to the nation has not yet been felt, but most health care economists predict that it will be significant. By 2050, it is estimated that there will be another 117 million people in the country. A larger percentage of these people will be older than age 65, nonworking dependents with more expensive health care needs. At the same time, the number of physicians and nurses as a percentage of the population will shrink. As a nation, we are the victims of better public sanitation and an effective health care system. People are living longer and it is more expensive to care for them as they age. Not only do they have more health problems, but their chronic illnesses and debilities are more expensive than acute illnesses. The Department of Health and Human Services reports that 90% of health care expenses go to treating chronic conditions, and 77% of people over the age of 65 years have two or more chronic conditions. The notion that keeping people healthy will save money is an attractive theory, but unfortunately it is incorrect. It has been shown that healthy people who live longer will spend more money for health care over their lifetimes than unhealthy people. Several studies, including one by Boston College’s Center for Retirement Research, have calculated individual health care spending over a lifetime and have concluded that healthier people should save more for future health-related expenses. Someone who has an unhealthy lifestyle might die of complications of obesity, hypertension or diabetes in his or her 60s, whereas a healthy person is more likely to survive into his or her 90s and require years of

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

are doing now and full commitment to changing how we deliver and finance health care in this country. Although I consider most of my columns to be opinion pieces, most of what I have written here is not my personal philosophy or politics; it is arithmetic. There are legitimate differences of opinion about the role of the government, the participation of the private sector, the responsibilities of health care recipients, rationing,

tort reform and other issues raised by the health care debate. You undoubtedly have opinions about all of them. The numbers, however, are different. They cannot be interpreted, spun or manipulated. We know where they are headed and beyond that I don’t think it’s much of a stretch to conclude that health care is headed for a difficult future. In this column I am not offering any easy solutions because there are none.

There are only difficult ones that require compromises with features that will be difficult to digest for almost everyone. The first step in finding a solution is to recognize the magnitude of this problem as well as its inevitability. There will be some pain for all. As physicians, as citizens and as advocates for our patients, we will be called on to participate in the solution. We can’t afford to stand on the sidelines. ■

Aspiration Patients with impaired gag reﬂex and patients prone to regurgitation or aspiration should be observed during the administration of MoviPrep. Use with caution in these patients.

This time, the problem is too big and we cannot temporize by manipulating the details. As the expression goes, just do the numbers. And you can start with 65. care at the end of life to manage dementia, arthritis, fractured hips, pneumonia and other medical consequences of aging. Does this mean we should not promote healthy lifestyles? Absolutely not. As a profession, we should promote practices that lead to longer lives but we should realize that we are proposing the more expensive alternative and healthy living is not going to solve our financial problems. The global food shortage problem noted above seems to have an easy solution, but I’m not quite so sanguine about our national health care problem. The dual realities of our expanding and aging population are going to make many things progressively more difficult and health care delivery and financing will be our biggest and most immediate problem. Although I appreciate that there are a lot of concerned and earnest people engaged in important issues such as donut holes, the sustainable growth rate formula, the constitutionality of mandated health care and so on, there is a much larger, more serious problem on the immediate horizon. That problem is how are we going to continue to pay for what we are doing. Some look at problems and say that the devil is in the details and solutions will be found merely by attending to these details. This time, however, the problem is too big and we cannot temporize by manipulating the details. As the expression goes, just do the numbers. And you can start with 65. I have concluded that the numbers tell us that we need bold ideas, a radical departure from what we

MOVIPREP® (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution, 100g/7.5g/ 2.691g/1.015g/5.9g/4.7g) The following is a brief summary only. See complete prescribing information on www.moviprep.com or request complete prescribing information by calling 1-800-508-0024. INDICATION AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older. CONTRAINDICATIONS MoviPrep is contraindicated in the following conditions: • • • • • •

Gastrointestinal (GI) obstruction Bowel perforation Gastric retention Ileus Toxic colitis or toxic megacolon Hypersensitivity to any components of MoviPrep

WARNINGS AND PRECAUTIONS Serious Fluid and Electrolyte Abnormalities Advise patients to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep consider performing postcolonoscopy lab tests (electrolytes, creatinine, and BUN). Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment. Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. MoviPrep should be used with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities [such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs)] or in patients with known or suspected hyponatremia. Consider performing pre-dose and postcolonoscopy laboratory tests (sodium, potassium, calcium, creatinine, and BUN) in these patients. [See DRUG INTERACTIONS] Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing MoviPrep for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy ECGs should be considered in patients at increased risk of serious cardiac arrhythmias. Seizures There have been rare reports of generalized tonic-clonic seizures and/or loss of consciousness associated with 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 abnormalities resolved with correction of fluid and electrolyte abnormalities. Use caution when prescribing MoviPrep for patients with a history of seizures and in patients at increased risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia. Renal Impairment Use with caution in patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs). Advise these patients of the importance of adequate hydration, and consider performing pre-dose and postcolonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. (Colonic) Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis 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 stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. Use in Patients with Significant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate. Use with caution in patients with severe ulcerative colitis.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency Since MoviPrep contains sodium ascorbate and ascorbic acid, MoviPrep should be used with caution in patients with glucose6-phosphate dehydrogenase (G-6-PD) deficiency, especially G-6-PD deficiency patients with an active infection, with a history of hemolysis, or taking concomitant medications known to precipitate hemolytic reactions. Contains Phenylalanine Phenylketonurics: Contains aspartame 233 mg per treatment which corresponds to 131 mg of phenylalanine per treatment (after hydrolysis of the aspartame molecule in-vivo to aspartic acid and phenylalanine). ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the MoviPrep trials, abdominal distension, anal discomfort, thirst, nausea, and abdominal pain were some of the most common adverse reactions to MoviPrep administration. Since diarrhea was considered as a part of the efficacy of MoviPrep, diarrhea was not defined as an adverse reaction in the clinical studies. Tables 1 and 2 display the most common drug-related adverse reactions of MoviPrep and its comparator in the controlled MoviPrep trials. Table 1: The Most Common Drug-Related Adverse Reactions1 ( 2%) in the Study of MoviPrep vs. 4 Liter Polyethylene Glycol plus Electrolytes Solution

Malaise Nausea Abdominal pain Vomiting Upper abdominal pain Dyspepsia 1

Cardiovascular: Tachycardia, palpitations, hypertension, arrhythmia, atrial fibrillation, peripheral edema. General: Hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritus, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration. Nervous system: Syncope, tremor, seizure. Renal: Renal impairment and/or failure. DRUG INTERACTIONS Drugs That May Increase Risks Due to Fluid and Electrolyte Abnormalities Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate. [See WARNINGS] Potential for Altered Drug Absorption Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman 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 MoviPrep is administered to a nursing woman.

MoviPrep® (split dose) N=180 n (% = n/N)

4L PEG + E2 N=179

Pediatric Use The safety and effectiveness of MoviPrep in pediatric patients has not been established.

n (% = n/N)

35 (19.4) 26 (14.4) 24 (13.3) 14 (7.8) 10 (5.6) 5 (2.8)

32 (17.9) 36 (20.1) 27 (15.1) 23 (12.8) 11 (6.1) 2 (1.1)

Geriatric Use Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identiﬁed differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Drug-related adverse reactions were adverse events that were possibly, probably, or deﬁnitely related to the study drug. 4L PEG+E is 4 liter Polyethylene Glycol plus Electrolytes Solution

Table 2: The Most Common Drug-Related Adverse Reactions1 ( 5%) in the Study of MoviPrep vs. 90 mL Oral Sodium Phosphate Solution

Abdominal distension Anal discomfort Thirst Nausea Abdominal pain Sleep disorder Rigors Hunger Malaise Vomiting Dizziness Headache Hypokalemia Hyperphosphatemia

MoviPrep® (evening only) y (full dose) ( dose) N=169 n (% = n/N)

90 mL OSPS2 N=171

101 (59.8) 87 (51.5) 80 (47.3) 80 (47.3) 66 (39.1) 59 (34.9) 57 (33.7) 51 (30.2) 45 (26.6) 12 (7.1) 11 (6.5) 3 (1.8) 0 (0) 0 (0)

70 (40.9) 89 (52.0) 112 (65.5) 80 (46.8) 55 (32.2) 49 (28.7) 51 (29.8) 121 (70.8) 90 (52.6) 14 (8.2) 31 (18.1) 9 (5.3) 10 (5.8) 10 (5.8)

n (% = n/N)

Drug-related adverse reactions were adverse events that were possibly, probably, or deﬁnitely related to the study drug. In addition to the recording of spontaneous adverse events, patients were also speciﬁcally asked about the occurence of the following symptoms: shivering, anal irritations, abdominal bloating or fullness, sleep loss, nausea, vomiting, weakness, hunger sensation, abdominal cramps or pain, thirst sensation, and dizziness. 2 OSPS is Oral Sodium Phosphate Solution

Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions. Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age. These adverse events included upper gastrointestinal bleeding from a Mallory-Weiss tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation. Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse events have been identiﬁed during postapproval use of MoviPrep. Because they 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 events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to MoviPrep, or a combination of these factors.

PATIENT COUNSELING INFORMATION • Advise patients who require a diet low in phenylalanine that MoviPrep contains aspartame – a maximum of 233 mg per treatment. This sweetener, after hydrolysis in the body, provides 131 mg of phenylalanine to the patient. • Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. • Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquids. Examples of clear liquids are: water; clear fruit juices without pulp including apple, white grape, or white cranberry; strained limeade or lemonade; coffee or tea (Do not use any dairy or non-dairy creamer); clear broth; clear soda; gelatin (without added fruit or topping); popsicles (without pieces of fruit or fruit pulp). • Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. • Tell patients not to take other laxatives while they are taking MoviPrep. • Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. • Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider. 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. For additional information, call: 1-866-SLXP(7597) To report adverse events, call: 1-800-508-0024 Manufactured for: Salix Pharmaceuticals, Inc. 8510 Colonnade Center Drive Raleigh, NC 27615 www.salix.com © 2013 Salix Pharmaceuticals, Inc. All rights reserved.

MOV-RALAB7-092013

Seeing is believing

patient approved 9 OUT OF 10

MoviPrep® has proven 89% excellent or good cleansing when used as a split dose1

patients would take 2 MoviPrep again

° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° Comprehensive patient support, including a live nurse help line (1-855-4MOVIRX), a downloadable prep kit, and educational materials ° In clinical trials, no differences in safety and tolerability between younger and geriatric patients

physician trusted

-Most common adverse reactions for split dosing (incidence 5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence 5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness

NEARLY 8 MILLION MoviPrep prescriptions 3 written in the US since 2006

www.MoviPrep.com CONTRAINDICATIONS MOVIPREP® is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep. Please see Brief Summary of complete Prescribing Information for MoviPrep on reverse. References: 1. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 2. Ponchon T, Boustière C, Heresbach D, et al. A low-volume polyethylene glycol plus ascorbate solution for bowel cleansing prior to colonoscopy: the NORMO randomised clinical trial [published online ahead of print June 14, 2013]. Dig Liver Dis. doi: 10.1016/j.dld.2013.04.009. 3. Symphony Health Solutions, Pharmaceutical Audit Suite (PHAST), September 2006 through June 2013. Website: www.MoviPrep.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597). MoviPrep® is a registered trademark and PM| AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. MOV 13/11-2

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

First-Line Treatment Strategies for

Helicobacter pylori Infection RICHARD J. SAAD, MD, MS, AND WILLIAM D. CHEY, MD Department of Internal Medicine Division of Gastroenterology U University of Michigan Health System Ann Arbor, Michigan Dr. Saad has no relevant conflicts of interest. Dr. Chey has served as a consultant for AstraZeneca and Takeda Pharmaceuticals.

elicobacter pylori is a major m cause of chronic gastritis and peptic ulcer d disease (PUD); it is closely linked with gastric muco mucosa-associated lymphoid

gast adenocarcinoma; and tissue (MALT) lymphoma and gastric une it is causally associated with unexplained iron-deficiency anemia, primary immune throm thrombocytopenia (formally termed idiopathic thrombocytopen thrombocytopenic purpura), and vitamin B12 deficiency.

Given these known and potential complications of chronic H. pylori ylorii infecough it has tion, its identification mandates effective eradication (Table 1). Although ation therbeen more than 3 decades since the discovery of H. pylori, no eradication r, there has apy has been identified that guarantees a 100% cure rate. Moreover, been a tendency toward reduced efficacy of eradication regimens over time, largely because of the development of antibiotic resistance to H. pylori. In clinical practice, the initial course of eradication therapy generally offers the greatest likelihood for treatment success. Therefore, careful selection of firstline eradication therapy is essential. The most important factors to consider when choosing an initial course of eradication therapy are prior antibiotic exposure of the patient and, if available, the regional antibiotic-resistance profile of H. pylori.

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

Table 1. Indications for Helicobacter pylori Testing as Recommended By Expert Panels American College of Gastroenterology (2007)1

Maastricht/Florence Consensus Conference (2012)6

Asia-Pacific Consensus (2009)10

Established indications: • Active PUD • Confirmed history of PUD but not previously treated for H. pylori • Gastric MALT lymphoma • Following endoscopic resection of early gastric cancer • Uninvestigated dyspepsia (if H. pylori prevalence >20%) Controversial indications: • Functional dyspepsia • Use of NSAIDs (especially for patients with a history of PUD or those initiating NSAID therapy) • Unexplained iron deficiency • Populations at increased risk for gastric cancer

• PUD • Gastric MALT lymphoma • Following endoscopic resection of early gastric cancer • Uninvestigated dyspepsia (if H. pylori prevalence >20%) • Functional dyspepsia • Prior use of NSAIDs with a history of PUD • Long-term NSAID use or use of lowdose aspirin • Long-term PPI use (>1 y) • Unexplained iron deficiency, ITP, or vitamin B12 deficiency • First-degree relative with gastric cancer • Severe pan-gastritis, corpus-predominant gastritis, or severe mucosal atrophy • Chronic gastric inhibition for more than 1 y • Environmental risk factors for gastric cancer (eg, heavy smoking or high exposure to dust, coal, quartz, cement, or quarry work)

• PUD • MALT lymphoma • Atrophic gastritis • Following resection of gastric cancer • First-degree relative with gastric cancer • If desired by patient (following full consultation with physician) • Functional dyspepsia • NSAID-naive users • Before long-term aspirin use, if at high risk for PUD and PUDrelated complications • Long-term low-dose aspirin use, with a history of upper gastrointestinal bleeding or perforation • Screening strategy in communities with high incidence of gastric cancer • Unexplained iron deficiency or ITP

ITP, idiopathic thrombocytopenic purpura; MALT, mucosa-associated lymphoid tissue; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor; PUD, peptic ulcer disease

Eradication Therapy A variety of treatment regimens have been developed for the eradication of H. pylori, typically employing an antisecretory agent combined with 2 or 3 drugs possessing antimicrobial activity, taken concomitantly or sequentially, for periods ranging from 3 to 14 days (Table 2). The overwhelming majority of recent clinical trials evaluating the efficacy of eradication therapy have been performed in southern Europe and Eastern Asia. This is an important consideration, given the regional variability in H. pylorii strains and H. pylorii antibiotic-resistance patterns.

LEGACYY FIRSTT-LINEE ERADICATION N THERAPIES In 2007, the Practice Parameters Committee of the American College of Gastroenterology (ACG) provided the most recent recommendations for the treatment of H. pylorii infection in the United States.1 For an initial course of eradication therapy, the expert consensus panel recommended 14 days of treatment with a proton pump inhibitor (PPI), clarithromycin, and amoxicillin (clarithromycin-based triple therapy), or 10 to 14 days

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

of treatment with a PPI or histamine-2 receptor antagonist, bismuth, metronidazole, and tetracycline (bismuth quadruple therapy). In cases of an allergy to penicillin, metronidazole was recommended in lieu of amoxicillin for clarithromycin-based triple therapy or bismuth quadruple therapy. Eradication rates were reported to be 70% to 85% for clarithromycin-based triple therapy, and 75% to 90% for bismuth quadruple therapy.1 Clarithromycin resistance in the setting of clarithromycin-based triple therapy is substantial, with a 2010 meta-analysis demonstrating an eradication rate of only 22% in the presence of clarithromycin-resistant H. pylori strains compared with 90% for clarithromycin-sensitive strains.2 As such, the ACG committee recommended avoiding clarithromycin -based triple therapy in patients with a history of repeated macrolide antibiotic exposure, for any indication, as this has been shown to increase the likelihood for clarithromycin-resistant H. pylori.3 This concern was recently reaffirmed in a large study assessing the association between antibiotic-resistance profiles and outpatient antibiotic exposure in more than 2,200 patients

Table 2. Evidence-Based, First-Line Treatment Regimens for Helicobacter Pylorii Infection Legacy Therapies

Treatment Duration, d

Practical Considerations

Standard-dose PPIa bid + clarithromycin 500 mg bid + amoxicillin 1,000 mg bid

7-14

• 7 d recommended in Asia • 10-14 d elsewhere (US)

Standard-dose PPI bid + clarithromycin 500 mg bid 7-14 + metronidazole 500 mg bid

• 10-14 d of therapy more effective than 7 d • Use in penicillin-allergic pts

Bismuth subsalicylate 525 mg qid + metronidazole 250 mg qid + tetracycline 500 mg qid + ranitidine 150 mg bid or standard-dose PPI bid

10-14

• Use in penicillin-allergic pts • May consider doxycycline 100 mg bid if tetracycline unavailable

Standard-dose PPI bid + amoxicillin 1,000 mg bid for first 5 d; followed by standard-dose PPI bid + clarithromycin 500 mg bid + tinidazole 500 mg bid for subsequent 5 d

• Requires validation in North America

Standard-dose PPI bid + amoxicillin 1,000 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid or metronidazole 500 mg tid

3-10

• Requires validation in North America • Trend toward greater eradication efficacy with longer duration of therapy

Levofloxacin 250 mg qd + omeprazole 40 mg qd + nitazoxanide 500 mg bid + doxycycline 100 mg qd (PM dosing)

7-10

• Superior to standard triple therapy in US clinical trial

Emerging Therapies

bid, twice daily; PPI, proton pump inhibitor; pts, patients; qd, every day a

Standard-dose PPI: omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, or rabeprazole 20 mg; esomeprazole 40 mg once daily is equivalent to standard-dose PPI bid.

in 18 European countries.4 Additionally, another recent study identified an increased risk for antibiotic resistance based on the number of previous exposures to antibiotics (Table 3).5 International guidelines have presented similar recommendations for first-line eradication therapy, with some notable differences. The fourth Maastricht/Florence Consensus Conference, comprising 44 experts from 24 countries, presented its most recent H. pylori treatment recommendations, primarily for the European community, in 2012.6 In regions of low clarithromycin resistance, clarithromycin-based triple therapy was recommended as the initial therapy of choice, with bismuth quadruple therapy as an alternative. However, in regions where the clarithromycin resistance rate exceeded 15% to 20%, bismuth quadruple therapy was recommended as the initial therapy of choice. In 2004, the H. pylorii clarithromycin resistance rate in the United States was reported at 12.9%.7 Unfortunately,

there has been no organized national surveillance of H. pylorii antimicrobial resistance in the United States since that time. In comparison, a recent large-scale, multicenter study involving 18 European countries found an overall clarithromycin resistance rate of 17.5%.4 Antibiotic-resistance rates varied widely in different regions of Europe, highlighting the difficulties of designing a “one-size-fits-all” approach to first-line therapy for any region or country (Table 4).4 Clarithromycin-resistance rates in Asia also are highly variable, ranging from 3.7% in Thailand to 85% in a population of children in Beijing.8,9 The Second Asia-Pacific Consensus published its expert panel recommendations in 2009 for Asian populations.10 The panel concluded that the use of high-dose, twice-daily PPI therapy increased the success of clarithromycin-based triple therapy, largely based on the results of a meta-analysis of randomized controlled trials (RCTs) that demonstrated a cure rate of 82% with twice-daily high-dose

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Table 3. Effect of Prior Antibiotic Exposure on Risk for Antibiotic-Resistant Helicobacter pylorii Infection in a UK Population5 Prior Antibiotic Exposure

Antibiotic Sensitivity

Number of Patients (patients with antibioticresistant H. pylori, %) 0 Courses

1 Course

≥2 Courses

RRa (95% confidence interval)

Quinolone

Levofloxacin

114 (4)

7 (14)

11 (27)

1.8 (1.24-2.49)

Metronidazole

114 (28)

13 (38)

5 (100)

1.6 (1.46-1.75)

Clarithromycin

103 (7)

21 (19)

8 (25)

1.5 (0.92-2.41)

Erythromycin

Clarithromycin

104 (8)

15 (20)

13 (15)

1.1 (0.82-1.59)

Ratio at o of o the t e risk s for o resistance es sta ce per pe unit u t increase c ease in number u be of o courses cou ses of o therapy. t e apy

PPIs compared with 74% with twice-daily standard-dose PPI therapy. A 7-day course of clarithromycin-based triple therapy was recommended as the initial first-line therapy, despite the panel’s acknowledgment of rising clarithromycin resistance in Asian countries and its negative effect on eradication rates. The panel also recommended bismuth quadruple therapy as an alternative to clarithromycin-based triple therapy. An important caveat regarding the use of bismuth quadruple therapy deserves mention. There has been a shortage of tetracycline in the United States since 2011 because of production issues. As of mid-January, the FDA anticipated an improvement in tetracycline availability for 2014, although there was no guarantee. In the meantime, there are limited clinical data to suggest the substitution of tetracycline with doxycycline at a dose of 100 mg twice daily.11-13

EMERGING G FIRST T-LINE E ERADICATION N THERAPIES Sequential therapy was introduced in 2000 to address the diminishing efficacy of clarithromycinbased triple therapy.14 This treatment regimen—which consists of a PPI plus amoxicillin for 5 days, followed by a PPI, clarithromycin, and tinidazole for an additional 5 days—was associated with an eradication rate of 93.5% in a pooled analysis of 15 Italian studies including more than 1,800 patients.15 A subsequent systematic review and meta-analysis of 10 clinical trials totaling 3,006 patients, which directly compared sequential therapy with clarithromycin-based triple therapy for eradication of H. pylori, reported an odds ratio (OR) of 2.99 in favor of sequential therapy (95% confidence interval, 2.473.62; number needed to treat, 7); in patients with clarithromycin resistance, the OR for eradication was 10.21 in favor of sequential therapy (95% CI, 3.01-34.58).16

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

However, 8 of these 10 clinical trials were performed in Italy, with the other 2 trials from Korea and China, calling into the question the generalizability of the results. Indeed, subsequent studies of sequential therapy from other parts of the world have yielded differing results. For example, a recent multicenter trial comprising 1,463 adults from 6 Latin American countries found clarithromycin-based triple therapy marginally better than sequential therapy, with an eradication rate of 82.2% compared with 76.5%, respectively (difference, 5.6%; 95% CI, –0.04% to 11.6%).17 Additionally, a recent Turkish trial reported a cumulative eradication rate of only 66.5% in 200 adults receiving 1 of 2, 14-day sequential therapies as first-line therapy for H. pylorii infection (either lansoprazole plus amoxicillin for 1 week, followed by a second week of lansoprazole, clarithromycin, and metronidazole, or lansoprazole, clarithromycin, and tetracycline).18 Furthermore, a large study from Taiwan found that preexisting clarithromycin resistance may reduce the efficacy of sequential therapy, and that eradication rates might be improved by extending therapy duration to 14 days (Table 5).19 A recent systematic review and meta-analysis of RCTs—totaling 46 trials and 13,532 patients, conducted through May 2013— compared sequential therapy with either preexisting or new therapy.20 In this study, the overall eradication rate of sequential therapy was 84.3% (95% CI, 82.1%86.4%). Sequential therapy was superior to 7 days of clarithromycin-based triple therapy (relative risk [RR], 1.21; 95% CI, 1.17-1.25); however, sequential therapy was only marginally superior to 10 days of clarithromycinbased triple therapy (RR, 1.11; 95% CI, 1.04-1.19) and was not superior to 14 days of clarithromycin-based triple therapy (RR, 1.00; 95% CI, 0.94-1.06) or bismuth quadruple therapy (RR, 1.01; 95% CI, 0.95-1.06).

Table 4. Helicobacter pylorii Resistance to Antibiotics Based on Country of Residence in European Adults4 Region

Number of Resistant Strains/ Total Number Tested

Resistance, % (95% confidence interval, %)

Northern Europea

31/401

7.7 (5.4-10.7)

Western/Central Europeb

136/725

18.7 (16.1-21.7)

Southern Europec

165/767

21.5 (19.9-25.5)

Northern Europe

31/401

7.7 (5.4-10.7)

Western/Central Europe

135/725

18.6 (15.9-21.6)

Southern Europe

101/767

13.1 (11.0-15.8)

Northern Europe

115/401

28.6 (24.3-33.1)

Western/Central Europe

318/725

43.8 (40.2-47.3)

Southern Europe

228/767

29.7 (26.5-32.9)

Clarithromycin

Levofloxacin

Metronidazole

Northern Europe: Finland, Ireland, Lithuania, Norway, The Netherlands, United Kingdom. Western/Central Europe: Austria, Belgium, France, Germany, Hungary, Poland. c Southern Europe: Croatia, Greece, Italy, Portugal, Slovenia, Spain. b

Based on these data, the ACG guideline expressed cautious optimism for sequential therapy, and recommended formal validation in the United States.1 To date, there have been no RCTs that have evaluated the efficacy of sequential therapy in the United States. Because of the divergent results of international studies and a lack of US data, it is difficult to offer an unqualified endorsement of sequential therapy for the treatment of US patients with H. pylorii infection. The Second Asia-Pacific Consensus also concluded that there were insufficient data to recommend sequential therapy as a first-line eradication therapy for H. pylori infection in Asian populations.10 Likewise, the fourth Maastricht/ Florence Consensus Conference recommendation states: “In areas of low clarithromycin resistance, clarithromycin-containing treatments are recommended for ﬁrst-line empirical treatment.”6 A treatment regimen primarily developed to address the complexity of sequential therapy is non-bismuth quadruple therapy, or so-called “concomitant therapy.” This regimen consists of a PPI, amoxicillin, clarithromycin, and an imidazole given concomitantly for 3 to 10

days. The initial clinical trial, from Germany, reported an eradication rate of 91% in 46 patients receiving a 5-day concomitant first-line therapy consisting of omeprazole, clarithromycin, metronidazole, and amoxicillin.21 A meta-analysis of 19 clinical trials of concomitant therapy for the treatment of 2,070 patients with H. pylorii infection revealed a mean cure rate of 88%. 22 Furthermore, in the RCTs in which concomitant therapy was compared with clarithromycin-based triple therapy (984 patients), the cure rate was 90% compared with 78%, respectively (OR, 2.36; 95% CI, 1.67-3.34).22 Nearly all of the trials evaluated were performed in Europe or Asia, with 1 study performed in Latin America. Treatment duration ranged from 3 to 10 days, with cure rates ranging from 83% to 91%, with a trend toward higher cure rates with longer durations of therapy. As with sequential therapy, no RCTs evaluating concomitant therapy in North American populations have been published. Given the lack of data from North America, the ACG guideline provides no recommendations for the use of concomitant therapy in the United

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

Table 5. Effect of Resistance to Clarithromycin and Metronidazole on Efficacy Of Sequential Therapy for Helicobacter pylorii in a Taiwanese Population19 Eradication Rate, n/N (%) Antibiotic-Resistance Profile of H. Pylori

14-Day Sequential Therapya

10-Day Sequential Therapy

14-Day Triple Therapyb

Cla-S, Met-S

116/117 (99)

123/129 (95)

98/109 (90)

Cla-S, Met-R

30/33 (91)

29/37 (78)

39/42 (93)

Cla-R, Met-S

10/14 (71)

7/10 (70)

9/16 (56)

Cla-R, Met-R

0/1 (0)

3/7 (43)

2/4 (50)

bid, twice daily; Cla, clarithromycin; Met, metronidazole; R, resistant; S, sensitive a

Sequential therapy: lansoprazole 30 mg bid + amoxicillin 1 g bid for first 5 or 7 d, followed by lansoprazole 30 mg + clarithromycin 500 mg bid + metronidazole 500 mg bid for subsequent 5 or 7 d.

Triple therapy: lansoprazole 30 mg + amoxicillin 1 g bid + clarithromycin 500 mg bid for 14 d.

States. A recent large, multicenter, randomized trial in Latin America found clarithromycin-based triple therapy superior to 5 days of concomitant therapy, with eradication rates of 82.2% and 73.6%, respectively (difference, 8.6%; 95% CI, 2.6%-14.5%).17 Given these data, if concomitant therapy is used, a duration of 7 to 10 days seems appropriate. The fourth Maastricht/Florence Consensus Conference recommended the use of concomitant therapy if bismuth-based quadruple therapy is not available.6 One first-line treatment regimen, called â&#x20AC;&#x153;LOADâ&#x20AC;? therapy, is notable; data on LOAD derive from an RCT performed in the United States. This 4-drug combination, consisting of levofloxacin, omeprazole, nitazoxanide, and doxycycline administered for 7 or 10 days, was superior to a 10-day course of amoxicillin, clarithromycin, and lansoprazole in an open-label, randomized study of 270 patients; eradication rates were 89%, 90%, and 73%, respectively.12 Other first-line levofloxacin-based triple therapies have been evaluated in clinical trials yielding mixed results. Currently, levofloxacin-based tripledrug regimens are largely reserved for salvage therapy in patients with persistent H. pylorii infection despite an initial course of therapy.23

ROLE

OF F

PROBIOTICS

There is growing interest in the use of probiotics as adjuvant therapy in the treatment of H. pylori infection. Emerging evidence suggests an inhibitory effect of Lactobacillus and Bifidobacterium species on H. pylori. Furthermore, these probiotic strains also may help to reduce the side effects of eradication therapies and improve compliance with therapy.24

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

A recent meta-analysis of 10 clinical trials of adjuvant probiotics in patients with H. pylorii infection demonstrated increased cure rates with probiotic supplementation (pooled OR, 2.066; 95% CI, 1.398-3.055).24 Additionally, probiotics reduced the incidence of total side effects (pooled OR, 0.305; 95% CI, 0.117-0.793). The majority of these studies were performed in China, and there was great variability in the probiotics used, as well as the treatment regimen employed. Although probiotic therapy for H. pylorii infection seems promising, many important questions remain, including the optimal dose, the time of dosing (before, during, or after eradication therapy), and the duration of therapy. There is some evidence suggesting that Lactobacillus may be a useful adjuvant therapy for treating H. pylori infection.25

Conclusion Clarithromycin-based triple therapy and bismuth quadruple therapy for 10 to 14 days remain the most universally recommended and most commonly prescribed first-line eradication regimens for H. pylorii infection. Ten- to 14-day sequential, 7- to 10-day concomitant, and 10-day LOAD quadruple regimens are gaining popularity as alternative choices for first-line treatment. There is clear evidence that the presence of clarithromycin-resistant H. pylori significantly reduces the efficacy of clarithromycin-based triple therapy, and to a lesser extent, sequential therapy. Although antibiotic resistance rates are available for many parts of Europe and Asia, this information is lacking in the United States. Therefore, it is critical for clinicians to ask patients about previous macrolide exposure. In

Key Questions 1. Is there a penicillin allergy? 2. Has a macrolide antibiotic been taken in the past (for any reason)?

(–) Penicillin (–) Macrolide

(–) Penicillin (+) Macrolide

(+) Penicillin (–) Macrolide

(+) Penicillin (+) Macrolide

Treatments:

Treatment:

Clarithromycin-based triple therapy

Bismuth quadruple therapy

Sequential therapy?

PCM

Sequential therapy

Concomitant therapy? LOAD therapy?

Concomitant therapy LOAD therapy?

(+) = penicillin allergy or macrolide exposure (–) = no penicillin allergy or macrolide exposure Clarithromycin-based triple therapy = PPI + clarithromycin + amoxicillin PCM = PPI + clarithromycin + metronidazole Bismuth quadruple therapy = PPI + bismuth + tetracycline + metronidazole Sequential therapy = PPI + amoxicillin for 5 days, followed by PPI + clarithromycin + imidazole (tinidazole or metronidazole) for subsequent 5 days Concomitant therapy = PPI + clarithromycin + amoxicillin + imidazole (tinidazole or metronidazole) LOAD therapy = levofloxacin + PPI + nitazoxanide + doxycycline

Figure. A practical approach to the selection of first-line Helicobacter pylori eradication therapy.

regions where clarithromycin resistance is known to be greater than 15% to 20%, or if a patient has a history of more than 1 previous course of macrolide antibiotics, for any indication, clarithromycin-based triple therapy, and arguably sequential therapy, should be avoided in favor of bismuth or LOAD quadruple therapies. Obtaining a complete medical history of allergy or intolerance to any of the commonly prescribed antibiotics also will assist in the most appropriate choice of treatment (Figure). Gone are the days when physicians can freely

prescribe clarithromycin-based triple therapy for all patients with H. pylorii infection. Although this regimen remains useful in specific circumstances, a strategy that uses information regarding previous antibiotic use, regional antibiotic susceptibility, and drug allergies will assist the clinician in making the best treatment choice for an individual patient.26 In this day and age of superbugs and epidemic Clostridium difficile infections, responsible care demands a fresh look at how we manage this common and important infection.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2014

References 1.

Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102(8):1808-1825.

2. Luther J, Higgins PD, Schoenfeld PS, et al. Empiric quadruple vs. triple therapy for primary treatment of Helicobacter pylori infection: systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol. 2010;105(1):65-73. 3. McMahon BJ, Hennessy TW, Bensler JM, et al. The relationship among previous antimicrobial use, antimicrobial resistance, and treatment outcomes for Helicobacter pylori infections. Ann Intern Med. 2003;139(6):463-469. 4. Megraud F, Coenen S, Versporten A, et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2013;62(1):34-42. 5. McNulty CA, Lasseter G, Shaw I, et al. Is Helicobacter pylori antibiotic resistance surveillance needed and how can it be delivered? Aliment Pharmacol Ther. 2012;35(10):1221-1230. 6. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut. 2012;61(5):646-664. 7. Duck WM, Sobel J, Pruckler JM, et al. Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States. Emerg Infect Dis. 2004;10(6):1088-1094. 8. Vilaichone RK, Yamaoka Y, Shiota S, et al. Antibiotics resistance rate of Helicobacter pylori in Bhutan. World J Gastroenterol. 2013;19(33):5508-5512. 9. Liu G, Xu X, He L, et al. Primary antibiotic resistance of Helicobacter pylori isolated from Beijing children. Helicobacter. 2011;16(5):356-362. 10. Fock KM, Katelaris P, Sugano K, et al. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol. 2009;24(10):1587-1600. 11. Wang Z, Wu S. Doxycycline-based quadruple regimen versus routine quadruple regimen for rescue eradication of Helicobacter pylori: an open-label control study in Chinese patients. Singapore Med J. 2012;53(4):273-276. 12. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori. Am J Gastroenterol. 2011;106(11):1970-1975. 13. Akyildiz M, Akay S, Musoglu A, et al. The efficacy of ranitidine bismuth citrate, amoxicillin and doxycycline or tetracycline regimens

INDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

as a first line treatment for Helicobacter pylori eradication. Eur J Intern Med. 2009;20(1):53-57. 14. Zullo A, Rinaldi V, Winn S, et al. A new highly effective short-term therapy schedule for Helicobacter pylori eradication. Aliment Pharmacol Ther. 2000;14(6):715-718. 15. Zullo A, De Francesco V, Hassan C, et al. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis. Gut. 2007;56(10):1353-1357. 16. Gatta L, Vakil N, Leandro G, et al. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol. 2009;104(12):3069-3079. 17. Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet. 2011;378(9790):507-514. 18. Kadayifci A, Uygun A, Kilciler G, et al. Low efficacy of clarithromycin including sequential regimens for Helicobacter pylori infection. Helicobacter. 2012;17(2):121-126. 19. Liou JM, Chen CC, Chen MJ, et al. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet. 2013;381(9862):205-213. 20. Gatta L, Vakil N, Vaira D, et al. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. BMJ. 2013;347:f4587. 21. Treiber G, Ammon S, Schneider E, et al. Amoxicillin/metronidazole/ omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter. 1998;3(1):54-58. 22. Gisbert JP, Calvet X. Update on non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori. Clin Exp Gastroenterol. 2012;5:23-34. 23. Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol. 2006;101(3):488-496. 24. Wang ZH, Gao QY, Fang JY. Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy. J Clin Gastroenterol. 2013;47(1):25-32. 25. O’Connor A, Molina-Infante J, Gisbert JP, et al. Treatment of Helicobacter pylori infection 2013. Helicobacter. 2013;18(suppl 1):58-65. 26. Greenberg ER, Chey WD. Defining the role of sequential therapy for H pylori infection. Lancet. 2013;381(9862):180-182.