The September 2012 Digital Edition of Gastroenterology and Endoscopy News by McMahon Group

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 9 • September 2012 40th ANNIVERSARY 1972–201 2

Adenoma Detection Rate an ‘Imperfect’ Measure of Quality

New Drugs, Policy Changes Offer Gastros Ways To Help Patients Manage Obesity

BY CAROLINE HELWICK BY CHRISTINA FRANGOU SAN DIEGO—Are adenoma detection rates (ADRs) the best way to measure the quality of colonoscopy? “The ADR is imperfect but better than some proposed replacements,” said Douglas K. Rex, MD, in a lecture at the 2012 Digestive Disease Week (DDW) see ADR, page 12

Novel Test Identifies IBD Subtypes BY DAVID WILD SAN DIEGO—A new diagnostic test incorporating 17 serologic, genetic and inflammatory markers is 87% accurate in identifying inflammatory bowel disease (IBD) and 93% accurate in differentiating ulcerative colitis (UC) from Crohn’s disease (CD), according to research presented at the 2012 Digestive Disease Week (DDW) meeting. see IBD Test, page 14

After a series of national policy changes and drugg approvals this summer, gastroenterologists have new w tools to help their patients who struggle with obesity. In late June, the U.S. Preventive Services Task Force (USPSTF) recommended that all adults be screened for obesity during their checkups—a directive geared to primary care physicians, but all physicians are asked to heed the recommendations. The USPSTF also called on clinicians to refer patients with a body mass index (BMI) of 30 kg/ m2 or greater to intensive multicomponent behavioral interventions, or to offer these patients interventions. Several days later, the FDA approved Belviq (lorcaserin hydrochloride; Eisai Pharmaceuticals) as an addition to a reduced-calorie diet and exercise for chronic weight management. Belviq was the first anti-obesity drug to be approved in the past 13 years,

The Future of Gastroenterology Practices: Is Bigger Better?

and marked a significant shift in FDA policy. For the past decade, the agency has been reluctant to approve new diet drugs, largely because of a history of product withdrawals and serious side effects. Weeks after endorsing Belviq, the FDA also approved Qsymia (Vivus Pharmaceuticals), which combines the anti-seizure/migraine drug topiramate and the appetite-suppressant phentermine. “Obesity threatens the overall well-being of patients and is a major public health concern,” said Janet Woodcock, MD, director of the FDA’s see Obesity, page 18

I N S I D E EXPERTS’ PICKS Best of Digestive Disease Week (DDW): Part 3 Experts share their favorite abstracts from the 2012 DDW meeting ....................page 8

BY MONICA J. SMITH KNOXVILLE, TENN.—A common refrain at the 2012 GI Roundtable, a meeting that explored strategies to help medical practices remain successful in a rapidly changing health care environment, was “bigger is better.” But more than half of gastroenterology practices today are small, with no more than five physicians and most with less than 10. Staying small and independent may take some innovative thinking as demand grows for lower-cost, high-quality health care services, said experts who spoke at the meeting.

Frank G. Gress, MD

Edward Loftus Jr., MD

see Gastro Practice, page 20

Corporate Spotlight Covidien Acquires BÂRRX Medical, Launches GI Solutions Initiative see pages 6 & 7

PRODUCT ANNOUNCEMENT see page 47 for product information

Prometheus Launches Anser™ IFX To Help Guide Management of IBD Patients Using Infliximab

Clean Freak

Effective cleansing in all bowel segments, including the right colon Percent of patients with NO RESIDUAL STOOL by colon segment1* Colon Segment

Cecum Ascending Descending Transverse Sigmoid/Rectum

SUPREP Bowel Prep Kit split-dose regimen (n=63) 91%† 91%† 92% 92% 94%

4-Liter Prep same-day regimen‡ (n=66)§ 67% 69% 84% 82% 81%

*This clinical trial was not included in the product labeling. †P≤0.02 vs 4-Liter Prep. Statistically signiﬁcant difference. ‡ Standard 4-Liter Prep (sulfate-free PEG electrolyte lavage solution). § One patient was excluded who took the preparation but refused colonoscopy. Three patients had one or more segments that could not be evaluated because the procedure was stopped for poor preparation before cecal intubation.

SUPREP Bowel Prep Kit achieved “excellent” bowel cleansing in patients based on investigator grading1,2 • Split-dose regimens of SUPREP Bowel Prep Kit and MoviPrep®|| were equivalent in colon cleansing2 • Signiﬁcantly more patients had “excellent” preps with SUPREP Bowel Prep Kit compared to MoviPrep (63% vs 53%, respectively; P=0.043¶)2 MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution) is a registered trademark of Salix Pharmaceuticals, Inc. ¶ Statistically signiﬁcant difference. ||

Important Safety Information SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. Please see brief summary of Prescribing Information on adjacent page.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

From the Literature

Screening Colonoscopy Sharply Decreases Colorectal Cancer Incidence, CRC-Related Morality, New Study Confirms BY MONICA J. SMITH Consistent with other trials published in recent years, a new study comparing colonoscopy-screened individuals with a nonscreened group

of people found that colonoscopy with polypectomy appears to significantly reduce both the incidence of colorectal cancer (CRC) and CRCrelated mortality in the general population (Manser CN et al. Gastrointest Endosc 2012;76:110-117).

“This study confirms some prior studies, such as the Brenner study [[Ann Intern Med 2011;154:22-30] and the Kahi and Rex study [Clin Gastroenterol Hepatoll 2009;7:770775], that showed a reduction in incidence and mortality from colorectal

cancer,” said Sidney J. Winawer, MD, Paul Sherlock Chair in Medicine, Memorial-Sloan Kettering Cancer Center, New York City, who was not involved in the current study. To compare CRC incidence and related mortality among individuals who have and have not undergone colonoscopy, the researchers followed 1,912 patients screened between June 2000 and June 2001 and 20,774 nonscreened individuals over a period of about six years. The participants resided in a relatively rural area of Switzerland with little population migration. Eleven boardcertified gastroenterologists who had each conducted at least 200 procedures performed the colonoscopies.

The researchers concluded that a single screening colonoscopy—provided that it is quantitatively

SUPREP Bowel Prep Kit. Because the quality of cleansing matters. • Effective bowel cleansing

2,3

in all bowel segments

• ACG-recommended split-dose regimen

in incidence of CRC and

• No sodium phosphate

CRC-related mortality in

BRIEF SUMMARY: Before pprescribing, g pplease see full Prescribing Information and Medication Guide for SUPREP® Bowel Prepp Kit (sodium sulfate, ppotassium sulfate and magnesium g sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. CONTRAINDICATIONS: Use is contraindicated in the followingg conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allergies g to components p of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prepp Kit is an osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. Use is contraindicated in the followingg conditions: ggastrointestinal (GI) obstruction, bowel pperforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allerggies to components of the kit. Use caution when pprescribingg for ppatients with a historyy of seizures, arrhythmias, y impaired p ggagg reflex, regurgitation g g or aspiration p , severe active ulcerative colitis, impaired p renal function or ppatients takingg medications that mayy affect renal function or electrolytes. y Pre-dose and ppost-colonoscopy ECG’s should be considered in ppatients at increased risk of serious cardiac arrhythmias. y Use can cause temporary p y elevations in uric acid. Uric acid fluctuations in ppatients with ggout mayy pprecipitate p an acute flare. Administration of osmotic laxative pproducts mayy pproduce mucosal aphthous p ulcerations, and there have been reports of more serious cases of ischemic colitis requiring q g hospitalization. p Patients with impaired p water handlingg who experience p severe vomitingg should be closelyy monitored includingg measurement of electrolytes. y Advise all patients p to hydrate y adequately q y before, during, g and after use. Each bottle must be dilutted with water to a final volume of 16 ounces and ingestion g of additional water as recommended is important p to ppatient tolerance. Pregnancy: g y Pregnancy g y Category g y C. Animal reproduction p studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive p capacity. p y Pediatric Use: Safetyy and effectiveness in ppediatric ppatients has not been established. Geriatric Use: Of the 375 ppatients who took SUPREP Bowel Prepp Kit in clinical trials, 94 (25%) were 65 years of age g or older, while 25 (7%) were 75 years of age g or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose p (2-day) y regimen g were observed between ggeriatric ppatients and yyounger g ppatients. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP mayy not be absorbed completely. p y ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal ppain, nausea, vomitingg and headache. Oral Administration: Split-Dose p (Two-Day) y Regimen: g Earlyy in the eveningg pprior to the colonoscopy: ppy Pour the contents of one bottle of SUPREP Bowel Prepp Kit into the mixingg container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume onlyy a light g breakfast or have onlyy clear liquids q on the dayy before colonoscopy. py Dayy of Colonoscopy py (10 to 12 hours after the eveningg dose): Pour the contents of the second SUPREP Bowel Prepp Kit into the mixingg container pprovided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy.y Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F). Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.suprepkit.com SU-13280T

in a substantial reduction

• Low volume

References: 1. Rex DK, DiPalma JA, Rodriguez g R, McGowan J, Cleveland M. A randomized clinical study comparingg reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage g solution as ppreparation p for colonoscopy. py Gastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez g R, McGowan J, Cleveland MvB. A randomized clinical studyy evaluatingg the safety and efﬁcacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenteroll. 2009;104:2275-2284. 3. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2010.

well performed—results

January, 2012

nonsymptomatic individuals. The gastroenterologists found and removed 1,279 polyps from 565 of the screened individuals. In all, 225 CRCs were detected: 213 in the nonscreened group (1%) and 12 in the screened group (0.6%). The cancers were T1 or T2 in 72% of those with CRC in the screened group, and in 19.7% of those with CRC in the nonscreened group. One of the 12 subjects with cancer in the screened group and 51 of the 213 subjects in the nonscreened group died as a result of their CRCs. Risk factors, such as smoking and family history, were similar in both groups. The researchers concluded that a single screening colonoscopy— provided that it is quantitatively well performed—results in a substantial reduction in incidence of CRC and CRC-related mortality in nonsymptomatic individuals. The study authors did note a few limitations, such as the small size of the cohort and that screened see Screening Colonoscopy, page 11

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

HAL Consequences of Too Much Artificial ‘Intelligence’ David Cossman, MD Vascular Surgeon Los Angeles, California Like Robert Frost, beloved poet who in his dotage couldn’t read his lines at John F. Kennedy’s inauguration, I wondered how the end would come for me. Was it going to be fire or ice as Frost explored in his poem? A perforated tic or a demyelinating disease? My bone marrow gone wild? The shakes? My eyes? What was going to separate me from my beloved diamond-jawed needle holder? None of the above. It’s worse: The electronic medical record (EMR). All those sleepless, sweaty nights tossing and turning, assaulted by imaginary career-ending illnesses and I’m finally being taken down by the EMR monstrosity my beloved hospital decided to go live with on March 3, 2012, a day that will live in infamy. And they’re serious this time. We got $1,000 and eight continuing medical education (CME) credits for taking the mandatory eight hours of training, which was only a tad worse than waterboarding. Unlike the aborted attempt nearly a decade ago, EMR implementation is mandated now by the Patient Protection and Affordable Care Act (PPACA) and the Centers for

Medicare & Medicaid Services (CMS) in the hallowed name of patient safety, cost containment and, presumably, national security. Cost containment is clearly a joke. According to my calculations (which I will be happy to share with you upon request), implementation will cost nearly $300,000 per bed, or about 50% more than the cost to build the hospital from scratch (pity me, I’m still a bricks-and-mortar guy in a virtual world). There are nearly 1 million staffed hospital beds in the country; so countrywide implementation will cost $350 billion or roughly half the total expenditures of the nation’s 5,700 hospitals in 2010. I know poor penmanship is a problem, but what else am I missing to justify this expense, especially when the health care business is already reeling from reduced reimbursements from a national treasury that would technically be in default of its obligations were it not for the inexplicable faith and confidence of the Chinese in our future ability to make good on our debts. The cost is staggering. The software and hardware expense is a drop in the bucket. The rollout is being supervised by a mercenary army of red-jacketed “super users” who are bused in daily from expensive off-campus lodging to prevent the hospital from coming to an

I can only think of HAL, the soft-spoken but sinister onboard computer in Stanley Kubrick’s “2001: A Space Odyssey.” Mr. Kubrick’s cautionary tale should remind us all about the limits of technology and the willful abrogation of our unique human qualities to a machine that can think only in 0s and 1s.

see HAL, page 26

EHR Adoption by Physicians Reached 55% in 2011 Physicians Split Regarding Satisfaction With EHR Systems BY GEORGE OCHOA In 2011, 55% of physicians had adopted electronic health record (EHR) systems, according to a report from the Centers for Disease Control and Prevention’s (CDC) National Center for Health Statistics (NCHS Data Brief, July 2012;98). Although the percentage is “on par” with an earlier report (NCHS Data Brief, November 2011;79) that measured 2011 EHR adoption among office-based physicians (57%), lead author of the current report Eric Jamoom, PhD, MPH, MS, senior service fellow, CDC, NCHS, Hyattsville, Md., said “EHR adoption has been trending upward in the last few years.” “The CDC report and other reports point to a tipping point, where most physicians have some sort of EHR,” said Robert Rowley, MD, health care and health

information technology consultant, Danville, Calif., and author of the 2012 report, “An Analysis of EHR Use in the U.S. in 2011,” in an interview. “Two years ago, that was not the case.”

those using an EHR system, 74% said it has resulted in enhanced overall patient care. “Physicians generally have positive views of their systems and the impact of those systems on their

‘Less than 50% of physicians who had adopted EHR were very satisfied; 15% were dissatisfied. It’s important to understand why physicians are dissatisfied.’ —Ellen J. Scherl, MD

Among key findings in the CDC report is that 77% of adopting physicians report their system meets federal “meaningful use” criteria, the objectives that must be met to qualify for incentive payments from the Centers for Medicare & Medicaid Services, Dr. Jamoom noted. Eighty-five percent of adopting physicians report they are either veryy (38%) or somewhat satisfied (47%) with their EHR system. Of

practice,” said Dr. Jamoom. However, the numbers can be interpreted differently. Ellen J. Scherl, MD, director, Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, NewYork-Presbyterian Hospital/Weill Cornell Medical College, New York City, said in an interview, “Less than 50% of physicians who had adopted EHR were very satisfied;

15% were dissatisfied. It’s important to understand why physicians are dissatisfied. Then we might increase enrollment past 55% if we understood the issues behind dissatisfaction.” About 50% of physicians who are nonadopters plan to purchase a system (27%) or use one they already purchased (21%) within the next year. Most adopters use stand-alone systems (59%), where the data and application functionality are delivered onsite; the rest used Web-based systems (41%), where system and data are housed off-site. The CDC report did not separate gastroenterology as a specialty, but Dr. Jamoom said, “We may in the near future have information or estimates related to [that] specialty. It’s important to understand the experience of different specialists and adoption by different specialists.” see EHR, page 26

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2012

LETTER TO THE EDITOR

ASCs Should Welcome CMS

Corrections

Re: â&#x20AC;&#x153;CMS Unveils Major Changes for ASCs,â&#x20AC;? by Christina Frangou. Gastroenterology & Endoscopy News May 2012;63:1,59.

The article â&#x20AC;&#x153;Pancreatic Exocrine Insufficiency Part 2 of o 2: Treatment and Therapeutic Considerations,â&#x20AC;? which ch appeared as an insert in the June 2012 issue of Gastroenterology & Endoscopy News, omitted one of the dosage strengths of the pancreatic enzyme preparation, Creon. The Table on page 3 of the article should have contained information on the lowest dosage of the product, Creon 3,000 (lipase, 3,000; amylase, 15,000; protease, 9,500). Full prescribing information for Creon is available at www.rxabbott.com/pdf/creon_PI.pdf.

To the Editor: Most ASCs [ambulatory surgery centers] have their own quality control in the form of patient satisfaction surveys and QA [quality assurance] committees that monitor complication rates, hospitalization rates, etc. Medicare requirements for these should be welcomed by ASCs and their partners, which now gives them an opportunity to be transparent and â&#x20AC;&#x153;visibleâ&#x20AC;? on the Web. The sight of an ambulance carrying a patient from the ASC to a hospital is very unsettling to the patients in the waiting room who are waiting for their turn. â&#x20AC;&#x153;Self-policingâ&#x20AC;? and incorporating bylaws with â&#x20AC;&#x153;teethâ&#x20AC;? will ensure quality and foster close working relationships. Even hiring an outside independent â&#x20AC;&#x153;quality monitorâ&#x20AC;? to review all complications would not be a bad idea. Chakrapani Prakash, MD, FACP Board-certified gastroenterologist Toms River, New Jersey

The article â&#x20AC;&#x153;The Best of Digestive Disease Week 2012: Part 1,â&#x20AC;? which appeared on page 6 of the July 2012 issue of Gastroenterology & Endoscopy News, did not include the byline of the writer, David Wild; Gastroenterology & Endoscopy Newss regrets the error. The article â&#x20AC;&#x153;New Anti-TNF, Golimumab, Effective in Moderate to Severe UC,â&#x20AC;? which appeared on page 12 of the July 2012 issue of Gastroenterology & Endoscopy News, contained a mistake: The total number of anti-TNFâ&#x20AC;&#x201C;naive patients with moderate to severe ulcerative colitis who were randomized to one of three treatment arms in the study was 774, not 759, as was stated in the article.

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INFECTIOUS DISEASE SPECIAL EDITION

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COVIDIEN, COVIDIEN with logo, Covidien logo and “positive results for life” are U.S. and internationally registered trademarks of Covidien AG. Other brands are trademarks of a Covidien company. © 2012 Covidien. - L-0182-00 Rev. A (ECO #12418)

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Covidien Acquires BÂRRX Medical, Launches GI Solutions Initiative

Corporate Spotlight

In a strong positive step for care of gastrointestinal (GI) diseases, Covidien earlier this year finalized its acquisition of BÂRRX Medical, Inc. Covidien is a leading global provider of health care products with almost $12 billion in annual revenues. BÂRRX, as part of its integration into Covidien, will continue a concentrated focus on its core GI therapies. As another facet of the integration, Covidien announced a rebranding of its popular HALO ablation system, which is FDA-cleared for treatment of all grades of Barrett’s esophagus, a disease estimated to possibly affect 5.6% of the U.S. population.1 The HALO360+ ablation system, the company’s initial product and the backbone of its clinical trials, is now called the Barrx™ 360 RFA balloon catheter. Its mainstay focal device, the HALO90 ablation catheter, is now the Barrx™ 90 RFA focal catheter. Expanded focal devices include the Barrx™ 60 RFA focal catheter, released in February, and the Barrx™ ultra long Barrx™ 360 RFA Balloon Catheter RFA focal catheter, released in May. Barrx™ technology, which has been used in more than 100,000 patient cases, delivers radiofrequency energy in a unique way, optimizing the removal of unwanted diseased tissue yet minimizing injury to normal esophageal tissue. The Barrx™ flex RFA energy generator and the Barrx™ electrode array on each catheter are designed to work in concert to achieve a uniform, superficial depth of ablation between approximately 500 to approximately 1,000 microns, effectively eliminating Barrett’s esophagus in 98.4% of patients.2 Future product developments are planned as part of the GI Solutions initiative, as are other strategic programs that provide synergies with existing offerings dedicated to GI care. Covidien has approached the integration of the BÂRRX business as an industry partner, making a long-term commitment in support of treatment for digestive-related conditions.

Barrx™ 60 and 90 RFA Focal Catheters

About Covidien Covidien is a leading global health care products company that creates innovative medical solutions for better patient outcomes and delivers value through clinical leadership and excellence. Covidien manufactures, distributes and services a diverse range of industry-leading product lines in three segments: medical devices, pharmaceuticals and medical supplies. With a 2011 revenue of $11.6 billion, Covidien has 43,000 employees worldwide in more than 65 countries, and its products are sold in more than 140 countries. 1. Hayeck T, Kong CY, Spechler SJ, Gazelle GS, Hur C. The prevalence of Barrett’s esophagus in the US: estimates from a simulation model confirmed by SEER data. Dis Esophagus. 2010;23(6):451-457. 2. Fleischer DE, Overholt BF, Sharma VK, et al. Long-term (2.5 Year) follow-up of the AIM-II Trial for ablation of Barrett’s esophagus: results after primary circumferential ablation followed by secondary focal ablation. Gastrointest Endosc. 2007;65(5):AB135. Abstract S1292.

Please visit www.barrx.com or call 888-662-2779

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Experts’ Picks:

The Best of Digestive g Disease Week 2012: Part 3 COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy Newss asked the experts: What were your favorite abstracts presented at this year’s Digestive Disease Week meeting? Following is a collection of selected abstracts and comments on the meeting as provided by two experts in the field.

Frank G. Gress, MD Professor of Medicine Chief, Division of Gastroenterology and Hepatology SUNY Downstate Medical Center Brooklyn, New York

Mo1291.

Radiofrequency Ablation for Biliary Metal Stent Occlusion: Evolution of a Novel Endoscopic Technique and Proof of Concept (Kallis Y et al) This British study investigated the efficacy of a radiofrequency ablation (RFA) catheter in clearing occluded self-expanding metal stents (SEMS) used for inoperable malignant bile duct obstruction. The RFA catheter is placed directly in the lumen of the occluded SEMS. The researchers conducted the procedure in six patients with pancreatic cancer, three patients with cholangiocarcinoma and two with hepatic metastases. All patients had SEMS occlusion due to tumor ingrowth. According to the investigators, all of the procedures were performed successfully with full re-establishment of stent patency in 10 of the 11 patients for a median of 146 days following the procedure.

‘This study showed that RFA is effective in ablating obstructions caused by malignant tissue ingrowth and can restore full patency and perhaps reduce rates of cholangitis.’ —Frank G. Gress, MD

Although the first six patients in the series also received a second SEMS, the researchers determined “this was not necessary to maintain patency” and discontinued this practice in the last five patients. There were no significant adverse events (AEs), and stents maintained patency for a median 146 days following RFA. Five patients experienced SEMS re-occlusion after a median 131 days (range, 37-602 days), and four underwent successful repeat RFA. The median post-RFA hospital length of stay (LOS) was three days (range, one-11 days). Dr. Gress: Secondary tumor ingrowth can occur with any type of stent and is a challenging problem

for endoscopists. The current approach to managing obstructions, which involves placing a second stent inside an existing stent, can be costly when using a SEMS. This study showed that RFA is effective in ablating obstructions caused by malignant tissue ingrowth and can restore full patency and perhaps reduce rates of cholangitis, although this was not specifically examined here. The length of post-RFA patency in this study was similar to that seen with conventional management using a secondary SEMS and this small pilot trial suggests that RFA may have a potential role in managing biliary SEMS occlusion due to tumor ingrowth.

Mo1365.

Do Scheduled Stent Exchanges for Plastic Biliary Stents Result in a Reduced Incidence of Cholangitis when Compared with Metal Biliary Stents? (Larsen MC et al)

Mo1370.

Covered Versus Uncovered Metal Stents for Unresectable Malignant Biliary Obstruction: A Comparison of Resource Utilization (Ryou M et al) Both of these studies were conducted at Harvard Medical School and Brigham and Women’s Hospital in Boston. The first trial by Larsen et al compared re-occlusion and cholangitis rates with regularly exchanged plastic stents to both covered and uncovered SEMS, in patients with malignant biliary obstruction. They reviewed medical records from 210 of their patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) with biliary stent placement between 2008 and 2009 and compared rates of mortality, need for ERCP for cholangitis, and cholangitis-related hospital LOS among those receiving plastic, uncovered or fully covered metal stents. Patients were followed for a mean of 301 days following stent placement. The investigators found a mortality rate of 3.95% among the plastic stent recipients compared with 19.1% in the group that received uncovered SEMS and 17.6% in the fully covered SEMS group (P≤ P 0.001 for plastic vs. both metal stents). Furthermore, 9.6% of plastic stent recipients developed cholangitis compared with 16.7% of uncovered metal stent recipients (P=0.09). P In the fully covered stent group, 4.3% of patients developed cholangitis (P=0.38, P compared with plastic stents). The mean hospital LOS following stent implant among plastic stent recipients was 6.15 days, compared with a mean 11.5- and 8.5-day LOS in the uncovered and fully covered metal stent groups, respectively (P=NS). P There

were no diffferences in proceduree-related complications between the three grooups, the researchers rep ported. In the secon nd study, Ryou et al retrospectively reviewed d medical records from 98 consecutive patieents who underwent ERCP and covered or uncovered SEMS placement for palliation of unresectable malignant obstruction between 20088 and 2009. The invesstigators compared d hospital LOS, time to re-occlusion, mortality, incidence of cholangitis and health care costs. Patients were a mean 54 years of age and 59% were male. The researchers found that biliary re-occlusion occurred after a mean of 170 days following stent placement in the covered SEMS group compared with a mean of 77 days among uncovered SEMS recipients (P=0.07). P Furthermore, 4.3% of covered stent recipients developed cholangitis and required a mean 8.25 days of related hospital LOS, whereas 16.7% of patients administered an uncovered stent experienced cholangitis, which was associated with a mean 11.5 days of hospital LOS (P=0.038 P for both measures). Mortalities in the covered SEMS group occurred after a mean 286 days compared with 149 days in the uncovered group (P=0.02). P Hospitalization expenses and overall resource use also were lower in the covered stent group, the authors reported.

‘The results suggest that the tried-andtrue plastic stents we’ve been using for years may have an important role in improving outcomes if they are replaced on a regular interval schedule.’ —Frank G. Gress, MD Dr. Gress: These are interesting studies. The rationale behind the study by Larsen et al was that the increased incidence of occlusion seen with plastic stents left in place versus metal SEMS might be minimized and occlusion preempted (with lower rates of cholangitis) by following a regular stent exchange schedule.

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The data from the retrospective, single-center study showed longer survival and lower rates of cholangitis with scheduled exchange plastic stents compared with fully covered and uncovered metal SEMS. Although the authors did not specify the schedule of exchange, plastic stents normally are exchanged every three to six months. The results suggest that the tried-and-true plastic stents we’ve been using for years may have an important role in improving outcomes if they are replaced on a regular interval schedule. A prospective, randomized controlled trial is warranted to definitively answer this. The study by Ryou et al addresses the controversy over whether to use covered or uncovered metal SEMS. The idea here is that there is less tumor ingrowth with covered stents compared with meshed uncovered metal stents. The researchers found reduced health care costs as well as reduced mortality and longer periods of patency with covered stents so the study supports the idea that covered stents prevent occlusion and tumor ingrowth. I’d like to see a similar study comparing plastic and covered metal stents, which I would imagine would show plastic stents that are regularly exchanged are associated with an even more dramatic reduction in health care use as well as morbidity and mortality.

Edward Loftus Jr., MD Professor of Medicine Chair, Inflammatory Bowel Disease Interest Group Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota

865.

PIANO: A 1,000 Patient Prospective Registry of Pregnancy Outcomes in Women With IBD Exposed to Immunomodulators/Biologic Therapy (Mahadevan U et al)

This multicenter study, funded by the Crohn’s & Colitis Foundation of America, examined prospective data from 1,115 pregnant women with inflammatory bowel disease (IBD). Of these women, 896 had completed pregnancy at the time of abstract presentation. Of these patients, 326 received no medications, corticosteroids, antibiotics or aminosalicylates; 204 were treated with azathioprine (AZA) or 6-mercaptopurine (6-MP); 291 received infliximab, adalimumab, certolizumab or natalizumab; and 75 had been treated with a combination of immunomodulators and biologics during pregnancy. Data showed that 5.9% of all infants had congenital anomalies, with no significant differences between the groups. There was a significantly higher rate of spontaneous abortions among those receiving biologics alone compared with those unexposed to immunomodulators or biologics (risk ratio [RR], 2.56; 95% confidence interval [CI], 1.07-6.12; P<0.05). Compared with the same unexposed group, individuals receiving combination therapy were more likely to have preterm births (RR, 1.83; 95% CI, 1.01-3.31; P<0.05). Subgroup analyses revealed no association between treatment type and pregnancy outcomes in patients with Crohn’s disease (CD). However, patients with ulcerative colitis (UC) who received biologics alone were

significantly more likely than patients with UC who were not administered biologics or immunomodulators to experience spontaneous abortions (RR, 4.85; 95% CI, 1.48-15.9; P<0.05). Furthermore, patients with UC who were receiving combination immunomodulator/biologic therapy had significantly higher rates of complications

‘This is the biggest and best study yet on pregnancy outcomes in women with IBD.’ —Edward Loftus Jr., MD of any kind than did patients with UC who did not receive a biologic or an immunomodulator, the researchers reported (RR, 2.97; 95% CI, 1.76-5.02; P<0.05). In an analysis excluding patients treated with certolizumab—a drug associated with less placental drug transfer than infliximab and adalimumab—infants born to women receiving combination therapy were 1.38 times as likely as those born to women unexposed to immunomodulators or biologics to develop infections within one year of birth (95% CI, 1.01-1.80; P<0.05). Dr. Loftus: This is the biggest and best study yet on pregnancy outcomes in women with IBD. The most reassuring aspect was that there did not seem to be a signal for increased risk for congenital anomalies in women on either immunomodulators or biologics, or on a combination of the two. The increased risk for spontaneous abortions in women on biologics might be due to the fact that women on these medications have greater disease activity and severity than those not receiving biologics. Indeed, previous studies have demonstrated that IBD activity/severity is the biggest factor driving adverse pregnancy outcomes.

943b.

Vedolizumab Induction Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized Placebo-controlled Double-blind Multicenter Phase 3 Trial (Feagan B et al) GEMINI 1, which was conducted at several international centers, examined the effectiveness of vedolizumab induction therapy for treating patients with refractory UC. The induction phase of the study included 895 patients with UC whose disease was refractory to prior treatment with corticosteroids, thiopurines or anti-tumor necrosis factor (TNF) agents. Subjects had moderate to severe UC, with baseline Mayo scores at 6 or greater and endoscopic subscores at 2 or greater. All induction-phase participants received two induction doses of IV vedolizumab 300 mg, a novel selective α4β7 integrin inhibitor, two weeks apart. One month

‘This drug met primary end points for both the induction and the maintenance studies. This is very exciting.’ —Edward Loftus Jr., MD

after the second induction dose, 47.1% of participants who met clinical response criteria were randomized to receive placebo (n=126) or 300 mg of the drug every four weeks (n=125) or every eight weeks (n=122), all for 46 weeks. For this maintenance phase of the study, researchers defined clinical response as a reduction of

3 points or greater in overall Mayo score, a reduction in Mayo scores of 30% or greater compared with baseline and a significant reduction in rectal bleeding. An intent-to-treat analysis showed 44.8% (56 of 125) of monthly drug recipients and 41.8% (51 of 122) of bimonthly drug recipients achieved clinical remission, defined as a Mayo score of 2 or less and no individual subscores greater than 1, 52 weeks after administering the initial dose. In contrast, 15.9% (20 of 126) of those randomized to the placebo group following induction treatment were in clinical remission at 52 weeks (P<0.0001). Results also showed 56% and 51.6% of monthly and bimonthly patients, respectively, experienced mucosal healing at 52 weeks, compared with 19.8% for placebo (P<0.0001). A subset of 45.2% and 31.4% of monthly and bimonthly drug recipients, respectively, who began the study receiving corticosteroids were able to discontinue steroid use while achieving remission at 52 weeks compared with 13.9% in the placebo group (P≤ P 0.133 for both treatment groups vs. placebo). Rates of AEs, serious AEs and serious infections were similar in all three groups, the researchers said.

‘We desperately need a new mechanism of action. This drug may very well provide it.’ —Edward Loftus Jr., MD

Dr. Loftus: This drug met primary end points for both the induction and the maintenance studies. This is very exciting. Anti-TNF therapies are great, but unfortunately we have a growing population of sick IBD patients who are refractory to, or intolerant of, anti-TNF therapy. We desperately need a new mechanism of action. This drug may very well provide it. Thus far, there doesn’t appear to be any safety signal for serious AEs. Vedolizumab is an improvement over natalizumab (Tysabri [Biogen Idec/ Elan]). Although both block α4 integrin, vedolizumab is more gut-specific because it blocks only α4β7 and theoretically should not cause progressive multifocal leukoencephalopathy (PML). No cases of PML associated with vedolizumab have been reported.

943c.

Accelerated Step-Care Therapy with Early Azathioprine (AZA) vs. Conventional Step-Care Therapy in Crohn’s Disease. A Randomized Study (Cosnes J et al) This randomized, open-label controlled trial was conducted in 24 centers between 2005 and 2010. Researchers assigned 71 people recently diagnosed with CD who were at risk for disabling disease to receive AZA 2.5 mg/kg and 71 similar patients to receive AZA on demand. These patients had no history of immunosuppressant or biologic use, or surgery. Patients were followed for a median 35 months. The investigators found that 62% of those assigned to the on-demand AZA group required AZA after a median 5.6 months. There were no significant differences between the two groups in terms of time spent in remission. Of patients administered early AZA, 29% required additional treatment with anti-TNF agents, similar to the 26% of those in the on-demand group who see Best of DDW, page 10

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Best of DDW continued from page 9

needed additional anti-TNF treatment (P=NS). Three percent and 13% of early AZA and on-demand AZA patients, respectively, required unplanned perianal surgery, but this difference was not statistically significant (P=0.055). Similarly, 11% of those who received early AZA and 21% of patients who received the drug as needed required intestinal surgery, but this difference also did not reach statistical significance (P=0.11).

‘At this point, we don’t have evidence that accelerated step-up AZA therapy is better than standard step-up treatment.’ —Edward Loftus Jr., MD

Median Crohn’s Disease Activity Index scores and C-reactive protein levels did not differ between groups, the researchers reported. Dr. Loftus: The thinking in this study

was that an accelerated step-up approach might be better than a standard step-up approach in patients with CD. The end point was the proportion of trimesters, or four-month blocks, that patients were in

remission, free of steroid use and of antiTNF use, in the first three years. The researchers found no difference between the two groups. It appears that this was an underpowered study. Interestingly, a secondary analysis showed a nonsignificant trend toward fewer intestinal surgeries in the early AZA group and, perhaps, if the study had been larger, would a difference have been apparent? Regardless, at this point we don’t have evidence that accelerated step-up AZA therapy is better than standard step-up treatment. This study also tells us we aren’t very good yet at picking out the high-risk patients. Despite the authors selecting patients with early CD whom they thought were at high risk for developing disabling CD, at the end of the study, more than one-third of the patients in the standard step-up group had not yet met criteria for needing AZA. We need better ways to risk-stratify our patients. Once we can, then the high-risk patients probably need to go directly to top-down therapy and the truly low-risk patients can go with standard step-up therapy. ■ Dr. Gress reported no relevant conflicts of interest. Dr. Loftus has received research support from Abbott Laboratories, Amgen, Braintree Laboratories, Bristol-Myers Squibb, Genentech, Janssen Biotech, Millenium-Takeda, Pfizer, Shire Pharmaceuticals and UCB. He has served as a consultant for Abbott Laboratories, Bristol-Myers Squibb, Pfizer and UCB.

Comment on this article at gastroendonews.com What were your favorite abstracts presented at this year’s Digestive Disease Week meeting? 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 “Comment on This Article” 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 • SEPTEMBER 2012

Screening Colonoscopy continued from page 3

participants made up only 10% of the population, a relatively short followup and the lack of randomization. Dr. Winawer pointed out a few other caveats. “There are some striking differences that may not mean anything,” he said, in terms of lifestyle choices in diet and exercise and in socioeconomic status. “But the main thing is that we really don’t know what went on with the nonscreened population during a six-year follow-up; a portion of them may have been screened. We don’t know that it’s truly a nonscreened population. This is a study that compares a subset of the population with a larger population that has many unknown factors going on.”

Engl J Med 2012;366:687-696). But unlike the Swiss study, which was a screening study, the National Polyp report comes from surveillancebased follow-up. “Nevertheless, we were able to demonstrate a polypectomy effect, which is basically what their study and all these studies show,” Dr. Winawer said. That effect, he explained, is the initial detection of cancer followed

by an effect on incidence and mortality from subsequent cancers that might have evolved had it not been for polypectomy. “It’s a polypectomy effect that reduces the incidence and a large proportion of the mortality effect,” Dr. Winawer said. “This study does add to the body of literature demonstrating that colonoscopy—and in this case, screening colonoscopy—does have a

beneficial effect,” Dr. Winawer said. “But the specific incidence and mortality figures can only be looked upon in this study, as well as all prior studies, as good estimates. The accurate, precise demonstration will have to await the randomized trials that have been initiated.” ■ Dr. Winawer reported no relevant financial disclosures.

‘This study does add to the body of literature demonstrating that colonoscopy—and in this case, screening colonoscopy—does have a beneficial effect.’ —Sidney J. Winawer, MD

With only one CRC-related death in the screened group over a period of seven years (including the screening year), it is difficult to interpret the 88% reduction in CRC mortality reported by the group, Dr. Winawer noted. “But they do show an incidence reduction of 69%, which is similar to that of the National Polyp Study, and in the same ballpark as the Brenner and Kahi studies.” The Swiss researchers did note that their findings were similar to those of the National Polyp Study, but suggested that the latter’s use of epidemiologic data as a reference is problematic due to the possibility that prognostic patterns in the screened population could be different from those in historical controls. “The National Polyp Study was very similar to theirs,” as far as general population comparison methodology, Dr. Winawer said. “We used general population SEER [Surveillance, Epidemiology and End Results] data, which is what they did with their population.” The most recent findings of the National Polyp Study suggest that polypectomy leads to a 50% reduction in mortality (Zauber AG et al. N

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ADR continued from page 1

meeting. Dr. Rex, who is professor of medicine at Indiana University School of Medicine, Indianapolis, was involved in creating the original Multi-Society Task Force benchmark 10 years ago.

‘What we are trying to accomplish with the ADR is to prevent colorectal cancer. So the ADR is a surrogate, which by definition is suboptimal. But should an alternative for ADR be introduced?’ —Douglas K. Rex, MD

The ADR, which aimed to bring much-needed quality indicators to colonoscopy, was derived from the prevalence of adenomas from four screening colonoscopy studies, which found rates of approximately 32% in men and 18% to 20% in women. Although the true prevalence of adenomas was much higher, the task force arbitrarily set the ADR benchmark at rounded numbers below the mean: 25% in men and 15% in women. Dr. Rex explained that the task force estimated the greatest gains in cancer prevention would come from getting the worst detectors to move up to mid-level detectors. “We were also concerned that if we set the detection targets at the true prevalence rates, we would make the targets unachievable for many endoscopists.”

Defining Detection Targets A number of measures have been proposed as possible alternatives to ADR for determining the quality of mucosal inspection during colonoscopy. But setting targets for adenoma detection is tricky, Dr. Rex said. Issues include whether sufficient data are available for the proposed measure to establish a detection target; whether it is feasible for clinicians to make the proposed measurement; whether the measurements result in “gaming,” that is, whether clinicians will change their behaviors to ensure reaching the target; and whether the measurement will result in behaviors that increase risks or costs. “What we are trying to accomplish with the ADR is to prevent colorectal cancer. So the ADR is a surrogate, which by definition is suboptimal,” he said. “But should an alternative for ADR be introduced?” In his lecture, Dr. Rex described the

ADR, a list of alternative proposed measurements and his opinions of them: • ADR: A valid complaint is the need to manually enter the pathology report into the endoscopic database. ADR is hard to game, but might contribute to a “one and done” mentality, in which endoscopists remove one adenoma and don’t look carefully for more. Dr. Rex noted that “one and done” is more likely the result of the reimbursement system than the ADR standard. • Interval cancers: This avenue is not practical. Delays are inherent in measurement and confidence intervals are wide. However, it is hard to game the measurement. • Large or advanced adenomas: This method “would introduce chaos” as lesions less than, but close to, 1 cm would be called large adenomas so they would be counted. • Polypectomy detection rate (PDR): This is a good option. It’s the easiest to measure, and information is taken from the endoscopy report. • Determining adenomas per colonoscopy: Overall, this is the best target. Perhaps, it is the best measure of the quality of inspection, especially if the number of polyps visualized is documented by photography. This method might increase costs if it incentivizes separating polyps in the same section of bowel into different pathology bottles. Dr. Rex feels that the PDR and adenomas per colonoscopy both deserve serious consideration as replacements for ADR, but said more studies should be performed. Focusing on PDR, he noted that multiple retrospective studies show correlation between ADR and PDR. “The major concern,” however, “is that [PDR] incentivizes removal of the one set of lesions we think is not associated with cancer, i.e., distal hyperplastic polyps. Thus, it might be gamed when used prospectively.” Although he would like to see PDR prospectively studied, Dr. Rex said it could be used now if ADR is not feasible. The suggested target is 35%, according to a study presented at this year’s DDW meeting.

Setting a New Threshold? “There is no question that ADRs are increasing over time, so it’s fair to ask whether the ADR targets were set at the right level,” Dr. Rex said. Subsequent observational data from a 50,000-person screening study done in Poland supported the threshold set in 2002, finding that doctors with ADRs above the 20% target provided much better

protection from interval cancers compared with doctors with lower ADRs (Regula J et al. N Engl J Medd 2006;355:1863-1872). New evidence would be needed to support any revisions, he emphasized. “Given the evidence from the Polish study, it’s now harder to change the targets than it was to arbitrarily set them below the mean adenoma prevalence rates in 2002,” he said. Whether any increase in the recommended targets would be better is currently unclear. “We know it would increase

polypectomy pathology costs and the numbers of surveillance exams, but we don’t know if raising the targets will improve cancer detection. “We need additional evidence before raising the ADR targets above their current levels. We need to know that raising the target will improve outcomes, such as better detection of advanced adenomas and/or greater prevention of cancer,” Dr. Rex concluded. “Currently, the only validation study we have supports the levels set somewhat arbitrarily 10 years ago,” he said. ■

ADR May Be Higher in Practice Than Current Recommended Benchmark BY CAROLINE HELWICK SAN DIEGO—As part of a large study undertaken to improve adenoma detection rates (ADRs), Susan Coe, MD, a third-year gastroenterology fellow at Mayo Clinic, Jacksonville, Fla., and colleagues examined ADRs in average-risk patients undergoing screening colonoscopy and found rates as much as 66% higher than the current benchmarks. Dr. Coe presented the results at the 2012 Digestive Disease Week meeting (abstract 798). “These data prompt the question of whether the benchmarks should be pushed forward,” said senior investigator Michael B. Wallace, MD, Department of Gastroenterology & Hepatology, who spoke at a press briefing. “In the last few years there’s been intense focus on quality in colonoscopy and how we measure that. A large number of studies have suggested that the numbers may be considerably higher.” The study examined gender-specific ADRs in a screening population of 864 persons at Mayo Clinic, Jacksonville. The data on average-risk patients (no prior polyps or family history of colorectal cancer) were culled from 2,400 colonoscopies performed. Researchers found that overall ADR was 34% versus the current benchmark of 20% ((P<0.0001). ADRs were 41% for male patients and 25% for female patients, each significantly higher than the current benchmarks of 25% ((P<0.0001) and 15%, respectively (P ( =0.0003). Male and female patients were similar with regard to age and race, and also in terms of percentages of advanced, sessile or proximally located polyps. Males were more likely to be taking aspirin. Among patients with adenomas, large adenomas were observed in 32% to 37% of patients, advanced adenomas in about 5%, flat adenomas in 13% to 16% and proximal lesions in 72% to 75%. The study had several limitations. Data were collected as part of a larger study focusing on improving ADR, during which half of the endoscopists received an educational intervention that may have influenced detection rates. Also, the study was performed in an academic setting among experienced endoscopists, and researchers lacked information on the percentage of first-time screenings. “We conclude that current ADR benchmarks may be lower than the true detection rates for both genders,” Dr. Coe said, “but further studies in multiple practice settings are needed before recommendations can be made.” Dr. Wallace added that the current findings “do not specifically answer the question” of whether the current guidelines should be revised, “but they do tell us that a higher proportion of patients have adenomas than the current benchmarks suggest.” Dr. Coe reported no conflicts of interest. Dr. Wallace has received grant/research support from Boston Scientific, Cook, Fujinon, Mauna Kea Technologies and Olympus.

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Demystifying Sessile Serrated Polyps Two Experts Break Down the Basics the proximal colon,” Dr. Rex observed. Dr. Lieberman agreed that the failure to recognize SSPs is a problem, and not only in terms of malignant SAN DIEGO—Sessile serrated polyps (SSPs) are receivtransformation. ing more attention recently, but challenges remain in “The significance of these lesions is that when SSPs the understanding, recognition and management of are found in the proximal colon, there is often a synthem. chronous advanced neoplasm elsewhere in the colon, ‘The significance of these lesions is that Douglas K. Rex, MD, professor of medicine at Indiand they also may be associated with increased risk of ana University School of Medicine, Indianapolis, and when SSPs are found in the proximal advanced neoplasia in surveillance.” David A. Lieberman, MD, professor of medicine at colon, there is often a synchronous He added, “The message is that if you do identify a Oregon Health & Science University, Portland, led a proximal serrated polyp, you should be especially careful advanced neoplasm elsewhere in the session at the 2012 Digestive Disease Week meeting to look for other advanced conventional adenomas, and colon, and they also may be associated devoted to this issue. make sure patients come back for surveillance.” Dr. Rex said he prefers the term sessile serrated pol- with increased risk of advanced neoplasia The CARE (Complete Adenoma Resection) study ypss rather than sessile serrated adenomas (SSAs). He said found the strongest predictor of incomplete polyp SSP is the more accurate term and is less confusing in surveillance.’ removal to be serrated status (Pohl H et al. Gastroen“because most of these lesions are not dysplastic.” —David A. Lieberman, MD terologyy 2011;140:S719. Abstract Tu1006). The rate of However, he added, “Sessile serrated adenoma and sesincomplete resections was 7.2% for conventional adesile serrated polyp are both used in nomas, but rose to 31% for SSPs, the literature and should be con“meaning that only 69% of the Table. sidered synonymous.” serrated lesions were successfully Serrated lesions as a class removed,” Dr. Rex noted. Risk Level Suggested Surveillance include hyperplastic polyps (gobDr. Rex offered the following let cell, microvesicular and mucinsuggestions for successfully removHigh 1y poor); SSPs or SSAs, which should ing SSPs: Know the endoscopic Hyperplastic polyposis (>5 sessile serrated adenomas, be characterized as with or without signs of serrated lesions, define proximal to sigmoid, with two >10 mm) cytologic dysplasia; and traditional the lesion edges using a contrast Moderate 3 y (similar to high-risk adenomas) serrated adenomas (TSAs). agent and high-definition scope, Serrated polyp with dysplasia or ≥10 mm Although TSAs are quite leave the mucus cap in place until rare, accounting for 0.1% to 1% resection is attempted and remove Low ≥5 y (similar to low-risk adenomas) of polyps found during screena rim of normal mucosa en bloc, if Serrated polyp without dysplasia in proximal colon ing (depending on size), SSPs possible. are somewhat more common, Elaborating on these practice Very low 10 y accounting for 0.2% to 2.4%, Dr. pearls, he said, “When a lesion is Classic hyperplastic polyp Lieberman noted. in the 6 to 10 mm range, I just Dr. Rex estimated the true Adapted from Terdiman JP, McQuaid KR. Gastroenterologyy 2010;139:1444-1447. grab it without contrast injection. prevalence of SSPs to be around When lesions are bigger, we prob5%, “which makes them about as ably should inject them in order common as advanced conventional to see them better. I try to pick up adenomas,” he said. SSPs with cytologic dysplasia cona little of the normal rim of the mucosa around it, even ‘If you do identify a proximal serrated stitute 10% to 15% of all SSPs in published reports. if I am using electrocautery, to better achieve complete The vast majority of SSPs are found in the proximal polyp, you should be especially careful resection, because the edge is probably where we are colon; they tend to be CpG island methylator pheleaving residual disease.” to look for other advanced conventional notype–high and sometimes microsatellite instability Dr. Lieberman added, “Be concerned about the ser(MSI)–high. MSI is seen more often in the SSP with adenomas, and make sure patients come rated polyp with cytologic dysplasia. They may have cytologic dysplasia, a lesion that is more capable of back for surveillance.’ crossed the line and may be on the path to cancer. Be accelerated evolution to cancer. The same characteristics especially careful [that] you have removed all the poten—David A. Lieberman, MD tial tissue.” are seen in interval cancers, and SSPs appear to account for a disproportionate share of these, Dr. Rex said. BY CAROLINE HELWICK

chance an expert pathologist would call it an SSP,” he said. The corollary is that many endoscopists consider proximal colon serrated lesions 1 cm or greater to be SSPs regardless of the pathology report.

Natural History

Identification In general, it is difficult for endoscopists to differentiate SSPs from hyperplastic polyps. “It is easy to separate SSAs or hyperplastic polyps from conventional adenomas by their endoscopic appearance, but differentiating SSPs from hyperplastic polyps is more difficult, as they are characteristically indistinct,” Dr. Rex said. SSPs and hyperplastic polyps share many endoscopic features of proximal colon serrated lesions, including mucus caps, adherent debris, disruption of the vascular pattern, pale color, paucity of surface blood vessels and indistinct edges. “The larger and more proximal the lesion, the greater

Recent investigations have suggested that “O” type pits on the surface of serrated polyps are highly specific for SSPs, and that SSPs tend to have a cloud-like surface, irregular shape and dark spots inside the crypts. Whether these are truly characteristic of SSPs requires further study.

Detection and Removal Adenoma detection rates are notoriously variable, ranging three- to sixfold within a single practice. Detection of SSPs demonstrates even more variability, with ranges of seven- to 18-fold reported in the literature. “This means that clinicians at the lower end of the detection range are missing 95% of serrated lesions in

The natural history of SSPs is not well understood, mainly because endoscopic recognition is still poor and the histologic definition is not uniform, Dr. Lieberman said. “Not having uniformity in terminology makes it challenging to understand the natural history,” Dr. Lieberman said. “These are the pieces of the puzzle that we need to have in order to understand the natural history.” This lack of clarity has implications for surveillance and “leaves us with uncertainty regarding recommendations,” he added. Nevertheless, some recommendations have been made for incorporating serrated polyps in surveillance strategies (Table). ■

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Deep Ulcerations at Diagnosis Signal Worse Disease Course For Children With Crohn’s Disease Early Treatment With Anti-TNF Agents Recommended BY CAROLINE HELWICK SAN DIEGO—In children newly diagnosed with Crohn’s disease (CD), the presence of deep ulcerations at diagnosis greatly increases the risk for moderate to severe disease at one year; however, this risk is greatly diminished by the use of antitumor necrosis factor (TNF)-α agents within three months of diagnosis, according to findings reported at the 2012 Digestive Disease Week (DDW) meeting. The presence of deep ulcerations at diagnosis in adults with CD also heralds a worse clinical outcome, but similar data have not been available in children until now. Investigators identified 1,088 children with CD and analyzed 333 with complete outcomes data. This included 169 with deep ulcerations at diagnosis (70% with one to two segments and 30% with three or more segments) and 164 without deep ulcerations at diagnosis. Worse outcomes at one year were observed in patients with deep ulcerations at diagnosis and in those lacking treatment with immunomodulators or anti-TNF agents within three months of diagnosis; alternatively, the use of anti-TNF agents dramatically reduced the likelihood of active disease at one year, reported lead author Jeffrey Hyams, MD, of Connecticut Children’s Medical Center in Hartford. “Whether this means we should start treatment early with anti-TNF agents is the key question we struggle with,” he said. Information from this study will help researchers develop a paradigm to predict which patients may benefit from aggressive early treatment, he said. Researchers assessed disease activity in patients using the Pediatric Crohn’s Disease Activity Index (PCDAI)

IBD Test continued from page 1

Marla Dubinsky, MD, director of the Pediatric Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center in Los Angeles, believes the tool can be used when a definitive IBD, CD or UC diagnosis remains hazy, despite clinical, endoscopic and histologic findings. “The serologies, in particular, add additional information in cases of diagnostic uncertainty,” said Dr. Dubinsky, who was not involved in the development of the instrument. Prometheus launched the new test as an improvement on IBD Serology 7, which measures serologic levels of several

and the Physician Global Assessment. Controlling for confounding factors, the key analyses identified the following odds ratios (ORs) for developing moderate to severe disease at one year (defined as PCDAI score >30): • OR 0.05 for treatment with anti-TNF therapy in patients with deep ulcerations at presentation versus no treatment of patients with deep ulcerations; • OR 0.14 for treatment with anti-TNF therapy within three months of diagnosis versus no antiTNF treatment; • OR 2.7 for the presence of deep ulcerations at presentation versus no deep ulcerations; • OR 7.1 for no treatment with anti-TNF therapy

antibodies associated with both CD and UC, including anti-Saccharomyces cerevisiaee (ASCA), perinuclear antineutrophil cytoplasmic antibodies (pANCA), antibody to outer membrane porin C (anti-OmpC) and anti-CBir1 flagellin (anti-CBir1). IBD Serology 7 also included a diagnostic algorithm to help interpret the findings. According to a Prometheus representative, the sensitivity and specificity of the IBD Serology 7 suffered from its reliance on serology markers alone and from low sensitivities of ASCA in CD and ANCA in UC. In contrast, the new test measures the presence of serologic markers included in the Serology 7, as well as two additional markers, anti-Fla-X, anti-A4 Fla2.

within three months of diagnosis versus antiTNF treatment; and • OR 20.7 for no treatment with anti-TNF therapy within three months of diagnosis and the presence of deep ulcerations at presentation versus treatment in this affected group. “The study has some limitations,” Dr. Hyams acknowledged. Treatment was not protocoldriven, endoscopic documentation was not required, mucosal healing was not evaluated and medication adherence was not measured. The study is currently underpowered to determine whether the number of segments matters. “But we believe that in this well-characterized, large cohort, the presence of deep ulcerations at diagnosis is associated with a much greater likelihood of moderate to severe disease at one year, and that the use of anti-TNF agents within the first three months dramatically reduces the likelihood,” he said. DDW session moderator Ryan Carvalho, MD, of Nationwide Children’s Hospital in Columbus, Ohio, said his take-home message is that “deep ulcers matter in kids, too.” He added that long-term data are needed to evaluate safety, especially freedom from infection and maintenance of efficacy, including avoidance of surgery, “but for now,” he suggested, “if you see lots of deep ulcerations, consider using the drugs early to give the best chance for achieving and maintaining remission at one year.” ■ Dr. Hyams disclosed that he serves on advisory committees or review panels for Abbott Laboratories, Centocor and UCB; he has received grants/research support from Abbott Laboratories and Centocor. Dr. Walters has relationships with all companies that manufacture anti-TNF agents. Dr. Carvalho reported no conflicts of interest.

‘The serologies, in particular, add additional information in cases of diagnostic uncertainty.’ —Marla Dubinsky, MD

Prometheus says the addition of these two markers may help identify subsets of patients that could have been missed otherwise.

The new instrument also tests for genetic markers—including ATG16L1, NKX2.3, STAT3 and ECM1—that are see IBD Test, page 16

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DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Study Suggests No Significant Link Between Accutane and IBD BY DAVID WILD SAN DIEGO—A French study comparing use of the acne drug isotretinoin (Accutane) between 4,400 patients with inflammatory bowel disease (IBD) and nearly 40,000 controls found a higher, but statistically nonsignificant, rate of isotretinoin use among patients with ulcerative colitis (UC) and lower rates of isotretinoin use among patients with Crohn’s disease (CD), compared with controls. The results, presented at the 2012 Digestive Disease Week meeting, add to evidence that suggests there is no association between the use of the drug and risk for IBD (abstract 400). The findings fall in line with results from a prior case–control study, which revealed slightly higher rates of isotretinoin use among patients with UC and lower rates of isotretinoin use among patients with CD than controls (Crockett SD et al. Am J Gastroenteroll 2010;105:1986-1993). “Taken together, the results of prior studies and this study suggest that if there is a connection between isotretinoin use and UC, the absolute risk for [developing]

UC from the drug is very small,” said lead author Seth Crockett, MD, MPH, assistant professor in the Department of Gastroenterology at the University of North

Research in Epidemiology and Population Health, Gustave Roussy Institute, Villejuif, France, and his team analyzed claims from the French National Health Insur-

‘Taken together, the results of prior studies and this study suggest that if there is a connection between isotretinoin use and UC, the absolute risk for [developing] UC from the drug is very small.’ —Seth Crockett, MD

Carolina at Chapel Hill. “Furthermore, there is no epidemiologic data showing a positive association between isotretinoin and CD.” However, cases of IBD have been reported in isotretinoin users and some believed there might be a drug–disease correlation. Roche Pharmaceuticals discontinued sales of isotretinoin in 2009 after IBD-related class-action lawsuits were filed against the company in several countries. To address this contentious assertion, Antoine Racine, MD, from the Center for

ance system filed between 2008 and 2010. The investigators used International Classification of Diseases, 10th edition codes to identify IBD cases diagnosed during this period, including 2,829 patients with CD, 1,568 with UC and five with indeterminate IBD. They compared isotretinoin use between patients with IBD in the year prior to diagnosis and 39,850 randomly selected, age- and gender-matched controls without IBD. Their analysis excluded individuals older than age 40 years as well as those with IBD-related claims submitted prior to the study period. The median

accurate in distinguishing UC from CD, he reported. “The [assay] represents an innovative approach in biomarker development, incorporating current advances in pathophysiology with state-of-the-art biostatistical analysis,” Dr. Plevy said. “As we further refine and redefine the tremendous clinical heterogeneity that we refer to as CD and UC, such approaches will grow in importance as adjuncts to clinical diagnosis.” According to Dr. Dubinsky, one potential application of the test would be to help clinicians who are considering a referral for colectomy to determine more confidently whether the patient has a “CD-like” or “UC-like” phenotype. “The genetic markers are interesting but need to be interpreted with caution, since these genes may be present in both UC and

CD, as newer genetic association studies are demonstrating,” she said. Further work needs to be done to identify completely nonoverlapping genes and thereby improve on instruments like [this one].” Ellen Scherl, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College and NewYorkPresbyterian Hospital, in New York City, explained that some test findings are prognostic of disease activity and therefore can help clinicians select more appropriate treatments. “High ASCA-IgG and ASCA-IgA titers in Crohn’s disease patients have been found to predict strictures, so you might want to follow a more aggressive treatment path in patients with these findings,” Dr. Scherl told Gastroenterology & Endoscopy

age of the populations ranged from 25 to 28 years. Dr. Racine’s team found 0.2% (seven of 2,829) of patients with CD and 0.4% (10 of 1,568) of patients with UC submitted an isotretinoin claim during the year prior to diagnosis compared with 0.5% (214 of 39,850) of patients without IBD. Statistical analyses revealed that patients with UC were nearly 30% more likely than controls to have an isotretinoin claim on file in the year prior to diagnosis, although the difference was not statistically significant (odds ratio [OR], 1.29; 95% confidence interval [CI], 0.68-2.44). Conversely, patients with CD were significantly less likely than controls to have submitted an isotretinoin claim during the year prior to diagnosis (OR, 0.40; 95% CI, 0.19-0.85). The odds ratio of an isotretinoin claim among all IBD cases during the year prior to diagnosis was 0.68 (95% CI, 0.41-1.10). “These results from a large nationwide database do not argue for a role of isotretinoin in IBD onset,” the authors concluded. ■ Drs. Crockett and Racine reported no conflicts of interest.

IBD Test continued from page 14

linked to defective bacterial handling or autophagy, dysregulated signaling pathways and impaired epithelial barrier function in IBD. The tool also tests for several inflammatory markers, including intercellular adhesion molecule 1, vascular cell adhesion molecule 1, vascular endothelial growth factor, C-reactive protein and serum amyloid A. Additionally, the tool includes an integrated algorithm, which interprets the relationships between the serologic, genetic and inflammatory findings and provides an initial prediction of IBD and a subsequent differential diagnosis of UC or CD. Scott Plevy, MD, associate professor of medicine in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill’s School of Medicine, and colleagues presented findings of the Prometheus-funded study of the tool at the DDW meeting (abstract 166). The trial included 437 well-characterized IBD and non-IBD patients. According to Dr. Plevy, the test demonstrated sensitivity rates of 74% in predicting IBD, 89% in identifying CD and 98% in recognizing UC. Corresponding specificity rates were 90%, 81% and 84% for IBD, CD and UC, respectively. Overall, the test was 87% accurate in distinguishing IBD from non-IBD and 93%

News. “As we enter the era of personalized medicine, we’ll find these diagnostics more and more helpful in helping us select the most effective therapies.” Dr. Scherl cautioned against using the tool for initial patient screening, saying that colonoscopy remains the gold standard. Prometheus recently announced the market launch of its Anser IFX assay (see “Prometheus Launches New Monitoring Test To Help Guide Management of IBD Patients Using Infliximab,” page 47). ■ Dr. Dubinsky is a consultant for Prometheus Laboratories. Dr. Plevy is a consultant for Prometheus Laboratories and has received royalty payments for intellectual property that may have been licensed to Prometheus. Dr. Scherl has received grant/research funding and is a consultant for Prometheus Laboratories.

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Nonresponders to First Anti-TNF Less Likely To Respond To Second or Third Anti-TNF ‘In cases where a third anti-TNF BY DAVID WILD SAN DIEGO—The likelihood of clinical response to anti-tumor necrosis factor (TNF) drugs among patients with inflammatory bowel disease drops with each successive treatment attempt with this class of drugs, according to a retrospective study presented at the 2012 Digestive Disease Week meeting (abstract 267). The findings should help clinicians identify those patients most likely to respond to a third-line biologic, said senior investigator Ashwin Ananthakrishnan, MD, MPH. Among patients who switched to a third anti-TNF as a result of drug intolerance or loss of response to two previous anti-TNF agents, almost half discontinued treatment within a year. “If a patient has responded previously to anti-TNF therapy, it is reasonable to try a third anti-TNF drug,” said Dr. Ananthakrishnan, an instructor in medicine at Harvard Medical School and faculty member at the Gastrointestinal Unit at Massachusetts General Hospital, both in Boston. “In cases where a third anti-TNF is administered, if there is no response by three months or the patient failed to respond to a first anti-TNF, the chance of subsequent response is low and one

should consider therapies with alternate mechanisms of action.” Dr. Ananthakrishnan and colleagues examined medical records from 57 patients with Crohn’s disease and six patients with ulcerative colitis, all of whom were treated at their institution over a five-year period with a third anti-TNF agent after nonresponse, loss of response or intolerance to two prior anti-TNF agents. At the time of initiation of the third anti-TNF, patients had disease for a mean of 12 years. In nearly 90% of cases, certolizumab (Cimzia, UCB) was the third anti-TNF drug administered. Overall, 31% of patients discontinued treatment with the third anti-TNF at six months, with the number of discontinuations increasing to 45% at one year, 63% at two years and 75% at three years. Statistical analyses revealed that those who did not respond to a first anti-TNF agent were 6.4 times as likely to discontinue treatment with the third anti-TNF agent early as those who experienced loss of response or were intolerant to a first anti-TNF (P<0.01). Furthermore, individuals with persistent disease three months into treatment with a third antiTNF were 3.2 times as likely as those who did respond within three months to discontinue treatment early (P<0.01). The study provides a snapshot of

is administered, if there is no response by three months or the patient failed to respond to a first anti-TNF, the chance of subsequent response is low and one should consider therapies with alternate mechanisms of action.’

—Ashwin Ananthakrishnan, MD, MPH real-world anti-TNF response rates to date, but, according to William Sandborn, MD, it does not reflect the “much more nuanced approach to treatment that we are heading toward. “Some patients with primary nonresponse to anti-TNF don’t have enough drug, and loss of response can be due to anti-drug antibodies or insufficient drug, in which case increasing doses may lead to better response,” said Dr. Sandborn, chief of the Division of Gastroenterology and director of the University of California San Diego Inflammatory Bowel Disease Center, University of California San Diego Health System, who was not

involved in the study. “There are also other causes of symptoms in patients who have sufficient drug and are actually in endoscopic remission, and these patients need to continue the anti-TNF agent they are on,” Dr. Sandborn added. “However, patients with sufficient drug but active endoscopic disease should switch to a different class of drugs.” ■ Dr. Sandborn is a consultant and has received research support from Abbott Laboratories and Janssen; he also is a consultant for UCB. Dr. Ananthakrishnan reported no conflicts of interest.

Presence of Anti-Infliximab Antibodies Not Predictive Of Infliximab Concentration, Inflammation in IBD BY DAVID WILD SAN DIEGO—Antibodies to infliximab can limit the drug’s efficacy when treating Crohn’s disease (CD) even when high serum concentrations of infliximab are present, according to a study presented at the 2012 Digestive Disease Week meeting (abstract 565). Although the clinical quandary posed by the new study needs to be better understood, Marla Dubinsky, MD, director of the Pediatric Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center in Los Angeles, believes that further investigation along this line of inquiry will ultimately help clinicians better guide treatment. “It’s clear that insights like these are moving us out of an era where we blindly escalate doses or switch drugs in nonresponsive patients and into an era where treatment decisions are tailored to a number of parameters,” said Dr. Dubinsky, who was not involved in the study. Assay-based serum drug monitoring is a growing practice used to fine-tune individual treatment choices and drug dosing, and is part of the rapidly evolving field of personalized medicine, said lead investigator Brian

Feagan, MD, director of clinical trials at the Robarts Research Institute in London, Ontario, Canada. Dr. Feagan and colleagues from several centers in Canada, the United States and Europe examined 2,021 serum samples from 532 individuals with CD who took part in four prospective clinical trials or cohort studies of infliximab. The investigators analyzed serum samples for infliximab levels and antibodies to infliximab using a novel high performance liquid chromatography–based fluid-phase assay (manufactured by Prometheus). The new assay allows for simultaneous measurement of both infliximab and anti-infliximab antibody levels, compared with previous assays, which could not detect antibodies if infliximab was present in the blood. The investigators also recorded levels of C-reactive protein (CRP), an inflammatory marker of disease activity, and conducted statistical analyses to document associations between the three variables. The researchers found that, in the absence of antibodies, serum infliximab levels below 3 mcg/mL were significantly associated with high CRP levels (median CRP concentration, 5.65 ng/mL), whereas infliximab levels above this threshold were associated with lower CRP levels (median CRP, 1.50 ng/mL; P<0.001 for

high vs. low infliximab levels). However, when antiinfliximab antibodies were present, serum infliximab levels did not correlate with median CRP concentrations (median CRP, 8.40 ng/mL when infliximab was less than 3 mcg/mL vs. 9.90 ng/mL when infliximab was 3 mcg/mL or greater). The results challenge the current understanding of infliximab’s pharmacokinetics, Dr. Feagan said. “These findings have surprised many people. We don’t know why we’re seeing high infliximab levels despite the presence of antibodies, but it may be that serum drug levels do not tell the whole drug concentration story. Perhaps there are other mechanisms that impact drug concentrations which we need to understand. We might need to look outside of serum—for example, in tissue— to better evaluate drug concentrations.” Dr. Feagan added, “The clinically relevant question is whether administering more drug can overcome the effect antibodies seem to have on the efficacy of infliximab. At the moment, nobody knows the answer to this.” ■ Dr. Feagan serves on the advisory committee for Prometheus Laboratories, Inc., and Dr. Dubinsky is a consultant for Prometheus.

Obesity continued from page 1

Center for Drug Evaluation and Research, in a statement. “Qsymia, used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition.” Neither of the new anti-obesity drugs is on the market yet, but both are expected by late 2012 or early 2013. Prior to Belviq and Qsymia, the only prescription drug approved for long-term treatment of obesity was orlistat, marketed as Xenical (Roche). Orlistat also is sold over the counter in a lower dose as Alli. The FDA recommended that the U.S. Drug Enforcement Administration (DEA) classify Belviq as a scheduled drug. Once the DEA has provided the final scheduling designation, the company will announce when Belviq will be available to patients and physicians in the United States. Belviq is not recommended for pregnant women, and should used with caution in patients with congestive heart failure. The approved labeling for Belviq recommends that the drug be discontinued in patients who fail to lose 5% of their body weight after 12 weeks of treatment, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment. With Qsymia, too, the approval comes with restrictions. The drug must not be used during pregnancy, for patients with glaucoma or hyperthyroidism, and, because Qsymia can increase heart rate, usage in patients with unstable heart disease or stroke within the past six months is not recommended. Regular heart rate monitoring is recommended for all patients, especially when starting the drug or when increasing the dose. The FDA approved Qsymia with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a medication guide advisingg patients about important safety information as well ass elements to assure safe use that include prescriber traaining and pharmacy certification. In its recommendation, which came prior to the two new drrug approvals, the USPSTF foun nd that there is significant evi-dence that intensive, multicomponent behavioral interventions for obese adults leads to an average weight loss of 4 to 7 kg, an nd improves glucose tolerancee and other physiologic risk factors for cardiovascular disease.

Opportunity for Gastroenterologists The approval of the new drugs along with the policy changes provide an opportu unity for gastroenterologists to take a more proactive app proach to managing obesity in their patients, said Amy Foxx-Orenstein, MD, asssociate professor of medicine at Mayo Clinic, Phoenix. “This is a ch hance not just to take care of a symptom that’s related to obesityy but to encourage a full lifestyle chaange.” Although other specialists often

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

see obese patients after they have already developed severe health problems related to weight, gastroenterologists see patients while their weight is in transition, she said. “We’ve got an opportunity before our patients have shifted from being overweight to being obese, or before they develop complicated symptoms, to take a preventive health care approach,” said Dr. Foxx-Orenstein, who advocated a greater focus on obesity among gastroenterologists during her 2007-2008 tenure as president of the American College of Gastroenterology. “If patients are already obese, then we can take an interventional approach.” Dr. Foxx-Orenstein said she expects to prescribe the new drugs when they come to market. She’s anticipating that her patients will be interested in these treatment options. Community gastroenterologists should also consider prescribing the new medications when their patients are committed to changing their weight, said Dr. Foxx-Orenstein. Lisa Ganjhu, DO, gastroenterologist at St. Luke’sRoosevelt Hospital Center, in New York City, said she expects primary care physicians or obesity specialists to take the lead in prescribing new obesity drugs. “I have not [prescribed Belviq], yet. I am not sure I will. I would like to see it being used by others and see what their outcomes are prior to considering it.” She said she is watching to see if Belviq will play a role in the management of nonalcoholic steatohepatitis. “This may be the ideal population to use the drug in. I would just be concerned about the potential long-term adverse outcome.”

‘This is a chance not just to take care of a symptom that’s related to obesity but to encourage a full lifestyle change.’ —Amy Foxx-Orenstein, MD

The new drugs do come with important restrictions. Both should be used in conjunction with a balanced diet and exercise, and both should be taken for life in patients who respond to and can tolerate the drugs. “For many people, obesity is a lifelong condition, but we don’t always think of it—or treat it—as such,” said Amy Egan, MD, MPH, deputy director for safety in FDA’s Division of Metabolism and Endocrinology Products, in a statement.

‘For many people, obesity is a lifelong condition, but we don’t always think of it—or treat it—as such.’ —Amy Egan, MD, MPH

Medical Devices for Obesity Treatment Overall, gastroenterologists and device manufacturers have been frustrated with the slow process of trying to get approval for devices and endoscopic procedures that could potentially facilitate weight loss and treat obesity, said Steven A. Edmundowicz, MD, professor of medicine and chief of endoscopy, Washington University School of Medicine, St. Louis. The hope is that the FDA follows the recent drug approvals with greater willingness to approve devices for obesity management. To this end, the FDA has recently made steps toward speeding up that approval process. Earlier this year, the FDA held a panel meeting with physicians and device manufacturers and will generate a consensus statement based on those results. The statement is expected to outline the criteria the FDA will use for obesity devices in terms of the risk to the patient and the effectiveness, or how much weight loss, the devices are going to be able to generate in trials. “What we’re hoping for in endoscopy and gastroenterology are new effe effective tools that we can use in addition to the medicatiions that are currently available or gooing to be available,” said Dr. Edmu undowicz. Th he recent changes indicate that the ggovernment recognizes the obesityy crisis and is starting to implemeent change, said Dr. Ganjhu. Bu ut patients have to be willing to chan nge, as well, she said. In New York City, where trans fatts are banned in restaurant food, goovernment officials are now debatiing a ban on super-sized sodas. Consu umers and the food industry, hoowever, have fought back, saying tthe government is overreaching iinto people’s personal lives. “I find the argument frustratiing. Simple changes can make great reesults if only they are made,” said Drr. Ganjhu. ■ Drs. Foxx-Oren nstein and Ganjhu reported no relevant conflicts of interest. Dr. Edmundowicz reported havin ng an ownership interest in Beacon Mediical, Check-CAP and Endostim, and actingg as a consultant for Boston Scientiffic, Fortimedix, Merit Medical and O Olympus.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Gastro Practice

‘Remaining a totally independent practice is not what this is

continued from page 1

all about. Being able to control your own destiny is what this is

“We’re all getting the point that remaining a totally independent practice is not what this is all about,” said James S. Leavitt, MD, of Gastro Health, P.L., in Miami. “Being able to control your own destiny is what this is about. Being able to choose who your partners will be in a way that will be most effective for you and your patients and the care you give is what this is all about.” Predictions about what health care reform will bring are mere conjecture at this point, he said. But one thing is clear: “We can’t wind up with 30% of our GDP [gross domestic product] on health care; something’s got to give. “It’s been estimated that if we could move toward proven successful practices and adopt some of those practices in low-cost areas, we’d see a 30% reduction in health care costs—$700 billion or $800 billion per year in savings. That’s substantial, and we wouldn’t compromise the quality of care at all.” In essence, he said, to remain independent while offsetting climbing health care costs, and to maintain care in less-expensive outpatient settings, gastroenterologists will need to adopt services—such as electronic medical records and sophisticated information technology (IT)—and practices—such as tight internal accountability and strong physician leadership— that will make them competitive. But this may require some clever collaboration. “A coordinated approach to health care delivery is going to be critical. This doesn’t necessarily mean being in an integrated network; it means creating your own integrations,” Dr. Leavitt said. “You need to start thinking about how you are going to prove that you are critical to people.” Gastroenterologists today are very busy, with skills and procedures that are in high demand. “But competitive processes and technologies and reimbursement systems are right over the horizon, and when they come, they will come swiftly,” said Bergein Overholt, MD, co-founder and managing partner of Gastrointestinal Associates, a group of 13 physicians based in Knoxville. “So innovating now in anticipation of declining reimbursement and competing technologies is a critical step for the gastroenterology group to prepare for the future.”

Regional Variation Models of integration and the need to integrate vary by region and by physician availability, demand for services and ingrained practice patterns. For the solo gastroenterologist in a rural practice, integration may not be such a pressing concern. “Some of these doctors can remain

independent forever—there’s no competition, no one who is going to force them out of business or hire around them,” said Tom Deas, MD, medical director, Fort Worth Endoscopy Center, Fort Worth, Texas. “But when you get into larger metropolitan areas where the competition is stiffer, being bigger does provide some benefits.” In some areas, expansion of a single-specialty gastroenterology practice makes sense. Dr. Deas pointed to Minnesota Gastroenterology, a group of 70 or 80 GIs, as a successful example of this model. “They’ve done a marvelous job developing good-quality initiatives and performance standards for the physicians. And they’re working closely with health plans in a partnership agreement,” he said. “They’re a single-specialty gastroenterology group that has found a way to develop relationships where they aren’t being threatened to the point of needing to sell out.” Dr. Leavitt’s group in Florida, too, has found success with this model. “Dr. Leavitt’s group has gotten smaller practices to be a part of it, and that gives them negotiation leverage with payers; it allows them to invest more in the infrastructure of IT and in ancillary services,” Dr. Deas said. “In his particular region that’s what works best.” For the most part, however, Dr. Deas views the utility of the large single-specialty practice as a bit limited. “It doesn’t really get to the concept of coordination of care,” he said. “In the reform era, we’re talking about a greater integration of care delivery so that gastroenterologists are working with surgeons or internists and with the hospital to achieve more efficient, affordable, better quality care,” Dr. Deas said. His group of 16 gastroenterologists has focused its integration process around an independent practice association (IPA) that includes 600 physicians from all different specialties—primary care, urology, cardiology, “the whole bit,” Dr. Deas said. “The IPA has become the organizational home for the integration. We’re still an independent gastroenterology practice. We established a relationship with the hospital and the IPA that provides a way to deal with an integrated care model.” This model might be one to consider in lieu of merging with a multispecialty group or being bought out by a hospital in a large metropolitan area, but again, that would be contingent on the pressures a practice faces in its immediate surroundings. “It’s quite different depending on the region and what some of the competing

about. Being able to choose who your partners will be in a way that will be most effective for you and your patients and the care you give is what this is all about.’ —James S. Leavitt, MD

forces are,” Dr. Deas said. “If you’ve got a hospital system in the practice of hiring gastroenterologists to compete with local practices, you have a much different issue than what we have here, which is a hospital system that is much happier to partner with us in the IPA than to become an employer of gastroenterologists.” Of course, the desire to be and to remain independent varies on a physician basis. “The more autonomy you desire, the more likely you will be happy with a small practice. The less you want to be involved in practice management and just go to work, see patients and get a paycheck, the more likely you will prefer a larger group. It’s very much a personality decision,” Dr. Deas said. In opposition to perceived threats to independence, Dr. Deas thinks most practices are in a pretty good position these days. “We have more business than we can deal with. Many practices have incorporated revenue streams from pathology and anesthesia,” he said. “I haven’t talked to any gastroenterology practices that are suffering economically. People worry about it, but the reality seems to be quite

different from all the anxiety.” Nonetheless, it is wise to be prepared. “Right now, the accountable care organization is a concept; it’s being tested. My advice to physicians is to identify the big, more forward-thinking players in your community and work on aligning yourself with them,” Dr. Deas said. “This doesn’t have to be anything more than working with the hospital where you take call and see patients, assisting them in some of their quality initiatives and managing their endoscopy unit, and developing a friendly co-working relationship.”

A Spectrum of Integration At this year’s Digestive Disease Week meeting, Irving Pike, MD, who recently took up the reins of chief medical officer for John Muir Health, Walnut Creek, Calif., quoted from the 1993 strategic plan of Sentara Healthcare in Virginia, where he used to practice, on the importance of both independent physicians and those who work as employees of a health care system. “Grace Hines, the vice president of corporate strategies at Sentara, stated, ‘We have employed physicians and independent physicians, and they’re both

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

‘Innovating now in anticipation of declining reimbursement and competing technologies is a critical step for the gastroenterology group to prepare for the future.’ —Bergein Overholt, MD

with these groups, similar to what has been going on in New York. Formerly, most New York gastroenterologists practiced office-based endoscopy, but the number of ambulatory surgery centers (ASCs) in the area is growing. “The hospitals there have gone into a joint venture with these groups and with Physicians Endoscopy, a third-party [ASC] management company, to build ambulatory endoscopy centers together,” Dr. Pike said. With this arrangement, hospitals recoup some revenue they had lost, and they bring expertise in negotiations that may result in a financial agreement amenable to everyone involved. “The physicians make more than they did in the office setting, so that’s a win for them,” Dr. Pike said. “And with Physician Endoscopy involved, there is a third party running it, so there won’t be fingerpointing from the hospitals to the doctors or from the doctors to the hospitals.” The last point on the spectrum is the employed physician. “That’s where physicians are employed and fully aligned with a health-system medical group,” Dr. Pike said. “They follow policy; they help develop and then follow procedure; and their compensation, benefits and infrastructure is derived from the system or in some states from associated foundations.”

US Gastro important resources for our community. … We simply have to find an effective way of organizing our physician relations so that we can partner with all of them to achieve optimal outcomes for the patients we serve together.’ ” Dr. Pike’s group of 32 physicians in southeast Virginia found they could provide everything Sentara needed and could work collaboratively with the system. “By doing so, the group could remain independent and Sentara had no need to employ other gastroenterologists. As long as we provided what they needed, there would be no reason for them to bring that into the community,” he said. “But when physicians take an adversarial stance in the community and they want to remain independent, they essentially push the health system to hire physicians.” He recalled another specialty group that elected not to do consultations or cover the emergency room (ER), but to practice only on an outpatient basis, a decision they considered more economical. “So Sentara recruited 14 physicians in that specialty, and they now cover the hospital and compete with those doctors on the outpatient basis,” Dr. Pike said.

“Physicians need to be aware of their strategy and to fully think it through.” At this new stage in his career, Dr. Pike is helping John Muir Health formulate a plan to integrate with the local physician community. What he would like to see in all specialties is a spectrum of medical groups ranging from those that have no formal agreement with a health system to those that are fully employed by one. Each model would fulfill an important role. “Those who have no formal agreement would be physicians who practice good medicine, who want to use our healthsystem facilities to send their patients to our hospitals for imaging and to have their labs drawn,” Dr. Pike said. “They’re welcome, we’re glad to have them.” The next point in the spectrum would be contracted physicians who take up a service-line agreement. “They may contract to run an endoscopy unit efficiently or build a hepatology clinic to bring in new services,” Dr. Pike said. “Or we might give them a group medical directorship contract to build adequate coverage in our ER or consultation in our hospitals.” He described forming a joint venture

In Dr. Leavitt’s opinion, health care reform is being driven by the demand for transparency and consolidation, and smaller practices wishing to remain independent will need to invest heavily in the services that will help them meet those demands. “We will have to not only provide quality, but to prove it, and this will take a lot of resources,” he said. “Staying independent and aggregating into larger groups makes sense economically because you can spread the cost of providing that type of service over a larger number of people.” Consolidation, he said, is happening in many areas of health care, “whether it’s payer aggregation, hospital aggregation or physician group aggregation—you’re seeing consolidation of all these businesses. In my opinion, if physicians are the only ones not aggregating, we will lose our place in the market.” It could be difficult for smaller gastroenterology practices to purchase, build or engage in the systems and programs that would help control cost and drive quality. To this end, Dr. Leavitt is working on developing a national consortium, US Gastro, through which independent gastroenterology practices can join forces.

“The whole idea of US Gastro is to provide services that would otherwise cost individual practices not just money, but thought, time and personnel, and to aggregate those functions so that we can perform at a high level and be accountable for the type of care we give,” he said. Basically, the goal of US Gastro is to provide support for smaller gastroenterology practices that want to remain independent. “US Gastro would help in providing the IT, some of the back office billing services and some of the practice management-type services that may not be done as well in smaller offices due to cost,” said Dr. Deas. “They also would be involved in developing quality measures. It essentially would become a home—not that these practices would merge into one entity, but US Gastro would provide services to help them become more efficient.” The idea for US Gastro sprang to life a couple of years ago among a group of physicians speculating about the future. “We were talking about this movement that is occurring in which doctors are selling their practices out of fear,” Dr. Overholt said. “We knew this was going to come to gastroenterology, so we decided we wanted to do something that would allow gastroenterology practices to remain independent, and to remain clinically and financially strong.” At this point, US Gastro has identified potential CEO candidates and is in various stages of negotiation with primary investors. “It’s taken us a long time,” Dr. Overholt said. “But we are talking to various partners and people who have the experience of making something like this work.” It remains to be seen, however, what the demand for such an entity will be. “It is not clear to me that the small practices will see value in it,” Dr. Deas said. “Most are profitable and have plenty of work and may not be willing to pay a percentage of their revenue for these services. The larger groups already have many of these services.” Furthermore, he said, gastroenterology is not under quite the same pressure as other specialties when it comes to initiatives on quality and cost. “Cardiologists, orthopedists, general surgeons and nephrologists are higher on the total cost curve than gastroenterology,” Dr. Deas said. “So we’ll have to see what happens when people start paying attention to what we’re doing.” ■ Drs. Deas and Pike reported no relevant conflicts of interest. Drs. Leavitt and Overholt have a relationship with US Gastro.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Gastros Push To Prove Quality and d Value Quality and Value Plans Becoming Essential for Reimbursement BY MONICA J. SMITH KNOXVILLE, TENN.—Evaluating health care anywhere in terms of quality is mere conjecture without a system in place to measure and demonstrate that quality is being provided. To this end, gastroenterologists across the United States and

in other countries are looking at ways to meet quality standards. “The quality and value plan nationally is an attempt to quantify and answer whether we are providing the best quality [care] and the best value,” said John Allen, MD, MBA, national quality advisor for Minnesota Gastroenterology, Minneapolis.

“In terms of payer initiatives and accountable care organizations [ACOs], the trend is moving toward a valuebased reimbursement, which means you have to demonstrate how good a job you’re doing at a cost that is equal to or less than it was before,” he said. “To get down to the nitty gritty, the quality and value plan is an approach by practices to

‘In terms of payer initiatives and accountable care organizations, the trend is moving toward a valuebased reimbursement, which means you have to demonstrate how good a job you’re doing at a cost that is equal to or less than it was before.’ —John Allen,, MD,, MBA A

Ingenuity Delivered! begin to put some type of quantification on the value they bring to patients, payers, purchasers and referring providers for what we do.” Quality programs in any area of medicine exist to ensure that certain standards are achieved. “There are guidelines put out and met, but there’s no purpose in saying what should be routinely done and accomplished unless there is some monitoring to make sure these things are done,” said Robert A. Enns, MD, Pacific Gastroenterology Associates, Vancouver, Canada. A wrinkle to meeting quality standards in gastroenterology is that, unlike in other areas of medicine, some components of gastroenterology practice are performed by non-gastroenterologists. “For instance, endoscopy is performed by general internists, general surgeons, colorectal surgeons, family practitioners and, in some areas, nurses,” Dr. Enns said. “So for gastroenterologists, it is ideal to have some type of system that looks at benchmarks and makes sure, for example, that a colonoscopy done in one city is the same as a colonoscopy done in another city. What we’re really looking for is a continuity of care, and the elevation of the level of patient care that results in the best outcomes for the patient.”

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At the core of any quality and value plan, philosophically at least, are questions: How do you define quality in the context of your practice, and what are you measuring? Ideally, quality and value plans in gastroenterology will eventually extend to management of gastroesophageal reflux disease, Barrett’s esophagus, inflammatory bowel disease and all areas of gastroenterology with clinical practice guidelines that can be followed and

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

practices would be supportive of a bigger organization [i.e., Minnesota Gastroenterology], so it’s not just individual practices with free autonomy, but each supports the bigger mission and follows evidence- or consensus-based clinical care guidelines,” Dr. Allen said. “The other part of the covenant is that they agree to be transparent and measured, and that they will agree to a process of quality improvement,” he explained. “This means feedback, which we’ve developed through dashboards; talking to peers; and when there doesn’t

seem to be improvement, going to a formal peer-review structure where they agree to be monitored closely as they change and improve care.” The implementation of a quality and value plan also requires information technology that can capture and measure data, and a point person who can drive the plan. “You have to have a defined series of dashboard elements. We divided those into three components: financial, operational and clinical outcomes,” Dr. Allen said. “Then you have to set up your

DIFICID™ (ﬁdaxomicin) tablets Brief Summary of Prescribing Information

measured. For now, however, gastroenterology quality and value plans are limited to endoscopic procedures with clearly defined and accepted metrics for quality. “We’re focusing at this stage on colonoscopy for two main reasons,” said Dr. Enns. “One, colonoscopy is perhaps the most common endoscopic procedure performed now; and two, colonoscopy has well worked out benchmarks, indications, completion rates and complications. We have fairly good guidelines stating how one should perform colonoscopy. It’s perhaps the easiest [component of gastroenterology care] to look at and self-monitor.” But there are different perspectives to consider even in a procedure as clearly laid out as colonoscopy. “You could define quality from before the procedure, during the procedure and after the procedure,” Dr. Enns said. “You could also define quality from a patient perspective, physician perspective, nurse perspective, even from an environmental perspective, i.e., the endoscopy unit. For instance, cleaning the scopes would be an endoscopy unit or environmental perspective,” he said. “There are multiple ways of looking at quality, and all of them are equally important.”

Buying In Another essential component to the implementation and success of a quality and value plan is cooperation within the practice: an understanding of physicians and staff as to why the plan is needed and what it will require from them, and a willingness from all involved to participate. To facilitate such compliance, Minnesota Gastroenterology set up a governance covenant across the entire practice. “We had each of our partners sign a covenant stating that their individual

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile. 1.1 Clostridium difficile-Associated e Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections. 5.2 Development of Drug Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies. Table 1. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials

System Organ Class Preferred Term

DIFICID (N=564)

Vancomycin (N=583)

n (%)

Blood and Lymphatic System Disorders Anemia

14 (2%)

12 (2%)

Neutropenia

14 (2%)

6 (1%)

process where one person is the champion around quality and value improvement in your practice. [That person has] to be given enough authority and responsibility to make this happen, so it can’t be a junior partner—it has to be someone with the clout to drive through that process of feedback and change.”

Motivating Partners Most physicians want to provide quality care, but not all are enthusiastic about implementing a quality and value plan in see Quality and Value, page 25

7 DRUG INTERACTIONS Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract. 7.1 Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range [see Clinical Pharmacology (12.3) in the full prescribing information].] Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established. 8.5 Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects. In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age) [see Clinical Pharmacology (12.3) in the full prescribing information].] However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients. 10 OVERDOSAGE No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months. Manufactured for Optimer Pharmaceuticals, Inc., San Diego CA 92121 by Patheon, Inc. DIFICID™ is a trademark of Optimer Pharmaceuticals, Inc.

Gastrointestinal Disorders Nausea

62 (11%)

66 (11%)

Vomiting

41 (7%)

37 (6%)

Abdominal Pain

33 (6%)

23 (4%)

Gastrointestinal Hemorrhage

20 (4%)

12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, ﬂatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash

Product protected by US Patent Nos. 7,378,508; 7,507,564; 7,863,249; and 7,906,489 Optimer Pharmaceuticals, Inc. 10110 Sorrento Valley Road, Suite C San Diego, CA 92121 (858) 909-0736 © 2011 Optimer Pharmaceuticals, Inc. All rights reserved.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Quality and Value continued from page 23

their practice, largely because they don’t know what sort of effect the plan will have on them personally and on the practice as a whole. “Motivation is a process of educating your partners,” said Bergein F. Overholt, MD, Gastrointestinal Associates, Knoxville, Tenn. “They need to understand that the marketplace is demanding the demonstration of quality and value. I think doctors are more aware that the marketplace, whether it’s the payer, primary care physician groups, ACOs or patients, is moving in that direction, but achieving quality and value requires a process of education that can take a significant amount of time— six months to a year.” One thing Dr. Allen did to motivate his partners toward embracing a quality and value plan was to show them that there was in fact room for improvement in their practice. “The very first step I took in 2005 was to demonstrate variability among the partners in adenoma detection rates,” he said. “We found a sevenfold difference among partners. Putting that graph up, without names, was incredibly motivating because of course everybody thought they were doing a great job, but it was clear that one-third of the practice was below national standards,” he said. “Identifying specific data that shows we are not as good as we think is highly motivating to competitive physicians.” This sort of competitiveness may extend beyond one practice or group of practices to influence others, Dr. Enns suggested. “As soon as certain groups start to report that they’ve done this and demonstrated that, other groups will often be quite motivated to participate.” A bit farther down the road, positive reinforcement can be helpful. “The Canadian Association of Gastroenterology has incorporated an endoscopy unit recognition award. The idea is to start with simple things, to give physicians, nurses and endoscopy units the feel of how a recognition program works, how a quality program works,” Dr. Enns said. Right now this recognition is a certificate or plaque that acknowledges a group’s participation in and adherence to a quality and value plan, but Dr. Enns anticipates such certificates could increase in value. “In other words,

people want to have a certificate demonstrating they have participated in a quality program, and hope that as people come in for procedures they will recognize the importance of that. So this is a way to motivate endoscopy units without requiring financial reward.” Although many physicians are encouraged by the implementation of a quality and value plan, a bit of push back is common. “There’s certainly resistance, which is why you need to have a fair process in place,” Dr. Allen said. “That has to be fully transparent, and it has to be led by a champion

who has a fair amount of diplomatic skill to talk to those who are resistant.” This point person needs to be able to listen to the ideas of others—the best idea is not always the first or the most apparent one—and to maintain a positive attitude throughout the process of establishing and working the bugs out of any program. “Quality and value point toward good medicine,” Dr. Overholt said. “The majority of physicians in a group will support a quality and value plan, and with their support and positivity, you will wear out any resistance over time.”

Financial Rewards ‘It sounds easy, but it isn’t. You’ve got to develop a whole process within your practice to measure [benchmarks] and report them, then translate that into a financial reward for the physicians.’ —Bergein F. Overholt, MD

Although providing quality care is a reward in itself, there is hope that groups participating in a quality and value plan will benefit financially as well. One of the motivational steps Dr. Allen suggests is attempting to negotiate a better payment contract for those who participate in a quality and value plan and who show adherence and improvement over time. “We are seeing payers moving slowly toward this model,” he said. Furthermore, “we have an internal incentive program of $10,000 annually for meeting two to four specific quality standards that are agreed on up front for all of our partners,” Dr. Allen said. “That is, from the revenue Minnesota Gastroenterology brings in, we extract $10,000 per partner and put it in an identified quality pool. If you meet certain quality standards, you get your $10,000 back. If you don’t, it goes to the other partners.” Dr. Overholt is working on a financial angle of the quality and value plan that will reward internally those physicians who reach benchmarks; this will require both identifying which benchmarks to use and figuring out how to measure them. “It sounds easy, but it isn’t,” he said. “You’ve got to develop a whole process within your practice to measure these things and report them, then translate that into a financial reward for the physicians.” External financial rewards may reveal themselves over time for practices that demonstrate quality and value. “Increased patient referrals and ultimately improved third-party reimbursement rates will occur for the groups that show quality and cost-effective care,” Dr. Overholt said. “And that’s the essence of the quality and value program.” ■ Drs. Allen and Overholt reported no conflicts of interest.

T best-read publication in gastroenterology offers an e-newsletter that The alerts you to highlights from the most recently published issue. Register to receive the FREE e-newsletter at www.gastroendonews.com. w

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

HAL continued from page 4

utter standstill on “go-live day.” I must have a “Here Comes Stupid,” sign on my back because the red jackets are on me like bees on honey to help me with really complex tasks like signing an op note or discharging a patient. They are of unflagging good cheer because it’s fun knowing how to do something that no one else can do, especially when they’re doctors. Almost like teaching residents how to do surgery, don’t you think? Helping someone in need is always satisfying and a nice way to spend your day, just like the practice of medicine used to be. I have to admit, including a college calculus course that I had to drop before I failed, I have never felt so utterly incompetent and clueless. Performance anxiety is not good for a surgeon.

As for patient safety, if it takes you about half an hour to figure out if you did or did not cancel the Lasix, and if you did, was it implemented, how safe can the system be? The Joint Commission dehisced over abbreviations because some poor lady missed her pain med (MSO4) and had a prodigious bowel movement instead (MgSO4), but it doesn’t seem at all concerned that virtually every doctor will privately confess that the system is running them, not vice versa. Important information is lost in noisy, unnecessary piles of data. Doctors are clicking without understanding what they’re doing or not doing. Just because technology permits permanent capture of every heartbeat and blood pressure of every patient every second of every hour

just physicians who have said “no mas” and thrown in the towel rather than take the training. Presumably many of these casualties were, like me, aging physicians already on the cusp, waiting to be nudged into retirement. Nevertheless, if you add up their loss and the incalculable loss of productivity from the rest of us twisting in the Kafkaesque confusion of the EMR, trying to execute simple tasks that used to be automatic, the delivery of health care is being forced to endure a productivity drain of tsunami-like proportion. And so it ends for me, not with a bang, but a whimper. Not even fire or ice. How humiliating. As for patient casualties, we’ll see how vigilant the Joint Commission, CMS and other anti-physician reg-

Data doesn’t enter

We’ve steadily been moved

itself. That’s where

down the career ladder from

you and I and all our

doctors to providers, to

colleagues in health

caregivers, to compliance

care come in.

officers, to data entry clerks.

Besides the cost of implementation, evidence already is accumulating that doctors order more, not fewer, imaging studies when EMR is used. Remember that PPACA was revenue-neutral by imputing $77 billion in savings to EMR use. That money is about as real as the $140 billion in savings from Medicare physician pay cuts that never happened. Given the cost of implementation, which is exceeding expectations by a factor of 3 so far, and the unexpected lack of frugality on the part of ordering physicians, the Beltway spinmeisters need to find a new explanation for how EMR is going to bank $77 billion. So much for cost containment.

EHR continued from page 4

Dr. Rowley commented, “Gastroenterology is well represented among attesters, those who successfully attested for meaningful use in 2011. Gastroenterologists in office-based practice need to get a gastroenterology template for a general EHR product. A template is a shortcut way to document different options, such as reflux, hepatitis and lower GI [gastrointestinal] bleeding.”

of every day, is it necessarily desirable to do so, especially when it requires the entire workforce to divert its attention to enter all the data? Data doesn’t enter itself. That’s where you and I and all our colleagues in health care come in. We’ve steadily been moved down the career ladder from doctors to providers to caregivers to compliance officers to data entry clerks. Maybe I should study to be a “super user.” Rumor has it a super user pulls down $200 per hour. I wouldn’t be surprised if one of them used to be a neurosurgeon. I am told there have been 400 casualties of implementation at my hospital. No, not patients, thank God;

Dr. Scherl indicated that progress was still needed with EHRs. “There should be consensus panels on optimization strategies for introduction and implementation of EHRs and meaningful use. Patients and physicians should be involved. Ultimately, the EHR should be a way of increasing communications.” Among the issues to address: “We have to look at benefit to patient and cost–benefit to insurer and physician. We need to increase accurate communication.

ulators are in reporting EMR-related errors. My guess is they will do exactly what they have always accused surgeons of doing—bury their mistakes. The investment in money and credibility will have been too great to honestly assess the fallibility of the EMR, which will be officially off message. It’s only been a few weeks, but so far I’ve seen the machine find pedal pulses in amputated limbs and aver that the spiritual needs of a patient dead for more than four hours have been met (to say nothing of the corpse’s 0 out of 10 pain score and “no need for restraints” after being zipped up in a see HAL, page 29

‘Remote access to a patient’s chart is less significant if the data are not accurate.’ —Ellen J. Scherl, MD “Remote access to a patient’s chart is less significant if the data are not accurate,” she added. Dr. Scherl cited a paper on the evolution of medical record-keeping and how that history might inform discussion of the EHR (Siegler EL. Ann Intern Med d 2010;153:671-677). “In the future, increasingly physicians and health care providers

will communicate through EHRs. Therefore, systems will need to evolve to protect patient privacy and will also need to communicate with each other.” Drs. Jamoom and Scherl reported no conflicts of interest. Dr. Rowley is a former chief medical officer and continuing equity stakeholder in Practice Fusion.

Introducing

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Indication and Important Safety Information Prepopikâ&#x201E;˘ (sodium picosulfate, magnesium oxide, and anhydrous citric acid) 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 events (>1%) following Prepopik administration. Please see brief summary of Prescribing Information on the following page.

ÂŠ 2012 Ferring Pharmaceuticals Inc. PREP_NAJA_001_0812

To learn more, scan this code with your smartphone, or go to www.prepopik.com.

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

HAL continued from page 26

body bag). These malaprops are comical and inconsequential but demonstrate an inherent capacity of the EMR to make mistakes no human could ever make, even on a bad day. Will The New England Journal of Medicine, the Institute of Medicine, et al go after the serious safety deficiencies of EMR with the same zeal (and exaggeration) they demonstrated in exposing physician error, real and imagined? Alleged physician mistakes spawned a huge industry to eliminate mistakes. The Department of Energy was created in 1975 and charged its 32,000 employees with ending U.S. dependence on foreign oil and lowering the price of gas, which was $1.25 per gallon at the time, with imported oil being 30% of consumption. Now at 70% and more than $4 per gallon, one has to wonder what those 32,000 folks have been doing. For all the cost and committed people power, the patient safety movement has been about as successful. But hold their feet to the fire at your own risk. My guess is we won’t be seeing an officially sanctioned commission anytime soon to study the shortcomings of EMR. As an aside, I’m going to miss the old chart. It was how I got to know so many of my colleagues and how they got to know me. I honestly felt I knew many doctors I never met just by communicating with them through the chart. I knew from the chart that when I needed a quick opinion from a cardiologist for pre-op clearance not to call the one who wrote five-page progress notes in multicolored ink. I learned who could cut to the chase, who embellished and who said and knew nothing. It amazed me that the cardiac surgeon who wrote notes that looked like he was on a New York subway could sew coronaries with 7-0. I wondered how the dyslexic neurosurgeon avoided wrong-side surgery. I tried to leave intimations of myself in my entries, hoping my work would be useful and appreciated. Now we’re all going to communicate in the same quackquack click-click language of 0s and 1s. With all its mind-boggling capacity for choice, collation and storage, the EMR still has no frontal lobe, and save for our names, all distinctive traces of ourselves will be lost. And isn’t that exactly the purpose of this enterprise? The final extinction of what health planners always believed to be the primary impediment to rational health care policy and implementation: you and me. Those who have pushed for the EMR believe that humanity is code for error and risk and that individuality and

creativity are the enemies of safety and cost containment. The EMR is intended to do what the government, insurers and hospital administrators have wanted to do for a long time now, but their heavyhanded methods have met resistance from physicians who had some leverage because they admitted patients. The doctors won’t fare as well negotiating their preferences with the machine as they did against hospital administrators who still

needed to fill beds. The EMR is a sanitary way of cultural cleansing, replacing older physicians who demanded a certain level of autonomy with hospitalists who, as employees, are more responsive to the administration’s wishes. Resistance will be minimal because the hospitalists are younger, sit at the keyboard all day and are far more facile with the EMR than older counterparts who will die off from EMR fatigue. The days of herding

cats are over for hospital administrators. Want a cheaper antibiotic to replace a more expensive one? Done. Want 100% compliance with a particular deep vein thrombosis prophylaxis regimen? Done. No committees. No whining from older doctors spoiled from years of having their own way. No one seems to be particularly concerned that the lack of humanity in the see HAL, page 30

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OPINION

HAL continued from page 29

EMR will inevitably, but by necessity, spill over into how medicine is actually practiced. We’ve all seen the spectacle of residents and medical students walking in and out of a patient’s room without ever looking up from their PDAs. We’ve all seen rows of nurses at the computers entering data like office workers while poor Mrs. Oemelmahay exsanguinates in room 6122. We’ve all been miffed by the OR staff for being glued to their computers instead of paying attention to the operation. Servicing the voracious requirements of the EMR is a full-time job and we’ve all been conscripted as data entry drones as a condition of our staff appointment. Of all the things I remember most from my surgical training, it was my professor telling me to always make human contact with a patient in some way every time I walked into a room. Sit on the bed, push the dinner tray a little closer or prop someone up in bed so they didn’t look and feel like a victim. To this day, I try to honor that teaching by physically touching a patient in some way, but all it gets me is a stern rebuke from the nurse epidemiologist and a citation for not washing my hands. I’d hate to see the agar plate from a computer keyboard swab, but it’s my hand and my patient’s hand that are considered dirty. About 20 or 30 years ago, all the journals had article after article about humanizing medicine and training doctors to be more compassionate and less mechanical. Remember all the noise about how we’re people and not robots? Remember how they wanted us to read Shakespeare and not just the Physician’s Desk Referencee so we would be more sensitive to the human condition? Remember when we were told that comfort was 90% of the cure? Insincere lip service is all that talk turned out to be. If it were genuine, computers would have been incorporated into humanistic care instead of becoming the agents of its destruction. It is no accident, however, that the computer is being allowed to define how we practice instead of enhancing it. Modern central planners see the human caregiver as a mistake-prone reservoir of pathogens that needs to be programmed to be safe, clean and effective. Dehumanization of medicine has actually become a goal, and EMR the perfect excuse to attain that goal. Of course, this will be denied up and down because even those pushing the EMR know how ugly a world it is they are creating, but are willing to pay the price because they’re counters, not doctors. Their mission is unmistakable: Control through central intelligent design and elimination of the quaint but archaic doctor–patient relationship.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Time will tell the consequences of removing the human element from the practice of medicine. I can only think of HAL, the soft-spoken but sinister onboard computer in Stanley Kubrick’s “2001: A Space Odyssey” that turned on the spaceship and its crew seeking new horizons for mankind. HAL mutinied. Instead of guiding mankind to new achievement, the anthropomorphic computer threw the crew and spaceship backward in time and space to the planet of the apes to start all over again from primitive beginnings. Mr. Kubrick’s cautionary tale should remind us

all about the limits of technology and the willful abrogation of our unique human qualities to a machine that can think only in 0s and 1s. The moral hazard of turning our backs on our human exceptionalism, flawed as it might be, is especially dangerous in the delivery of health care that should be grounded in compassion, trust, commitment and personal accountability. There aren’t enough gigabytes to make those. Clearly, there are those who think we can get by without them, and unfortunately, they’re the ones in charge.

As currently designed, it is hard to identify a single need of a patient or a doctor that the EMR addresses. For those forced to use it, it is a time-consuming distraction that eats into the art of practicing medicine and takes us away from our patients. Th e commercial designers of these systems were clearly given priorities for use by their potential customers that service their needs and not those of doctors and patients. A test drive of any of the new EMR software packages makes it obvious that those priorities are regulatory compliance,

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

coding, risk management and boxing physicians into carefully circumscribed practice patterns. We have no choice but to comply, but we need to be aware that there is more at stake than just our time and equanimity. Our integrity is on the line. The “smart phrases” that allow us to populate screens with data with a few clicks are really sanitized prepackaged lies the machine makes on our behalf to satisfy payers and regulators. I used to get a pang of guilt when I wrote in my own hand to get that a patient’s chest was clear to percussion and auscultation when

my stethoscope was collecting dust in the trunk of my car. The hook, or “sell,” of the new system is untold efficiency like doing an entire imaginary history and physical examination with just a click or two. Over time, canned goods will separate us from the authenticity of our work. Everything we do will get authenticated ad nauseam, but our work product will lack freshness and personality, and the vitality of the practice of medicine will wither. “Hard stops” will force us to make choices we never intended just to move on and get our

work done. Resistance to default choices will wane because it isn’t easy to impose one’s will when other choices have been preselected as preferable. Ordering gastrointestinal and deep venous thrombosis prophylaxis will take one-twentieth the time as not ordering it. In time, all doctors will assume the clone-like fungibility that policymakers believe is central to controlling cost, limiting liability for hospitals and evaluating treatment protocols. It is inevitable that within 10 years, the practice and culture of modern medicine and surgery that was formed

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in the image of the Oslers and Halsteds will be recast in the mechanistic image of the computer. What was our tool will become our master. For those of us who spent half our lives looking for x-rays in the file room and searching archives for old op reports, digitized storage and transmission of information is a miracle for which we give thanks every day. It has allowed us to take better care of our patients, and even spend more time with them. However, current EMRs threaten to remove the human imprimatur from see HAL, page 32

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

HAL

ACT NOW!

continued from page 31

medical care. That they eliminate the only rational, readable, coherent, contemporaneous and sometimes even delightful human narrative of what actually happened and replace it with indecipherable gobbledygook when clarity is required is only part of the problem. That they force us to compromise our integrity and attest to all kinds of things is only part of the problem. That they are expensive, timeconsuming and a productivity drain of

unimaginable proportion is only part of the problem. The big problem is that HAL is once again stalking us with the sweet siren song of untold efficiencies, cost containment and protection from human fallibility if we only move over to the passenger seat and let it drive. Don’t believe a word of it. Medicine cannot be practiced on autopilot. We will crash and burn without the human touch at the controls. ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Physicians, Pharmacists Team Up To Investigate CPOE Errors BY BRUCE BUCKLEY A physician–pharmacist research team at Brigham and Women’s Hospital, in Boston, has data-mined a decade’s worth of computerized prescriber order entry (CPOE) system error reports. Their findings—reported at an informatics meeting last year and now bolstered by more recent data—have shed new light on the types of errors that sometimes plague this

medication safety technology. Pull-down menu mishaps, interoperability snafus and incorrect dosing instructions are just a few of the common errors the researchers uncovered, according to Gordon Schiff, MD, the associate director of the Center for Patient Safety Research and Practice at Brigham and Women’s Hospital, and the study’s principal investigator. The results offer current CPOE users a roadmap for improving their own

systems, with an important added benefit: “We’ve gained the ability to create and test a new taxonomy for understanding CPOE-related errors,” Dr. Schiff said. The investigators embarked on their research two years ago, to gain a deeper insight into why the use of CPOE systems—designed to avoid medication errors inherent in handwritten and verbal orders—was creating a whole new category of alarming mistakes. Their investigation began with a search of

the rich database of medication errors reported to the United States Pharmacopeia (USP) MEDMARX program in the decade leading up to 2010. The aim was to mine the collection of more than a million voluntary reports, looking for patterns in CPOE-linked errors that could be distilled into a coded classification system, and one that might provide a new tool for preventing costly errors. “With the rise in computerized prescribing, we’re hearing more and more about unintended consequences and frustrations related to CPOE,” Dr. Schiff said. “We thought that understanding the errors increasingly being reported—particularly med errors related to CPOE— was very important.”

Pull-down menu mishaps, interoperability snafus and incorrect dosing instructions are just a few of the common errors the researchers uncovered.

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What Errors Occur, and Why The first results of their investigation were unveiled in a poster at the 2011 annual meeting of the American Medical Informatics Association, in Washington, D.C. They have since been refined. Of the approximately 1.04 million errors reported to MEDMARX from 2004 to 2010, just over 63,000 listed CPOE as the source. Of those, the team reviewed more than 10,000, according to Andrew Seger, PharmD, RPh, a senior research pharmacist at Brigham and Women’s, and a co-investigator for the study. The team was aided by USP’s decision, in 2003, to add a new field in the MEDMARX reporting form allowing users to check CPOE as the error source. The presence in some reports of free-text narratives describing what had gone wrong and why gave them the basic research material needed to explore the language that researchers and clinicians can use to describe CPOE-related errors. Funded by a grant from the National Patient Safety Foundation, the team of three pharmacists and a physician spent a year sorting and analyzing the narratives into logical categories. The result was the creation of 262 codes classifying what had happened and why and what might have been done to prevent the errors. Among the leading “what” codes were missing or incorrect directions for taking see CPOE Errors, page 34

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

CPOE Errors continued from page 33

medications; missing number/quantity or wrong number ordered; wrong dose or strength; and duplicate drug ordered. The top “why” codes included multiple systems (two or more electronic systems); use of system or sigmaa abbreviations; profiling issues (failure to do or perform correctly); and inexperienced end users (see Table for more details). “Certain ‘whys’ are unique to computers,” Dr. Schiff said, such as pull-down menu errors where the wrong line is selected. But he added, “We were particularly struck by the problems of interoperability,” the classic one being ordering systems trying to communicate with different types of pharmacy systems “and somehow things go wrong in those handshakes. “One thing we observed was the possibility of putting in too many zeros and having a 10-fold overdose,” Dr. Schiff said. Some systems have decision-support functions that include dosage-range checking, but “it’s inconsistent and varies from drug to drug,” he said.

all of the errors went through. It turned out that several months earlier the system had been upgraded, but when it went live again everyone forgot to turn the alerts back on. “I don’t want to claim we’re going to save anyone’s life by this study or change the way computerized prescribing is done,” Dr. Schiff said, “but who knows, in this one hospital, we may have actually saved a life or two.”

The Institute for Safe Medication Practices’ Take

‘We were particularly struck by the problems of interoperability,’ the classic one being ordering systems trying to communicate with different types of pharmacy systems ‘and somehow things go wrong in those handshakes.’ —Gordon Schiff, MD

Benefits to Stakeholders Dr. Seger said a key goal of the team’s work was to a create a classification system that vendors could use to “develop systems that are more clinically feasible, not only for physicians but also for pharmacists and patients in the ambulatory care setting and pharmacists and nurses on the inpatient side.” He also saw a potential “for assisting information technology developers, for people implementing and using these systems, and for those in the safety world to make sure the systems they have installed are in fact working properly within the design parameters of prescribing systems.” He continued, “Obviously there are a lot of very smart clinicians out there, but the complexity of our medical system makes it very difficult for any single person to try to maintain a knowledge base for every possible iteration of what may go on with a medication.” Dr. Seger added, “We want to use computers in a way that assists us in our care of patients, but we also want to make sure that we’re not introducing new errors; or at least if we are, then we’re taking steps to reduce them.” The second phase of the project involved what Dr. Schiff described as “kicking the tires, where we went out and tried to replicate these errors in real-life systems.” What they found, he said, was that in many cases, medication orders in which errors had deliberately been introduced “sailed right through with no warnings.” According to Dr. Schiff, “the most shocking example was a system in which

Table. Common “What” and “Why” Codes For CPOE-Related Errors Top “What” Codes

Top “Why” Codes

1,763

Unknown

4,542

Missing number/quantity or wrong number

766

Multiple systems (two or more electronic systems)

1,072

Wrong dose or strength

751

Use of system or SIG abbreviation

416

Unknown

611

Profiling issues: failure to do or perform correctly

377

Wrong schedule

497

Failure to follow established protocol or procedures

366

Duplicate order— same exact drug

422

Inexperienced end user

362

Overdose or potential overdose

316

Lack of computer training/ system knowledge

276

Wrong formulation/ dosage form

309

Hybrid system (electronic and paper)

182

Order not processed or delayed

304

Typing error

182

Patient potential for extra dose

289

Medication reconciliation issue

170

Wrong drug

266

Lack of clinical knowledge

162

Routing issue

248

Routing/mapping issue

155

Order was confusing: comment field has conflicting information

232

Communication issues

147

Wrong time selected

218

Nursing administration issues 136

instructions

CPOE, computerized prescriber order entry; SIG, drug label dosage instructions (short for signatura).

Michael R. Cohen, ScD, MS, RPh, president of the Institute for Safe Medication Practices (ISMP), said that while the use of CPOE systems has led to “a vast improvement over handwritten prescriptions, we certainly get error reports” associated with CPOE use. Lately, he said, ISMP has been dealing with CPOE systems employing standard schedules that limit practitioners’ dosing flexibility. For example, he said, if a drug is supposed to be given every 12 hours—say, 8 p.m. and 8 a.m.—and a starting dose is ordered for 6 p.m., the system automatically schedules the next dose for 8 p.m., “so it’s almost a duplication of a single dose. We’ve been hearing a lot of things like that lately.” Wrong-patient errors also are cropping up more frequently, Dr. Cohen said. These can happen, he said, when doctors have two or more patient screens open and don’t realize that the patient they are typing in an order for is not the one they had in mind. In some CPOE systems, he said, a warning message asks if the order being entered is for the right patient. But that feature doesn’t exist in all systems, he said, adding, “in too many cases, it’s up to the vendor to decide whether to do something or not.”

A Role for Federal Oversight? To ensure greater standardization among systems, Dr. Cohen suggested some form of government oversight might be required, either by the FDA or the Office of National Coordinator for Health Information Technology. These agencies, he said, could bring together panels of experts representing both practitioner and vendor interests and task them with coming up with standard solutions for all systems. For now, Dr. Cohen wants to encourage more reporting from CPOE users about the kinds of problems they’re encountering and errors that are occurring. “We need more and more feedback,” he said, “so that when things go wrong, we can get vendors to really focus on improvement efforts.” ■.

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Obituary: The Metropolitan-Memorial Medical Center Patient Chart, 1902-2012 Pioneer in Medicine, Friend of Physician and Patient, Dies at 110 Leo A. Gordon, MD General Surgeon Los Angeles, California Surrounded by family, friends, medical students and residents from all specialties, the patient Medical Chart died

peacefully at midnight on Feb. 29, 2012 at the Metropolitan-Memorial Medical Center. Chart was 110 years old. Born in February 1902, Chart spent her early years at the County Hospital for the Indigent. As the county hospital grew, it was renamed as the Metropolitan

Hospital in 1928. With this growth, Chart played an integral role in the development of many medical advances in the city. She propelled countless staff members to positions of influence and fame as the city and its medical community

The MetropolitanMemorial Medical Center Chart is survived by her only remaining relative, the Metropolitan-Memorial Medical Center Electronic Medical Record, who was

VIOKACETM (pancrelipase) tablets, for oral use Brief Summary of Prescribing Information for VIOKACE (pancrelipase). See package insert for full prescribing information. INDICATIONS AND USAGE VIOKACE (pancrelipase) is a combination of porcine-derived lipases, proteases, and amylases. VIOKACE, in combination with a proton pump inhibitor, is indicated in adults for the treatment of exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Fibrosing Colonopathy: Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age. Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.2) in full prescribing information].] Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range. Potential for Irritation to Oral Mucosa: Care should be taken to ensure that no drug is retained in the mouth to avoid irritation of oral mucosa, and/or loss of enzyme activity. VIOKACE should not be crushed or chewed [see Dosage and Administration (2.1) and Patient Counseling Information (17.1) in full prescribing information].] Potential for Risk of Hyperuricemia: Caution should be exercised when prescribing VIOKACE to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels. Potential for Viral Exposure from the Product Source: VIOKACE is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that VIOKACE will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported. Allergic Reactions: Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued VIOKACE treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient. Potential for Exacerbation of Symptoms of Lactose Intolerance: VIOKACE tablets contain lactose monohydrate. Patients who have lactose intolerance may not be able to tolerate VIOKACE. ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions].] 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The short-term safety of VIOKACE was assessed in a single, multicenter, randomized, parallel, placebo-controlled, double-blind study of 50 patients, ages 24-70 years, with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis or pancreatectomy. VIOKACE Tablets (20,880 USP units of lipase per tablet) or placebo were administered as 22 tablets per day (6 tablets with 3 meals and 2 tablets with 2 of 3 snacks). Duration of exposure ranged from 6 to 7 days. The majority of the subjects were Caucasian (96%) and male (82%). The most common adverse reactions (greater than or equal to 7%) were biliary tract stones and anal pruritus. Table 1 enumerates adverse reactions that occurred in at least 1 patient (greater than or equal to 3%) treated with VIOKACE at a higher rate than with placebo. Two adverse reactions reported in greater than one patient were biliary tract stones and anal pruritus. TABLE 1 Adverse Reactions Occurring in at Least 1 Patient (greater than or equal to 3%) in Chronic Pancreatitis or Pancreatectomy MedDRA Primary System Organ Class/ Adverse Reactions Blood And Lymphatic System Disorders Anemia Gastrointestinal Disorders Anal pruritus Abdominal pain Ascites Flatulence

Treatment Group VIOKACE Placebo (N=30) (N=20) 1 ( 3%)

2 ( 7%) 1 ( 3%) 1 ( 3%) 1 ( 3%)

0 0 0 0

TABLE 1 Adverse Reactions Occurring in at Least 1 Patient (greater than or equal to 3%) in Chronic Pancreatitis or Pancreatectomy (continued) General Disorders and Administration Site Conditions Edema peripheral 1 ( 3%) 0 Hepatobiliary Disorders Biliary tract stones 2 ( 7%) 0 Hydrocholecystis 1 ( 3%) 0 Infections and Infestations Viral infection 1 ( 3%) 0 Nervous System Disorders Headache 1 ( 3%) 0 Renal and Urinary Disorders Renal cyst 1 ( 3%) 0 Skin and Subcutaneous Tissue Disorders Rash 1 ( 3%) 0 Postmarketing Experience: Post-marketing data for VIOKACE have been available since 2003. The safety data are similar to that described below. 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. Pancreatic enzyme products (delayed and immediate-release) with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash. DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic g effects: Pregnancy Category C. Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VIOKACE should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes. 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 VIOKACE is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency. Pediatric Use: The safety and effectiveness of VIOKACE in pediatric patients have not been established. In general, delayed-release (enteric-coated) capsules should be used for pediatric patients. Due to greater degradation in the gastric environment, VIOKACE, a non-enteric-coated, pancreatic enzyme replacement product, may have decreased bioavailability and therefore may be less efficacious than enteric-coated formulations. Thus, use of VIOKACE in pediatric patients may increase the risk of inadequate treatment of pancreatic insufficiency and result in suboptimal weight gain, malnutrition and/or need for larger doses of pancreatic enzyme replacement [See Warnings and Precautions]. ] The efficacy of VIOKACE was established in adult patients with concomitant proton pump inhibitor (PPI) therapy. The long-term safety of PPI use in pediatric patients has not been established. Geriatric Use: Clinical studies of VIOKACE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. OVERDOSAGE There have been no reports of overdose in clinical trials or post-marketing surveillance with VIOKACE. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2) in full prescribing information and Warnings and Precautions].] High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions].] NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase. Marketed by: Aptalis Pharma US, Inc 22 Inverness Center Parkway Birmingham, AL 35242 USA Manufactured by: Confab Laboratories, Inc. St. Hubert, Canada VIOKACE and APTALIS are trademarks. © 2012 APTALIS PHARMA US, INC.

scheduled to speak at Chart’s memorial service, but was the unfortunate victim of an error message and could not attend.

grew. She served as the basic element of medical education as generations of medical students and residents analyzed her, interpreted her and used her to further their education. Additionally, Chart served as the basic unit of research, generating thousands of scientific papers that benefited thousands of patients. She fostered the careers of many prominent members of the medical staff. Chart grew up alongside her classmate, the Memorial Hospital. As Memorial grew into the Memorial Medical Center, Chart evolved from a few poorly organized pages into a well-developed chronology of patient disease and treatment. A fascinating and often contentious competition arose between the Charts as the two hospitals expanded and competed for patients and for medical recognition. In 1986, the Metropolitan Chart married the Memorial Chart in a muchpublicized Chart wedding. Now known as the Metropolitan-Memorial Medical Center Chart, a period of rapid growth ensued. This growth led to Chart’s expansion and refinement. Chart was now divided into easily accessible physician orders, progress notes, laboratory data, nurses’ notes, medications and subpoenas. When interviewed in 1996, one enterprising

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2012

to so many patients for so many years. The physicians and students recorded that care in a distinctly unique manner. Just as a novel has its own plot, character development, intrigue, suspense and surprises, so did Chart reflect the same elements, but in the context of human disease and recovery.â&#x20AC;? Chart was preceded in death by her

life partner, Index Medicus, who died in 2004. The Metropolitan-Memorial Medical Center Chart is survived by her only remaining relative, the MetropolitanMemorial Medical Center Electronic Medical Record. The Electronic Medical Record was scheduled to speak at Chartâ&#x20AC;&#x2122;s memorial

service, but was the unfortunate victim of an error message and could not attend. A second memorial service was held at the Wilmington Shredding Company on Thursday, May 24, 2012. The Chart family requests that in lieu of flowers, memorial contributions be made to the Metropolitan-Memorial Medical Center Medical Library. â&#x2013; .

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reporter asked about Chartâ&#x20AC;&#x2122;s much-discussed increasing girth. The reply, in the good-natured manner that became her hallmark, was: â&#x20AC;&#x153;Too many consultants, too many tests and too many note-happy medical students!â&#x20AC;? Chart had several children, most notably in the Progress Note wing of the family. Chartâ&#x20AC;&#x2122;s oldest son, Illegible, was dismissed from the hospital staff in 1990. Other childrenâ&#x20AC;&#x201D;Meaningless, Incomprehensible and Puzzling remained up until the mid-2000s. Chart was most proud of her other childrenâ&#x20AC;&#x201D;Insightful, Helpful and Stunningly Brilliant. They survive and continue to maintain a strong presence at the medical center. She leaves behind a rich legacy of medical progress interlaced with crystalline insight and occasional humor. Chartâ&#x20AC;&#x2122;s two stepdaughters, Agree With Above and Agree With Below, delivered moving eulogies at the recent memorial service. Dr. Ralph Eggerton, III, president of the Metropolitan-Memorial Medical Center Emeritus Society, said: â&#x20AC;&#x153;We shall always remember Chart. We will remember the many notes that reflect not only the patientâ&#x20AC;&#x2122;s disease and progress, but also the spirit and personality of the physicians who delivered such great care

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Customized Software Addresses Physician ‘Alert Fatigue’ From Excessive Electronic Drug–Drug Interaction Warnings BY SUSAN BIRK BALTIMORE—An ongoing, pharmacistled process of clinical decision support (CDS) customization is the only way for hospitals and health systems to establish an electronic medication safety management system that is truly meaningful, according to John R. Horn, PharmD, a professor of pharmacy and associate director of pharmacy at the University of Washington, Seattle. This customization, based on the organization’s unique practice patterns, protocols and range of clinical services, takes time and is not easy, but it is the best method currently available for preventing “alert fatigue” among physicians due to excessive, unfiltered warnings about drug–drug interactions (DDIs) and drug allergies, said Dr. Horn, during a presentation at the American Society of Health-System Pharmacists (ASHP) 2012 Summer Meeting. Virtually all of the electronic health record (EHR) systems on the market come with extensive databases of DDIs and allergies designed to alert physicians to potential medication safety problems, said Dr. Horn. These CDS tools can help hospitals meet the Centers for Medicare & Medicaid Services’ EHR meaningfuluse requirements for medication safety. But they also can frustrate the physicians who have been forced, with the advent of computerized prescriber order entry, to spend their time overriding countless alerts that are clinically irrelevant to their practice and their patients. “The problem is getting that clinical decision support software to interact with the prescribers in a manner that provides the expected benefit without producing unintended or unexpected adverse consequences,” Dr. Horn said in an interview. Those consequences can include desensitization to all alerts, even clinically important ones. Turning off the alerts—a common response by hospitals—is a bad idea that can hinder medication safety efforts, he said (Table). So is attempting to turn off selected warnings for selected prescribers, or modifying the system to send alerts to pharmacists and not to physicians. This latter option, which requires pharmacists to call physicians to discuss drug alerts, “creates an adversarial relationship that is a very ineffective way to mitigate the risk for drug interactions,” he said. “At our institution, we do not want our pharmacists dealing with physicians at this level.” The customization process should be

based on a careful evaluation of the risks and benefits of clinically relevant drugpair interactions, with the goal of creating a system that requires further action by the physician only for DDIs that the institution classifies as serious, said Dr. Horn. That action could involve selecting an alternative for one of the two drugs, prescribing the two drugs and monitoring

the patient or documenting the rationale for overriding the alert. “Every institution has a top tier of drug interactions that they consider to be most problematic,” he said. “That’s where we focus most of our attention [at the University of Washington]. We go through every single interaction pair in the list and reassess its severity ranking.”

The customized system retains the complete DDI and allergy database but places less clinically relevant information in the background and allows physicians to sidestep it without disrupting their normal workflow. Physicians see and are required to take action regarding DDIs deemed “major” by the institution, whereas those classified as “moderate” or

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

“modest” still appear but do not require physicians to stop and document a substitution or other course of action. “That then avoids the problem of alert fatigue, which is why people turn the alerts off. They’re not turning things off because they think they’re bad; they’re turning them off because they’re irritating,” said Dr. Horn. “We’re trying to prevent patients from being harmed … and that’s why I think the risk–benefit approach is a reasonable way to think about [these interactions],” he added. “It’s really the way physicians

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think about any drug they prescribe. The solution is not to turn the less important ones off; the solution is to the fix the ones that you want to actually produce an alert.” Dr. Horn stressed the importance of establishing a set of rules for the severity rankings, applying them consistently, communicating them to the clinical staff and asking for input from clinicians about specific drug pairs that they feel merit special attention. He recommended assigning ongoing responsibility for customization to a small committee that can see Customized Software, page 41

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

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US Endoscopy Releases Take-Out Transport Pad for Safe Transportation of Endoscopes On Aug. 15, US Endoscopy announced the release of the TakeOut transport pad, a single-use pad designed for convenient and safe transportation of an endoscope to the reprocessing room. “Infection control guidelines and compliance are topics of focus in the GI units today. The Take-Out transport pad is a safe and efficient way to help protect staff from exposure

The Take-Out transport pad is a singleuse pad designed for convenient and safe transportation of an endoscope to the reprocessing room. Photo courtesy of US Endoscopy

to biomaterial while protecting equipment during transportation,” said Gulam Khan, CEO, president and cochairman of US Endoscopy. The Society of Gastroenterology Nurses and Associates has issued guidelines requiring enclosed transportation of an endoscope (www. sgna.org/Portals/0/Education/Practice%20Guidelines/InfectionControlStandard.pdf). According to US

Endoscopy, the Take-Out transport pad helps units comply with these guidelines by completely enclosing the dirty endoscope within the pad; the absorbent material helps minimize the leaking of fluids and provides protection for the endoscope. For more information, visit www. usendoscopy.com. —Based on a press release from US Endoscopy

Customized Software continued from page 39

stay abreast of the literature and monitor decisions regarding system changes that reflect the new information. At the University of Washington, for example, a subcommittee of the Pharmacy Patient Safety Committee meets monthly to review new information about interactions and internal reports and concerns from physicians. “We’ve set up a formal process so that everything comes to one place,” said Dr. Horn. The subcommittee then reports changes to the clinicians who will be affected. The customization process also should look at existing clinical safeguards and eliminate electronic drug interaction alerts related to protocols that are in place already, Dr. Horn advised. For example, a hospital that already has a rule for mitigating the side effects of administering antacids and antibiotics to a patient could turn off these electronic alerts because the institution already addresses the problem in another way. Marianne Ivey, PharmD, MPH, associate professor in the Division of Pharmacy Practice and Administrative Sciences at the University of Cincinnati, questioned the need for every hospital to create its own customized CDS system. She acknowledged that some customization of CDS is important in every health care environment but suggested that a significant portion of the laborious stratification of drug interactions into serious, moderate and rarely occurring classifications possibly could be done centrally and more cost-effectively by an organization such as ASHP and then made available to the profession as a whole. A system of pharmacist-filtered drug alerts also could offer an effective alternative strategy for some institutions, she noted. “Pharmacists don’t mind seeing those alerts because they believe that’s their job, while physicians only want to be bothered by those that have been filtered by the pharmacist.” ■ Dr. Horn disclosed that he is a partner with H&H Publications. Dr. Ivey reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

US Endoscopy Announces Release of Reach Overtube for Small Bowel Examination On July 19, US Endoscopy announced the release of the Reach overtube, a new device that will give endoscopists a more direct path to the small bowel during enteroscopy procedures. In most cases, the small bowel can be examined by using push enteroscopy, but available methods and devices used to navigate the small bowel are expensive and require extensive training. Additionally, endoscopists may encounter the problem of endoscope looping in the stomach. “Looping of the endoscope in the stomach prevents the endoscopist from achieving a depth that may be required to reach findings in the small bowel,” explained Gulam Khan, president, CEO and co-chairman of US Endoscopy. “The Reach overtube is a simple, cost-effective solution to minimize endoscope looping and allow the targeted area to be reached.” The Reach overtube offers a more direct path to small bowel findings

The Reach overtube has a tapered tip and helps minimize endoscope looping.

by splinting the endoscope from the lower esophageal sphincter to the pylorus. The device also minimizes reformation of gastric loops; allows for the scope to probe farther; and promotes one-to-one movement during advanced therapy. For more information, visit www. usendoscopy.com. ■ —Based on a press release from US Endoscopy

Inadequate Bowel Preps:

The Reach overtube from US Endoscopy

A Problem With Potentially Serious Consequences

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

gastroendonews

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

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

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Drug for Osteoarthritis Linked to Liver Injury Case Series Shows Symptoms of Liver Injury After Initiation of Flavocoxid BY GEORGE OCHOA Flavocoxid (Limbrel, Primus Pharmaceuticals), a prescription medical food used to treat osteoarthritis, may cause liver injury, according to a recent case series published in the June 19 issue of Annals of Internal Medicine (Chalasani N et al.

2012;156:857-860). The setting for the case series was the Drug-Induced Liver Injury Network Prospective Study, an ongoing multicenter, prospective, observational study that enrolls patients with suspected drug-induced liver injury and collects data for mechanistic research. Researchers identified 877 patients who were enrolled in the

study between 2004 and 2010 with suspected drug-induced liver injury. Of these, four women developed liver injury after initiating treatment with flavocoxid. The four patients were aged 57 to 68 years and were treated with flavocoxid 250 to 500 mg twice daily for arthritis or musculoskeletal pain symptoms. Within one to three months of starting

How Common Are Inadequate Bowel Preps? • In a review of over 236,000 outpatient colonoscopies, bowel preparation was inadequate in almost 24% of procedures4 • In another review of over 93,000 colonoscopies, bowel preparation was inadequate in 23% of procedures5

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

Low*

49.1

Intermediate*

% of Patients

40 30 20

High*

34.2

33.1

20.0 15.4

10 0

Easy†

12.4

Difficult† Difficulty of Colonoscopy

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

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

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flavocoxid, the patients developed signs and symptoms of mild to moderate liver injury, including jaundice, abdominal pain, pruritus, fever and rash. The patients also had elevated levels of alanine aminotransferase (range, 741-1,540 U/L), alkaline phosphatase (range, 286-770 U/L) and serum bilirubin concentrations (34.3-356 mcmol/L [2.0-20.8 mg/ dL]). Liver biopsies in two patients revealed moderate acute hepatitis. Tests for viral hepatitis and imaging studies for biliary obstruction were negative. Each patient’s liver injury began to resolve within days of stopping flavocoxid. Liver biochemistry values normalized within three to 12 weeks after flavocoxid treatment was stopped. Flavocoxid was identified as the likely cause of liver injury in three patients and a possible cause in one. No patient showed evidence of residual or chronic injury. Although the mechanisms of liver injury due to flavocoxid were not assessed in this study, flavocoxid contains catechins, one of which (epicatechin) may be the ingredient that causes liver injury, suggested the authors. As a medical food, flavocoxid does not require formal premarketing safety and efficacy studies, the authors stated. In an editorial published in the same issue (Ann ( Intern Med 2012;156:894-895), Reichenbach and Jüni argued that this study suggests that medical foods may not always be safe. “Given the widespread use and potential harm of medical food and food supplements, the policy of marketing these products in the absence of clinical evidence may need to be reconsidered.” ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

FDA Approves New Low-Volume Colon-Cleansing Drug for Colonoscopy On July 16, Ferring Pharmaceuticals Inc., received FDA approval to market Prepopik (sodium picosulfate, magnesium oxide and citric acid) to cleanse the colon during colonoscopy preparation. Prepopik is expected to be available for purchase in October. Prepopik is an orange-flavored, dualacting, stimulant and osmotic laxative. One dose of Prepopik consists of two packets of powder, each dissolved in cold water and taken at separate times. Patients should take Prepopik in a split-dose regimen, the night before and the morning of colonoscopy. If not possible, patients can choose the day-before regimen, and take Prepopik in the afternoon and evening before colonoscopy. Patients taking Prepopik must consume additional fluids during and after use to reduce the risk for fluid and electrolyte imbalance. Aversion to bowel preparation solutions, particularly the substantial liquid volume requirement, has been a barrier to patients completing colonoscopies successfully. “Successful bowel prep is critical for gastroenterologists to clearly see any polyps or abnormalities, yet the sheer volume of prep solutions can prevent patients from

adequately completing their prep regimens, leading to suboptimal visualization of the colon,” Douglas K. Rex, MD, director of endoscopy at Indiana University Hospital, and professor in the Department of Medicine, Division of Gastroenterology and Hepatology, University of Indiana School of

GI POSITIONS

Medicine, Indianapolis said in a statement. Once it becomes commercially available, Prepopik will be the lowest-volume active ingredient colon preparation on the market, requiring patients to consume only 10 ounces of solution. The FDA’s approval was based on two Phase III studies examining the safety and effectiveness of Prepopik in 1,200 adult patients before colonoscopy, comparing the splitdose regimen and the day-before regimen with a control preparation of polyethylene glycol plus electrolyte solution and two 5-mg bisacodyl tablets. Both studies revealed that Prepopik was as effective as the control in cleansing the colon; when administered in the split-dose regimen, Prepopik was better than the control. The most common side effects of Prepopik include nausea, headache and vomiting. As a condition of approval, Prepopik’s manufacturer, Ferring Pharmaceuticals, must conduct studies to determine if the drug can be used safely and effectively in children. For more information, visit www. prepopik.com. ■ —Based on a press release from the FDA

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Sony Boasts First Medical-Grade Monitor Using OLED Technology On July 11, Sony Electronics introduced the first medical-grade monitor, model PVM-2551MD, based on organic light-emitting diode (OLED) technology. This technology, which recently received FDA 510(k) clearance, is expected to provide advantageous displays in a variety of medical fields, including endoscopy, laparoscopy and general surgery. “Already showing tremendous advantages for surgeons in other parts of the world, the new Sony OLED monitor will now enhance surgical viewing in the [United States] and become the ‘must have’ medical display,” said George Santanello, general manager of Sony Medical Systems Division, in a statement. The OLED technology has a faster response time than LCD and offers true-to-life color reproduction, high resolution and almost no motion blur. The 25-inch monitor incorporates Sony’s TRIMASTER electroluminescence technology, so it can achieve pure black, faithful-to-the-source signal. This strong color reproduction will allow surgeons to observe subtle details, such as the faint color difference between various tissues and blood vessels. Other features of the product include a high level of contrast, 10-bit signal processing, slim and lightweight design, and

Gastroenterology & Endoscopy News’

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

Please send product news to:

cgordon@mcmahonmed.com

lower power consumption requirements to enhance energy efficiency. The Sony OLED medical-grade monitor, PVM-2551MD, is currently available for sale with pricing available upon request. For more information, visit www.sony.com. ■ —Based on a press release from Sony Electronics

Sony’s organic light-emitting diode (OLED) Medical Monitor, PVM-2551MD Photo courtesy of PRNewsFoto/Sony Electronics

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

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

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery. Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

FDA Approves New Drug To Help With Weight Loss On July 23, the FDA approved comorbidity, such as hypertension, Qsymia (Vivus, Inc.) to complement type 2 diabetes or dyslipidemia. a reduced-calorie diet and exercise for chronic weight management. The drug is approved for obese adults (those with a body mass index [BMI] of ≥30 kg/m2) or overweight adults (BMI ≥27 kg/m2) who have at least one weight-related Qsymia, manufactured by Vivus, Inc.

“Qsymia, used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, in a statement.Qsymia is a combination of two FDA-approved

The Liver Meeting The 63rd Annual Meeting of the American Association for the Study of Liver Diseases

2012

NOVEMBER 9–13, 2012 H Y N ES CO N VEN T IO N C E NTE R • BOSTON, MASSACH USE TTS USA

ADVANCE REGISTRATION AND HOUSING IS OPEN — ACT NOW ensure a reservation at the hotel of your choice, and secure your place in popular ticketed sessions. Save $100 by registering for the Annual Meeting on or before October 12. The Liver Meeting® 2012 — which includes AASLD’s 63rd Annual Meeting — is where the cutting edge in the study and treatment of liver and biliary disease is deﬁned. With an expected attendance of more than 8,500 hepatologists and hepatology health professionals from around the world, The Liver Meeting® 2012 is the ﬁeld’s must-attend event.

www.thelivermeeting.org

drugs: phentermine (indicated for short-term weight loss in overweight or obese adults who are exercising and eating a reduced-calorie diet), and topiramate extended-release (indicated to treat types of seizures in people with epilepsy and to prevent migraine headaches). The recommended daily dose of Qsymia contains 7.5 mg of phentermine and 46 mg of topiramate extended-release; it also is available at twice that dose. Researchers evaluated the safety and efficacy of Qsymia in two randomized placebo-controlled trials in which approximately 3,700 obese and overweight patients (some of whom had weight-related conditions) were treated for one year. All patients were on a reduced-calorie diet and exercise regimen. After one year of treatment, patients had an average weight loss of 6.7% with the recommended dose and 8.9% with the higher daily dose of Qsymia compared with placebo. Approximately 62% and 69% of patients in the recommended and highest daily dose groups, respectively, lost at least 5% of their body weight compared with about 20% of patients in the placebo group. The investigators recommended that patients who do not lose at least 3% of their body weight by week 12 of treatment should either discontinue Qsymia or increase to the higher dose. If after 12 weeks on the higher dose, patients do not lose at least 5% of their body weight, they should discontinue the drug. The most common side effects of Qsymia are paresthesia, dizziness, altered taste sensation, insomnia, constipation and dry mouth. Qsymia cannot be used in patients with glaucoma or hyperthyroidism. Women should have a negative pregnancy test before starting Qsymia; data show that a fetus exposed to topiramate in the first trimester has an increased risk for oral clefts. Qsymia also is not recommended for patients with recent or unstable heart disease or stroke because the drug was shown to increase heart rate. Vivus, Inc., will need to conduct 10 postmarketing requirements to assess the effect of Qsymia on the risk for major adverse cardiac events. Currently, Qsymia will only be dispensed through specially certified pharmacies. For more information, visit www.qsymia.com. ■ —Based on a press release from the FDA

NEW PRODUCT ANNOUNCEMENT

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2012

Prometheus Launches New Monitoring Test To Help Guide Management of IBD Patients Using Infliximab Prometheus Anser™ IFX Designed To Help Identify Potential Causes for Loss of Treatment Response On July 31, Prometheus Laboratories Inc., announced the market launch of its proprietary new-generation monitoring test, Prometheus Anser IFX. The assay measures drug and drug antibody levels in one sample in patients with inflammatory bowel disease (IBD) using infliximab, helping physicians to identify potential causes for loss of treatment response and helping to guide patient management decisions. This is the first commercial test using Prometheus’ proprietary homogeneous mobility shift assay platform technology. Prometheus intends to use this platform for subsequent introductions of additional tests targeted to other biologic agents being used to treat a variety of autoimmune diseases. Approximately 50% of IBD patients using infliximab may experience a loss of treatment response during their treatment. For some patients, this loss of treatment response may be the result of insufficient infliximab levels; for others, the loss may be due to the development of antibodies to infliximab (ATI). If the loss of treatment response is due to ATI, increasing the infliximab dose—the most common treatment approach—may be less effective than switching to another treatment agent. The Prometheus Anser IFX test was verified with more than 3,000 IBD clinical patient samples. “The need for Prometheus Anser IFX is high, and its availability marks the latest milestone in our continuing commitment to significant advancements in personalized medicine for gastroenterologists, patients and health care providers,” said Joseph M. Limber, president

and CEO of Prometheus. “Prometheus Anser IFX provides

significant value to the IBD patient using infliximab and his or her treating physician, potentially saving time and effort in guiding treatment

The following is a brief summary only; see full Prescribing Information for complete product information.

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

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

whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

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

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC

Number (%) of Patients

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

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

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

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

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

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

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

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

decisions when response to infliximab is lost.”

MedDRA Preferred Term

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

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

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

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

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure. Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension

Postmarketing Experience The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Infections and Infestations Cases of C. difﬁcile-associated colitis have been reported [see Warnings and Precautions (5.2)]. General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

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

There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium. The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients, based upon plasma AUC comparisons. Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

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

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

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

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

Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC␶) of rifaximin was about 10-, 13-, and 20fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)]. Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.

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

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16-1

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS 75% of patients develop HE recurrences, even on lactulose.1 Protect your patients with Xifaxan 550 mg continuously from the moment they experience their ﬁrst overt episode.

58% proven reduction in the risk of overt HE breakthrough2† 50% proven reduction in the risk of HE-related hospitalizations2‡§

Prescribe. Protect. Repeat.

Visit booth 731 at ACG to learn more about protecting your HE patients *HE=hepatic encephalopathy. † Over a 6-month period; P<0.0001 vs placebo.2 ‡ Over a 6-month period; P=0.0129 vs placebo.2 § HE-related hospitalization deﬁned as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.2

IMPORTANT SAFETY INFORMATION XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age. In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. XIFAXAN has not been studied in patients with MELD scores >25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C). XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. The most common adverse reactions occurring in >8% of patients in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), ascites (11%), muscle spasms (9%), pruritus (9%), and abdominal pain (9%). Xifaxan550 is not available for sale outside the U.S. Xifaxan550 is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see adjacent brief summary of Prescribing Information.

Clostridium difﬁcile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range

References: 1. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):10121017. 2. Xifaxan [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.

www.Xifaxan550.com

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

Clostridium difficile: Epidemiology, Transmission, and Treatment LAWRENCE J. BRANDT, MD

PAUL FEUERSTADT, MD

Emeritus Chief Division of Gastroenterology Montefiore Medical Center Bronx, New York

Staff Physician Gastroenterology Center of Connecticut Hamden, Connecticut

lostridium difficile infection (CDI) is a leading cause of

nosocomial gastrointestinal illness and places a high burden on our health care system, with estimates of up to 3 million

cases and an expenditure of $3.2 billion annually.1 This review discusses the changing epidemiology, transmission, risk factors, diagnostic tools, and treatment of both index and recurrent CDI.

Hypervirulent strains of C. difficile throughout North America and Europe have contributed to this epidemic—an increase in treatment failures for both index and recurrent infections is driving research to discover more effective treatment strategies. As a result, a variety of therapies, including antibiotic and probiotic regimens, immunotherapy, investigational vaccines, and fecal microbiota transplantation (FMT), all have been used to treat CDI with varying success.2-5

Epidemiology INCIDENCE The incidence of CDI in the United States is increasing at an alarming rate. Based on data from various medical centers throughout the United States, it is estimated that the incidence doubled between 1996 and 2003 from 31 to 61 per 100,000 population.6 During a similar time frame, a single center in St. Louis, MO, showed a parallel trend, with the incidence of CDI increasing from 8.5 to 15.9 per 1,000 hospital admissions.7 An estimated 500,000 cases of CDI occur in the United States each year, causing 15,000 to 20,000 deaths annually.1 This trend is not isolated to North America, however, and a Belgian study reported a 3.75-fold increase in the incidence of CDI from 2000 to 2003 compared with 2004 to 2007.8

VIRULENCE The current manifestations of CDI are quite different from those detailed in the hallmark publications by Hall and O’Toole in 19359 and those of Bartlett and colleagues in the late 1970s.10 Today, hypervirulent

I N D E P E N D E N TLY DEVELOPED BY MCMAHON PUBLI SHI NG

strains that cause severe disease, as well as community-acquired (CA) infections not associated with antibiotic use, are routinely observed. Severe disease is thought by some authorities to result from hypervirulent strains, such as NAP1/BI/027 (North American pulsed-field type 1 [NAP1], restriction-endonucleaseanalysis type BI, and polymerase chain reaction [PCR] ribotype 027), which is resistant to fluoroquinolones.1,11 This strain produces 10 times more toxin A and up to 23 times more toxin B than other strains and also produces a third toxin, referred to as binary toxin.12 C. difficile was previously considered a hospitalacquired (HA) infection, but with the emergence of the NAP1/BI/027 strain, CDI increasingly is being observed in the community. Although there do not seem to be significant differences in the presentation and outcomes for patients with CA-CDI compared with HA-CDI,13 groups previously considered at low risk for CDI currently are becoming increasingly infected, such as young, healthy individuals without prior exposure to hospitals or antibiotics, peripartum women,1,11 patients with inflammatory bowel disease or cirrhosis,7,14 organ transplant patients, and immunocompromised individuals. As more studies look into the changing epidemiology, risk factors, and outcomes for CDI, clinical guidelines for the management of the infection are rapidly changing.15-17

Risk Factors Various risk factors for disease acquisition and severity are important to consider. Nasogastric tubes, prolonged hospital stays—especially in the ICU—and exposure to

GAST ROE NT E ROLOGY & E NDOS COPY NE WS • S E P T E MB E R 2012

proton pump inhibitors, hydrogen pump blockers, corticosteroids, or other immunosuppressives all are associated with an increased risk for CDI in hospitalized patients.1,11 Risk factors associated with severe CDI and poor outcomes include being aged 65 years or older, fever, nasogastric tube placement, immunosuppression, cognitive impairment, and recent endoscopy.18,19 Peak white blood cell (WBC) counts, peak creatinine levels during admission, and WBC counts at the time of admission with CDI all have been associated with an increased risk for colectomy and shortterm mortality in patients with CDI.20,21 Of note, patients exposed to corticosteroids within 15 days of CDI diagnosis were found to have a 30-day mortality rate twice that of patients not treated with these agents.22 Reducing patients’ exposure to these factors whenever possible might decrease the risk for both infection and severe disease. In addition to health care facility sources, C. difficile also has been detected in a variety of animals and pets (eg, cats, dogs, horses, cattle, swine) and food products, including various meats and ready-to-eat salads.23,24

Transmission Understanding the transmission of CDI is key to reducing the frequency of this epidemic and requires some insight into its pathogenesis. Kyne et al described the initial need for normal colonic microbiota to be altered, possibly by antibiotics. Once a person with intestinal floral disturbance ingests C. difficile, it colonizes in the large bowel, leading to the release of toxins A and B in the colon and subsequent symptomatic colitis.25 There are 2 forms of the bacterium: vegetative and spore. The latter can survive on environmental surfaces such as countertops, door handles, faucets, and toilet seats for years. It is the survival ability of the spores that has contributed to the growth and persistence of this epidemic. Preventing the transmission of CDI involves reducing or eliminating the various factors listed above. Antibiotic therapy alters the normal colonic microbiota that serve as a protective barrier against CDI. Most antibiotics predispose patients to CDI, even those used to treat CDI (eg, metronidazole and vancomycin).26,27 The antibiotics most frequently implicated in causing CDI and diarrhea include ampicillin, amoxicillin, cephalosporins, clindamycin, and the fluoroquinolones.28,29 Minimizing the inappropriate use of antibiotics in all patients, especially CDI-susceptible patients (eg, hospitalized elderly patients), can help prevent infection. The incidence of CA-CDI has increased, but HA-CDI is still of major importance when discussing transmission30; patients may infect others in the community upon discharge from the hospital. Between 10% and 30% of hospitalized patients treated with antibiotics are estimated to be colonized with C. difficile.31-33 Throughout the hospital and infected patients’ homes, many hard external surfaces can be contaminated with C. difficile, including toilet seats, doorknobs, countertops, and bedpans. Caregivers must be aware that their stethoscopes, hands, and possibly clothing also may transmit the infection.31,32 Fekety et al wrote guidelines for the prevention of C. difficile

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

transmission that include limiting the use of antimicrobial agents; washing hands before and after interacting with each patient; isolating patients with CDI from uninfected patients; wearing gloves when interacting with all patients with CDI; disinfecting all C. difficile–contaminated objects with sodium hypochlorite, alkaline glutaraldehyde, or ethylene oxide; educating hospital staff about the infection; and practicing good hand hygiene.34 It is important to note that alcohol-based sanitizing agents are not as effective at eradicating CDI as hand washing with soap and water; all caregivers of patients with CDI need to thoroughly wash their hands and even their stethoscopes for effective infection control.35

Diagnosis Testing for CDI should be performed on any patient who has acute diarrhea and who has received antibiotics within 3 months of presentation, or any patient who develops diarrhea within 72 hours of admission to the hospital. It is not recommended to test formed stool because treatment is indicated only for patients with symptomatic diarrhea.33,36 Only stools from patients with diarrhea should be tested. A stool sample should be obtained immediately after a bowel movement and submitted to the laboratory in a watertight container. There are several methods to analyze a stool for CDI, including culture, tissue culture cytotoxicity assay, enzyme-linked immunosorbent assay (ELISA), PCR, and glutamate dehydrogenase (GDH) testing, but in daily clinical practice, only detection of toxin or toxigenic isolates is relevant. ELISA is the most common method used to detect toxin antigens because it is inexpensive, fast (results are usually available in less than 6 hours), and highly specific. The main problem with this test is a relatively low sensitivity (~90%), leading to a slight risk for false-negative results.37,38 The tissue culture cytotoxicity assay remains the gold standard for CDI diagnosis because of its high sensitivity and specificity39; however, it is not commonly used because it is expensive, requires technical expertise, and results take 1 to 3 days to develop. Because cultures for C. difficile need anaerobic conditions and several days are needed to obtain results, this method is rarely used for nonepidemiologic purposes. PCR assays also are less commonly performed than ELISA because of their price, but this methodology offers a highly sensitive and specific test that is likely to become widely used in the future. In certain institutions, a progression of diagnostic tests is performed. For example, a GDH assay might initially be performed. This test is highly specific for C. difficile. If the assay is negative, then no further testing is performed. If it is positive, an ELISA is performed; if the ELISA is positive, it confirms a toxinproducing form of C. difficile with no further testing required. However, if the ELISA is negative, a PCR is then performed. If the PCR is positive, the patient has toxin-producing C. difficile; negative results indicate that the patient has non–toxin-producing C. difficile. This type of sequenced testing optimizes the specificity of diagnosis and is cost-effective, although perhaps not as expedient as performing only a PCR test.

With the observed epidemiologic changes of CDI, there is an increased urgency for more accurate, rapid testing also capable of detecting hypervirulent strains. The FDA recently approved the Cepheid Xpert C. difficile/Epi assay.40 This method offers a rapid test for toxin B and can detect the NAP1/BI/027 strain. Most practicing clinicians must rely on whatever diagnostic tools are available at their local laboratory or institution to test for CDI. Clinicians must understand the risk for false-positive or false-negative results with the methods available at their institution because this information might affect their decision making. Repeat testing after a negative result is discouraged because less than 5% of such tests are positive and repeat testing increases the likelihood of false positives. Testing for cure also is not recommended because toxin tests may remain positive for as long as 30 days after resolution of symptoms.

Treatment The first step in managing patients with CDI requires discontinuing any antibiotics that might be contributing to the infection whenever possible; 15% to 25% of cases will resolve without any further therapy.41,42 Because discontinuation of antibiotics is not always feasible—and this conservative measure alone is not appropriate in patients with persistent symptomatic disease—antibiotic therapy and other interventions must be considered. The Table (page 5) gives an overview of current treatment recommendations for CDI. Metronidazole is the first-line treatment for patients with mild to moderate CDI because of its efficacy and low cost. A 2007 Cochrane Review found that metronidazole (usually given as 500 mg orally 3 times daily for 10-14 days) had similar efficacy to vancomycin for nonsevere CDI43; however, as the C. difficile epidemic continues to grow, the rate of treatment failure and the number of patients who experience relapses or recurrences are increasing as well. Data from the 1980s and 1990s showed that metronidazole had a low treatment failure rate (<5%),41,44 but recent studies have observed failure rates as high as 38%.45,46 Some blame hypervirulent strains for the reduced efficacy of metronidazole, but a study that compared a cohort from 1998 with one from 2004 to 2006 showed that metronidazole failure rates were similar and remarkably high in both groups (35%).47 Moreover, the incidence of NAP1/BI/027 was similar in patients who were treated successfully with metronidazole (21%) and those who experienced treatment failure (26%; P=0.67).47 Metronidazole is usually well tolerated, but about 1% of patients experience systemic side effects, including nausea and a metallic taste; peripheral sensory neuropathy may be seen with prolonged treatment.41 Because of the risks for birth defects associated with metronidazole, it should not be used in pregnant women. Metronidazole remains the first-line therapy for patients with mild to moderate disease and has the potential benefit of not causing vancomycin-resistant enterococci (VRE). Vancomycin is considered first-line therapy for

patients with moderate to severe CDI. Oral vancomycin has minimal systemic absorption, resulting in high concentrations in the colon, thus minimizing its systemic side effects and theoretically making it an ideal treatment. Zar and colleagues compared the efficacy of metronidazole with that of vancomycin in patients stratified by disease severity. In patients with mild disease, the efficacy of metronidazole was similar to that of vancomycin (90% vs 98%; P=0.36); patients with severe disease were significantly more likely to respond to treatment with vancomycin than with metronidazole (97% vs 76%; P=0.02).45 Vancomycin is indicated for the treatment of moderate to severe CDI in pregnant women, children aged 10 years or younger, and patients who either failed or are intolerant to metronidazole.34 Vancomycin 125 mg 4 times daily is as effective as 500 mg 4 times daily.48 It is recommended to use the lower dose with most patients; the higher dosing is reserved for critically ill patients. In the latter group, vancomycin may be given orally, by nasogastric tube, or via enema while IV metronidazole is administered.

Recurrent CDI Recurrent CDI is observed in 15% to 30% of patients who successfully complete an initial treatment,49 and is usually seen 2 days to 2 months after completion of therapy. It is likely that initial treatment failure occurred in some of these patients and that they never fully cleared the infection. Wilcox et al ribotyped strains of C. difficile in index and recurrent disease and found that 56% of recurrences were caused by a different strain from the one that caused the initial infection.50 Most clinicians and authors do not distinguish relapse (ie, same strain) from recurrence (ie, different strain). Regardless of whether the strain that causes CDI recurrence is the same or different from the one that caused the original infection, patients who are unable to generate immunoglobulin G (IgG) against C. difficile toxin A are more likely to have repeat infections.49 Other risk factors for recurrent infection include those listed above for index infection and also being aged 65 years or older, increased WBC counts during initial infection, low serum albumin levels, and antibiotic use between the initial treatment and the recurrent infection.1,11 It seems that the greatest risk factor for recurrent infection is a recurrence itself—up to 65% of patients who have 1 recurrence may have future episodes.51

TREATMENT

RECURRENT CDI

When managing patients with recurrent CDI, it is important to eliminate the possibility of post-CDI irritable bowel syndrome52 and other causes of diarrhea.49 Similar to the index presentation, once a diagnosis has been confirmed, clinicians should again attempt to limit or eliminate any potential offending antibiotics if possible. If a patient must remain on antibiotics, switching to one that is less commonly associated with CDI is advised, if possible. Antibiotics A 10- to 14-day treatment course with the antibiotic

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used to treat the initial infection is still recommended. Vancomycin is recommended for patients with a moderate to severe recurrence, regardless of which antibiotic was used initially. Most authors recommend another traditional course of vancomycin for recurrent CDI, but a tapered-pulsed regimen also is being used, despite the absence of robust evidence to prove its value over a standard course of therapy for either the first or second recurrence of CDI. Theoretically, tapered-pulsed therapy allows the antibiotic-resistant spore form of the organism to convert into the antibiotic-sensitive, vegetative form as the antibiotic is withdrawn slowly and, in the final stages of tapering, is given on alternate days. Theoretically, spores convert to their vegetative form on days when vancomycin is not administered, and vegetative forms are killed on the days when the drug is taken.14 In one study, patients who had a standard 10- to 14-day course of antibiotics had recurrence rates of 43% to 54%, respectively, compared with 31% in those who underwent a tapered regimen (gradually lowered doses) and 14% in those who underwent a pulsed regimen (every 2-3 days). There are many variations of tapered-pulsed and pulsed regimens of vancomycin, none of which have been studied alone or against each other. Although this tapered and other such regimens are widely used and effective in many patients, the recurring and chronic use of antibiotics to treat recurrent CDI has its downside, especially in terms of the intestinal microbiota. Vancomycin is a broadspectrum antimicrobial agent with activity against almost all gram-positive aerobic and anaerobic organisms. As a result, it may increase host susceptibility to CDI by killing many of the normal intestinal microorganisms; its use also predisposes patients to VRE and other organisms. In addition to maintaining an altered state of bowel flora,10 continued use of vancomycin may cause C. difficile resistance, although such resistance currently is rare.51 Probiotics By restoring the “balance” of the normal colonic microbiota, probiotics are believed to help restore the “colonization resistance”—or, protective barrier—of intestinal microflora. Saccharomyces boulardii has been the most extensively studied probiotic for recurrent CDI, It is believed that S. boulardii releases a protease that inactivates C. difficile toxin receptors, thereby preventing symptomatic disease.3 However, McFarland et al conducted a systematic review and meta-analysis of S. boulardii and concluded that although there is strong evidence that this probiotic is effective to prevent antibiotic-associated diarrhea, the evidence for its efficacy in the treatment of CDI as an adjunct to antibiotics is weak.53 There also have been documented cases of fatal fungemia with this agent in immunocompromised patients and in patients with central venous pressure catheters, so its use in these patients is not recommended.54 Other studies using Lactobacillus spp either have been too small or have failed to show efficacy for recurrent CDI.

Novel Therapies for CDI Along with the increasing virulence of CDI, treatment

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failure and disease recurrence have become more common. In response to this trend, several new treatments are being studied, including alternative antibiotics, C. difficile toxin–binding resins, monoclonal antibodies against toxins A and B, C. difficile vaccination,2 and FMT.

NITAZOXANIDE Nitazoxanide is a nitrothiazolide that is commonly used to treat intestinal parasites such as cryptosporidia and giardia. A breakdown product of nitazoxanide, tizoxanide, actively inhibits the anaerobic metabolism of C. difficile; because approximately two-thirds of each dose is excreted in the feces, this medication potentially offers an alternative treatment. When the in vitro efficacy of nitazoxanide was investigated in 127 strains of C. difficile (including the most common and most virulent ribotypes), it showed excellent bactericidal activity.55 A double-blind, placebo-controlled study that compared nitazoxanide 500 mg twice daily for 7 days with metronidazole 250 mg 4 times daily for 10 days found that 82.4% of patients receiving metronidazole and 89.5% of patients receiving nitazoxanide responded to treatment. The results proved that nitazoxanide is noninferior to metronidazole for first-line therapy.56 A separate study that investigated patients who failed conventional treatment with metronidazole found that nitazoxanide 500 mg twice daily had a 74% response rate and a 54% cure rate.57 Nitazoxanide appears to have adequate efficacy in the treatment of CDI, but it is not superior to current treatments and thus likely will remain a third-line alternative used after other regimens fail. In three small series, a total of 16 of 20 patients had no further recurrences when treated with 2 weeks of rifaximin after a 2-week course of vancomycin. However, a recent randomized controlled trial of rifaximin showed no significant decrease in CDI recurrences after standard CDI treatment with vancomycin.58 Moreover, high-level resistance to rifampin and rifaximin is now being seen, even in patients without prior exposure to these drugs, as exposure to rifaximin becomes increasingly common in hospitals for the treatment of hepatic encephalopathy. Rifaximin is not recommended for recurrent CDI unless susceptibility testing for rifampin is available.59

RIFAXIMIN Rifaximin is a poorly absorbed rifamycin derivative that inhibits bacterial transcription and protein synthesis. Following its FDA approval for traveler’s diarrhea, many uses for this antibiotic have been studied, including small intestinal bacterial overgrowth, hepatic encephalopathy, and CDI. In vitro studies of rifaximin for the treatment of CDI have shown promising results,60 but some studies also have shown the development of rifaximin resistance.61 One small case series of 3 post–liver transplant patients who failed standard initial treatment found that vancomycin followed by a 28-day course of rifaximin (400 mg 3 times daily) resulted in resolution of diarrhea in all patients within 48 hours of treatment; all remained symptom free at 6-month follow-up.62 Rifaximin 100 to 200 mg twice daily following

Table. Treatments for C. difficile Infection Treatment

Indication

Administration

Comments

Metronidazole

Mild to moderate CDI

500 mg PO or IV tid for 10-14 d

First-line therapy for mild to moderate CDI, but increasing rates of refractory infection are being observed.

Vancomycin

Moderate to severe CDI

125-500 mg PO qid for 10-14 d

Lower dose should be given to most patients, reserving the higher dose for those who are critically ill. Oral, nasogastric, or rectal therapy may be combined with IV metronidazole in critically ill patients.

Recurrent CDI

Tapered-pulse PO therapy

It is unclear whether this should be used after the first or second recurrence, but this is a very effective treatment. There are no robust and controlled trials yet performed that prove efficacy.

Saccharomyces boulardii

Prevention of recurrent CDI

500 mg PO bid for 28 d. Usually started after 7 d of antibiotic treatment.

Avoid using in immunosuppressed patients, patients in an ICU, or patients with a central venous pressure catheter. Should not be given chronically. Data showing efficacy are not robust.

Nitazoxanide

Index infection or recurrent CDI

500 mg PO bid for 7 d

This medication has been shown to be noninferior to metronidazole, but further studies are needed to clarify its role in CDI.

Rifaximin

Recurrent CDI

200 mg PO bid to 400 mg PO tid for 28 d. May be given as a “chaser” after completion of vancomycin therapy for recurrent CDI.

Variable dosing between studies and lack of well-controlled trials limit the understanding of the usefulness of this treatment.

Fidaxomicin

Index infection

200 mg PO bid for 10 d

Approved by the FDA to treat CDI. This medication is noninferior to vancomycin and is associated with a significantly lower rate of recurrent infection. No data are available on recurrent CDI.

Toxin binders

Symptomatic adjunct to antibiotic treatment

4 g PO tid or qid for the same duration as the antibiotic therapy

Toxin binders such as cholestyramine should be used to control symptomatic diarrhea but not as the only treatment. Should not be used within 4 hours of administration of anti-C. difficile antibiotics.

Immunoglobulins Refractory CDI

IV infusion at a dose of 400 mg/kg (IVIG) of body weight given with antibiotic therapy in patients with hypogammaglobulinemia

May help treat refractory/ recurrent infections in patients with hypogammaglobulinemia by enhancing overall efficacy of treatment and minimizing further recurrences.

Fecal microbiota • Recurrent/ transplantation refractory CDI • Unclear role in severely ill CDI patients as first-line therapy

60 or 300 cc of fecal suspension from a healthy donor that is placed via the upper route or colonoscopically throughout the colon, respectively

Excellent preliminary results in patients with severe and refractory disease. Best methodology is yet to be clarified.

bid, twice daily; CDI, Clostridium difficile infection; IVIG, intravenous immunoglobulin; PO, by mouth; qid, 3 times daily; tid, 4 times daily

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treatment completion with vancomycin for recurrent CDI also showed efficacy in a separate case series.63 Although these results are encouraging, they must be confirmed with large-scale trials. Currently, the use of rifaximin following vancomycin for the treatment of recurrent CDI is considered to be useful.

FIDAXOMICIN Fidaxomicin, a narrow-spectrum macrocyclic antibiotic, is a promising new antimicrobial treatment for CDI.64 A study that compared fidaxomicin with vancomycin in patients with recurrent CDI found a lower rate of recurrence with fidaxomicin than with vancomycin (20% vs 36%; P=0.045).65 A head-to-head comparison of fidaxomicin 200 mg 3 times daily with vancomycin 125 mg 4 times daily for 10 days found that fidaxomicin was noninferior to vancomycin, with clinical cure rates of 88.2% and 85.8%, respectively. The rates of recurrence were significantly lower in the fidaxomicin group than in the vancomycin group (15.4% vs 25.3%; P=0.005).66 For patients with the NAP1/BI/027 strain, the rates of clinical cure and recurrence were similar for fidaxomicin (78.7% and 27.1%, respectively) and vancomycin (80.7% and 20.9%, respectively).66 Adverse events from fidaxomicin, although rare, include nausea, vomiting, headache, and abdominal pain. In May 2011, the FDA approved fidaxomicin for the treatment of C. difficile–associated diarrhea.67 Fidaxomicin is a good alternative to vancomycin and is less frequently associated with disease recurrence. There are no studies to date on use of fidaxomicin to treat recurrent CDI.

TOXIN BINDERS C. difficile toxins A and B are the main mediators of symptomatic CDI, and theoretically, binding resins should help to control CDI by binding the toxins without altering the colonic microbiota. Using 4 g of binding resin 3 or 4 times daily, older studies have found varying efficacy, from 36% with colestipol to 68% with cholestyramine.4 Tolevamer was designed as a synthetic polysterol that also is capable of binding C. difficile toxins, but it was shown to be significantly less effective than both vancomycin and metronidazole in clinical trials, resulting in the discontinuation of its production.68 Toxin binders act to control diarrhea while another agent is used to treat the active infection. There have been no controlled trials of these agents, and their use is not widely recommended because they may bind to the antibiotics being used for treatment, unless these medications are given several hours apart from each other.

IMMUNOTHERAPY Patients with elevated levels of serum IgG against toxin A are less likely to develop symptomatic infection, whereas patients with low levels following infection are more likely to have recurrent disease.49 Passive immunization with IV immunoglobulin (IVIG) is another therapeutic intervention that attempts to supplement a patient’s immune response to CDI. Several small studies using IVIG (usually 400 mg/kg of body weight) in patients with

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severe or recurrent disease have shown mixed results. One trial found up to a 100% response rate,69 whereas others found significantly lower efficacy.70 IVIG may have its greatest benefit in patients with hypogammaglobulinemia. Antibodies more specific to CDI have been developed as well. Lowy et al conducted a double-blind, placebo-controlled trial that compared patients receiving metronidazole or vancomycin alone with those receiving metronidazole or vancomycin in combination with fully human monoclonal antibodies to C. difficile toxins A and B (10 mg/kg of body weight). Overall, patients receiving antibodies in combination with the antibiotic were less likely to have recurrent infections (7% vs 25%; P<0.001). Patients infected with the NAP1/BI/O27 strain showed a trend toward lower rates of recurrence as well (8% vs 32%; P=0.06).5 Targeted antibody treatments seem to be a very encouraging future option in the management of CDI.

FECAL TRANSPLANTATION Fecal transplantation, also known as fecal bacteriotherapy, or preferably fecal microbiota transplantation (FMT) because we do not know which of the living organisms or metabolic products in stool are effective in the various diseases for which this therapy has been used, is another promising and interesting treatment option. The rationale behind FMT is simple: Antibiotics and other factors disrupt the normal balance of the colonic microbiome, and by reintroducing normal microbiota via donor feces, a balanced and species-diverse community of microorganisms with “colonization resistance” can be reestablished.25 Compared with stools from patients who had antibioticassociated diarrhea not associated with C. difficile and those with just a single episode of CDI,71 patients with recurrent CDI had a decreased species richness in their stool. There was a specific absence of Bacteroidetes and Firmicutes phyla, suggesting that this microbiome “fingerprint” is characteristic of recurrent CDI and that FMT might be a possible treatment modality.71 The clinical use of FMT dates back to 1958, although the bulk of published work, which is still very limited, has come in the last 2 decades.72,73 Initially, retention enemas were the most common technique for FMT, but fecal infusion via duodenal tube,74 rectal tube,75 and colonoscopy76-78 recently have been reported. One case series of 18 patients with CDI (17 had FMT via colonoscopy, 1 via gastrostomy) showed that 15 of 18 patients were cured with no relapses noted. The 3 patients who failed to respond had severe colitis.76 In a series of 12 patients with recurrent or refractory disease in whom donor feces were infused at colonoscopy, all 12 had prompt symptomatic cure within hours to days, with no adverse events.77 In another separate case series of 19 patients with recurrent CDI using a similar technique, 18 of 19 patients immediately responded to treatment. Three patients ultimately had recurrent infection following treatment, but all 3 recurrences occurred immediately after antibiotic treatment, making a de novo infection rather than FMT treatment failure the likely cause.78 There is no consensus opinion at this time on which

technique to perform FMT is best. Self-administered enemas are being used increasingly, although with enemas only the splenic flexure is reached79; with colonoscopy, the entire colon and ileum can be recolonized and the extent and severity of disease can be observed while the treatment is given.78 Regardless of the route of administration, FMT appears to be an effective treatment for refractory or recurrent CDI, with a cure rate of approximately 90% in more than 350 case reports from around the world.80,81 Further research on FMT is needed to clarify the optimal delivery methods, appropriate donors, and situations most appropriate to use this technique. A large randomized controlled trial, FECAL (Fecal therapy to Eliminate Clostridium difficile–Associated Longstanding diarrhea), was recently concluded in Norway. This trial compared patients with refractory CDI who received standard high-dose vancomycin with patients who received high-dose vancomycin followed by FMT; the results have not yet been published.66 Another trial, which was recently approved by the National Institutes of Health, will compare donor and recipient stool infused into recipients who have had at least 3 episodes of recurrent CDI in a doubleblind, randomized controlled fashion.

Conclusion CDI is an epidemic that continues to evolve. As we understand more about this infection, its risk factors, its modes of transmission, and potential treatments, we will be better equipped to both effectively prevent new cases and treat existing ones. Currently, several promising treatments beyond metronidazole and vancomycin are available, the most promising of which include fidaxomicin and FMT for treatment of refractory CDI.

Gastrointestinal and Liver Disease. 9th ed. Philadelphia, PA: Elsevier Inc.; 2010. 13. Feuerstadt P, Nunez JC, Rahimi E, Das R, Brandt LJ. S1228 community-acquired Clostridium difficile-associated disease (CA-CDAD): characterization of an urban disease. Gastroenterology. 2010; 138(5 suppl 1):S208-S209. 14. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: a national and tertiary center perspective. Am J Gastroenterol. 2010;105(1):106-113. 15. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769-1775. 16. Ben-Horin S, Margalit M, Bossuyt P, et al. Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and Clostridium difficile infection. Clin Gastroenterol Hepatol. 2009;7(9):981-987. 17. Surawicz C, Brandt LJ, Binion D, et al. Guideline for the treatment of C. difficile infection. Am J Gastroenterol. In press. 18. Pepin J, Valiquette L, Gagnon S, et al. Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027. Am J Gastroenterol. 2007;102(12):2781-2788. 19. Kyne L, Merry C, O’Connell B, et al. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing. 1999;28(2):107-113. 20. Feuerstadt P, Aroniadis OC, Brandt LJ. S1273 standard admission lab values as predictors of outcome in patients with colon ischemia, Crohn’s disease, and Clostridium difficile associated disease. Gastroenterology. 2008;134(4 suppl 1):A215-A216. 21. Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 2005;40(11):1591-1597. 22. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease. Am J Gastroenterol. 2010;105(9):2040-2049. 23. Curry SR, Marsh JW, Schlackman JL, Harrison LH. Prevalence of Clostridium difficile in uncooked ground meat products from Pittsburgh, Pennsylvania. Appl Environ Microbiol. 2012;78(12):4183-4186. 24. Keessen EC, Gaastra W, Lipman LJ. Clostridium difficile infection in humans and animals, differences and similarities. Vet Microbiol. 2011;153(3-4):205-217.

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AUTHOR DISCLOSURES—Dr. Brandt is a consultant for Optimer Pharmaceuticals, Inc. Dr. Feuerstadt is a member of the speaker’s bureau for Optimer Pharmaceuticals, Inc. DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the authors. Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright © 2012, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.

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