July 2013 by McMahon Group

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 7 â&#x20AC;˘ July 2013

DDW 2013

New Colonoscope Offers Sweeping, 330-Degree Views of the Colon

Simeprevir Shines In Hep C Trial

Fuse Generates â&#x20AC;&#x2DC;Hugeâ&#x20AC;&#x2122; g Interest at DDW Meetingg BY DAVID WILD ORLANDO, FLA.â&#x20AC;&#x201D;Of patients who relapsed following treatment with peginterferon (PEG-IFN)based therapy for chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, 80% experienced rapid and sustained virologic response with triple therapy including PEG-IFN-2a, ribavirin (RBV) see Simeprevir, page 20

Sedasys Approved; Who Will Use It? BY AUDREY ANDREWS BY MONICA J. SMITH On May 3, the FDA granted premarket approval for a computer-assisted sedation delivery system that allows administration of propofol (Diprivan, AstraZeneca) without an anesthesiologist for patients who are not considered to need one. Some are heralding the new see Sedasys, page 16

ORLANDO, FLA.â&#x20AC;&#x201D;A new colonoscope that provides three simultaneous full-spectrum images of the colon detected significantly more adenomasâ&#x20AC;&#x201D;and missed significantly fewerâ&#x20AC;&#x201D;in findings presented at the 2013 Digestive Disease Week (DDW) meeting. Ian M. Gralnek, MD, MSHS, associate professor of medicine/gastroenterology at the Rappaport Family Faculty of Medicine Technion-Israel

Institute of Technology in Haifa, Israel, presented data on the Fuse Full Spectrum Endoscopy (Fuse) system in a study that rigorously compared the new technology with traditional, forward-viewing (TFV) colonoscopy in a tandem endoscopy study design. â&#x20AC;&#x153;Compared with TFV colonoscopy, Fuse found significantly more adenomas, had a significantly lower adenoma miss rate and impacted colonoscopy surveillance recommendations,â&#x20AC;? Dr. Gralnek said. â&#x20AC;&#x153;Our results are very compelling. We believe see Fuse, page 14

I N S I D E

Doctors Tested in Boston Bombings

EXPERTSâ&#x20AC;&#x2122; PICKS The Best of Digestive Disease Week (DDW): Part 1 Experts share their favorite abstracts from the 2013 DDW meeting ................................................................................................ page 6

BY BRIGID DUFFY The morning of April 15, 2013 started as a typical Marathon Monday for Tim Lepore, MD. At 68 years old, Nantucketâ&#x20AC;&#x2122;s only surgeon laced up his trainers and made his way to the starting line of his 45th consecutive Boston Marathon. By mid-morning, long after the elite runnersâ&#x20AC;&#x2122; dust had settled, Dr. Lepore joined the second

Manoop S. Bhutani, MD

Klaus Mergener, MD, PhD, MBA

Prateek Sharma, MD

see Boston, page 42 Supported by

5)& 4$*&/$& #&)*/% 104*5*7& 1"5*&/5 065$0.&4

Introduction Increasing efforts to reform health care and contain medical expenditures have accelerated the push to define, capture, and enforce quality measures for delivered care. This trend is evident particularly for procedural and preventative measures that can have a marked effect on patient outcomes and health care costs, such as the use of colonoscopy for screening and surveillance for colorectal cancer (CRC). Although the use of colonoscopy as a CRC screening tool has reduced patient mortality, variability in endoscopistsâ&#x20AC;&#x2122; performance, which has been demonstrated for adenoma detection rates (ADRs), assessment of bowel preparation, complication rates, use of appropriate screening and surveillance intervals, and effective polyp resection, suggest that objective measures are needed to evaluate performance and improve quality. This review discusses the current and emerging landscape regarding quality indicators and benchmarks for colonoscopy.

Colonoscopy Quality Improvement: Quality Indicators and Benchmarks see page 8

Quality Measurement for Colonoscopy-Based Screening And Surveillance Colonoscopy is the dominant screening UFTU GPS $3$ JO UIF 6OJUFE 4UBUFT 6OMJLF CBTJD testing used to screen for other diseases (eg, blood pressure measurements and lipid profile reviews as preventative steps in cardiovascular disease; glucose testing for diabetes mellitus), colonoscopy is highly operatordependent: The quality of this procedure is dependent on the skill and training of the gastrointestinal (GI) endoscopist. Other factors such as adequacy of bowel preparation have a significant effect on the success and cost-effectiveness of colonoscopy programs. Efforts to increase the quality of colonoscopy have been in effect for more than a decade.4 5IF 64 .VMUJ 4PDJFUZ 5BTL 5 'PSDF PO Colorectal Cancer and a combined task force of the American Society for Gastrointestinal Endoscopy and the American College of Gastroenterology have published recommendations for measuring quality in the technical performance of colonoscopy.4,5 These publications are comprehensive in their scope, covering multiple aspects of pre-procedural evaluation and patient selection, intraprocedural technical performance, and postprocedural monitoring of complications.

However, resources for measuring quality may be limited, thereby creating a need to identify priority quality indicators that should be measured in all clinical programs (Table).6-9 Ideal quality indicators are easy and thus feasible to measure; possess clinical relevance (are related to important outcomes); and illustrate substantial variation in performance among endoscopists. Several measures within colonoscopy-based CRC screening/surveillance satisfy these criteria.

Cecal Intubation Rate Current recommendations are that endoscopists should be able to achieve cecal JOUVCBUJPO JO BU MFBTU PG BMM DPMPOPTDPQJFT BOE PG TDSFFOJOH DPMPOPTDPQJFT 4,5 Cecal intubation is defined as passage of the colonoscope tip fully into the cecal caput, with visualization of the mucosa between the appendiceal orifice and the ileocecal valve. Photodocumentation of the appendiceal orifice and ileocecal valve is expected. Low cecal intubation has been associated with an increased risk for interval cancer in the proximal colon.

Adenoma Detection Rate "%3 JT UIF GSBDUJPO PG QBUJFOUT ZFBST of age and older undergoing initial screening colonoscopy who have one or more conventional adenomas detected.4,5 ADR is the most important colonoscopy quality marker as it relates directly to the principle goal of colonoscopy: detection and resection of precancerous lesions and thereby protection against CRC. ADRs below the recPNNFOEFE UISFTIPME PG GPS B NJYFE gender patient population predicted a GPME IJHIFS SJTL GPS EFWFMPQJOH BO JOUFSval cancer after colonoscopy. Guidelines SFDPNNFOE UIBU UIF "%3 CF BU MFBTU JO NFO BOE JO XPNFO 4,5 and there is considerable variability in the ADR among FOEPTDPQJTUT 'JHVSF A number of efforts to improve ADR in poor performers have been unsuccessful, but recently some effective strategies have been identified.

Education Effective methods for improving ADRs have involved some element of education, typically focused on lesion recognition and improved examination technique. Endoscopists should understand the full range of appearances of precancerous lesions in the colon and be able to recognize flat and depressed conventional adenomas as well as serrated lesions in the proximal colon. Sessile serrated polyps (a term synonymous with sessile serrated adenoma) are invariably sessile or flat, have a pale color, and often have a â&#x20AC;&#x153;mucus capâ&#x20AC;? on the surface and/ or adherent debris that often clusters at the MFTJPO FEHF 5IF .BZP $MJOJD +BDLTPOWJMMF T &26*1 &OEPTDPQJD 2VBMJUZ *NQSPWFNFOU 1SPKFDU USJBM SBOEPNJ[FE PG UIF JOTUJtutionâ&#x20AC;&#x2122;s faculty to an educational intervention that focused on lesion recognition and specific colonoscopic techniques, such as examining carefully behind folds, to improve ADRs; educational intervention resulted in an JNQSPWFNFOU JO UIF "%3 GSPN UP Withdrawal Technique Barclay et al found that ADRs were well stratified according to whether endoscopists had an average withdrawal time in normal colonoscopies greater than or less than 6 minutes. Endoscopists whose withdrawal times were greater than 6 minutes detected more than twice as many patients with adeOPNBT UIBU XFSF DN PS MBSHFS JO TJ[F *O B subsequent study, the group evaluated the effect of an educational program combined with enforced 8-minute withdrawal times. 5IF UJNFS TPVOEFE FWFSZ NJOVUFT EVSJOH withdrawal, and served as a reminder that the FOEPTDPQJTU TIPVME TQFOE BU MFBTU NJOVUFT examining each quarter of the colon length. This intervention produced across-the-board JNQSPWFNFOUT JO "%3T 'JHVSF 6 Bowel Preparation Bowel preparation quality also affects ADR. Split-dose and same-day bowel preparations are the most important development in bowel preparation efficacy in the

Appropriate Use of Screening/ Surveillance Intervals Another determinant of the overall utility of colonoscopy for CRC prevention is the interval between examinations. Although detailed evidence-based guidelines have been published with recommended intervals for screening/surveillance examinations based on age, risk factors, and observations during colonoscopy, there is considerable variability in guideline adherence in clinical practice. All current recommendations are UIBU CFHJOOJOH BU BHF DPMPOPTDPQZ TIPVME CF QFSGPSNFE GPS TDSFFOJOH FWFSZ ZFBST in average-risk persons. The recommended interval is 5 years for certain high-risk family histories (CRC in multiple first-degree

Table. High-Yield Quality Indicators of Colonoscopy-Based Screening and Surveillance for CRC and Suggested Interventions To Improve Performance Quality Indicator

Suggested Interventions To Improve Performance

ADR

Comprehensive education and training Timer-enforced withdrawal â&#x2030;Ľ8 min Split-dose or same-day bowel prep Recognition of right-sided sessile serrated adenomas

Assurance of appropriate Distribution of a wallet-size card with a summary of post-polypectomy guidelines to all endoscopists Placement of guideline charts near computers used for typing endoscopy reports, and distribution screening/surveillance Reinforcement of the guidelines in a monthly continuous quality improvement meeting intervals ADR, adenoma detection rate; CRC, colorectal cancer Adapted from references 6-9. 6 9.

8 ("4530&/5&30-0(: &/%04$01: /&84 t +6-:

1.2

QBTU EFDBEFT *O B SFUSPTQFDUJWF TUVEZ PG NPSF UIBO DPMPOPTDPQJFT VTF PG split-dose bowel preparations resulted in a marked improvement in bowel preparation quality and an increase in ADRs from UP P Another study suggested that, for patients who are scheduled for afternoon colonoscopy, early morning/ same-day bowel preparation resulted in a better quality examination compared with previous-day or split-dose preparations. Split- and same-day dosing of bowel preparations have their greatest benefit in the proximal colon. Colonoscopy is consistently more effective in preventing distal compared with proximal colon cancer, an effect that may result partly from the tendency of bowel preparation quality to be worse in the cecum and right colon when preparations are given entirely the day or evening before colonoscopy. Additional potential causes of worse protection against proximal cancer include the rightward distribution of lesions that are endoscopically more subtle (including flat and depressed conventional adenomas and serrated lesions), and the more rapid movement through the polyp-cancer sequence in tumors that are microsatellite unstable or hypermethylated. Both of these molecular features are more common in tumors arising in the proximal colon.

Adenoma Per Subject (mean)

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

Adenoma Detection Rate

Douglas K. Rex, MD, FACP, FACG

50 40 30 20 10 0

1.0 0.8 0.6

0.0 0.0

& & & & & Endoscopic Study ID Number

These interventions resulted in an improvement in the compliance rate with guidelines postintervention (P GSPN BU CBTFMJOF UP 9

Quality Reporting and Oversight Currently, there are no mandatory reporting/tracking systems in place for quality measures for colonoscopy and CRC detecUJPO TVSWFJMMBODF JO UIF 6OJUFE 4UBUFT )PXever, the landscape for regulatory and reimbursement continues to evolve, shifting from quantity to quality of health care delivery with motivators of either pay-for-qualityâ&#x20AC;&#x201C; performance or reimbursement penalties for failure to meet certain threshold metrics. Based on the quality markers discussed previously, tracking and reporting systems for colonoscopy quality indictors may include some combination of measuring adequacy of bowel preparation, ADRs, cecal intubation rates, and appropriate use of screening/surveillance intervals. Data that currently are being reported on a voluntary basis to the GI Quality Improvement Consortium (GIQuIC) and the American Gastroenterological Association (AGA) Digestive Health Outcomes RegistryÂŽ may help establish the most appropriate benchmarks for high-quality colonoscopy. Even if these reporting and tracking systems remain purely voluntary for the nearterm, groups that participate could realize TVCTUBOUJBM CFOFGJUT 'PS FYBNQMF RVBMJUZ metrics relative to targets or other practices could be used by groups to identify system errors and to identify practitioners within their groups who would benefit from additional training and education to improve overall group performance and patient outDPNFT 'VSUIFSNPSF HSPVQT UIBU QBSUJDJQBUF in these quality reporting systems will be well positioned in the likely event that quality measures will be used for accreditation/ credentialing purposes, marketing purposes, and reimbursement determinations. Participation in colonoscopy quality improvement has been made much easier

Post (rs P

0.2

0.4

0.6

0.8

1.0

Withdrawal Time, min

Figure 1. "EFOPNB EFUFDUJPO SBUF BNPOH JOEJWJEVBM endoscopists. FQSJOUFE XJUI QFSNJTTJPO GSPN -FF 3) 5BOH 5 34 .VUIVTBNZ 73 FU BM 2VBMJUZ PG DPMPOPTDPQZ XJUIESBXBM technique and variability in adenoma detection rates (with videos). Gastrointest Endosc

OPTFE XJUI $3$ BU BHF ZFBST However, there is clear evidence of systematic use of ZFBS JOUFSWBMT GPS TDSFFOJOH JO UIF .FEJDBSF population, despite evidence that the yield of repeat screening in 5 years is remarkably low in average-risk persons who have initial negative examinations, and recent evidence that the protective effect of a negative screening colonoscopy performed by a gasUSPFOUFSPMPHJTU FYDFFET ZFBST Several studies suggest that some gastroenterologists repeat colonoscopy for polyp surveillance either more or less frequently than guidelines recommend, which results in increased costs of care and risk for complications or increased risk for cancer, respectively. This over- or underuse of colonoscopy stems from a variety of potential causes, including unfamiliarity or disagreement with guidelines; systematic problems with health care management systems and patient tracking; suboptimal reimbursement arrangements (eg, either absence of reimbursement or financial incentives for overuse of colonoscopy); or noncompliance by patients or referring physicians. In one survey of endoscopists who reported familiarity with society guidelines regarding intervals for screening/surveillance, incorrect answers to common scenarios regardJOH BQQSPQSJBUF JOUFSWBMT XFSF HJWFO JO UP PG IZQPUIFUJDBM DBTFT In a study describing actual utilization of surveillance colonosDPQZ PG QBUJFOUT SFDFJWFE TVSWFJMMBODF PO UJNF UPP FBSMZ NFEJBO EJGGFSFODF ZFBST UPP FBSMZ BOE UPP MBUF NFEJBO EJGGFSFODF ZFBS UPP MBUF Sanaka et al investigated the utility of several interventions to improve adherence to recommended surveillance intervals: Distribution of a wallet-size card with a summary of post-polypectomy guidelines to all endoscopists; placement of guideline charts near computers used for typing endoscopy reports; and distribution and reinforcement of the guidelines in a monthly continuous quality improvement meeting.

Baseline (rs P=

0.4 0.2

Figure 2. Detection of adenomas before and after an intervention involving education and a timer designed to enforce colonoscopy withdrawal time of 8 minutes or more. 3FQSJOUFE XJUI QFSNJTTJPO GSPN #BSDMBZ 3- 7JDBSJ ++ (SFFOMBX 3- &GGFDU PG B UJNF EFQFOEFOU DPMPOPTDPQJD withdrawal protocol on adenoma detection during screening colonoscopy. Clin Gastroenterol Hepatol.

by the development of national registries such as GIQuIC and the AGA RegistryÂŽ that allow electronic submission of procedural data and which provide electronic feedback on group and individual performance with benchmarking.

Conclusion Variable performance in colonoscopy has now been demonstrated for adenoma detection, cancer prevention, cecal intubation, polyp resection effectiveness, and use of screening and surveillance intervals. Achievement of high levels of adequate bowel preparation reduces costs by reducing the need for early repeat procedures. Interest in colonoscopy quality continues to grow. Active participation in colonoscopy quality improvement programs will improve patient outcomes and position endoscopists for expected changes in health care assessment and reimbursement.

References -FWJO # -JFCFSNBO %" .D'BSMBOE # FU BM "NFSJDBO Cancer Society Colorectal Cancer Advisory Group; 64 .VMUJ 4PDJFUZ 5BTL 5 'PSDF "NFSJDBO $PMMFHF PG Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal canDFS BOE BEFOPNBUPVT QPMZQT B KPJOU HVJEFMJOF GSPN UIF "NFSJDBO $BODFS 4PDJFUZ UIF 64 .VMUJ 4PDJFUZ 5BTL 5 'PSDF PO $PMPSFDUBM $BODFS BOE UIF American College of Radiology. Gastroenterology. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology -FF 3) 5BOH 5 34 .VUIVTBNZ 73 FU BM 2VBMJUZ PG colonoscopy withdrawal technique and variability in adenoma detection rates (with videos). Gastrointest Endosc 4. 3FY %, #POE +) 8JOBXFS 4 FU BM 6 4 .VMUJ 4PDJFUZ 5BTL 5 'PSDF PO $PMPSFDUBM $BODFS 2VBMJUZ JO UIF technical performance of colonoscopy and the continuous quality improvement process for colonosDPQZ SFDPNNFOEBUJPOT PG UIF 6 4 .VMUJ 4PDJFUZ 5 'PSDF PO $PMPSFDUBM $BODFS Am J Gastroenterol. 5BTL 5. 3FY %, 1FUSJOJ +- #BSPO 5) FU BM "4(& "$( Taskforce on Quality in Endoscopy. Quality indicators for colonoscopy. Am J Gastroenterol. 6. #BSDMBZ 3- 7JDBSJ ++ (SFFOMBX 3- &GGFDU PG B UJNF dependent colonoscopic withdrawal protocol on adenoma detection during screening colonoscopy. Clin Gastroenterol Hepatol

Longcroft-Wheaton G, Bhandari P. Same-day bowel cleansing regimen is superior to a split-dose regiNFO PWFS EBZT GPS BGUFSOPPO DPMPOPTDPQZ SFTVMUT from a large prospective series. J Clin Gastroenterol. 8. 3FY %, "IOFO %+ #BSPO +" FU BM 4FSSBUFE MFTJPOT of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 9. 4BOBLB .3 4VQFS %. 'FMENBO &4 FU BM *NQSPWing compliance with postpolypectomy surveillance guidelines: an interventional study using a continuous quality improvement initiative. Gastrointest Endosc #BYUFS // 4VUSBEIBS 3 'PSCFT 44 FU BM "OBMZTJT PG administrative data finds endoscopist quality measures associated with postcolonoscopy colorectal cancer. Gastroenterology ,BNJOTLJ .' 3FHVMB + ,SBT[FXTLB & FU BM 2VBMJUZ indicators for colonoscopy and the risk of interval cancer. N Engl J Med $PF 4( $SPPL +& L %JFIM // 8BMMBDF .# "O FOEPscopic quality improvement program improves detection of colorectal adenomas. Am J Gastroenterol #BSDMBZ 3- 7JDBSJ ++ %PVHIUZ "4 FU BM $PMPOPscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med. (VSVEV 43 3BNJSF[ '$ )BSSJTPO .& FU BM *ODSFBTFE adenoma detection rate with system-wide implementation of a split-dose preparation for colonoscopy. Gastrointest Endosc F (PPEXJO +4 4JOHI " 3FEEZ / FU BM 0WFSVTF PG TDSFFOJOH DPMPOPTDPQZ JO UIF .FEJDBSF QPQVMBUJPO Arch Intern Med *NQFSJBMF 5' (MPXJOTLJ &" -JO $PPQFS $ FU BM 'JWF ZFBS SJTL PG DPMPSFDUBM OFPQMBTJB BGUFS OFHative screening colonoscopy. N Engl J Med. #SFOOFS ) $IBOH $MBVEF + 4FJMFS $. )PGGNFJTUFS . -POH UFSN SJTL PG DPMPSFDUBM DBODFS BGUFS OFHBUJWF colonoscopy. J Clin Oncol 4IBI 56 7PJMT $* .D/FJM 3 FU BM 6OEFSTUBOEing gastroenterologist adherence to polyp surveillance guidelines. Am J Gastroenterol. 4DISFVEFST & 4JOU /JDPMBBT + EF +POHF 7 7 FU BM The appropriateness of surveillance colonoscopy intervals after polypectomy. Can J Gastroenterol.

Disclosures Dr. Rex reported that he is an advisory board member for American BioOptics, Check-Cap, Epigenomics AG, Exact Sciences, and Given Imaging; has received grant/research funding from Braintree, Given Imaging, and Olympus; and has received speaking fees from Boston Scientific, #SBJOUSFF 'FSSJOH BOE 0MZNQVT

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Colonoscopy Quality Improvement: Quality Indicators and Benchmarks

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 • JULY 2013

FDA Moves To Regulate Fecal Microbial Transplantation BY GEORGE OCHOA The use of fecal microbial transplantation (FMT) as a treatment for Clostridium difficile infection has become increasingly common—a fact that has not escaped the FDA’s attention. In recent public statements, the FDA has made clear that it regards FMT as a biological product and drug that requires regulation.

“According to current federal law, a product intended for such use(s) would be an investigational new drug for which an Investigational New Drug application (IND) must be submitted,” FDA spokesperson Curtis Allen stated by email. “An IND is intended to assure that subjects are not exposed to unreasonable risks.” In a clinical emergency, different rules apply. In such cases, “the request to use [FMT] may be made via telephone or

other rapid means of communication, and authorization may be given by the FDA official over the telephone,” Mr. Allen wrote. “In these situations … treatment may begin prior to FDA’s receipt of the written IND submission that is to follow the initial emergency request.” However, no exception is made for non-emergency situations, in which “an IND for individual patient use … must be reviewed by the FDA before treatment with FMT may begin.”

Criticism of the FDA decision has come swiftly. According to Mr. Allen, at an FDA public workshop held in early May, some participants “expressed concerns about the administrative aspects of submitting an IND” and “expressed the concern that FDA involvement in the process would deprive ill patients of curative or palliative therapy.” “I have the greatest respect for the FDA and for the responsibility it has to protect the population against injury from inappropriate and unsafe products,” said Lawrence J. Brandt, MD, professor of medicine and surgery, Albert Einstein College of Medicine, New York City. “I do think, however, that the restrictions placed on FMT in the treatment of recurrent C. difficilee infection are unduly restrictive.”

‘An [Investigational New Drug application] for individual patient use … must be reviewed by the FDA before treatment with FMT may begin.’ —Curtis Allen, FDA spokesperson

SUPREP Bowel Prep Kit. Because the quality of cleansing matters. • Effective bowel cleansing2,3 in all bowel segments1

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

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 study 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.

BRIEF SUMMARY: Before pprescribing, g please p 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 patients p 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 post-colono p scopy 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 products p 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 patient p 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 yyears of age g or older, while 25 (7%) were 75 yyears 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 geriatric g patients p and yyounger g patients. p 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 provided. p 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 ©2012 Braintree Laboratories, Inc.

SU-13280T

January, 2012

Dr. Brandt, who is emeritus chief of the Division of Gastroenterology, Montefiore Medical Center, New York City, noted that thousands of FMT cases have been presented in various formats, with “an acknowledged serious adverse event frequency of close to zero.” The main point of a study presented at this year’s Digestive Disease Week meeting (abstract 998), of which Dr. Brandt was an author, “was that in a patient who has severe or complicated C. difficile infection not responding to antibiotics, FMT represents a potentially valuable therapy, with a cure rate of 92%.” Against such findings, Dr. Brandt suggested, concerns about long-term risks have to be put into perspective. see FMT, page 5

Vol. 64, No. 7 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

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

Farmington Hills, Michigan

FREDRIC DAUM, MD

Sacramento, California

Mineola, New York

PETER R. MCNALLY, DO

STEVEN M. FABER, MD Elizabeth City, North Carolina

RONNIE FASS, MD Cleveland, Ohio

BARBARA B. FRANK, MD Philadelphia, Pennsylvania

FRANK G. GRESS, MD Brooklyn, New York

Fort Carson, Colorado

TARUN MULLICK, MD St. Charles, Illinois

JOEL E. RICHTER, MD Tampa, Florida

DAVID ROBBINS, MD New York, New York

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Gainesville, Florida

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Memphis, Tennessee

New York, New York

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LETTER TO THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

FDA on FMT

Web Comment

Re: “Fecal Microbial Transplantation: An Increasingly Important Alternative for the Treatment of C. difficile,” by Allen Kamrava, MD, MBA, and Gary H. Hoffman, MD. Gastroenterology & Endoscopy News April 2013;64:6,8,12. Fecal microbial transplantation (FMT) is clearly a solution to Clostridium difficilee infection—after the new FDA announcement, do you believe this will increase the number of clinics offering FMT, professionally or otherwise? I am still not clear what the FDA is targeting to do. —“sanja” Via website June 14, 2013

Dear Reader, Thank you for your aptly timed question on this topic. The FDA regulation on FMT is discussed in the article on page 3 of this month’s issue: “FDA Moves To Regulate Fecal Microbial Transplantation.” Happy reading! Cynthia J. Gordon, PhD Managing Editor Gastroenterology & Endoscopy News

Correction Re: “FDA Approves New TNF Inhibitor, Golimumab, for Ulcerative Colitis,” by Monica J. Smith. Gastroenterology & Endoscopy News June 2013;64:12-13. In the aforementioned article, it was incorrectly stated that golimumab (Simponi, Janssen Biotech, Inc.), approved May 15 for the treatment of moderate to severe ulcerative colitis (UC) in adults, is administered intravenously. Golimumab, the third biologic therapy to be approved for the treatment of UC, is administered by subcutaneous injection. Additionally, the article stated that golimumab is marketed by Janssen Ortho Biotech, Inc.; the correct name of the company is Janssen Biotech, Inc. For more detailed information about golimumab, visit www. simponi.com.

FMT continued from page 3

Dr. Brandt said, “About 25,000 patients per year die of C. difficile infection in the United States. If you went over to each of them and said, ‘You can die from the C. difficile or you might die 20 years from now from a disease you might contract from the fecal transplant,’ what would most of them answer? “I do agree with the FDA that FMT therapy should be restricted to C. difficile infection, with use of a standard protocol for testing the recipient and donor and administering the transplant. I also believe that the results of every FMT should be entered into a central registry where the data can be periodically reviewed.” However, he said, “paperwork for the registry should be minimal so it doesn’t place an administrative burden on the already overworked physician.” ■ Dr. Brandt and Mr. Allen reported no conflicts of interest.

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Experts’ Picks:

The Best of Digestive Disease Week 2013: Part 1 COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy Newss asked three 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 three experts in the field. Manoop S. Bhutani, MD Professor of Medicine and Experimental Diagnostic Imaging Adjunct Professor of Biomedical Engineering Director of Endoscopic Research and Development Department of Gastroenterology, Hepatology and Nutrition University of Texas MD Anderson Cancer Center Houston, Texas

Validation of 2012 Modified Sendai Criteria for Predicting Risk of Cancer Development in Pancreatic Cysts (Lawson RD et al)

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Investigators at a single center set out to validate the clinical utility of the 2012 modified Sendai criteria. The criteria use clinical, radiographic and endoscopic ultrasound (EUS) features to stratify patients with cystic lesions of the pancreas (CLP) who may be at risk for developing pancreatic cancer. Researchers retrospectively reviewed data from 165 patients, 70% of whom were asymptomatic and had been referred for EUS evaluation of CLP. Patients were an average age of 68 years, and 61% were women. Those included in the analysis did not have suspected or diagnosed acute pancreatic pseudocysts or pancreatic cancer at the time of initial EUS. The researchers divided patients into two groups based on the modified Sendai criteria: Patients were classified as high risk if they showed signs of jaundice and had a pancreatic duct 5 mm in diameter or larger, a cyst 30 mm in diameter or larger and a mural nodule. Individuals without these features were considered to be at low risk for developing pancreatic cancer. Of the 58 patients who met the high-risk criteria, 9% developed pancreatic cancer during an average of three years of follow-up. In contrast, 1% of the 107 patients stratified as low risk developed pancreatic cancer (P=0.02). P Additionally, 85% and 63% of highrisk patients survived at three and five years, respectively, compared with 93% and 87% of low-risk patients (P=0.08). P Three of the high-risk patients succumbed to complications of pancreatic cancer. Dr. Bhutani: Pancreatic cysts are an increasingly important clinical problem. They are being detected with growing frequency due to widespread application of computed tomography (CT) and magnetic resonance imaging (MRI). A pancreatic cyst is identified in approximately 2% to

10% of individuals undergoing these imaging studies. Among the many controversies and emerging concepts regarding the management of patients with CLP is the appropriateness of the Sendai international guidelines, which were recently updated in Fukuoka (Tanaka M et al. Pancreatologyy 2012:12;183-197). The new Fukuoka guidelines clearly state that all of the items included in the Sendai criteria have only a low level of supporting evidence. Thus, they should be considered a “consensus” rather than an “evidence-based” guideline. Studies like this one by Lawson et al are extremely important because they validate the new guidelines. We still need to learn a lot more about the best strategies for management of pancreatic cystic lesions, and as results like these emerge we may revise the guidelines to be more evidence-based.

combination treatment with chem motherapy/ radiation.

Dr. Bhutani: Despite the 40% risk reduction assocciated with EUS in patiients with esophageal caancer, it is surprising thaat only 10% of the poopulation studied here underwent EUS. At MD Andersoon Cancer Center, EUS is an iintegral t l partt of evaluating esophageal cancer stage: The procedure complements cross-sectional imaging and plays an important role in making treatment deciUnder-Utilization of Endoscopic sions, which is done through discussions with thoUltrasonography (EUS) in Esophageal racic surgeons, medical and radiation oncologists, Cancer (EC) Despite Leading to Improved radiologists, pathologists and endosonographers. Survival Rates: Results From a Population-Based I encourage Dr. Wani and his colleagues to try Study (Wani S et al) to understand the reason for underutilization of EUS. Is it an access Researchers evaluated issue, reflecting a shortage of trained ‘At MD Anderson Cancer data from 5,247 patients endosonographers? Is there a lack Center, EUS is an integral diagnosed with esophaof education among gastroentergeal cancer between 1995 ologists, oncologists and surgeons part of evaluating and 2008 and registered regarding the clinical value of EUS esophageal cancer in the Surveillance, Epidein esophageal cancer? Or, is there a miology and End Results perception that EUS has no effect stage: The procedure (SEER) Medicare-linked on outcomes in patients with esophcomplements crossdatabase. They docuageal cancer? sectional imaging and mented rates of EUS and correlated these with date plays an important role of diagnosis, site of cancer, Phase I Trial in making treatment cancer histology, extent of of Endoscopic disease, initial treatment Ultrasound (EUS) Guided decisions.’ received and demographic Intratumoral Vaccination —Manoop S. Bhutani, MD characteristics. AdditionWith Recombinant Panvac-F ally, they compared survival and Systemic Panvac-V in rates among those who did Patients With Locally Advanced and did not undergo EUS during the month before, and Pancreatic Cancer (Repaka A et al) three months after, the date of cancer diagnosis. The investigators found that 10% of patients under- The recombinant poxvirus vaccine Panvac encodes went EUS within the four-month time frame. EUS was tumor antigens carcinoembryonic antigen and MUC-1 significantly more common among patients who were and the immune costimulatory antigens B7, leukocyte younger, were white and had esophageal adenocarcinoma function-associated antigen-3 and intercellular adhe(EAC). Additionally, patients who underwent EUS were sion molecule-1. It has shown efficacy in treating solid 46%, 40% and 39% more likely than those who did not colorectal and pancreatic tumors in mice (Akagi J et al. undergo EUS to be alive at one, three and five years fol- J Immunother 1997;20:38-47). lowing diagnosis, respectively. These survival differences This Phase I trial evaluated two dose levels of EUSheld up regardless of cancer stage, with the exception of guided local treatment in combination with systemic carcinoma in situ. EUS also was associated with a higher treatment in 13 patients with locally advanced inoperalikelihood of treatment with endoscopic mucosal resec- ble pancreatic adenocarcinoma. Local therapy consisted tion/ablation, chemotherapy, esophageal resection and of two EUS-guided fine-needle injections of Panvac-F,

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a fowl pox vector vaccine: Seven patients received 108 patients to undergo colorectal cancer (CRC) screening diagnostic utility of the PillCam SB2 (Given Imaging) plaque-forming units (PFUs) of the local injection and (55.7%), polyp surveillance (19.5%) or diagnostic colo- with the CapsoCam (CapsoVision), a capsule endoscope six received 109 PFUs. This was followed by systemic noscopy (24.8%) between January 2012 and March that offers 360-degree lateral viewing of the small bowel. therapy for up to 71 days: Systemic treatment included 2013. Eighty-eight patients underwent conventional Investigators asked 73 consecutive patients with one subcutaneous injection of Panvac-V (2×108 PFU), colonoscopy followed immediately by Fuse colonoscopy, obscure bleeding to ingest both capsules, one hour a vaccinia virus, along with four subcutaneous booster and 97 patients underwent the two procedures in reverse apart. Thirteen patients were excluded from the study injections of Panvac-F, in combination with granulocyte order. The same endoscopist performed both examina- because of technical issues, including five CapsoCam macrophage colony-stimulating factor. tions. Patients were a mean age of 56 years, and 101 capsules that were not returned by the patients, five At the time of abstract submission, two recipients of were women. CapsoCam recording failures, one uningested Capsothe low dose had survived at 15 and 30 months after Using traditional colonoscopy first, endoscopists Cam, one uningested PillCam SB2 and one PillCam treatment initiation. Three recipients of the high dose detected 28 adenomas, with Fuse colonoscopy reveal- SB2 recording failure. were alive at two, eight and 10 months. Two patients ing an additional 20 adenomas. In the 97 patients who Of the 60 patients who had complete examination in the low-dose cohort experienced rapid progression of underwent Fuse colonoscopy first, endoscopists detected data, the CapsoCam and PillCam SB2 yielded conlocal disease and were removed 61 adenomas, with cordant diagnoses in 36.6% of patients and concordant from the study after two weeks; conventional colo- negative findings in 45% of patients. The two devices those patients died at two and noscopy revealing yielded conflicting diagnoses in 18.3% of patients, ‘This Phase I study of intratumoral six months following trial onset. an additional five including six cases where only the PillCam SB2 sugThe remaining patients died adenomas. gested a positive diagnosis and five in which only the vaccination is a bold attempt to reach between 3.3 and 28 months after R e s e a r c h e r s CapsoCam suggested a positive diagnosis. The two the elusive goal of improving survival treatment began. determined the devices had similar diagnostic yields, but the Capsoin patients with pancreatic cancer.’ No patients with only local adenoma miss rate Cam revealed angiectasis in two patients in whom the disease at study onset experiof conventional PillCam SB2 did not (P<0.01). —Manoop S. Bhutani, MD enced progression to metastatic colonoscopy was The CapsoCam recordings required a mean 32 disease. 41.7% compared minutes to read compared with 26.2 minutes with the with a miss rate PillCam SB2. Dr. Bhutani: of 7.6% with Fuse (P<0.0001). Additionally, the increPancreatic cancer remains a lethal disease with mental adenoma detection rate with Fuse was 71.4% Dr. Mergener: an overall dismal prognosis and few long-term survi- compared with 8.2% with traditional colonoscopy Similar to the situation with the two colonoscopes vors. The concept of injecting anti-tumor agents into (P<0.0001). described above, current small bowel video capsule endothe pancreas using EUS in a safe and minimally invasive The median time to cecal intubation using conven- scopes have a limited field of view, approximately 160 fashion has intrigued endosonographers for a number tional and Fuse colonoscopy was 5.1 and 4.8 minutes, degrees. Several studies have demonstrated miss of years. Agents such as activated T lymphocytes, den- respectively, and the median withdrawal time was 5.6 rates for small bowel pathology, including neodritic cells and oncolytic viruses, as well as gene transfer and 6.2 minutes, respectively plasms, of approximately 20% using TNFerade (GenVec, Inc.), have been attempted (P<0.0001). Total procedure to 30% with current video with initially promising results; however, none of these times were a median 12.2 capsule endoscopy. The newly ‘CapsoCam [includes] four procedures ultimately had a significant effect on survival. and 14.5 minutes with condeveloped CapsoCam seeks cameras on its sides, thereby This Phase I study of intratumoral vaccination is a ventional and Fuse colonosto address this shortfall by allowing a circumferential bold attempt to reach the elusive goal of improving sur- copy, respectively (P<0.001). including four cameras on its vival in patients with pancreatic cancer. We hope subsides, thereby allowing a cirview of the entire small bowel sequent studies of this therapy will show an increased Dr. Mergener: cumferential view of the entire mucosa.’ survival rate. If they do, there may be the potential to We know from numersmall bowel mucosa. Addicombine this therapy with other treatment modalities, ous studies that identifying tionally, images are stored “on —Klaus Mergener, MD, PhD, MBA such as radiation and systemic chemotherapy, or to use colon polyps and early canboard,” and no external elecit as a preoperative neoadjuvant therapy to make a sig- cers reduces mortality from trodes or data transmission nificant impact in treating this devastating disease. ■ CRC. We also know that systems are needed. However, polyp detection rates vary widely between colonosco- the patient is required to retrieve and return the capsule Dr. Bhutani reported no relevant conflicts of interest. pists, and that lesions that are located behind folds are for image analysis. particularly challenging to identify. This prospective, multicenter comparative trial in It makes intuitive sense that an instrument with supe- patients with obscure bleeding concluded that Capsorior optics, such as the Fuse endoscope, could improve Cam found more small bowel angiodysplastic lesions Klaus Mergener, MD, the yield of colonoscopy. However, because of inves- compared with the PillCam SB2. The simultaneous PhD, MBA tigator bias and the inability to conduct this trial in a reading of four capsule images is not intuitive, however, blinded fashion, the current data need to be reproduced and further studies will need to confirm these findings Director of GI Hospitalist Services by independent investigators, and more needs to be and assess issues such as reading time, miss rates and Digestive Health Specialists learned about the reliability and cost of this particular patient acceptance in more detail. Tacoma, Washington endoscope system, as well as maintenance and service issues, before most endoscopy centers will feel comfortFinal Results of a Phase II, Open able switching to this new product. Label, Study Investigating Polyp Now that the need for improved optics is increasingly and Adenoma Detection Rate After Single Oral Comparing Traditional Forward-Viewing recognized, one can anticipate other equipment manu® Dose of Methylene Blue MMx Modified Release Colonoscopy with “Full Spectrum facturers redoubling their efforts to improve the field of Tablets Administered to Subjects Undergoing Endoscopy”: A Randomized, Multicenter Tandem view on their instruments as well. Outpatients Colonoscopy (Repici A et al) Colonoscopy Study—The FUSE Study (Gralnek IM et al) This study documented the detection rates of polyps Prospective First Comparison of an and adenomas in 96 consecutive patients who underAxial and a Lateral Viewing Capsule The Full Spectrum Endoscopy (Fuse) colonoscope went outpatient colonoscopy and received methylene (EndoChoice) provides a 330-degree view of the colon Endoscopic System in Patients with Obscure blue (MB)-MMX, an oral formulation containing 25 and has the identical physical dimensions of a standard Digestive Bleeding (Pioche M et al) mg of colon-release MB. Patients were asked to follow colonoscope. Researchers in three countries enrolled 185 Researchers from four sites in France compared the see Best of DDW, page 10

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Colonoscopy Quality Improvement: Quality Indicators and Benchmarks Douglas K. Rex, MD, FACP, FACG Director of Endoscopy Indiana University Hospital Professor Division of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis, Indiana

Table. High-Yield Quality Indicators of Colonoscopy-Based Screening and Surveillance for CRC and Suggested Interventions To Improve Performance Quality Indicator

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the percentage of screening exams in which at least one adenoma or CRC is detected, on the incidence of missed continued from page 7 CRC diagnoses. standard pre-colonoscopy bowel cleansing instructions The investigators identified patients in the Kaiser and received 100 mg of MB-MMX during and after database who had undergone colonoscopy for any indibowel cleansing. Individuals were a mean 58.8 years of cation between 1998 and 2010, were aged 50 years or age, and 40 were men. older, and whose iniAccording to the researchtial colonoscopy did ers, 79% of patients achieved not yield a diagnosis “adequate” bowel cleansing. of CRC. The analy‘This study provides an example MB-MMX led to consistent sis included 316,334 of a simple intervention, which, staining in most patients, and colonoscopy exams if confirmed in further studies was most effective in the right performed by 139 gasand transverse colon. Endostroenterologists, all to be effective and safe, may copists detected at least one of whom were expesignificantly alter our clinical polyp and at least one adenoma rienced endoscopists in 63.5% and 46.9% of patients, who had performed approach to colonoscopic respectively. The mean adenoma at least 300 colonosexaminations in size was 7.57 mm, and 41.7% of copies, including 75 patients with IBD.’ adenomas were less than 10 mm. screening colonoscoMB-MMX was not associated pies, during the study —Klaus Mergener, MD, PhD, MBA with adverse events, the researchperiod. After an initial ers reported. colonoscopy, 716 of the patients received a Dr. Mergener: CRC diagnosis. Patients were followed for 10 years, or This study provides an example of a simple until the performance of another colonoscopy without a intervention, which, if confirmed in furdiagnosis of CRC, a diagnosis of CRC, termination of ther studies to be effective and safe, may s i g - Kaiser health plan membership or until Jan. 31, 2011. nificantly alter our clinical approach to colonoscopic In statistical analyses controlling for predictors of examinations in patients with inflammatory bowel risk for CRC, including examination type, sex, age, disease (IBD). A 2010 medical position statement by race, family history of CRC and Charlson comorbidthe American Gastroenterological Association on the ity scores, the researchers found that endoscopists with diagnosis and management of colorectal neoplasia in lower ADRs were more likely to diagnose CRC subpatients with IBD noted that the sensitivity for detect- sequent to the initial colonoscopy than endoscopists ing dysplasia by chromoendoscopy is higher than that with higher ADRs. Compared with endoscopists in the of white light endoscopy, and it recommends that chro- highest ADR quartile (32.1% or higher), endoscopists moendoscopy with directed biopsies be done if endos- with ADRs less than 20.3%, ADRs between 20.3% and copists have experience with this technique (Farraye 25.2%, or ADRs between 25.3% and 32% were 1.74, FA et al. Gastroenterology 2010;138:738-745). How- 1.52 and 1.31 times, respectively, more likely to diagnose ever, dye spraying during colonoscopy is cumbersome a patient with CRC after an initial screening. Distal or and time-consuming, and is therefore not widely per- proximal location of CRC and patient gender did not formed in today’s clinical practice. Administering the alter the correlation between ADR and CRC diagnosis, dye orally, in tablet form, may represent a significant the researchers found. advantage if it results in the same degree of enhancement of colon pathology. Larger-scale, prospective tri- Dr. Sharma: als are ongoing to confirm these early results. ■ Identifying quality indicators in gastroenterology is a hot topic, and the issue has gained importance as physiDr. Mergener has received research support from cians are increasingly held accountable not only for the CapsoVision, GI View, Intromedic and Olympus. number of procedures they perform but also for conducting quality examinations. Some of these quality measures have been honing the quality of endoscopy, and one quality measure in this domain is ADR, which Prateek Sharma, MD looks at the percentage of patients coming in for colonoscopy who are diagnosed with at least one adenoma. Professor of Medicine The researchers, using a large health system database University of Kansas Medical School and thousands of colonoscopies, found a linear relationKansas City, Kansas ship between ADR and a finding of CRC. Similar findings were reported in a study from Europe, where researchers found ADR was an independent predictor of the risk for interval CRC after screening colonoscopy (Kaminski MF et al. N Engl J Medd 2010;362:1795-1803).These findings emphasize Physician Adenoma Detection Rate that ADR indeed appears to be a reasonable and useful Variability and Subsequent Colorectal quality indicator in colonoscopy. Cancer Risk Following a Negative Colonoscopy (Corley DA et al) The diagnostic Yield for detection Researchers studied the Kaiser Permanente Northern of Barrett’s Dysplasia by Advanced California health care system database to determine Imaging with targeted biopsies compared to the effect of adenoma detection rate (ADR), defined as

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conventional imaging with random biopsies: Meta Analysis and Systematic Review (Qumseya BJ et al) This systematic literature review included 14 studies comparing the diagnostic yield of conventional endoscopy with random biopsy to either chromoendoscopy or virtual chromoendoscopy with targeted biopsies in detecting Barrett’s esophagus (BE)-related dysplasia. The studies included a total of 843 patients with BE. Statistical analysis revealed that the use of either chromoendoscopy or virtual chromoendoscopy with targeted biopsies increased the diagnosis of esophageal dysplasia or cancer by 35% compared with the use of conventional imaging and random biopsy (P<0.0001). The researchers also found that conducting more biopsies improved the diagnostic yield of advanced imaging with targeted biopsies, although the trend was not statistically significant. Dr. Sharma: A number of new imaging modalities, including chromoendoscopy and virtual chromoendoscopy, have been used in patients with BE, but data on whether or not they improve detection of dysplasia or cancer have been conflicting. Past studies have been single-center or have included small numbers of patients. This meta-analysis pooled data from multiple studies and aggregated a significant sample size for evaluation. The data revealed that targeted biopsy added a significant diagnostic yield compared with a standard biopsy protocol. The data provide the gastroenterology community with solid evidence that we are at a point where we can begin using these imaging technologies routinely to help target our biopsies. More importantly, it tells us that if we perform targeted biopsies, we will be able to diagnose more patients with BE-related dysplasia.

‘The data revealed that targeted biopsy added a significant diagnostic yield compared with a standard biopsy protocol [and] provide the gastroenterology community with solid evidence that we are at a point where we can begin using these imaging technologies routinely to help target our biopsies.’ —Prateek Sharma, MD

A Clinical Prediction Model to Risk-Stratify Patients with Barrett’s Esophagus (BE): Results From a Large, Multicenter Cohort (Giacchino M)

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A team of investigators in several centers prospectively collected data from 3,677 patients with BE in an effort to identify risk factors associated with progression to high-grade dysplasia (HGD) or EAC. Most patients were white men; mean body mass index (BMI) was 28.3 kg/m2; mean age was 61 years; and mean length of BE see Best of DDW, page 28

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Colon Capsule Endoscopy ‘Not on Par’ With Colonoscopy BY CAROLINE HELWICK ORLANDO, FLA.—Colon capsule endoscopy (CCE) with the PillCam COLON 2 appears “adequate” for screening patients who are not candidates for optical colonoscopy (OC), but it is “not on par” with the gold standard, according

to Douglas K. Rex, MD, professor of medicine at Indiana University School of Medicine and director of endoscopy at Indiana University Hospital, both in Indianapolis. Dr. Rex presented the results of a comparative study of the two modalities at the 2013 Digestive Disease Week meeting. “PillCam COLON 2 had high

Table. False-Negatives in Colon Capsule Endoscopy

sensitivity for identifying patients with conventional adenomas greater than or equal to 6 mm among average-risk patients aged 50 to 75 years, but it was less effective in identifying patients whose only lesions greater than 6 mm were serrated,” Dr. Rex said. The second-generation PillCam capsule (PillCam COLON 2; Given

Histology of Patients With Largest Lesion False-Negative Reports ≥6 mm, % Conventional adenoma

Sessile serrated 26 polyp Hyperplastic polyp

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Adverse Reactions Hypersensitivity Reactions: Unpredictable adverse reactions (i.e. hypersensitivity, including anaphylaxis) are extremely rare. Localized allergic reactions may occur after prolonged or repeated use of any aminobenzoate anesthetic. The most common adverse reaction caused by local anesthetics is contact dermatitis characterized by erythema and pruritus that may progress to vesiculation and oozing. This occurs most commonly in patients following prolonged self-medication, which is contraindicated. If rash, urticaria, edema, or other manifestations of allergy develop during use, the drug should be discontinued. To minimize the possibility of a serious allergic reaction, Cetacaine preparations should not be applied for prolonged periods except under continual supervision. Dehydration of the epithelium or an escharotic effect may also result from prolonged contact. Precaution: On rare occasions, methemoglobinemia has been reported in connection with the use of benzocaine-containing products. Care should be used not to exceed the maximum recommended dosage (see Dosage and Administration). If a patient becomes cyanotic, treat appropriately to counteract (such as with methylene blue, if medically indicated). Use in Pregnancy: Safe use of Cetacaine has not been established with respect to possible adverse effects upon fetal development. Therefore, Cetacaine should not be used during early pregnancy, unless in the judgement of a physician, the potential benefits outweigh the unknown hazards. Routine precaution for the use of any topical anesthetic should be observed when Cetacaine is used. Contraindications Cetacaine is not suitable and should never be used for injection. Do not use on the eyes. To avoid excessive systemic absorption, Cetacaine should not be applied to large areas of denuded or inflamed tissue. Cetacaine should not be administered to patients who are hypersensitive to any of its ingredients or to patients known to have cholinesterase deficiencies. Tolerance may vary with the status of the patient. Cetacaine should not be used under dentures or cotton rolls, as retention of the active ingredients under a denture or cotton roll could possibly cause an escharotic effect. Routine precaution for the use of any topical anesthetic should be observed when using Cetacaine. Rx Only. Made in U.S.A. © 2013 Cetylite Industries, Inc. All rights reserved. Information is summary in nature and subject to change. Cetacaine and Cetylite are registered trademarks of Cetylite Industries, Inc. All other copyrights are the property of their respective owners.

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‘Given the capsule’s suboptimal detection of serrated lesions, along with technical exclusions, this examination is not on par with colonoscopy.’ —Douglas Rex, MD Imaging) has more sensitivity than the first-generation capsule, largely because of its varying frame speed, which increased from four to 35 frames per second when motion is detected. The angle view also increased from 156 to 172 degrees, and the capsule has an improved data recorder, Dr. Rex said. The multicenter study presented by Dr. Rex is the largest of three studies of the PillCam COLON 2. Its goal was to assess the accuracy and safety of the device compared with OC for identifying patients with lesions greater than 6 mm. The study’s 884 participants were an average-risk screening population, aged between 50 and 75 years. They first underwent CCE, and four to six weeks later, underwent OC with the endoscopist blinded to the CCE result. OC was repeated if CCE found a “false-positive” lesion of at least 6 mm. Colonoscopy performance was determined on a per-patient basis, with lesions matched by location (within the same or adjacent segments) and size. Non-adenomas detected by CCE were reported as a false-positive CCE event. Of the 884 patients enrolled, 689 were included in the analysis. The study excluded 195 patients (22%) for a number of reasons, including inadequate bowel cleansing, delayed or overly rapid transit times, protocol violations and patient withdrawals. “Median segmental and total transit times were both much shorter in this study, presumably because oral sulfate solution was substituted for sodium phosphate, due to safety concerns,” Dr. Rex explained.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Overall excretion rate for CCE was 91%, and 80% of participants had adequate bowel preparation. For OC, mean withdrawal time was 10.6 minutes in patients with no lesions, and 93% had adequate colon cleansing.

Per-Patient Capsule Performance With CCE, 16% of patients had adenomas of at least 6 mm (n=107) and 6% had adenomas of at least 10 mm. This amounted to a sensitivity of 88% and 92%, and specificity of 82% and 95%, respectively, Dr. Rex reported. “Lesions that were serrated, detected by capsule, were considered false-positives for this calculation,” he added. The prevalence of patients with polyps greater than 6 mm in size was 28%, and sensitivity was lower in this case, 81%; specificity was 93%. “Examining the false-negatives, we see a disproportionate percentage of patients were accounted for by lesions in the serrated class,” Dr. Rex said (Table). “A number of lesions appeared to be true lesions but were not verified as true and were counted as false-positives,” he added. Overall, the number of lesions 6 mm or larger was comparable between CCE (n=392) and OC (n=368), as it was for polpys 10 mm or larger (n=111 and n=114, respectively). OC detected four cancers in four patients, which were 10 to 80 mm. All four were detected by CCE on a per-patient basis. One cancer was not detected by the central CCE reader. This patient had a 10-mm adenocarcinoma in the sigmoid colon, which was visible on subsequent rereading, as well as two cecal lesions— an 11-mm tubular adenoma and a 7-mm hyperplastic polyp—both reported by the capsule reader, Dr. Rex said. There were no serious adverse events (AEs) with CCE and with OC. One patient was hospitalized for abdominal pain that resolved.

Issues With PillCam COLON 2 Dr. Rex said the study revealed some difficulties with CCE that should be appreciated, especially the higher rate of technical difficulties and the capsule’s inability to detect serrated lesions. Technical issues included the amount of preparation required, the inadequacy of bowel preparation in many patients and the capsule’s rapid transit time, factors not seen with OC, he noted. “Given the capsule’s suboptimal detection of serrated lesions, along with technical exclusions, this examination is not on par with colonoscopy,” he said. “However, it did very well in detecting patients with conventional adenomas and it could be an adequate exam for patients who are not candidates for colonoscopy. While

DDW 2013

Walter Coyle, MD, head of the Division of Gastroenterology/Hepatology at Scripps Clinic in La Jolla, Calif., enough for screening patients who can’t safely undergo said that the PillCam is “not ready for colonoscopy, or don’t want it, then it can be useful.’ prime time” but it does appear to have a —Walter Coyle, MD role, especially for patients who do not want colonoscopy and because concerns about radiation exposure have lessened that was perhaps the major technical States, where we take colonoscopy per- the enthusiasm for virtual colonography. issue, the capsule also did not perform formance very seriously, and given the “It’s not going to be as good as colonoswell in detecting lesions of the serrated fact that a fair number of patients were copy, but if it’s close enough for screening class, which was not looked at in ear- excluded for technical reasons, right now patients who can’t safely undergo cololier studies,” he told Gastroenterology & this test cannot be considered equivalent noscopy, or don’t want it, then it can be Endoscopy News. “I think in the United to colonoscopy.” useful,” Dr. Coyle said. ■

‘It’s not going to be as good as colonoscopy, but if it’s close

DDW 2013

Fuse continued from page 1

that Fuse is an advance in colonoscopy technology.” At a press briefing held at the DDW meeting, Dr. Gralnek indicated that interest in the technology at the meeting had been “huge.” Dr. Gralnek said, “We are all becoming aware that we miss adenomas. We need to do a better job at finding them, and we need better technology for this.” The Fuse system, developed by EndoChoice, shares similar technical features of standard colonoscopes but allows a 330-degree view of the colon, much broader than the 170-degree viewing angle of traditional colonoscopes. The Fuse colonoscope employs multiple imagers and projects the expanded view on three corresponding screens, instead of the one display used with TFV. With TFV, up to 31% of adenomas can be missed, primarily due to inadequate visualization of the proximal side of colonic folds and anatomic flexures within the colon (Siersema PD et al. World J Gastroenteroll 2012;18:34003408). The Fuse system fulfills the need for technology that will expand visualization, Dr. Gralnek said.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

adenoma detection rate (ADR) per colonoscopy type at first colonoscopy was numerically, but not significantly, improved with Fuse (Table). Dr. Gralnek noted that the study was powered as a per-lesion analysis and not as a per-patient analysis; therefore, perpatient ADRs coul d not be statistically evaluated. More than 1,000 patients would need to be studied to evaluate ADR as an end point on a per-patient basis, he explained.

Acceptance Among Gastroenterologists David Lieberman, MD, professor of medicine and chief of the Department of Gastroenterology and Hepatology at Oregon Health & Science University, in Portland, called the Fuse system a “very exciting technology.”

Table. Outcomes in Patients Undergoing Tandem Colonoscopy With TFV Versus Fuse TFV

Fuse

P Value

Additional adenomas detected (per lesion)

8.2%

71.4%

P<0.0001

Adenomas missed (per lesion)

41.7%

7.6%

P<0.0001

False-negative colonoscopies (per patient)

5.7%

P=0.02

ADR per colonoscope type at first colonoscopy

27.3%

33.0%

P=0.40

ADR, adenoma detection rate; Fuse, Fuse Full Spectrum Endoscopy; TFV, traditional, forward-viewing colonoscopy l

‘Compared

Tandem Study Design In the randomized, multicenter trial of the Fuse system, investigators followed a tandem colonoscopy design in which same-day, back-to-back colonoscopies using Fuse and TFV were performed by the same endoscopist. During the American College of Gastroenterology/ American Society for Gastrointestinal Endoscopy (ASGE) Presidential Plenary Session, Dr. Gralnek presented results on 185 patients, whose indications for colonoscopy included screening (55.7%), surveillance (19.5%) and diagnostic evaluation (24.8%). Among 88 patients who received TFV as their initial colonoscopy followed by Fuse, 28 adenomas/cancers were detected on the first pass with TFV, and an additional 20 adenomas/cancers were detected on the second pass using Fuse. “This amounted to a 71.4% increase in the number of adenomas found with Fuse,” Dr. Gralnek reported. In contrast, among 97 patients initially scoped with Fuse, 61 adenomas/cancers were found on the first pass with Fuse, and only five additional adenomas were seen on the second pass with TFV, for an 8.2% increase in adenoma detection via the conventional approach. The difference in this comparison was highly significant (P<0.0001). Significant differences also were observed in rates of missed adenomas and false-negatives. Additionally, the

colonoscopy surveillance schedule—the interval for follow-up colonoscopy was shortened for 53.3% of those patients.

with traditional, forward-viewing colonoscopy, Fuse found significantly more adenomas, had a significantly lower adenoma miss rate and impacted colonoscopy surveillance recommendations.’ —Ian M. Gralnek, MD, MSHS

Most of the 20 adenomas that were initially missed by TFV in the study were sessile lesions in the right colon, primarily tubular adenomas, 1 to 5 mm. The five adenomas missed by Fuse on the initial pass were all sessile lesions, tubular subtype and 1 to 5 mm in diameter; two were located in the right colon, and three were in the left colon. Discussing the Fuse system at the DDW press briefing, Dr. Gralnek described the “feel” of the new device, specifically the three-screen viewing system. “I have done about 75 cases myself, and I became comfortable using Fuse after about five cases. I focus on the center video monitor, and my peripheral vision picks up polyps that appear on the side monitors. It’s very intuitive.” The findings could theoretically change surveillance recommendations for some patients. Of the 15 patients who had the 20 missed adenomas with TFV, the use of Fuse changed their

Dr. Lieberman drew an analogy between using the Fuse system and driving a car: “You look out your front window, but you can also see things out of the side windows, too, such as a pedestrian standing on the curb,” he explained. “That could be a polyp, and you can see what angle you need to have in order to make your turn.” He said the findings from the comparison study “suggest that you may see more polyps” using Fuse. Frank Sinicrope, MD, professor of medicine and oncology at Mayo Clinic, Rochester, Minn., also acknowledged the advantages of the device over TFV. “It is acknowledged that a major limitation of our current forwardviewing colonoscopes is that they do not allow visualization behind mucosal folds, which can result in missed polyps, or even cancers. This limitation is an important factor that reduces the

effectiveness of colonoscopy for cancer prevention,” he noted. The study by Dr. Gralnek showed Fuse to be superior to TFV for the detection of adenomas, with significantly fewer missed adenomas, Dr. Sinicrope added. Because ADR is a key quality metric, these are “important data,” he said. However, more information is needed regarding the risk features of these adenomas, he said. It is also important to determine if Fuse can increase the detection of flat polyps because these lesions may lead to interval cancers and contribute to the observed reduction in efficacy of TFV in the right versus the left side of the colon. “This will be important to demonstrate in future studies, he said. He added that although Fuse could represent a true advance, it also might detect more adenomas and polyps that are simply harmless. “Detecting more polyps and adenomas does not necessarily indicate that a reduction in cancer risk or mortality will result. Many small adenomas may never develop into cancers, whereas the detection and removal of advanced adenomas is expected to translate into the prevention of future cancers. However, better adenoma detection and complete removal are necessary steps for colorectal cancer prevention. “Despite these issues,” he concluded, “the Fuse colonoscope represents an important advance in endoscopic technology that improves ADR, and thereby the efficacy of colonoscopy.” Colleen M. Schmitt, MD, of Galen Gastroenterology in Chattanooga, Tenn., who moderated the DDW press conference where the results were presented, noted that the miss rate in the control group was “at the top of the reported range,” which could exaggerate the differences between the two approaches. However, she added, a difference of even half of what was reported would be “important.” Dr. Schmitt, who is president-elect of the ASGE, said that the findings should be replicated in a community setting, pointing out that the 71% increase in the number of adenomas found was achieved “by expert hands.” Studies are needed, she said, to determine the ADR with Fuse “in the hands of general practitioners,” although she predicted the outcomes “will probably be better than what we are achieving now.” ■ Dr. Gralnek has served on an advisory committee or review panel for Given Imaging and Motus GI, and has served as a consultant for AstraZeneca, Given Imaging and PeerMedical. Drs. Lieberman, Schmitt and Sinicrope indicated no conflicts of interest.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Low ADR Linked to Increased Risk for Interval CRC, Mortality BY CAROLINE HELWICK ORLANDO, FLA.—Proof that endoscopists need to increase their adenoma detection rates (ADRs) was provided by two studies presented at the Presidential Plenary Session of the 2013 Digestive Disease Week meeting. Investigators from Kaiser Permanente analyzed experienced endoscopists and found an association between the lowest ADRs and a significantly increased risk for interval colorectal cancers (CRCs) and related deaths. Douglas Corley, MD, from Kaiser Permanente in Oakland, Calif., noted that ADRs have been linked to interval cancers, but data are scarce on advanced cancers, location of the cancers and subsequent deaths after colonoscopy. “There are also no data on whether a threshold ADR exists that should be targeted for intervention,” Dr. Corley said. His study found, in fact, that there is no threshold at which the magnitude of protection plateaus. “Patients whose colonoscopies were performed by endoscopists with lower ADRs were more likely to be diagnosed with subsequent CRC than patients whose endoscopists had higher ADRs,” he said. “Cancer risk increased linearly with decreasing physician ADR, and there was no clear threshold above which there was no further improvement.

CRC death for every 1% difference in ADR,” he said. The inverse relationships were observed for men and women, distal and proximal interval cancers, early- and late-interval disease, and advanced-stage interval and interval CRC deaths. “Our findings support the validity of ADR as a quality metric for colonoscopy, and they support the evaluation of interventions to determine if improving ADR will improve outcomes,” said Dr. Corley.

the researchers identified CRCs in 2,659 patients, in whom 159 CRCs were diagnosed within six months to five years of a negative colonoscopy, and 91 CRCs within six months to three years. This yielded a missed/interval CRC rate of 6% for the five-year window and 3.5% for the three-year window, according to study author N. Jewel Samadder, MD, assistant professor of medicine, University of Utah School of Medicine. He noted that the large commu-

‘We found a 3% increase in interval CRC risk and a 4% increase in risk for CRC death for every 1% difference in ADR.’ —Douglas Corley, MD

Table. ADR Quartile, %

Hazard Ratio

95% Confidence Interval

<19

1.91

1.44-2.52

19-24

1.77

1.27-2.47

24-28

1.64

1.23-2.18

28-33

1.34

0.97-1.84

ADR, adenoma detection rate

Findings Could Inform Future Recommendations

Kaiser Permanente Database Dr. Corley and his colleagues evaluated the association between physician ADR quartiles and the risk for subsequent CRC among patients who were aged 50 years or older and who were monitored for up to 10 years after undergoing colonoscopy by 136 experienced endoscopists. Physician ADR was the percentage of screening examinations in which at least one adenoma or a CRC was detected. The outcome was CRC that occurred six months to 10 years after any colonoscopy that did not initially detect cancer. Investigators excluded CRCs that occurred within six months after the index colonoscopy. The investigators identified 314,872 colonoscopy examinations that yielded 712 post-colonoscopy interval cancers. Physician ADR was linked to these cancers as an independent predictor following a negative colonoscopy (Table). ADR quartiles also were linked to death from CRC, with a 2.63 hazard ratio (HR) for patients whose physicians fell into the lowest ADR quartile compared with the highest, Dr. Corley reported. “We found a 3% increase in interval CRC risk and a 4% increase in risk for

with a lower stage than detected cancers at diagnosis (P=0.03) and with a distinct survival advantage compared with detected CRCs (HR, 0.63; P<0.001). Patients with missed/interval CRCs also were found to have more adenomas (57% vs. 33%) and more advanced adenomas (25% vs. 4%) at their index colonoscopy compared with the overall population (P<0.001), Dr. Samadder added. In a validation study of 37 missed/ interval CRCs detected at one participating site, the investigators confirmed that gastroenterologists who reached the cecum 92% of the time and who reported adequate bowel preps in 92% of cases performed all the examinations. “This means that patient and endoscopist factors may not explain the occurrence of missed/interval CRCs,” he said. “The association with proximal tumor location, higher adenoma/advanced adenoma rates, lower cancer stage and survival advantage compared with detected CRCs suggest tumor biology may play an important role in these cancers,” Dr. Samadder said. “Our data support further exploring the role of family history, microsatellite instability and serrated pathways in tumorigenesis of missedinterval CRC.”

‘I think the data from these papers could influence the ADR that we specify in the updated position statement.’ —Philip Schoenfeld, MD, MSc

Utah Cancer Registry Also reported at the Presidential Plenary Session, researchers from the Huntsman Cancer Institute at the University of Utah, Salt Lake City, examined the rate and predictors of missed/interval CRCs in a population-based study of 126,936 individuals aged 50 to 80 years who underwent colonoscopies between 1995 and 2009. Merging this colonoscopy data set with the statewide Utah Cancer Registry that is part of the Surveillance, Epidemiology, and End Results network,

nity population derived from academic medical centers and community hospitals throughout the state “reflects usual clinical practice” in the United States. In examining tumor location, missed cancers were more likely to be located in the proximal colon, whereas detected cancers were more commonly found in the distal colon and rectum. In fact, CRC occurrence could be independently predicted by a proximal colon location (relative risk, 2.24 vs. other sites; P<0.001), Dr. Samadder said. Missed/interval CRCs were associated

Commenting on the study, David Lieberman, MD, professor of medicine and chief of the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland, said the study by Corley et al is “a purposeful effort to take a look at what is the key end point—cancer after colonoscopy—and how it is related to the performance of the endoscopist. This is a strong and important study that provides strong evidence that ADR is an important quality measure.” Philip Schoenfeld, MD, MSc, associate professor, Department of Internal Medicine at the University of Michigan in Ann Arbor, who is co-authoring the updated “Quality Indicators in Colonoscopy” position paper for the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy, said the studies provided “elegant and groundbreaking data” that could inform guidelines. “We have not upped the thresholds for recommending ADRs of 25% in men and 15% in women at screening colonoscopy, although I think the data from these papers could influence the ADR that we specify in the updated position statement,” he said. ■ None of the researchers reported any conflicts of interest.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Sedasys continued from page 1

system, called Sedasys, as a revolution in sedation, whereas others are more tempered in their enthusiasm. “The Sedasys system will address the growing preference for propofol sedation in gastroenterology by more closely matching the skill level of the sedation delivery team with the actual requirements of less complex cases,” said Daniel Pambianco, MD, medical director, Charlottesville Medical Research, in Virginia, and principal investigator of the system, in a press release. “The technology will empower health care facilities to more effectively use their limited resources to deliver greater value in the increasingly resource-constrained U.S. health care environment.” Dr. Pambianco is a paid consultant to Ethicon Endo-Surgery, Inc., a division of which, Sedasys, is marketing the Sedasys system.

The monitoring side of the system is calibrated for standard measures of anesthetic depth: minimal, moderate, deep and general sedation. Patients entering deep sedation stop responding to the verbal commands. A display shows the operator how many seconds elapse before the patient responds to the command, and if the operator does not respond to the monitor for six minutes, the system automatically slows the delivery of propofol to ensure that sedation remains minimal to moderate. “The six-minute delay provides a working interval with moderately sedated patients who stop responding before the system automatically slows propofol delivery and brings them back toward the middle of the moderate sedation range,” explained Steven L. Shafer, MD, professor of anesthesiology at Stanford S f dU University i i School S h l of Medicine, Calif.

Widespread adoption of the system is

sedation. When the device is turned off, the system calculates what the maintenance rate would be if it were turned back on. “The machine titrates propofol in a manner consistent with propofol’s pharmacokinetic profile,” Dr. Shafer said. “It changes the propofol dose in a more responsive and logical manner than simply turning a propofol infusion rate up and down.” A critical safety feature built into the machine is that infusion is linked to the pulse oximetry and capnography measures. “If the oxygen saturation starts to fall, the system will turn off the infusion and automatically instruct the patient to breathe deeply,” Dr. Shafer said. “If the patient takes a deep breath, and that’s all that’s required for the oxygen saturation to return to the normal range, then Sedasyys turns the propofol back on, but at a lower infusion raate.”

Anesthesiologists Reallocated, Not Replaced

contingent on its acceptance by

Dr. Shafer envisions Sedasys facilitating an appropriate allocation of anesthesia resources, and potentially ffostering stronger working relationships between endoscopists and anesthesiologists. He does not think the sysstem will replace anesthesiologists, who will always be neeeded in cases where patients require deep sedation or gen neral anesthesia or who are at higher risk. In fact, a requ uirement for facilities using the Sedasys system is the im mmediate availability of an anesthesia professional for consultation or assistance. “Bu ut in patients who don’t require an anesthesiologist, Sedasyys provides much of the monitoring and vigilance we briing,” Dr. Shafer said.

gastroenterologists, who may have economic and reimbursement concerns about Sedasys, and many of whom consider the anesthesiologist an essential part of the endoscopy team, even beyond the role as sedation provider.

Widespread adoption of the system, however, is contingent on its acceptance by gastroenterologists, who may have economic and reimbursement concerns about Sedasys, and many of whom consider the anesthessiologist an essential part of the endoscopy team, even beeyond the role as sedation provider. Anesthesiologists, too,, have questioned whether the FDA has addressed con ncerns they raised before the agency’s approval of the devicce.

Sedasys comes with a training

How It Works

and which patients require an anesthesia

Sedasys is indicated for the IV administratioon of 1% (10 mg/mL) propofol injectable emulsion foor the initiation and maintenance of minimal to mod derate sedation, as defined by the American Society off Anesthesiologists (ASA) Continuum of Depth of Sedation guidelines, in ASA physical status 1 and 2 patients. Simply put, Sedasys combines anesthesia monitoring and drug infusion into a computer-assisted, patient-centric system. The monitoring side keeps track of standard measuress for patients undergoing general anesthesia, such ass blood pressure, heart rate, electrocardiography, oxygen saturation and capnometry. It also includes a feature that gauges sedation level by the patient’s ability to respond to stimulation, the automated-responsiveness measure (ARM). The ARM device is strapped to the patient’s hand and vibrates every 15 seconds. There is also an earpiece worn by the patient that sends the verbal command, “Squeeze your hand.” If the patient does not respond to the command by squeezing the ARM device, it sends a stronger vibration and louder command, which becomes stronger and louder on the third time if the patient still has not responded.

professional.

program that includes guidance to help endoscopists understand which patients can undergo sedation with the device

The Sedasys system is the first computer-assisted, personalized sedation system for gastrointestinal endoscopy procedures. Photo courtesy of Ethicon Endo-Surgery, Inc.

On the infusion side, Sedasys follows an algorithm constructed to maintain a steady concentration of propofol, increasing and decreasing the rate of infusion as needed to keep patients in the moderate range of

Thee widespread adoption of Sedasys could allow moree endoscopists to use fast-acting propofol, thus allow wing them to perform more procedures in a day, Drr. Shafer added. “A faster recovery from sedation facilitates patient thrroughput while improving the experience for each patieent.” Sed dasys comes with a training program that includes guidance to help endoscopists understand which patients guidan can undergo sedation with the device and which patients require an anesthesia professional. “I expect that endoscopists who learn to use Sedasys will become much more aligned with the anesthesiologists in their clinic,” Dr. Shafer said. Lawrence B. Cohen, MD, clinical professor of medicine, Icahn School of Medicine at Mount Sinai, New York City, agrees that the device offers a novel alternative to the status quo. see Sedasys, page 18

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DDW 2013

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

Sedasys continued from page 16

â&#x20AC;&#x153;The idea of a computer-controlled delivery system for propofol that provides checks and balances for under- and oversedation, compared with a doctor delivering it by a syringe and estimating and approximating what the dose should be, is really unique and exciting from a clinical standpoint,â&#x20AC;? Dr. Cohen said. â&#x20AC;&#x153;But how itâ&#x20AC;&#x2122;s going to play out in the clinical world is a much bigger question that expands beyond its clinical utility. The question that I and many others have is not so much about the device, but rather the willingness of gastroenterologists to adopt it, given the current state of health care reimbursement.â&#x20AC;?

acceptance relates to efficiency, an important commodity in endoscopy, and one that relies partly on having a skilled and knowledgeable team to manage patients from the time they arrive through the time they are discharged. â&#x20AC;&#x153;In many endoscopy units throughout the country, the anesthesia specialist has become an integral component of the team,â&#x20AC;? Dr. Cohen said. â&#x20AC;&#x153;They may be the person who brings patients from the

pre-procedure area into the procedure area, and then into the post-procedure area. They help with the pre-procedure assessment, start the IV and so on. These activities contribute to both the efficiency and safety of endoscopy. While a machine can achieve sedation, it will not be helpful in performing those other tasks.â&#x20AC;? Thirdly, no one knows whether the majority of patients will want to participate in their own sedation.

â&#x20AC;&#x153;How many of the patients we see for endoscopy have conditions that preclude their involvement, whether their cognitive status is not sufficient to understand the instructions, or because they have an arthritic condition that makes it difficult to grasp and squeeze, or because they simply donâ&#x20AC;&#x2122;t want to be the one making decisions?â&#x20AC;? Dr. Cohen said. Finally, it seems that some anesthesiologists have qualms about the system.

Obstacles to Acceptance First, there is the cost. Up-front costs may be minimal, but as Dr. Shafer explained it, Sedasys intends to follow the Hewlett Packard printer business model, wherein the printers themselves are practically free and the company makes money on toner cartridges.

â&#x20AC;&#x2DC;If youâ&#x20AC;&#x2122;re the doctor who delivers the sedation and the

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

one who does the procedure, you can get paid for the procedure, but not for the sedation.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Lawrence B. Cohen, MD â&#x20AC;&#x153;It is my understanding that Ethicon Endo-Surgery intends to place Sedasys with endoscopists who want to deploy it, but Ethicon will retain ownership, and will make their money on the disposable components that accompany the use of each Sedasys system,â&#x20AC;? he said. There is also ambiguity over reimbursement. Sedasys requires that an anesthesiologist be immediately available on-site, and that availability needs to be reimbursed. Also, there is no fee structure for overseeing computer-administered propofol sedation. Classically, endoscopists have considered the cost of the sedation they administer during endoscopy an inherent part of the professional fee they receive. â&#x20AC;&#x153;If youâ&#x20AC;&#x2122;re the doctor who delivers the sedation and the one who does the procedure, you can get paid for the procedure, but not for the sedation,â&#x20AC;? Dr. Cohen said. â&#x20AC;&#x153;Payors wonâ&#x20AC;&#x2122;t pay the endoscopist who administers sedation, but many still pay anesthesiologists. Because [Sedasys] eliminates the anesthesiologist, itâ&#x20AC;&#x2122;s not clear where the reimbursement will be.â&#x20AC;? The second potential obstacle to

INDICATIONS AND USAGE UCERISâ&#x201E;˘ is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage of UCERIS is one 9-mg tablet to be taken once daily in the morning with or without food for up to 8 weeks.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS UCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS. WARNINGS AND PRECAUTIONS t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B glucocorticosteroid, general warnings concerning glucocorticoids should be followed. t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH existing tuberculosis, fungal, bacterial, viral, or parasitic

infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. t *ODSFBTFE TZTUFNJD HMVDPDPSUJDPJE TVTDFQUJCJMJUZ 3FEVDFE MJWFS function affects the elimination of glucocorticosteroids. t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Most common adverse reactions (incidence â&#x2030;Ľ2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. DRUG INTERACTIONS Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. USE IN SPECIFIC POPULATIONS )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT of hypercorticism.

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

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

‘There has been a groundswell of opposition to the device since its [premarket] approval. Apparently, the anesthesia societies have mounted a multipronged effort to restrict or circumscribe its use.’ —Lawrence B. Cohen, MD “There has been a groundswell of opposition to the device since its [premarket] approval,” Dr. Cohen said. “Apparently, the anesthesia societies have mounted a multipronged effort to restrict or circumscribe its use.” On May 15, the American Society of

Anesthesiologists (ASA) posted on their website that they had launched a threepronged strategy to address its members’ questions and concerns (available at www. asahq.org). In an email, John M. Zerwas, MD, president of the ASA, offered the following statement:

“The ASA established an Ad Hoc Committee on SEDASYS® that is charged with reviewing the FDA’s restrictions for use and conditions of approval for the device and determining whether the FDA addressed ASA’s concerns and recommendations raised in our previous formal communications to the FDA. ASA will convene a meeting with [ Johnson & Johnson] representatives and will initiate a strategy to engage the

UCERIS™:

A POWERFUL, LOCALLY ACTING STEROID1-3 t

MMX® technology targets delivery of budesonide throughout the full length of the colon1,2

3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

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

and placebo at 8 weeks—10.2% vs 10.5%, respectively1*

www.UCERIS.com CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index [EI] score) after 8 weeks of treatment.1 *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

FDA’s Center for Devices and Radiological Health to discuss ASA’s questions and explore an enhanced role for ASA with the FDA relative to this device and other future devices.” ■ Dr. Pambianco is a paid consultant to Ethicon Endo-Surgery, Inc. Dr. Shafer is chair of the Anesthesia Advisory Board guiding the development of the Sedasys System. Dr. Cohen reported no conflicts of interest.

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

Simeprevir continued from page 1

and simeprevir, an experimental oral, once-daily HCV NS3/4A protease inhibitor (PI). Results from the Phase III PROMISE study were presented at the 2013 Digestive Disease Week meeting (abstract 869b). The findings led Gregory Gores, MD, executive dean for research at Mayo Clinic, Rochester, Minn., to speculate that simeprevir will soon be added to the clinicianâ&#x20AC;&#x2122;s HCV treatment toolbox. BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections. Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTN BOE "ESFOBM 4VQQSFTTJPO t 4ZNQUPNT PG TUFSPJE XJUIESBXBM JO UIPTF QBUJFOUT USBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t *ODSFBTFE 4ZTUFNJD (MVDPDPSUJDPTUFSPJE 4VTDFQUJCJMJUZ t 0UIFS (MVDPDPSUJDPTUFSPJE &GGFDUT Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1. Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

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

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

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

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

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

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

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

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

â&#x20AC;&#x153;The surprising efficacy of simeprevir triple therapy in patients who had relapsed after prior RBV plus PEG-IFN therapy, and in patients with advanced liver fibrosis, along with its once-daily dosing, minimal drugâ&#x20AC;&#x201C;drug interactions and good safety profile, make it likely the drug will be approved by the FDA for use in HCV patients,â&#x20AC;? said Dr. Gores, who was not involved in the research. Eric Lawitz, MD, professor of medicine 0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

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

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

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

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

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

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

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

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

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

at the University of Texas Health Science Center and vice president of scientific and research development at the Texas Liver Institute in San Antonio, and his colleagues randomized 260 patients with HCV GT1 to receive the triple therapy and 133 similar patients to receive an oral placebo with PEG-IFN/RBV, both for 12 weeks, in a double-blind fashion. Simeprevir recipients who experienced a drop in HCV RNA below 25 IU/mL after four to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

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

1-UCE13033 V1

weeks of treatment and who had undetectable HCV RNA at 12 weeks received an additional 12 weeks of PEG-IFN/ RBV alone, whereas those who did not meet these criteria received an additional 36 weeks of PEG-IFN/RBV treatment, for a total of 48 weeks. All placebo recipients received 36 weeks of PEG-IFN/RBV after the initial 12 weeks of placebo plus PEG-IFN/RBV treatment. Dr. Lawitz reported that 77% of patients who received simeprevir experienced a rapid virologic response (RVR), and 79% had a sustained virologic response 12 weeks after treatment completion (SVR12). In contrast, 3% of placebo recipients achieved RVR, and 37% achieved SVR12 (P<0.001 for simeprevir vs. placebo).

â&#x20AC;&#x2DC;The surprising efficacy of simeprevir triple therapy in patients who had relapsed after prior RBV plus PEG-IFN therapy, and in patients with advanced liver fibrosis, along with its once-daily dosing, minimal drugâ&#x20AC;&#x201C;drug interactions and good safety profile, make it likely the drug will be approved by the FDA for use in HCV patients.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Gregory Gores, MD

SVR12 rates among various patient subgroups were higher in the simeprevir arm compared with the placebo arm, Dr. Lawitz reported. These included patients with METAVIR scores of F0-F2 (82% vs. 41%), METAVIR scores of F3 (73% vs. 20%), METAVIR scores of F4 (74% vs. 26%), HCV GT1aa (70% vs. 28%), HCV GT1b see Simeprevir, page 21

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

FDA Grants Priority Review to Simeprevir for Combination Treatment of HCV Genotype 1 About a week before the 2013 Digestive Disease Week meeting in May, Janssen Research & Development, LLC, announced the FDA priority review of its new drug application for simeprevir (TMC435), an investigational NS3/4A protease inhibitor administered as a 150 mg capsule once daily with pegylated interferon and ribavirin for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection in adult patients. Simeprevir is jointly developed by Janssen and Medivir AB for the treatment of HCV genotype 1 chronic infection in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking

the HCV protease enzyme that enables the hepatitis virus to replicate in host cells. The regulatory submission for simeprevir is supported by data from three pivotal Phase III studies: QUEST-1 and QUEST-2 in treatment-naive patients, and PROMISE in patients who have relapsed after prior interferonbased treatment.

The FDA grants priority review to medicines that may offer major advances in care, or provide a treatment option where no adequate therapy exists. Under the Prescription Drug User Fee Act, the FDA review will begin approximately 60 days after receipt of the application and will aim to be completed within six months from the beginning of the review period.

Janssen expects the FDA to complete its review by November 2013. —Based on a press release from Janssen Research & Development, LLC

ScopeGuide Simeprevir continued from page 20

(86% vs. 43%), interleukin-28 B (IL28B) genotype CC (89% vs. 53%), IL28B B genotype GT CT (78% vs. 33%) and IL28B genotype GT TT (65% vs. 19%; P<0.001 for all). Only 7% of simeprevir recipients required 48 weeks of treatment, and rates of on-treatment failure and post-treatment relapse with the drug were 3% and 19%, respectively, compared with 27% and 48% with placebo. There were no differences in serious adverse events in the simeprevir and placebo groups. Dr. Lawitz said the study participants were a difficult-to-treat population and included those with prior treatment failure and compensated and fibrotic liver disease. “Hepatitis C is a complex disease, and we need multiple treatment options in order to provide our patients with the best possible chance of successful therapy,” he concluded. ■ Dr. Lawitz has received research support from Abbott Laboratories, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Medtronic, Merck & Co., Novartis, Presidio, Roche, Santaris Pharmaceuticals, Scynexis and Vertex Pharmaceuticals. Dr. Gores has no conflicts of interest.

Real-time, 3D visualization of the scope conﬁguration inside the colon

ADVANCING THE ART OF ENDOSCOPY Contact your Olympus Endoscopy Account Manager, or call 800-848-9024.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Zulu Diet Protective Against Colorectal Cancer in African Americans BY DAVID WILD ORLANDO, FLA.—A study in which urban African Americans swapped diets with semirural South African Zulus for two weeks suggests that African Americans could lower their risk for colorectal cancer (CRC) by eating less meat and more dietary fiber, thereby encouraging the proliferation of groups of anti-inflammatory intestinal microbes. “It seems from our findings that the increased incidence of CRC among African Americans may be due to the diminished amount of microbial fermentation that is related to consumption of a diet dominated by dietary fat and animal protein,” said lead investigator Stephen J. O’Keefe, MD, MSc, medical director of the Small Intestinal Rehabilitation & Transplant Center and of the Clinical Nutrition Service in the Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh. His team presented the findings at the 2013 Digestive Disease Week meeting (abstract 1965). Dr. O’Keefe and researchers from

several countries set out to explore the role of diet in contributing to the risk for CRC in African Americans, the population with the highest rate of CRC and CRC-related mortality in the United States. In contrast, CRC is nearly nonexistent among rural Africans. The researchers asked 20 African Americans in Pittsburgh to exchange diets with 20 semirural Zulu South Africans for two weeks. Participants in the former group cut their meat consumption and added putu, a corn-based porridge that is rich in complex polysaccharides and starches and a mainstay of the Zulu diet, to their daily diet. Conversely, the South Africans stopped eating putu for two weeks and added 600 g of meat to their daily intake. Overall, the Western-style diet was composed of approximately 51% fat, 27% protein, 20% carbohydrates and included 3 g of fiber per 1,000 kcal. The Zulu diet consisted of 17% fat, 15% protein, 68% carbohydrates and included 21 g of fiber per 1,000 kcal. The researchers found that African Americans on the Zulu diet had increased stool concentrations of acetate

and butyrate, along with higher intestinal populations of microbes that produce these shortchain fatty acids. Some research has shown that butyrate enhances the maintenance of colonic homeostasis (Vanhoutvin SA et al. PLoS ONE 2009;4:e6759). In contrast, the Zulu group experienced diminished populations of acetate and butyrate-producing bacteria, and proliferation of Bilophila wadsworthia, which metabolizes fat and has been shown to lead to inflammation in mice (Devkota S et al. Naturee 2012;487:104-108). The findings warrant further study, said Jay Kuemmerle, MD, interim chair of the Department of Gastroenterology, Hepatology and Nutrition at Virginia Commonwealth University in Richmond, who was not involved in the research. “Understanding the relationships between the intestinal microbiome and the body, and how they can be modified,

is crucial to our ability to alter the risk for CRC development,” Dr. Kuemmerle said. Dr. O’Keefe said that his group will be conducting further research to understand how dietary components select for certain groups of microbes that “create a potentially genotoxic environment in the colon, and conversely, how resistant starch or other dietary fiber sources may select for microbes that negate these effects.” ■ Drs. O’Keefe and Kuemmerle reported no conflicts of interest.

Diet, Exercise Program Fails To Halt Cardiovascular Events in Obese Adults BY GEORGE OCHOA The Data and Safety Monitoring Board (DSMB) of the National Institutes of Health has recommended that the intervention arm of the Look AHEAD (Action for Health in Diabetes) study be discontinued because it showed that an intensive diet and exercise intervention program, resulting in moderate weight loss, did not reduce major cardiovascular events in overweight and obese adults with type 2 diabetes. However, the board encouraged the study, which it funds, to follow all Look AHEAD participants to identify longer-term effects of the intervention. Half of the 5,145 participants in the multicenter study were randomly assigned to the intensive lifestyle intervention ntervention arm and the other half to a general program of diabetes support and education. Botth study arms received routine medical care by their health care providers. The primary outcome of the study was to measure the aggregate occurrence of major cardiovascular eventss, including cardiovascular death (such as fatal myocardial infarction and stroke),

nonfatal myocardial infarction and stroke, and hospitalized angina. “Cardiovascular morbidity and mortality—that was the important question,” said Rena Wing, PhD, professor of psychiatry, Alpert Medical School, Brown University, Providence, R.I., and chairwoman of the Look AHEAD study. The study was unique, she said, “in the sense that it was the first randomized trial to see if an intensive lifestyle intervention that resulted in weight loss in individuals with type 2 diabetes would actually help reduce the risk for cardiovascular morbidity and mortality. Patients were followed for up to 11½ years.” Lee M. Kaplan, MD, PhD, director, Obesity, Metabolism, and Nutrition Institute at Massachusetts General Hospital in Boston, who is not associated with the Look AHEAD study, said in an interview: “Long-term cardiovascular outcomes … are the areas of the greatest risk and d danger to patients— the outcomes tthat can kill you. This study looked att these outcomes with sufficien nt power to find a differe ence between study gro oups, if it had existed.” Dr. Wing said that the DS SMB “concluded that the study had reached itss answer. There were no diifferences between the

two groups in the number of participants with cardiovascular morbidity and mortality. The odds that a difference would be detected were very slight at this point.” However, she noted, “Both study arms had a much lower risk for developing heart disease than we expected. In both groups, these patients with type 2 diabetes were getting good medical management. Possibly this helped to reduce the risk.” The intensive lifestyle intervention did bring health benefits, Dr. Wing reported. “There were fewer symptoms of depression, less use of diabetes medication, better blood sugar control and improved sleep apnea. The level of physical functioning was better maintained. I would think for most patients it’s important to recommend lifestyle intervention because of better quality of life.” Patients in the intervention arm lost 9% of their body weight initially (almost 20 pounds), and maintained a reduction of 5% of body weight through the end of the trial (about 10 pounds), said Dr. Wing. Asked whether the Look AHEAD trial had implications for bariatric surgery as an alternative method of weight loss, Dr. Wing said, “Bariatric surgery produces larger weight loss. But there has not yet been a real randomized trial to see if it will reduce cardiovascular morbidity and mortality.” ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

More Evidence of Benefits of Vita amin D In Patients With Crohn’s Disease BY DAVID WILD ORLANDO, FLA.—Research presented at the 2013 Digestive Disease Week meeting suggests that gastroenterologists should consider including vitamin D monitoring, and if necessary, supplementation, as part of their workup in patients with Crohn’s disease (CD). Vitamin D supplementation was found to improve muscle strength and quality of life (QoL), relieve fatigue, help to maintain intestinal integrity and increase intestinal antimicrobial levels in patients with inactive CD. Bincy Abraham, MD, MS, director of the Baylor Clinic IBD Center at Baylor College of Medicine in Houston, who was not involved in the research, said the finding of improved muscle strength falls in line with her own clinical experience. Furthermore, the results support the role of intestinal permeability in the pathophysiology of CD, she added. “Vitamin D could help treat Crohn’s disease,” Dr. Abraham told Gastroenterology & Endoscopy News. Lead researcher Tara Raftery, a research dietitian and PhD candidate in clinical medicine at Trinity College Dublin, in Ireland, and her colleagues randomized 27 individuals with CD in clinical remission to receive 2,000 IU of vitamin D3 or placebo daily for three months.

In one analysis (abstract Sa1198), the researchers measured CD activity, fatigue and QoL using the Inflammatory Bowel Disease Questionnaire (IBD-Q) and several other validated tools. They also measured hand-grip strength and tested serum 25-hydroxyvitamin D (25[OH]D) levels. All of these parameters were similar between the two groups at baseline. According to Ms. Raftery, serum 25(OH)D levels rose from a mean 28 ng/mL at baseline to 36.7 ng/mL after three months in vitamin D recipients, whereas levels dropped from 20.7 ng/ mL at baseline to approximately 16 ng/ mL in placebo recipients. Those with 25(OH)D levels of at least 30 ng/mL at three months had significantly higher total IBD-Q QoL scores and bowel, systemic and social subscores than those with 25(OH)D levels less than 30 ng/mL (187.3 vs. 163.2, respectively; P<0.0001). Patients with 25(OH)D levels of at least 30 ng/mL at three months also reported significantly improved general and physical fatigue than those with levels below 30 ng/mL. Additionally, Ms. Raftery reported that vitamin D recipients had significantly stronger hand grip in both dominant and nondominant hands at three months compared with placebo recipients. “To our knowledge, these are the first findings to suggest potential benefits of

‘The current work suggests a potential role for vitamin D supplementation as an adjunct therapy in the management of CD for the prevention of disease flare-ups.’ —Tara Raftery

vitamin D supplementation on muscle strength, with corresponding benefits for fatigue and QoL in CD,” Ms. Raftery said. “We are now conducting larger, controlled studies to validate these results.” Another analysis of the same cohort (abstract Sa1197) looked at two proxy measures of small bowel intestinal permeability and gastroduodenal permeability: lactulose/mannitol ratio and sucrose secretion. Investigators found that vitamin D was associated with stable levels of both measures, whereas patients receiving placebo saw a drop in these measures, signifying increased intestinal permeability. Higher 25(OH)D levels also were associated with increases in mean plasma levels of the antimicrobial peptide, cathelicidin (LL-37), Ms. Raftery reported.

“Cathelicidins are produced by the gastrointestinal epithelium, and their production is dependent on sufficient circulating 25(OH)D,” she explained. “Cathelicidins also have roles in eliminating bacteria, viruses and fungi, and appear to help maintain and reestablish intestinal barrier integrity.” Ms. Raftery noted there is not enough evidence to recommend a CD-specific vitamin D supplementation strategy. However, she said, “The current work suggests a potential role for vitamin D supplementation as an adjunct therapy in the management of CD for the prevention of disease flare-ups.” ■ Ms. Raftery and Dr. Abraham reported no conflicts of interest.

Microbial Changes Persist, Even in Inactive Disease BY DAVID WILD ORLANDO, FLA.—Patients with inflammatory bowel disease (IBD) have distinct microbial populations in their sigmoid colon, even in the absence of endoscopic inflammation, researchers reported at the 2013 Digestive Disease Week meeting (abstract 263). The new finding strengthens the body of evidence linking microbial dysbiosis with IBD, one expert said. Results like this “will ultimately promote the development of rational microbiota-modulating strategies for IBD,” said Elena Verdu, MD, PhD, associate professor in the Division of Gastroenterology at McMaster University’s Department of Medicine, and member of the Farncombe Family Digestive Health Research Institute in Hamilton, Ontario, Canada. “This study adds to growing knowledge that there are compositional changes in the intestinal microbiome in well-characterized cohorts of patients with IBD,” said Dr. Verdu, who was not involved in the study. “With the advancement of new techniques to investigate compositional and metabolic changes in the intestinal microbiota, studies like this will continue to shed light

on the specific microbial components and mechanisms involved in IBD,” said Dr. Verdu. A team of researchers led by Andrea Tyler, BSc, PhD, and Mark Silverberg, MD, both from the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto, Ontario, compared the resident microbial populations in 115 sigmoid biopsy samples and 64 terminal ileum samples from 34 patients with Crohn’s disease (CD), 37 individuals with ulcerative colitis (UC) and 44 healthy controls. Some of the patients had clinically and endoscopically inactive disease. Dr. Tyler’s team sequenced microbial genes and identified 108 genera of microorganisms in the samples. In the sigmoid biopsy samples, the researchers found that individuals with inactive CD had significantly smaller populations of several organisms, including Ruminococcus, Roseburia, Clostridium and Faecalibacterium, compared with healthy controls (P<0.05). Sigmoid biopsy samples from patients with inactive UC also had reduced populations of the first three of these genera but the differences were not significant from those in healthy controls, they found. Although there were fewer differences in microbial populations detected in ileal biopsy samples between patients with inactive IBD and healthy controls, the

researchers found that patients with inactive CD had smaller ileal populations off Subdoligranulum and Ruminococcuss compared with healthy individuals. One finding that surprised Dr. Verdu was that patients with endoscopically active CD and UC had higher populations of Bifidobacteria in their sigmoid samples than did patients with IBD who did not have endoscopic inflammation. “This type of bacteria is considered to have antiinflammatory properties,” she noted. In an interview with Gastroenterology & Endoscopy News, Dr. Silverberg said he and his colleagues are continuing to investigate this finding. He added that his team’s research also is examining genetic data collected from the same study patients. They hope to document any correlations between specific microbial populations and genetic traits. “We are currently looking at histologic data from the same subjects to get an idea of what’s happening on the microscopic level,” he said. “There may be microbial changes in patients who are endoscopically normal but have microscopic inflammation.” ■ Drs. Silverberg, Tyler and Verdu reported no conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Positive Outcomes for Bariatric Surgery Stretch Nine Years in Study Diabetes Recurrence Remains Issue, but Positive Effects Preevail BY CHRISTINA FRANGOU Bariatric surgery patients continue to show significant improvements over their baseline diabetic status, glycemic control and cardiovascular risk up to nine years after surgery, according to the results of a new study. More than 85% of patients met the goals set out by the American Diabetes Association nearly 10 years later. However, the study also showed that 20% of patients had a recurrence of their type 2 diabetes mellitus (T2DM) after an initial remission, demonstrating that improvements fade somewhat over time. Lead study author Stacy Brethauer, MD, a bariatric and laparoscopic surgeon at the Cleveland Clinic in Ohio, acknowledged that the long-term remission rates are slightly lower than the short-term results that were previously reported. He stressed, however, that the study definitively shows that patients continue to experience markedly better diabetic control, improvements in diabetic nephropathy and control of cardiovascular risk factors compared with their presurgery status. “Although some would consider the recurrence of diabetes a failure, our data

and others must be measured against the known risks of poorly controlled diabetes in patients who do not undergo bariatric surgery,” he said. Dr. Brethauer presented the study in Indianapolis at the 133rd Annual Meeting of the American Surgical Association. “Patients who experience long-term remission or improvement—and patients who have recurrence but improved glycemic control—need to look at these longterm results in a positive light.” The study analyzed 217 patients with T2DM who underwent bariatric surgery between 2004 and 2007 and had at least five years of follow-up. Patients in the study had a mean excess weight loss of 54.9±26.7%. Results showed that, at a median follow-up of six years, 24% of patients maintained complete remission of their T2DM, whereas 26% had partial remission. Onethird of patients (34%) had improvements in their diabetic control. In the study group, 19% of patients who had a remission of their T2DM in the first five years after surgery eventually had their disease recur. The authors used a strict definition of remission: a glycated hemoglobin (A1c) of less than 6% and fasting blood

glucose less than 100 mg/dL off diabeetic medications. “This study was extremely weell done, scientificallly of the highest ord der,” said Walter J. Pories, MD, professor off surgery, biochemistry and d kinesiology at East Carolina University in Greenville, N.C. Medical speciaalists from outside the bariatric surgery field have been calling for strong evidencce supporting the claim that surgery has lasting asting i metabolic b li effects. ff Dr. Pories said this paper provided some of that evidence. “Keep in mind,” he said, “diabetes has doubled in prevalence over the last 10 years. That’s incredible.” According to the most recent data from the National Health and Nutrition Examination Survey, 52% of people with T2DM treated in the United States achieve the American Diabetes Association’s therapeutic goal of A1c below 7%. In this study, 80% met that goal at a median of six years after surgery, including 86% of gastric bypass patients. Before surgery, only 40% had an A1c lower than 7%.

Sttud dy investigatoors stressed that patients who u und derwent a bariatric prrocedure experienced llon ng-term improvements i n cardiovascular and diabeticc m markers. Long-term control rattes of low high-density lipoproteein, high low-density lipoprotein n, h hypertriglyceridemia and hyyperrtension were 73%, 72%, 800% and 62%, respectivelly. The patien nts most likely lik l to experience i a return of their diabetes were those who had been diabetic for the longest time period, those who lost less weight initially and those who had greater weight regain in the long term. Three-fourths of patients studied underwent Roux-en-Y gastric bypass, the bariatric procedure associated with the highest rates of weight loss and diabetic remission. Investigators said the study involved too few patients who had the increasingly popular sleeve gastrectomy or gastric banding to draw conclusions about long-term diabetic outcomes with non-bypass techniques. ■

From the Literature

Gastric Bypass Patients Often Relapse After Diabetes Remission BY GEORGE OCHOA Studies have shown that gastric bypass surgery can achieve diabetes remission, but a recent, large, long-term study suggests the remission may not always be permanent. In the study, of patients who initially had complete remission, 35.1% redeveloped diabetes within five years. When the patients who never remitted and those who relapsed were added together, more than half of the patients (56%) did not have durable remission of diabetes (Arterburn DE et al. Obes Surg 2013;23:93-102). However, there was evidence that patients who received earlier surgical intervention for their diabetes might have better outcomes. “What’s new and different [about this trial] is that we focused on relapse of diabetes after patients have remitted,” said David E. Arterburn, MD, associate investigator, Group Health Research Institute, Seattle, and lead researcher on the study. “We followed them longer—beyond their initial remission—and found that by five years, 35% of patients had redeveloped diabetes. No prior studies have

examined this question on this scale.” duration of remission was 8.3 years (3,019 days; Motivated by recent literature indicating the ben- 95% CI, 2,507-3,281 days). Factors significantly efits, at least short term, of bariatric surgery for associated with higher relapse rate included longer diabetes control, the researchers conducted a ret- diabetes duration, insulin use and poor preoperarospective cohort study of adults with type 2 diabe- tive glycemic control (hemoglobin [Hb]A1c ≥6.5%). tes who received Roux-en-Y In secondary analyses, gastric bypass from 1995 weight trajectories after to 2008 in three integrated surgery differed signifihealth care delivery sys- ‘We followed them longer—beyond cantly among never remittems, one in Minnesota and ters, relapsers and durable their initial remission—and found two in California. remitters (P=0.03). Patients “We involved patients that by five years, 35% of patients who never remitted had in real-world health care had redeveloped diabetes. No slightly less weight loss and systems, not academic greater weight regain than medical centers with highly prior studies have examined this those who remitted. Those specialized surgical teams,” question on this scale.’ who relapsed had similar if Dr. Arterburn said. “Our not slightly superior body —David E. Arterburn, MD study is a look at what hapmass index (BMI) maintepens to the average patient nance after surgery than in routine clinical care.” those with durable remisThe study included 4,434 adults. Overall, 68.2% sion. Preoperative BMI values did not differ signifi(95% confidence interval [CI], 66%-70%) had com- cantly ((P=0.93) among the three groups. plete diabetes remission within five years postsur“For most patients with type 2 diabetes, gastric gery. Among these, 35.1% (95% CI, 32%-38%) bypass is not a cure,” said Dr. Arterburn. redeveloped diabetes within five years. The median see Remission, page 29

Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM QFSGPSBUJPO UPYJD DPMJUJT PS UPYJD NFHBDPMPO HBTUSJD SFUFOUJPO PS JO QBUJFOUT XJUI B LOPXO BMMFSHZ UP BOZ PG UIF JOHSFEJFOUT JO 1SFQPQJL 1BUJFOUT TIPVME CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH PS TJHOT PG EFIZESBUJPO BGUFS UBLJOH 1SFQPQJL r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT GPMMPXJOH 1SFQPQJL BENJOJTUSBUJPO 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a ďŹ&#x201A;exible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t Superior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 â&#x20AC;&#x201C; 84% vs 74%, respectively, achieving â&#x20AC;&#x153;excellent or goodâ&#x20AC;? visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efďŹ cacy endpoint was the proportion of patients with successful colon cleansing deďŹ ned as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

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Reference: 1. Prepopikâ&#x201E;˘ Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

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was 3.5 cm. All patients had histologically confirmed BE, defined as intestinal metaplasia. The researchers identified 348 prevalent cases and 75 incident cases of HGD or EAC. After comparing clinical, demographic and lifestyle characteristics of patients with or without HGD or EAC, the investigators found a significant association between HGD or EAC and the following variables: age, BMI, BE length,

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;¢ JULY 2013

â&#x20AC;&#x2DC;In this study of a large cohort of BE patients, researchers found a number of significant variables and created a prediction model [for HGD or EAC] with a very high sensitivity and good specificity.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Prateek Sharma, MD

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current or past smoking, lack of aspirin or nonsteroidal anti-inflammatory drug use, presence of hiatal hernia, number of consecutive upper endoscopies showing nondysplastic BE and presence of visible lesions on the BE segment. After selecting the most predictive variables from this group, the researchers developed the following predictive formula:

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Y = (0.019 Ã&#x2014; age) + (0.864 if white) + (0.538 if male) + (0.050 Ã&#x2014; BE length) + (1.139 if visible lesion present) + (0.322 if hiatal hernia present) + (â&#x20AC;&#x201C;0.674 Ã&#x2014; number of consecutive endoscopies showing nondysplastic BE) â&#x20AC;&#x201C; 4.416 The researchers found that this formula captured 87.7% of all patients with HGD and EAC (area under the curve = 0.877; 95% confidence interval: 0.860.90; P P=0.01). The formula has a 90% sensitivity rate and a 69% specificity rate. Dr. Sharma: The majority of patients with BE do not develop dysplastic or cancerous BE, and investigators are always looking for risk stratification tools. Multiple biomarkers have been examined in this context, and a number have been evaluated. However, to date, no biomarker panel has proven accurate enough to be used as a risk stratification tool for BErelated HGD or EAC. In this study of a large cohort of BE patients, researchers found a number of significant variables and created a prediction model with a very high sensitivity and good specificity. The findings show that using patient characteristics, it may be possible to risk-stratify patients with nondysplastic BE to determine which patients are low risk and can be left alone, and which are high risk and should be treated aggressively. â&#x2013; Dr. Sharma has received grant funding from Cook Medical, NinePoint Medical, Olympus and Takeda Pharmaceuticals.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

continued from page 24

Dr. Arterburn and his colleagues identified three factors that they believe most strongly affect durable remission of diabetes after bariatric surgery: • How long did the patient have diabetes at the time of surgery? The longer the period, the less likely they were to have a remission and the more likely to relapse. • Was the patient on insulin therapy? Patients were less likely to remit and more likely to relapse if they were on insulin at the time of surgery. • Was the patient’s blood sugar controlled at the time of surgery? If blood sugar was poorly controlled at the time of surgery, the patient was less likely to remit and more likely to relapse. “These are all markers of how severe one’s diabetes is. We concluded that patients with more severe diabetes are likely to benefit less than patients with less severe diabetes. Patients with early diabetes appear to benefit more,” Dr. Arterburn said. “The biggest message is early intervention in diabetic patients with obesity,” said Jaime Ponce, MD, president, American Society for Metabolic and Bariatric Surgery, Gainesville, Fla. “Evaluate them for bariatric surgery at BMI of 35 [kg/m2], and at 30 to 35 with diabetes requiring more medications.” “Because patients who had earlier disease achieved a higher percentage of long-term remission, physicians and patients should consider earlier intervention”—within five to 10 years of diagnosis, said Philip Schauer, MD, director, Bariatric and Metabolic Institute, Cleveland Clinic, in Ohio. “If they wait until their diabetes is more advanced, they’ll have less of a chance for long-term remission.” Of the new research, Dr. Schauer said, “This study supports what other studies have shown: Not all patients will have a long-term remission.” However, he noted, “a lot of patients who are so-called relapsing are still in good blood sugar control. If their HbA1c is 6% to 7% compared with higher than 7% before surgery, their control is relatively good.” The potential benefits of a period of remission for patients who relapsed remain unclear, according to Dr. Ponce. “We still don’t know, in patients who got their diabetes back, whether they got a benefit in the years diabetes was in remission,” he said. “Out-of-control diabetes can increase the risk for retinopathy, nephropathy

and liver damage, and cause vascular changes and cardiac damage. They didn’t study the benefit out of those years. We need a longer study with a longer follow-up. Even a few years of benefit would be valuable.” “We do believe and hope to confirm with a future study that even a short period of diabetes remission [in patients who eventually relapse] will have long-lasting benefits compared with those who didn’t have remission or didn’t get surgery,” Dr. Arterburn said.

Limitations of the study noted by Dr. Ponce included not looking at results per variations in technique of bypass, and not having sufficient data to analyze differences in outcomes by race or ethnicity. Dr. Schauer noted the low five-year retention rate of 67.8%. “They’re missing a lot of patients at the five-year mark,” he said. “We would like to see retention rates of 80% to 90%.” Dr. Schauer stated that a definitive multicenter randomized controlled trial comparing medical and surgical

treatment is needed to determine the true effects of bariatric surgery on patients with diabetes. “[The study] should evaluate not just blood sugar control but occurrence of diabetic complications. Some might interpret this study as ‘surgery doesn’t cure everybody,’ which is true. But the real value of surgery is not just in achieving remission in some patients, which is remarkable, but its ability to substantially improve even those patients who don’t achieve remission.” ■

Remission

LAST WEEK HE COULDN’T TOLERATE A FEEDING, LET ALONE A WALK DOWN THE HALL. Nutrition can be a powerful ally. When combined with your expertise, nutrition has the power to support better outcomes. Our evidence-based solutions promote tolerance and absorption to help patients with GI dysfunction avoid complications.1-6 USE UNDER MEDICAL SUPERVISION References: 1. Sucher KP. Nutr Clin Pract. 1986;1:146-150. 2. Flack S et al. J Hum Nutr Diet. 2003;16:366. 3. Fried MD et al. J Pediatr. 1992;120:569-572. 4. Shea JC et al. Pancreatology. 2003;3:36-40. 5. Borlase BC et al. Surg Gynecol Obstet. 1992;174:181-188. 6. Dylewski ML et al. Nutrition Poster 72; A.S.P.E.N. Clinical Nutrition Week; February 11-15, 2006: Dallas, TX.

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utrition. The factor that can make a difference.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

New Guidelines Broaden Eligibility for Bariatric Surgery Stronger Emphasis on Diabetes Control; Sleeve Gastrectomy Gets Nod BY CHRISTINA FRANGOU In a major shift in policy, three major medical societies have changed their formal guidelines for bariatric surgery and expanded eligibility to include patients with mild to moderate obesity and diabetes or metabolic syndrome. Additionally, the societies—the American Society for Metabolic and Bariatric Surgery, the American Association of Clinical Endocrinologists and the Obesity Society—upgraded sleeve gastrectomy from investigational status to a “proven surgical option.” The changes will bring the U.S. guidelines in line with practices increasingly used around the country and reflect evidence that has emerged in the four years since the previous guideline was developed. “We’ve gleaned important new insights, cautions and best practices based on the thousands of studies that were published in medical journals in just the last four years alone, and these are reflected in the new guidelines,” said Daniel B. Jones, MD, professor of surgery, Harvard Medical School, Boston, and one of a 12-member panel that developed the guidelines. “Our goal was to make it a little easier for the practitioner to understand how strong the data are in favor of a practice, whether that be a psychological evaluation or a preoperative check of calcium and thiamine levels.” The guidelines were published online

March 25 in the journals of the three organizations: Endocrine Practice, Obesity and Surgery for Obesity and Related Diseases. They cover perioperative nutritional, metabolic and nonsurgical support for bariatric surgery patients. Among the 74 evidence-based recommendations, the panel called for the broadening of surgical eligibility for bariatric surgery. Patients with a body mass index (BMI) of 30 to 34.9 kg/m2 and diabetes or metabolic syndrome may be offered a bariatric procedure, “although current evidence is limited by the number of subjects studied and lack of long-term data demonstrating a net benefit,” said the authors. Two years ago, the International Diabetes Federation (IDF) was the first major organization to list surgery as a treatment option for patients with a BMI between 30 and 35 kg/m2 when diabetes cannot be adequately controlled by an optimal medical regimen. Despite the IDF’s recommendation, the notion of surgery for individuals with a BMI of less than 35 kg/m2 has remained quite controversial, especially among physicians and endocrinologists, said Francesco Rubino, MD, a metabolic and bariatric surgeon at the Catholic University of Rome, Italy. Dr. Rubino welcomes the new indication, saying the medical community must move away from a BMI cutoff for bariatric surgery. “BMI per se does not measure health or disease. You never see a diabetologist,

for instance, using BMI as a guide for diagnosis or treatment of diabetes.” Dr. Jones said the guideline will make surgery accessible to people who are struggling with many comorbidities of obesity but do not meet the previous BMI threshold. “As a bariatric surgeon and medical doctor, you hate to say to a patient, ‘you’re still too thin for surgery,’ especially when we know that the longer that they have diabetes, the more they weigh, the less likely that they will have a durable result.” The panel noted that there is currently insufficient evidence for recommending a bariatric surgical procedure specifically for glycemic control alone, lipid lowering alone or cardiovascular disease risk reduction alone, independent of BMI criteria. The panel also made a major addition to its list of “proven” primary bariatric and metabolic procedures by adding laparoscopic sleeve gastrectomy. The list now includes laparoscopic adjustable gastric banding, laparoscopic Roux-en-Y gastric bypass and laparoscopic biliopancreatic diversion (BPD), BPD/duodenal switch, along with laparoscopic sleeve gastrectomy. The guidelines do not recommend one primary procedure over another. Each procedure poses different risks and benefits, the panel said, and surgeons should select a surgical method based on each patient’s goals and motivations and the surgeon and institution’s expertise and experience. The authors did, however, observe that laparoscopic procedures are preferred over open bariatric procedures due to

lower early postoperative morbidity and mortality, a finding supported by grade B evidence. On the controversial issue of endoscopic and emerging bariatric procedures, the panel noted that other procedures are gaining attention, “such as gastric plication, electrical neuromodulation and endoscopic sleeves.” But, they said, these procedures lack sufficient outcome evidence and remain investigational. The panel dropped 90 recommendations from the 2008 edition, revised 56 and added two. The quality of evidence improved significantly in the past five years, with 40.4% of studies now considered high quality compared with only 16.5% in the previous version. In other new recommendations, the panel advised that women should avoid pregnancy before surgery and for 12 to 18 months after surgery. Women who do become pregnant after surgery should have nutritional surveillance and laboratory screening for deficiency every trimester, including iron, folate and B12, calcium and fat-soluble vitamins. The guidelines also recommend that patients undergo age- and risk-appropriate cancer screening before surgery. “It’s really just good medicine. It may be obvious to screen for sleep apnea in a patient who is obese; cancer is maybe not as obvious. Now, we have data showing that the cancer rate may be higher with obesity, and bariatricians and internists really need to be screening for that,” said Dr. Jones. ■

From the Literature

Study Rekindles Debate Over Bariatric Centers of Excellence No Difference in Outcomes With CoE Designation; Researchers Say Policy May Hinder Access BY CHRISTINA FRANGOU

The debate over bariatric centers of excellence (CoE) programs is ramping up once again with the publication of a study that calls on the Centers for Medicare & Medicaid Services (CMS) to reconsider its policy of restricting coverage to designated centers. The report, published in the Feb. 27 issue of the Journal of the American Medical Association, submits that perioperative complications and reoperations fell over the last decade but not because of the CMS policy (Dimick JB et al. 2013;309:792-799). “We could not attribute any outcome improvement to the CMS policy restricting performance of bariatric operations on Medicare patients to CoEs,” wrote lead author Justin

B. Dimick, MD, MPH, and his colleagues from the Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor. In 2006, CMS issued a national decision that limited coverage of weight loss surgery to CoEs

NTER OF TRIC CE A I R BA LENCE EXCEL

designated by the American College of Surgeons (ACS) or the American Society for Metabolic and Bariatric Surgery (ASMBS). At the time, many surgeons protested the decision, arguing that it restricted bariatric surgery to large established practices. In January, John Birkmeyer, MD, a study coauthor and the George D. Zuidema Professor of Surgery at the University of Michigan, formally asked the CMS to reconsider the facility certification requirement. As a result, CMS has opened a coverage analysis to review available evidence on tthe issue. The ASMBS challenged the request, saying the ssociety supports continuation of the CoE requirement. The society cited seven studies that “provide strong and compelling evidence” favoring the certification. “Lives have been saved, complications see CoEs, page 33

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Volume 64, Number 1 • January 2013

ACG 2012

IBS No Longer Only Functional Disorder

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search

BY DAVID WILD BY CHRISTINA FRANGOU LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8

Mesalamine Elicits Response in IBS BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

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

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

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

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

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

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

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

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

CoEs continued from page 30

have been prevented, readmissions have been averted, cost has been lowered and access has been broadened,” they wrote in a letter to CMS. In the new study, Dr. Dimick and his colleagues countered many of those arguments. They studied hospital discharge data from 12 states, looking at outcomes for Medicare patients undergoing bariatric surgery between 2004 and 2009. The results were

compared with those for non-Medicare patients over the same period. Unlike prior studies, investigators used a “difference-in-difference” analysis to adjust for temporal trends. They found no differences in safety (measured as risk-adjusted complications), serious complications or reoperations after the policy changed (8% vs. 7%, 3.3% vs. 3.6%, 1% vs. 1.1%, respectively). The analysis took into account patient factors, changes in procedure type and preexisting time trends toward improved outcomes.

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Investigators also found no difference in risk-adjusted complications, serious complications or reoperations for 179 CoE-designated institutions compared with 519 non-CoE institutions over the study period (5.5% vs. 6%, 2.2% vs. 2.5% and 0.83% vs. 0.96%, respectively). Researchers said, in effect, that bariatric outcomes improved over the past decade but these improvements may have resulted from evolving surgical techniques and use of different types of procedures. “This includes

transitioning from open to laparoscopic procedures and the increased use of laparoscopic adjustable gastric banding,” they wrote. Use of laparoscopic gastric banding jumped considerably, from 6% to 35% in Medicare patients and from 6% to 24% among nonMedicare patients. The disproportionate increase in gastric banding in Medicare patients suggests that the increased scrutiny of Medicare’s bariatric surgery population “influenced physician decision making,” said the authors. They argued that the CMS policy might unfairly limit patient access to bariatric surgery. A previous study in Texas found patients had a markedly increased travel distance after implementation of the CMS coverage decision (Livingston EH. Arch Surg 2009;144:319-325).

‘The CMS policy restricting coverage to CoEs has not been associated with improved outcomes for bariatric surgery, but may have had the unintended consequence of reducing access to care.’ —Dimick JB et al. JAMA 2013;309:792-799

“Therefore, the CMS policy restricting coverage to CoEs has not been associated with improved outcomes for bariatric surgery, but may have had the unintended consequence of reducing access to care,” said Dr. Dimick and his colleagues. This is the third study to refute the effectiveness of accreditation in bariatric surgery (Birkmeyer NJ et al. JAMA 2010;304:435-442; Livingston EH. Arch Surg 2009;144:319325), whereas seven studies have demonstrated positive effects of the policy. In an accompanying editorial, Caprice C. Greenberg, MD, PhD, associate professor of surgery and director of the Wisconsin Surgical Outcomes Research Program, confirmed that CMS and surgical societies are reexamining the CoE policy in bariatric surgery. She did not argue for or against dropping the CMS’ policy. Instead, she said CMS and surgical societies must find better ways to promote quality surgical care. The current approach to CoE accreditation is expensive, requires extensive documentation, see CoEs, page 34

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

CoEs continued from page 34

site visits and the collection of data that are not being optimally used, she said. “This is an opportune time to examine how the programs can evolve and whether restricting care to CoEs is still the best approach. “Money and effort currently invested by CoE sites could be reallocated to promote a more active approach to quality improvement,” Dr. Greenberg said.

The report’s publication was met with criticism from many in the bariatric surgery community. Among the chief criticisms, they say the CoE program incentivized hospitals to improve data collection, focus on processes of care specific to bariatric patients and invest in specialized equipment—all of which improved the quality of bariatric surgery in the United States. “The accreditation does not need to be viewed as restriction of access but as a venue to improve quality of care,” said Jaime Ponce, MD, president of

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the ASMBS and medical director for bariatric surgery, Hamilton Medical Center, Dalton, Ga. Dr. Ponce believes the study has significant flaws. It’s based on an administrative database, and such databases are not overly sensitive or specific for rates of complications, he said. He cited a 2011 study that showed 90-day readmission rates decreased 25% after the national coverage decisions, while reoperation declined 33% (Flum DR et al. Ann Surg 254:860-865).

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He stressed that the study shows both Medicare and non-Medicare patients experienced improved outcomes. “The national coverage decision not only helped to improve outcome for Medicare patients but also helped to improve outcome for non-Medicare patients as most payors follow Medicare rulings.” Finally, he said that accreditation is an ongoing process. Hospitals submit data so investigators can study patterns and identify best practices. “Accreditation is needed to get all the measures for quality and the benefits go beyond the data published by Dimick et al.” Most surgeons who spoke with Gastroenterology & Endoscopy News support continuing the CoE program but they noted that the process is flawed.

‘The accreditation does not need to be viewed as restriction of access but as a venue to improve quality of care.’ —Jaime Ponce, MD Ninh T. Nguyen, MD, chief of gastrointestinal surgery at UC Irvine Medical Center and president-elect of the ASMBS, said both the ASMBS and the ACS continue to support the accreditation process. They do recognize that the 125-case threshold can be difficult to achieve, and the new ASMBS-ACS quality program, the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, will likely have a lower institutional volume requirement based on peer-review literature. He added that “the bariatric surgery community uniformly disagrees” with the request for elimination of the facility requirement. Stacy Brethauer, MD, a bariatric surgeon at Ohio’s Cleveland Clinic, supports the accreditation requirement by CMS. The administrative claims data used in the Dimick study is “suboptimal” for evaluating surgical complications compared with clinical registry data, he said. Moreover, he said, the demise of the accreditation program could bring negative consequences, such as loss of critical hospital support for resources and loss of ability to track outcomes for quality improvement at a national level. “Without accreditation, we will have no data collection and our ability to navigate the next evolution in quality see CoEs, page 35

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Is This Really an Excellent Way To Make a Center of Excellence? The Unsettled Story of Bariatric Accreditation Programs and Their True Effect on Patient Care in 2006 has never been fulfilled despite the majority of our practices participating in a CoE process. There has been little useful information shared across practices, and access to care and insurance reimbursement have not increased. For those unfamiliar, a short recap is necessary. Approximately 10 years ago, it was deemed essential that an accreditation program be created for bariatric surgery.

Media reports of poor outcomes created concern that without an active CoE program, bariatric surgery would be in danger of being blacklisted. After lengthy discussion, both the American College of Surgeons (ACS) and the American Society for Metabolic and Bariatric Surgery (ASMBS) introduced separate programs. To administer the ASMBS program, a new independent entity called Surgical

Review Corporation (SRC) was formed. A majority of the ASMBS membership and their hospitals decided to participate in the SRC program because it was less expensive. A major reason was that participation in the ACS program for level 1 centers mandated use of the National Surgical Quality Improvement Program (NSQIP), which was very expensive. see Excellence, page 36

Daniel Cottam, MD Director, Surgical Weight Loss Center of Utah Director, Bariatric Medical Institute Salt Lake City, Utah

Mitchell Roslin, MD Chief of Bariatric and Metabolic Surgery Lenox Hill Hospital/North Shore-LIJ New York, New York If you are a bariatric surgeon with interest in the recent center of excellence (CoE) or accreditation struggle, it is hard to not be cynical. What our leaders promised us

CoEs continued from page 34

improvement and outcome reporting will be severely impaired.” Kelvin Higa, MD, program director of minimally invasive and bariatric surgery, Fresno Heart & Surgical Hospital, in California, called the Dimick study “important” and noted that the authors “make a compelling argument against CoE accreditation for Medicare patients.” But, he added, it’s not clear if the study is definitive enough to abandon accreditation. “For those of us who have had to live through the early days of our specialty, when patients were looked at as commodities with no support services by some surgeons and hospitals, we would certainly not like to see history repeat itself.” ■ Dr. Dimick reported serving as a consultant and having an equity interest in ArborMetrix Inc., which provided software and analytics for measuring hospital quality and efficiency but had no role in the study. Dr. Greenberg reported receiving an honorarium from the Michigan Bariatric Quality Collaborative to attend one of its collaboratives and discuss issues related to system performance and safety. Drs. Ponce, Nguyen and Higa have served or will serve as president of the ASMBS.

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GIAZO® (balsalazide disodium) is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older. Safety and effectiveness of GIAZO beyond 8 weeks have not been established.

CONTRAINDICATION GIAZO® (balsalazide disodium) tablets are contraindicated in patients with hypersensitivity to salicylates, aminosalicylates, or their metabolites or to any of the components of GIAZO tablets. Reference: 1. GIAZO Prescribing Information, 2012. Salix Pharmaceuticals, Inc.

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OPINION

Excellence continued from page 35

Achieving CoE status included the development of pathways, credentialing, documentation of equipment and consultant availability. A volume threshold of 125 cases was mandated. No differentiation was made for case or patient difficulty. The CoE programs’ strongest benefit was the 2006 national coverage decision by the Centers for Medicare & Medicaid Services (CMS), which stated that for coverage for bariatric surgery, the procedure would need

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

to be performed at a center approved by either the ACS or ASMBS. As can be expected with any new process, flaws in the methodology were uncovered. Certainly the system required updating and improvement. However, without collecting feedback from member surgeons or hospitals involved with the SRC, ASMBS leadership decided to end their contract with SRC. (The members of the ASMBS have never been told what happened or why a new system was needed. Two working

The following is a brief summary; please see complete Prescribing Information at www.Giazo.com. INDICATIONS AND USAGE GIAZO is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older. Limitations of Use: • Effectiveness of GIAZO in the treatment of female patients was not demonstrated in clinical trials. • Safety and effectiveness of GIAZO therapy beyond 8 weeks have not been established. DOSAGE AND ADMINISTRATION The recommended dose for induction of remission of ulcerative colitis in adult male patients is three 1.1 g GIAZO tablets to be taken 2 times a day with or without food (6.6g per day) for up to 8 weeks. CONTRAINDICATIONS GIAZO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates, or their metabolites or to any of the components of GIAZO tablets. WARNINGS AND PRECAUTIONS Exacerbations of Ulcerative Colitis Balsalazide is converted to mesalamine, which has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. In controlled clinical trials with GIAZO in adults with ulcerative colitis, 7% of male patients reported exacerbation of the symptoms of ulcerative colitis. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with GIAZO. Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis and renal failure, has been reported in patients given products that release mesalamine in the gastrointestinal tract. Evaluate renal function prior to initiation of GIAZO therapy and periodically while on therapy. Exercise caution when using GIAZO in patients with known renal dysfunction or a history of renal disease. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Because balsalazide is converted to mesalamine, use caution and consider liver function testing when administering GIAZO to patients with liver disease. ADVERSE REACTIONS GIAZO was evaluated in one placebo-controlled trial (168 treated with GIAZO), one active-controlled trial (210 treated with GIAZO); and a subset of these patients also participated in an uncontrolled, open-label, extension study (additional 187 treated with GIAZO). The population consisted of patients with ulcerative colitis; the mean age was 43.1 years, 49% were male, and 84% were white. In a placebo-controlled clinical trial, the most common treatment-related adverse events occurring in at least 2% of male patients taking 6.6 g/day of GIAZO and at a rate greater than placebo, were anemia, diarrhea, pharyngolaryngeal pain, urinary tract infection, arthralgia, insomnia and musculoskeletal pain. 10% of patients in the GIAZO group and 13% of patients in the placebo group discontinued treatment due to an adverse reaction. The majority of adverse reactions were mild to moderate in severity. The most common serious adverse reactions in both the placebo and GIAZO groups were gastrointestinal disorders, which were mainly associated with symptoms of ulcerative colitis. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies were performed in rats and rabbits at oral doses up to 2 g/kg/day, 2.5 and 4.9 times the recommended human dose based on body surface area for the rat and rabbit, respectively, and revealed no evidence of impaired fertility or harm to the fetus due to balsalazide disodium. 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.

systems existed at the time.) Members were told about the great opportunity to unite our program with the ACS. With great enthusiasm, the leaders outlined a system that would be based on the Michigan Surgical Collaborative. An attractive aspect of this system was that doctors were able to share data across practices easily. Discussions with John Birkmeyer, MD, medical director of the Michigan Surgical Collaborative, took place on integrating the ASMBS CoE system into the collaborative. However,

Mesalamine, a metabolite of GIAZO, is known to cross the placental barrier. Nursing Mothers It is not known whether balsalazide disodium or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GIAZO is administered to a nursing woman.

Many argue that an

Pediatric Use Safety and effectiveness of GIAZO tablets in pediatric patients have not been established.

essential to maintain the

Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products. GIAZO is converted into mesalamine in the colon. Caution should be taken to closely monitor blood cell counts during therapy.

integrity and trust of the

Clinical trials of GIAZO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing GIAZO. CLINICAL STUDIES A double-blind, placebo-controlled, multi-center trial was conducted in 250 adult patients with mildly to moderately active ulcerative colitis. Disease activity was assessed using a modified Mayo Disease Activity Index1 (MMDAI), which was a sum of four subscores (bowel frequency, rectal bleeding, endoscopic appearance, and physician’s global assessment), each ranging from 0 to 3, with higher scores indicating worse disease. The median baseline MMDAI score was 8 and the median baseline rectal bleeding subscore was 2. Patients were randomized 2:1 to receive 8 weeks of treatment with either GIAZO 3.3 g twice daily or placebo. After 8 weeks of treatment, the proportion of patients who met the definition of Clinical Improvement was greater for the GIAZO-treated group (55%) compared to the placebo group (40%) (P=0.0237). These differences were statistically significant in the overall population; however, these effects were entirely driven by the results in the male subpopulation (57% with GIAZO vs. 20% for placebo). Effectiveness of GIAZO was not demonstrated in the female subpopulation in the clinical trial (54% with GIAZO vs. 58% for placebo). POST MARKETING EXPERIENCE These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to products which contain or are metabolized to mesalamine, including balsalazide. Cardiovascular and Vascular: myocarditis, pericarditis, vasculitis Respiratory: alveolitis, pleural effusion, pneumonia (with and without eosinophilia) Gastrointestinal: pancreatitis Renal: interstitial nephritis, renal failure. Hepatobiliary Disorders: elevated liver enzymes (AST, ALT, GGT, LDH, alkaline phosphatase), elevated bilirubin, jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure, Kawasaki-like syndrome including hepatic dysfunction. Some of these cases were fatal. Dermatological: alopecia, pruritus HOW SUPPLIED GIAZO is available as oval, yellow, film-coated tablets containing 1.1 g balsalazide disodium, with BZT debossed on one side of the tablet. NDC 65649-102-02 Bottles of 180 tablets STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature. Reference: 1. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mild to moderately active ulcerative colitis: a randomized study. N Engl J Med. 1987;317:1625-9.

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it soon became apparent that this was not going to be a practical solution. As a result, an integrated committee of sincere surgeons comprised of representatives from the ACS and ASMBS was assigned to write new standards for the combined program. However, instead of creating a simple effective process, a very rigid blueprint for bariatric practice was suggested in an attempt to proliferate what they believed to be best-practice standards. Surgeons were told what operations they could do, and when and where they should

accreditation program is

public. The question is does it really do this? If we think back to the original stated goals of the center of excellence process, we would have to say it has not delivered on its promise. be performed. Additionally, the proper ages for surgical treatment and which procedures required institutional review board approval were described. Rather than have the center determine how to contact patients for follow-up and how to participate in performance improvement, strict adherence to their policy was mandated. Failure to follow these guidelines would result in termination of the CoE designation. The old program of broad principles to be filled in by the practices was replaced with strict rules. Thankfully, some of our past presidents and members of ASMBS saw this and raised the alarm. Furthermore, our field moves faster than documents like this can be written. As a result, even if we could agree on the best methodology, it would be outdated before it could be disseminated. During the period of time that we were discussing issues with our new system, Dr. Birkmeyer sent a well-written and researched letter to Medicare questioning whether CoE status was

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

necessary and suggesting that CMS should allow Medicare beneficiaries to have bariatric surgery in any facility. He noted that outcomes in bariatric surgery have improved throughout the country. Two large studies showed no improved outcomes at CoE centers compared with non-CoE centers (Livingston EH. Arch Surgg 2009;144:319-325; Birkmeyer NJ et al. JAMA 2010;304:435-442). Therefore, the requirement for coverage that bariatric surgical procedures be performed at a center certified by the ACS or ASMBS should be withdrawn, he

process, groups like the collaborative (owned by Blue Cross) will own the only large collection of outcomes data. Data can have multiple interpretations, and if we don’t have other large collections of data we will not have the facts or evidence to oppose whatever the insurance companies say. Thus, an independent physician database (or databases) is our best professional protection. Although the ASMBS has made errors, it is still our society. It is owned by us, those involved in patient care, and is not sponsored by an insurance company.

Likewise, it is not a software company either. We should seek out partners who can aggregate data and share the de-identified data with all members of the society much like we do with our journals. Surgeons will want to participate because it will make them better surgeons. This means we need to scrap the document that was up for public comment. It was a poor imitation of the Michigan Collaborative that relied on force to achieve compliance. Instead, we should find a creative method to find a flexible accreditation system that accumulates the relevant data

on primary procedures at reasonable cost. Whether we should combine with the ACS, create an independent solution or resuscitate the SRC should all be discussed and considered. What also needs to be understood is that the cost of failure will be very large in the future. It will mean that the most detailed outcomes on bariatric surgery will be owned by an entity sponsored by Blue Cross. If at some point, they do not have our patients’ best interests in mind, we will not have the necessary facts to protect our patients or our practices. ■

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argued. Dr. Birkmeyer is well respected and a former adviser to CMS. Based on his letter, CMS decided to open the national coverage decision and ask for public comment on this issue. This leads us to the question of whether we need a CoE program in 2013. Many argue that an accreditation program is essential to maintain the integrity and trust of the public. The question is, does it really do this? If we think back to the original stated goals of the CoE process, we would have to say it has not delivered on its promise. Thus, many may believe that we do not need a CoE process. Unfortunately, what seems simple is often not. The Michigan Collaborative sounds like a perfect system until you peel away the layers. Blue Cross of Michigan, which controls 70% of the insured lives in the state, sponsored the collaborative. This fact alone makes us even more convinced that we need an independent CoE system. If we do not develop an effective accreditation

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Continuous Care Nursing Increases Efficiency in Endoscopy BY MONICA J. SMITH LAS VEGAS—Continuous care nursing, where a nurse oversees a patient from the preparation phase to the completion of a procedure, has been advocated as a patient-centric model of care, according to recent research. Ziad F. Gellad, MD, MPH, assistant professor of medicine at Duke University Medical Center, Durham, N.C., and his

colleagues, used discrete event-simulation modeling—which simulates a system’s operations as a series of discrete chronological events—to assess the potential for continuous care nursing for improving the efficiency at their eight-room, hospital-based endoscopy unit. The researchers presented their findings at last year’s American College of Gastroenterology annual scientific meeting, where they explained that the first step was to create a

conceptual model of their endoscopy unit that tracks a patient’s care—and the resources available to provide that care—on a step-by-step basis. “Once we had a conceptual model built, we collected timed data that mapped the discrete events in the conceptual model,” Dr. Gellad said. With the model and time spans established, the team computed an appointment schedule representative of a typical day in the unit, in which about

41 procedures are performed. They then used software to animate the flow of patients and providers through the unit and establish a baseline for patient flow times, nurse utilization, procedure utilization and patient wait time.

‘The end result, as demonstrated by this study, is an improved patient experience and a more efficient endoscopy unit. Continuous care nursing

(PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older. CONTRAINDICATIONS

MoviPrep is contraindicated in patients with the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep. WARNINGS AND PRECAUTIONS Use with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities (such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), patients with known or suspected hyponatremia), patients at increased risk of cardiac arrhythmias, patients with a history of seizures or at increased risk of seizures such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, ARBs, or non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or inflammatory bowel disease, patients with impaired gag reflex or patients prone to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate. Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment. MoviPrep contains phenylalanine (233 mg per treatment). ADVERSE REACTIONS

In clinical trials, the most common adverse reactions for split dosing regimen (incidence 5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence 5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness. Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions. Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age. These adverse events included upper gastrointestinal bleeding from a MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation. In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration. DRUG INTERACTIONS Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate. Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

creates a win–win scenario

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed. Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman. Pediatric Use: The safety and effectiveness of MoviPrep in pediatric patients has not been established. Geriatric Use: Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep. STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). When reconstituted, store upright and keep solution refrigerated. Use within 24 hours. PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. s Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

Rx only

that everybody can benefit from, especially the patient.’ —Mark B. Pochapin, MD

At baseline, room utilization was 65%, prep nurse utilization was 46% and procedure nurse utilization was about 79%. Patients waited about 24 minutes to preparation time, and the duration of flow time, from preparation through procedure, was 111 minutes. “One of the powers of the model is that we can change the variables and structure in order to pose different questions,” Dr. Gellad said. “In this case, we changed the paradigm to a continuous care model.” The researchers found no statistically significant difference when they changed flow time according to the model, so they examined what would occur if they assumed time savings due to a decrease in patient hand-off. “We looked at 10%, 20%, 30%, 40% or 50% time savings in the procedure and preparation time,” Dr. Gellad said. They found that each reduction in procedure room preparation time led to a decrease in room utilization, nurse utilization, patient wait times and flow times, such that a 50% reduction in procedure room preparation time resulted in a 26% reduction in flow time. “The strength of this approach is that we have robust time-measurement data, and we have a validated model that we can use to ask questions without interfering with the clinical flow of the unit,” Dr. Gellad said. Limitations of the model include that it may not represent everyday practice and may not be applicable to other clinics. However, simulation modeling allows evaluation of new health delivery paradigms without interrupting the existing standard of care and may be a

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

From the Literature

Shorter Workweeks for Interns Do Not Promote Patient Safety A policy to shorten the workweek for interns in the United States has failed to improve their quality of life and has possibly put patients at greater risk for medical errors, a new study has found (Sen S JAMA Intern Med 2013;173:657-662). The 2011 policy change, recommended by the Accreditation Council for Graduate Medical Education, capped at 16 continuous hours the longest shift a first-year resident could work in the hope that doing so would ease the strain on physician trainees. But although the new rules have shortened the typical intern’s workweek from 67 to 64.3 hours, they haven’t encouraged residents to sleep more, helped them to avoid depression or increased their overall sense of well-being, the study found. Depression is linked to poor work performance; the new study found that twice as many interns meeting criteria

for depression as those with better emotional health reported having committed a medical error: 35.3% versus 17.8%, respectively. And more interns said they were afraid of making a serious medical error after the policy change than before the shift—23.3% versus 19.9% (P=0.007). The study was based on email surveys of 2,323 residents (and a

“

few graduating medical students) from a variety of medical specialties at 51 programs nationwide. The residents entered training in 2009, 2010 and 2011, after the rule change. “Given that increased sleep was a key [mechanism] through which the new duty-hour restrictions were intended to improve the health of residents, the lack of such

Our surveyors are active health care professionals. They bring ‘real world’ understanding to the process.

Frank Chapman Chair, AAAHC Standards Committee very useful tool for evaluating possible quality improvement measures. “Our conclusion is that continuous care may improve endoscopy unit efficiency, and the magnitude of that will depend on the time savings from eliminating patient hand-off,” Dr. Gellad said. Mark B. Pochapin, MD, director, Division of Gastroenterology, Sholz/ Leeds Professor of Gastroenterology and professor of medicine at New York University Langone Medical Center, in New York City, said that the continuity of nursing care is often overlooked in the assessment of an endoscopy unit, but the endoscopic procedure is only one component of the unit; the larger picture includes quality, efficiency and the overall patient experience, of which nurses, who spend the most time with patients, are a key element. “This study demonstrates the importance of nursing care that puts the emphasis on patient continuity. Not only does continuous care nursing improve the patient experience, but it also can enhance overall efficiency and improve communication during patient hand-off. The end result, as demonstrated by this study, is an improved patient experience and a more efficient endoscopy unit. Continuous care nursing creates a win–win scenario that everybody can benefit from, especially the patient,” Dr. Pochapin said. ■

an effect in the postimplementation cohort in our study is a cause for concern,” wrote the authors, led by Srijan Sen, MD, PhD, a psychiatrist at the University of Michigan in Ann Arbor. “Designing work schedules that account for circadian phase and explicitly training residents on practices to increase sleep time and improve sleep quality may be necessary.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

IOM Recommends Mandatory National System To Track and Trace Pharmaceuticals BY GEORGE OCHOA Congress should authorize and fund the FDA to establish a mandatory, national track-and-trace system for pharmaceuticals, according to an Institute of Medicine (IOM) report released Feb. 13. In the meantime, the report urged the FDA

to convene a working group of stakeholders to promote voluntary track and trace. This advice, labeled Recommendation 5-2, is part of Countering the Problem of Falsified and Substandard Drugs, written by an IOM committee (published by the National Academies Press in Washington, D.C.). The report concerns the global problem of illegitimate drugs,

whether they are falsified or fake, carrying a false representation of identity or source, or failing to meet accepted specifications. Many recommendations in the report apply to developing countries, but some, including the track-and-trace recommendation, are of special importance to the United States. The relevance of the track-and-trace

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recommendation was swiftly noted by the Pharmaceutical Distribution Security Alliance (PDSA), a coalition of pharmacies, distributors, manufacturers and others committed to strengthening the nation’s pharmaceutical distribution supply chain. “[PDSA] applauds the [IOM] for recognizing that new legislation is needed to protect all Americans from the threat of counterfeit drugs,” PDSA said in a statement. Indicators are “good” in Congress for “potential enactment into law,” Vince Ventimiglia, principal at FaegreBD Consulting, in Washington, D.C., and an advisor to PDSA, wrote in an email. “Key committee leadership and other important members of Congress in both congressional bodies have stated that supply-chain traceability legislation remains a high priority for enactment into law this year; the FDA has asked for increased authority of this nature and Congress has spent countless hours negotiating an effective policy.” But Gillian J. Buckley, PhD, MPH, a co-editor of the IOM report, was more cautious. “Realistically, it might take Congress a while,” Dr. Buckley said.

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ReposiTrak, a joint venture of Leavitt Partners and Park City Group, is a track-and-trace system that aims at an even larger scale than the national scale specified by the IOM recommendation. “ReposiTrak is a track-and-trace system with which we anticipate serving the entire global food supply system, as well as supplement nutraceuticals and pharmaceuticals,” said Randy Fields, MA, chairman of the Park City Group, in Salt Lake City. “It will keep track of all documents related to safety and compliance, track and trace movement of ingredients, and tell where inventory is now.” “Although we’re not in a position to talk about mandatory versus voluntary systems, the market is moving toward greater use of track and trace,” said Kristina Lunner, senior advisor at Leavitt Partners, in Washington, D.C. “The world is trying to agree on standards for identification. On a global scale, they want to agree on an identifier. It’s a huge obstacle and very expensive,” Mr. Fields said. “Our secret sauce is to track and trace without a common identifier. Our system is completely interoperable.” Another item relevant to the United States is Recommendation 5-1, which states, “State licensing boards should only license wholesalers and distributors that meet the National Association of Boards of Pharmacy [NABP] accreditation standards.” Dr. Buckley, who is study director for IOM’s Board on Global Health, explained that the NABP has high standards and a process that h in ncludes criminal background checks.

“Currently, three states require wholesalers to have NABP accreditation: Indiana, North Dakota and Wyoming,” Dr. Buckley said. “Any state having a low standard is a vulnerability for others.” Another part of Recommendation 5-1 is the establishment of a public database to share information on suspended and revoked wholesale licenses. Right now, according to Dr. Buckley, “if your license is revoked, you can go to another state and get a license there.” An international code of practice on

the global problem of falsified and substandard medicines, as specified by Recommendation 7-1, would potentially involve the United States as well as other countries. This is the committee’s “boldest recommendation, one that reaches out to the world,” co-editor Lawrence O. Gostin, JD, professor of global health law at Georgetown University Law Center, in Washington, D.C., said at a press briefing. The recommendation states, “The code should include guidelines on surveillance, regulation, and law enforcement, empowering states and the

international community to prevent and respond to drug quality problems.” “Every country has a stake in being part of that,” Dr. Buckley said. “Keeping bad medicine out of our supply is the FDA’s job.” However, “no matter how good the FDA is, in an era of global medicines, no country can totally act alone.” “These IOM reports are helpful,” said Rich McKeown, JD, Leavitt’s president and CEO. “They provide useful data for dialogue and development of strategic direction.” ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Boston continued from page 1

and third waves of runners who crossed the starting line on Hopkinton, Massachusetts’ Main Street. The air was a cool 50 degrees. The sky was overcast with an occasional spot of sourceless sunlight that added brilliance to the outstretched road ahead. All in all, conditions were idyllic for Dr. Lepore and the 26,383 other entrants who set out to compete in the 117th Boston Marathon. Months of training had been logged, and it was time for a 26.2 mile party.

‘We’ve practiced situations of mass casualty events, so when it happened, we knew what to do.’ —George Velhamos, MD

Dr. Lepore ran alongside his daughter, thankful and excited to be part of what he likened to Christmas morning. “I’m 68,” said Dr. Lepore. “I was never fast, I’m not any faster now, but it’s such a fun event. The crowd does basically everything except use cattle prods to get you going.” Like every third Monday in April for the past 44 years, Dr. Lepore made his way east toward Boston proper, past Hopkinton, Ashland and Framingham, quaint New England towns that might be described as “sleepy” 364 days out of the year, but crackle with electricity on Marathon Monday.

Everything was going according to plan as Dr. Lepore and his daughter coiled through Natick and Wellesley and turned onto Commonwealth Avenue at mile 18 when he received a call from his son. There had been an explosion. “Nobody else seemed to know it because things were going along smoothly,” Dr. Lepore said. “And then it became obvious something was going on because all the police vehicles took off.” By the time Dr. Lepore reached mile 19, just a mile and a half short of the infamous Heartbreak Hill, he and the remainder of the runners on the course were stopped. Their marathon was over. “Just like that, we were told, that’s it, we were done.” At that point, there was no knowing the extent of the terror that was happening just seven miles east.

Unanticipated Trauma In Copley Square, screams and moans cut through an eerie silence. Everywhere, runners and spectators with mangled extremities, pulverized muscles, abdominal wounds, ripped blood vessels, shattered bones and soft flesh filled with nails and ball bearings were taken up, one by one, and rushed to local hospitals. Medical tent volunteers who anticipated a day of treating dehydration, muscle cramps and hypothermia applied tourniquets to control catastrophic hemorrhaging before shuttling victims to ambulances. Just a few hundred feet away from the finish line of the world’s most prestigious running event, there was more trauma and bloodshed than most medical professionals would see in a lifetime. As patients arrived in droves at Boston Medical Center, Beth Israel, Brigham and Women’s

An injured person is transported to Tufts Medical on April 15 in the wake of the Boston bombings. Christopher Evans/Boston Herald

Hospital and Massachusetts General, surgeons saw the same gruesome leg injuries again and again. The same decisions had to be made, with little time to ruminate: “Should we amputate on this one? What about this leg?” But after a week of terror following the bombing, with most Americans— runners and non-runners alike—glued to their televisions, a glimmer of good news emerged from the tragedy. Of the more than 180 victims with injuries who made it to the hospital alive, all survived—a testimonial to fast care at the scene, on the way to hospitals, and in emergency and operating rooms. From an unprecedented horrific event in American history emerged unprecedented success in the way that doctors, nurses and paramedics handled a surgical surge that is seen usually only on the battlefields in Iraq and Afghanistan. Dr. Lepore, who felt a very personal loss both as a runner and a surgeon, acknowledged, “The loss was tremendous, and there are many life-changing injuries, but it could have been a lot worse. The tremendous response showed what each of those hospitals could do, and they all rose to the occasion.” The surgical response following the bombings provides many examples of collaboration and efficiency that are useful to surgeons seeking to improve their practice.

Preparedness

Heightened security at Tufts Medical Center in the aftermath of the bombings Greta Rybus/Getty Images for CNN

The ability to effectively organize in what had the potential to be a chaotic scene came down to disaster preparedness plans, according to George Velhamos, MD, chief of the Division of Trauma, Emergency Surgery and Surgical Critical Care at Massachusetts General Hospital. “If we want to make a change in survival,” Dr. Velhamos said,

“preparedness for the unexpected is absolutely necessary.” Preparedness for mass casualty events starts not with surgeons, but with the EMTs and paramedics who are the first to aid and transport victims on the scene. One of the first directives Boston EMS Chief James Hooley gave after the two bombs exploded near the finish line was for staff to alert hospitals of a potential mass casualty incident and to call for mutual aid. Eleven private ambulance services answered the call by immediately sending more than 40 ambulances to support Boston EMS and to help transport the injured to local hospitals. According to the Boston Public Health Commission, within three minutes of the bombings, all Boston hospitals were notified of the mass casualty incident, and within five minutes mutual aid ambulance partners were asked to assist in the response. Boylston Street was cleared of patients in 18 minutes, and 90 patients from the scene were transported to area hospitals in approximately 30 minutes. Beyond the rapid response to the bombing, Dr. Velhamos noted that the initial triage of patients was what enabled surgeons to work in an orderly fashion as patients started to arrive. “In the short time that we arrived to the ER, within that time, patients were already arriving. The hospital providers did an outstanding job with triaging patients according to their level of injury.” In many mass casualty events, the walking wounded are usually the first to flood nearby centers, not leaving enough space and resources for those who arrive later and are in greater need of care. But Dr. Velhamos remarked that this was not the case after the bombing because the Boston see Boston, page 46

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Boston continued from page 42

EMS System communicated so efficiently. As patients began to arrive at Mass General, Dr. Velhamos described the scene as “orderly and not chaotic.” Most surgeons see mangled extremities on a regular basis, but very few deal with more than 20 at one time. But for the surgeons at Mass General and other area hospitals, April 15, 2013 was merely a day in which years of preparation were finally put to use. “We’ve done disaster preparedness plans and simulation plans again and again, for many years,” said Dr. Velhamos. “We’ve practiced situations of mass casualty events, so when it happened, we knew what to do.” Many surgeons credit the contributions of the American College of Surgeons’ Committee on Trauma (COT) in the success of the surgical response following the bombings. The mission of the COT is to develop and implement meaningful programs for trauma care in local, national and international arenas, and to provide professional development and standards of care. “Without the COT,” Dr. Vehamos said, “we wouldn’t have trauma systems; we wouldn’t have trauma teams, centers, standard of codes of managing trauma patients, no policies or protocols. It is this exact system put together that allows us to practice at the level that we do.”

Fast-Acting Leadership Although disaster preparedness plans were instrumental in creating the infrastructure necessary in dealing with mass casualty, Carl Hauser, MD, a surgeon in the Division of Trauma and Surgical Critical Care at Beth Israel Deaconness Medical Center, explained that while the provisions of the COT are a great starting place, it is up to individual hospitals to make those provisions work. “In the fog of war,” said Dr. Hauser, “one size does not fit all; you have to adapt locally.” For the team at Beth Israel, adaptation meant designating local personnel with a strong knowledge of the hospitals’ resources as leaders. While one team examined patients as they were brought through the door, another team directed them to a specific OR, while another assigned a surgeon to individual victims in critical condition. “You need to be able to rely on the education of local personnel who will be able to adapt and know the hospital well enough to work out the logistics of where these people will go,” said Dr. Hauser. “It’s a secondary layer of triage.” Beyond figuring out logistics, it is crucial to rely on the most experienced staff to make the right call in individual cases, especially when it is not a matter of saving

Right: Boston Medical Center personnel wait for victims from the marathon bombings to arrive. Jim Davis/Globe Staff

one limb, but of saving as many limbs as possible within a group, and there isn’t time for deliberation. In the case of deciding to amputate a leg, for instance, it is standard protocol for a second surgeon to assent to the decision to amputate, but in situations of mass casualty, a second opinion is not always an option. “Management by committee in these circumstances leads to excess morbidity in the group as a whole,” said Dr. Hauser. “If two to three teams debate if a limb is salvageable, you thereby lose the ability to take care of two or three other patients over time. It’s the nature of mass casualty situations. You make your best call and you go with it.”

Damage Control Surgery Beyond the outstanding preparedness and fast-acting adaptation that all of the Boston area hospitals exemplified in the hours and days following the bombings was the implementation of damage control surgery—the single most important breakthrough in trauma care in the past 20 years. The accumulated knowledge of treating blast injuries gained over a decade of war in Iraq and Afghanistan has lent an unexpected value to saving civilian lives in Boston. According to a 2011 study in the British Journal of Surgery, traumatized lower limbs has become the signature injury in the conflict in Afghanistan, and with an increase in lower leg injuries has come greater innovation in treating them. The multitude of lower leg injuries that victims in Boston suffered were an-all-too familiar sight for surgeons who had served in the military. The principle of damage control surgery is to do just enough to stop hemorrhaging, control contamination and reduce fractures, with the understanding that further operations will be done when the patient is more stable. If a patient in critical condition is under anesthesia for too long, it can often do more harm than good.

‘If two to three teams debate if a limb is salvageable, you thereby lose the ability to take care of two or three other patients over time. It’s the nature of mass casualty situations. You make your best call and you go with it.’ —Carl Hauser, MD “It’s critical not to get too hung up on injuries that don’t affect life or functionality,” explained Dr. Hauser. The idea is to do the least possible to keep the patient alive with reasonable function, and recognize that on day 2 or 3 there will be more resources and more logistic capability. “There’s no use in clogging up the OR with doing things perfectly,” Dr. Hauser noted. When dealing with lower leg trauma, the single most important measure in damage control resuscitation is the use of tourniquets in the pre-hospital environment. A 2012 study published in The Journal of Bone & Joint Surgery, reported that the most common cause of death from injuries in both Iraq and Afghanistan was bleeding out. “It is an extremely simple yet underused tactic,” Dr. Velhamos noted. “Surgeons should work with their local EMS to ensure that tourniquets are provided in each ambulance.” After a patient arrives on the scene, the next step is rapid amputation and ongoing, thorough cleaning of the wound, including removal of dead, damaged or infected tissue. It is a process that requires coordination between vascular surgeons who repair torn blood vessels, orthopedic surgeons who stabilize the bone, and plastic surgeons who clean the wound. Determining functionality of the limb is paramount, as there is a very real risk for a patient dying while surgeons try to salvage non-functioning tissue. In other words,

there is a big distinction between saving a leg and saving the function of a leg. “The worst thing is to put vessels, bone and muscle together, and still have a leg that cannot move. It becomes more of a burden to the patient, and they might fare much better with a prosthesis,” explained Dr. Velhamos. In treating the blast victims, nearly all of the amputations performed were guillotine amputations, in which bleeding and contamination are controlled, but a surgeon does a follow-up procedure to close the stump in the following days. As Dr. Hauser put it, “In times of mass casualty, things don’t have to look pretty on day 1.” While for many patients the path to recovery will be long and arduous, with hospital visits, stiffness from torn muscles, scars from operations and arthritic joints, Dr. Velhamos recalls the moment when patients woke up, having a memory of blood spilling out of their legs, and being told they would live. It was, bizarrely, a happy moment, and many patients have the stellar communication, efficiency and training of the staff of local Boston hospitals to thank. But what was an extraordinary event in the lives of many victims and their families was just another day on the job for Dr. Velhamos. “Trauma knows no boundaries,” he explained. “It cuts across race, age and social status. As trauma surgeons, we see it every day. We have seen it all.” ■

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

A Great Read Frederick L. Greene, MD Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina As a former English major, I often have been wracked with self-criticism for failing to read enough good books during my medical career. Too much of my time has been spent perusing medical journals and absorbing surgical texts and other related material. But on occasions, I have strayed from this traditional habit and have read both fiction and nonfiction, which has been rewarding and has even added to my ability to engage in conversation with friends and nonmedical colleagues. I also have become particularly intrigued when a fellow surgeon authors a nonmedical work. This always piques my interest and arouses the enviable thought that maybe I could write like that! Such is the feeling engendered by Cliff Walkingg (Cedar Ledge Publishing, 2011) by Stephen Russell Payne, MD. Steve Payne, a practicing surgeon from Vermont, has published fiction, nonfiction and poetry in a number of northeastern periodicals. His first novel, Cliff Walking, is a spellbinding tale of love, domestic violence, rural bigotry, courtroom intrigue and mentoring relationships that unfolds in an idyllic community on the rocky coast of Maine. The characters are superbly crafted with the artfulness of a painter as Steve Payne creates each with brush strokes that evoke warmth, admiration, sympathy, fear or loathing. The story line is woven with a meticulous yet rapidly flowing style that creates a sense of unstoppable energy with the turn of every page. The juxtaposition of the physician and storyteller is not unique. Some who come to mind are Anton Chekhov (multiple short stories and The Cherry Orchard), d Robin Cook (Coma), Michael Crichton (The Andromeda Strain), Arthur Conan Doyle (The Adventures of Sherlock Holmes), Khaled Hosseini (The Kite Runner) r and Abraham Verghese (Cutting For Stone). I especially have admired those who blend their work as physicians and authors. Steve Payne continues to be an active surgeon while pursuing his passion as a writer. Cliff Walkingg depicts the beauty of the coast of eastern Maine and the unique individuals who intersect in this environment. More importantly, the novel’s title refers to the “fine line” and the precipices that we all traverse that could cause us to lose balance if we are not careful. I felt so moved by Payne’s book that I wanted to write this column to make sure that my fellow physicians could take

tthe opportunity too be as moved ass I was. One peervasive theme in n Payne’s novel is the nightmare an nd global consequences qu brought about by domestic abuse. We, as physicians, have seen the traumatic and emotional consequences resulting from abusive relationships. Unfortunately, for

NEW

surgeons like me, our total experience is frequently in the emergency department or operating room. This intervention is obviously too late. Our colleagues in primary care have highlighted the prevention, or at least early recognition, of this syndrome. My concern is that the signs and symptoms of a battered patient may easily escape us in the outpatient setting unless we are sensitive and open to the diagnosis. The theme of Cliff Walking brings this concept to the boiling point.

Kudos to Stephen Payne for his successful surgical career and for telling a story that saddened me to reach the final page. The author blends his many surgical experiences in caring for women with breast cancer, helping those suffering from the ravages of abusive relationships and understanding the consequences of addiction to create a compelling and unforgettable story. Experience it for yourself—Cliff Walkingg is a great read. ■

In bowel preparation

The NEW Combination Makes the Difference Introducing Suclear Provides the ﬂexibility and convenience of two dosing regimens (same-day, split-dose), with success* achieved in 90% of patients1,2 Significantly more “excellent” preps* with Suclear vs HalfLytely (47.7% vs 35.6%, respectively; P=0.01†) in same-day dosing comparison1 – Prep time was 33% less with Suclear compared to HalfLytely (3.7 hours vs 5.5 hours, respectively; P<0.001†)1 Equivalent rates of excellent cleansing* between Suclear and MoviPrep®‡ (51.9% vs 51.4%, respectively) in split-dose comparison1 Cecum reached in almost all patients using Suclear (split-dosing: 100%; same-day dosing: 99%)1 * *Based on investigator grading. † Statistically signiﬁcant difference. ‡ MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies.

IMPORTANT SAFETY INFORMATION Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution) is a combination of osmotic laxatives 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 Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reﬂex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. 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 the recommended (sodium sulfate, potassium sulfate, and magnesium sulfate ﬁnal volume.

NEW

Please see brief summary of Full Prescribing Information on adjacent page.

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Narcotics, Corticosteroids Double Threat for Pneumonia In Patients With IBD BY ROSEMARY FREI, MSC Gastroenterologists should hold back on prescribing corticosteroids; avoid narcotics, if possible; and be more forthcoming with pneumococcal vaccination for their patients with inflammatory bowel disease (IBD). These were among the main

conclusions a group of clinician-researchers made after studying risk factors for pneumonia in patients with IBD. Millie D. Long, MD, MPH, assistant professor of medicine at the University of North Carolina at Chapel Hill, and her colleagues found that corticosteroid use within the previous 120 days was associated with a nearly twofold increased risk

‘The long-term complications of corticosteroids, including bone health, risk for diabetes and cataracts, are well known, but this work underlines the important infectious short-term risks of corticosteroids as well.’

NEW (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

Introducing Suclear The NEW combination for dosing flexibility High success rates in same-day and split-dose regimens1,2 Cecum reached in nearly 100% of patients1 Significantly less prep time compared to HalfLytely1 References: 1. Data on ﬁﬁle. Braintree Laboratories, Inc., Braintree, MA. 2. Suclear [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2013.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution). INDICATIONS AND USAGE: A combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: Suclear is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. 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 the recommended final volume. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 362 patients who took Suclear in clinical trials, 90 (25%) were 65 years of age or older, while 29 (8%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger subjects. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of each Suclear dose may not be absorbed completely.y Concurrent use of stimulant laxatives and Suclear may increase the risk of mucosal ulcerations or ischemic colitis. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Consume only clear liquids (no solid food or milk) and avoid alcohol on the day before colonoscopy until after completion of the colonoscopy. Split-Dose (2-Day) Regimen (Preferred Method): Dose 1 – Evening before the colonoscopy (10 to 12 hours prior to Dose 2): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Refill the container and drink another 16 oz. of water over the next 2 hours, and another before going to bed. Dose 2 – Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Complete drinking the solution at least 2 hours before the colonoscopy. Consume only clear liquids until 2 hours prior to colonoscopy. Day-Before (1-Day) Regimen (Alternative Method): On the evening before the colonoscopy: Dose 1 (begin at least 3 ½ hours prior to bedtime): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Drink another 16 oz. of water over the next 2 hours. Dose 2 (approximately 2 hours after starting Dose 1): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Refill the container and drink another 16 oz. of water before going to bed. Consume only clear liquids until 2 hours prior to 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.braintreelabs.com ©2013 Braintree Laboratories, Inc.

SU-14168

March, 2013

—Millie D. Long, MD, MPH

for developing pneumonia in patients with IBD, compared with IBD patients with no corticosteroid steroid use within this period. Narcotic use was associated with a 2.28-fold increased risk. Other medications, including biologic agents and proton pump inhibitors (PPIs), also drove up the risk for pneumonia. The results of the retrospective cohort study involving more than 100,000 patients were published in The American Journal of Gastroenterologyy (Long MD et al. 2013;108:240-248). “The long-term complications of corticosteroids, including bone health, risk for diabetes, and cataracts, are well known, but this work underlines the important

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

Commentary by Dr. Mullick Inflammatory bowel disease (IBD) requires the use of steroids at times for treatment. Although the medications are useful to help quell disease, often side effects can manifest. In this month’s Found in Translation, one such study points out a couple of key issues in regard to treatment of IBD. First, steroids and the other medications we use to treat IBD do have side effects and consequences in addition to their benefits. Steroids cause weight gain, irritability, osteoporosis and cataracts, and also make patients more susceptible to infections. Other agents commonly used, like anti-TNF agents,

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

infectious short-term risks of corticosteroids as well,” said Dr. Long. “Improvement and implementation of vaccination protocols among providers who care for patients with IBD is one step toward mitigating this pneumonia risk. Additionally, use of corticosteroid-sparing agents in those [patients] who require repeated courses should be the standard of care, as is already recommended by all of the GI [gastroenterological] societies.” The impetus for this study was the fact that community-acquired pneumonia is the leading infectious cause of death in the United States and also that patients with IBD, particularly those on immunosuppressants, are vulnerable to infections. To perform the first epidemiologic study of pneumonia risk factors in IBD patients, the team analyzed data from the LifeLink Health Plan Claims Database, Inc., from January 1997 to December 2009. They focused on 108,604 adults who were under the age of 64 years, had been enrolled in their health plan for at least six months before being included in the database, did not have any lapses of more than one month in pharmacy coverage and had claims related to IBD. The average follow-up period was 24 months (range, one to 138 months).

have less common but very serious side effects, such as reactivation of tuberculosis or heart failure, and lymphoma, among others. As a result, judicious use and monitoring for side effects are important in patients taking medications for IBD treatment. Second is the topic of vaccinations in patients with IBD. This is a hot topic. Although live vaccinations including polio, varicella zoster, MMR, yellow fever, typhoid and others are contraindicated, it is important for vaccinations to be given in a timely manner to other household members who could be vectors for exposure to IBD patients. Additionally, vaccination with pneumococcal vaccine at an appropriate time prior to immunosuppression is beneficial. Maintenance vaccination with DPT is important every 10 years. Overall, beneficial effects of vaccinations for patients with IBD can prevent a lot of unnecessary infections. Being proactive with your patients is tantamount to success with this measure. Lastly, watch out for side effects of the immunosuppressive agents. Catching problems earlier can lead to quick resolution of patients’ symptoms.

Slightly more than half of the patients (56,403) had ulcerative colitis (UC), and 50,932 patients had Crohn’s disease (CD). The remainder had IBD of unknown type. The investigators compared this group with 434,416 people in the database who did not have IBD. The characteristics of the IBD and non-IBD cohorts were similar, except those with IBD had more health care use, immunosuppressive medication use and PPI use. The IBD individuals also had higher rates of liver disease, chronic see Pneumonia, page 51

Table. Risk for Pneumonia in Patients With IBD Medication Typea

IBD (n=23,784)

Crohn’s Disease (n=12,025)

Ulcerative Colitis (n=11,645)

Biologic agent

1.32 (1.11-1.57)b

1.30 (1.07-1.58)

1.44 (1.00-2.08)

Thiopurine

1.32 (1.00-1.27)

1.06 (0.92-1.23)

1.26 (1.03-1.53)

Corticosteroid

1.91 (1.72-2.12)

1.80 (1.55-2.08)

2.05 (1.75-2.39)

PPI

1.15 (1.04-1.26)

1.17 (1.03-1.04)

1.12 (0.97-1.29)

Narcotic

2.28 (2.09-2.48)

2.17 (1.93-2.46)

2.42 (2.13-2.75)

IBD, inflammatory bowel disease; PPI, proton pump inhibitor a Any use in previous 120 days b Adjusted odds ratio (95% confidence interval)

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.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

From the Literature

Depression, Certain Antidepressants Linked to C. difficile Infection BY GEORGE OCHOA Depression is a risk factor for Clostridium difficile infection (CDI), and so are certain antidepressants, according to a recent study published in BMC Medicine (Rogers MA et al. 2013;11:121). The study comprises two separate studies: The first is a nationally representative investigation of older adults, and the second is an

1978

—

inquiry into hospitalized adults in a single center. The first study included participants from the Health and Retirement Study, a longitudinal, nationally representative study of older Americans, with data linked to files from the Centers for Medicare & Medicaid Services. Patients with depression included not only those diagnosed with major depression but those with other depressive disorders. In all cases, the

diagnosis of depression was made before the diagnosis of CDI. Of 16,781 participants during the period from 1992 to 2006, 404 had been diagnosed with CDI at least once. The rate of CDI was 282.9 per 100,000 person-years in patients with depression, and 197.1 per 100,000 person-years in patients without depression. After fully adjusting for demographic and other characteristics, the odds of developing CDI

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were 36% greater in individuals with major depression ((P=0.016) and 35% greater in individuals with depressive disorders ((P=0.021). Other related factors also increased the risk for developing CDI: The odds were 41% greater in people who felt sad ( 0.008); 47% greater in people with (P= emotional, nervous or psychiatric problems ((P=0.041); 54% greater in widowed individuals ((P=0.001); and 25% lower in people who lived with others ((P=0.007). “This study provides good evidence, given that this is a nationally representative sample,” said lead author Mary A.M. Rogers, PhD, MS, research assistant professor in the Department of Internal Medicine at the University of Michigan in Ann Arbor. The study shows that “the link between depression and Clostridium difficile is probable.” Participants in the second study were adult patients hospitalized in the University of Michigan Health System from August 2010 to February 2012 (N=4,047). Of these patients, 468 tested positive for C. difficile whereas 3,579 tested negative. Certain antidepressants were associated with CDI. In patients who received mirtazapine, the odds of testing positive for C. difficile were twice as high as in patients who did not receive that antidepressant (odds ratio [OR], 2.14; P=0.003). Fluoxetine also was associated with a positive C. difficile test (OR, 1.92; P=0.012), although other drugs in that class—selective serotonin reuptake inhibitors—were not. There was a significant interaction between mirtazapine and trazodone: For a patient receiving both drugs, the odds for having a positive C. difficile test were 5.72 times greater than in patients receiving neither agent ((P=0.001). “The first study is methodologically better than the second one because it was a national sample. The second study was based on one site,” said Dr. Rogers. Douglas A. Drossman, MD, president of the Center for the Education and Practice of Biopsychosocial Care, Chapel Hill, N.C., who was not associated with the paper, said in an interview, “There’s nothing novel with regard to stress or depression affecting bacterial flora and potentially making the intestines more susceptible to infection. The only novelty might be if antidepressants are increasing susceptibility to infection. But in this paper, you can’t discern if it’s antidepressants or depression that is causing the increased susceptibility.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Pneumonia continued from page 49

obstructive pulmonary disease (COPD) and chronic kidney disease. The annual incidence of pneumonia was 138 per 10,000 patients in the IBD cohort compared with 76 per 10,000 patients in the non-IBD cohort. On multivariate analysis, the researchers found the risk for pneumonia was higher in patients with CD relative to non-IBD individuals, than in those with UC relative to non-IBD individuals, at 1.71 and 1.41, respectively. In a bid to perform the most thorough analysis possible with the available data, the researchers conducted a nested case–control analysis (Table). This revealed that pneumonia was associated with a higher number of comorbidities, including having COPD. Additionally,

“To show an additional effect of antidepressants over and above the patient being depressed, you would need to compare a group who are depressed and receiving antidepressants with a group who are depressed and not receiving antidepressants,” added Dr. Drossman, who is also an adjunct professor of medicine and psychiatry at the University of North Carolina School of Medicine, Chapel Hill. “The authors don’t do that.” “It is somewhat difficult to determine whether it is the depression itself or the antidepressants that may be related to CDI,” Dr. Rogers acknowledged. “However, we also found that individuals who were widowed and those who live alone have a greater risk for developing CDI. For these individuals, we might be able to tease out whether there is an independent role for antidepressants.” Asked if this study should affect clinical practice, Dr. Drossman responded, “I’d worry if it did because it might affect clinical judgment in the wrong direction—i.e., to take people who are depressed off antidepressants out of the possibly erroneous belief that they would cause infection.” “For now,” Dr. Rogers advised, “physicians should carefully monitor patients with depression who require antibiotics, especially in health care settings such as hospitals and nursing homes.” She added, “We don’t recommend that people change their habits with antidepressants until there is more evidence.” ■ Drs. Drossman and Rogers reported no conflicts of interest.

patients with pneumonia not only had higher health care utilization, they also had higher rates of immunosuppressant medication use. “Pneumococcal vaccination is safe, effective, widely available and known to prevent complications of pneumococcal pneumonia,” the investigators stated in the study. “Unfortunately, current vaccination efforts in the IBD population are lagging.” They issued a call to action, noting that “the optimal time to vaccinate individuals with IBD is likely at diagnosis.”

When asked to comment on the study, David Rubin, MD, professor of medicine, co-director of the Inflammatory Bowel Disease Center, and associate section chief for educational programs, University of Chicago Medicine, said that although the administrative database nature of the study limited any assessment for severity of the disease, this was a “well-done analysis.” He agreed that vaccination is important for patients with IBD who require immunosuppressant therapy. “Clinicians should remember that

patients on anti-TNF [tumor necrosis factor] therapies are also at increased risk for fungal pneumonia and reactivation of latent tuberculosis, both of which could coexist with or be confused for bacterial pneumonia,” said Dr. Rubin. “Therefore, the IBD patient with fever and respiratory symptoms should be carefully evaluated for all of these possibilities, especially when they do not respond to initial antibacterial therapy.” ■ Drs. Long and Rubin reported no relevant conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Doctor Group Claims GPOs Causing Chronic Drug Shortages BY TED AGRES

‘As a re ‘A resu sult lt of th lt this is misgu isguid ided d leg egiisl islati lati tion on, the GPOs now exert a stranglehold on the

Frustrated with ongoing shortages of key drugs, entirre hospital supplies marketplace. They’ve e a new grassroots group led by physicians is callrigged the market.’ ing for the repeal of federal legislation that permits group purchasing organizations (GPOs) to —P Phill hiillllip lip p L. Z Zw wei e g, g, MBA A engage in what they call collusive and anticompetitive activities. Several senior U.S. lawmakers have asked the Government Accountability Office (GAO), the investigative arm of Congress, to look into the allegations that GPOs are at least partly responsible for the nation’s drug shortages. “We are convinced that the anticompetitive contracting and pricing practices, kickbacks and self-dealing of hospital GPOs are the root cause of this public health emergency,” said anesthesiologist Robert A. Campbell, MD, co-chair of the new group, Physicians Against Drug Shortages (PADS). “We’re launching a national campaign to build public awareness of these anticompetitive practices and press Congress to halt them,” said Dr. Campbell, who also is vice president of the Pennsylvania Society of Anesthesiologists and a executive director of PADS. Mr. Zweig worked for state delegate to the American Society of Anesthesi- medical device companies between 1999 and 2008 but ologists (ASA). no longer has financial ties to the industry. His current Dr. Campbell described PADS as “a small group of work with PADS is pro bono, he said. physicians who met at the recent ASA meeting. After “Our goal is to end the generic drug shortage crisis a totally unsatisfactory panel on drug shortages, we by restoring integrity and free market competition to chose to exchange emails and explore an economic the broken generic injectable marketplace, and indeed, explanation for drug shortages. Our solution will save to the entire U.S. health care supplies industry,” Mr. at first $35 billion per year in health care costs. Once Zweig said. “To accomplish that, we’re pushing for the competitive forces are restored in the health care sup- repeal of the Medicare anti-kickback safe harbor proply chain, even more savings will be realized.” vision, which created the GPO ‘pay to play’ scheme in Any attempt to link GPOs to drug shortages is an the first place. As a result of this misguided legislation, “irresponsible and dangerous distraction,” countered the GPOs now exert a stranglehold on the entire hosCurtis Rooney, president of the Healthcare Supply pital supplies marketplace. They’ve rigged the market. Chain Association (HSCA), a trade association rep- PADS intends to end their reign of terror.” resenting 14 GPOs, including the nation’s five largest. PADS, Mr. Zweig added, does not want to abolish “The true cause of drug shortages is manufacturing GPOs, but rather return them to the pre–safe harbor problems, disruptions and barriers to entry in getting system—“which worked fine from the early 1900s to new suppliers online when there is a disruption in sup- the early 1990s.” ply. The fact is that GPOs are taking a variety of creBut Phil Johnson, oncology director at Premier Inc., ative and innovative steps to reduce drug shortages,” the nation’s second largest GPO by purchasing volume, Mr. Rooney told Gastroenterology & Endoscopy News. said the accusation that GPOs have eliminated free market forces is “uninformed and wrong.” Leveraging Purchasing Power “In fact, GPOs encourage the free market by comGPOs negotiate contracts with manufacturers and petitive bidding and multiple rewards for the best supvendors of pharmaceuticals and other medical products plier performance,” Mr. Johnson said. “Consider that on behalf of their customers, typically hospital groups Premier represents approximately 2,700 hospitals and and other large health care organizations. About 72% more than 90,000 non-acute sites. Our members deterof all hospital purchases are made through GPO con- mine the acceptable drugs or medical supplies within a tracts. GPOs leverage their collective purchasing power therapeutic category, and Premier obtains strong conin order to keep costs low for their customers. Vendors tracts ensuring multiple vendors and product choices. pay GPOs “administrative” fees, typically based on a With GPOs, the best drugs within the category, as percentage of sales and capped by law at 3%. GPOs determined by our member providers—physicians and have been allowed to collect these fees since 1986 pharmacists—develop strong contracts with competithrough a “safe harbor” provision added to the Social tive pricing.” Security Act’s Anti-Kickback Statute, which would However, a June 2012 report by the House Commitotherwise prohibit the practice. tee on Oversight and Government Reform concluded “By exempting GPOs from criminal prosecution that GPOs have contributed to the current shortage for taking kickbacks from vendors, [the exemption] of generic injectable medications because of pressures has given rise to monumental conflicts of interest and that the purchasing organizations exert on manufacturperverse incentives that have undermined competition ers and suppliers. “Companies that cannot produce a and innovation and inflated costs in the health care drug at large enough output levels to take advantage supplies, devices and generic drug marketplace—with of the economies of scale—often because they lack the tragic consequences,” said Phillip L. Zweig, MBA, guaranteed source of demand that GPOs provide—will

stop producing the drug or will neglect to enter the market,” the House report stated.

Congressional Probe The controversy surrounding GPOs is not new. Over the years, hospital systems have claimed that GPOs have saved them billions of dollars annually in purchasing costs, while lawmakers and others have worried about the anticompetitive or unethical practices of GPOs. The GPO industry has adopted voluntary codes of conduct, and since 2005, many companies have participated in an annual survey of their contracting practices. In November 2012, six senior members of the House of Representatives asked the GAO to investigate whether GPOs are a “driving cause” of drug shortages. The lawmakers—Democrats Edward J. Markey (Mass.), John Dingell (Mich.), Frank Pallone (N.J.), Diana DeGette (Colo.), and Henry A. Waxman and Anna G. Eschoo (Calif.)—also said that shortages of critical drugs have forced hospitals and other providers to rely on unregulated compounding pharmacies, such as the New England Compounding Center, the Framingham, Mass., firm that has been blamed for last year’s deadly outbreak of fungal meningitis and other infections caused by contaminated epidural steroid injections. “As Congress fully investigates all the causes of the tragic meningitis outbreak in an effort to protect patients in the future, we need to look at the role GPOs play in the occurrence of drug shortages that could lead to increased reliance on compounding pharmacies,” Mr. Markey said in a statement. Expert practitioners and academics concurred. “This broken generic drug market, which is the direct consequence of unethical GPO drug purchasing contracts legalized by Congress, must be fixed immediately,” said Joel B. Zivot, MD, medical director of the cardiothoracic intensive care unit at Emory University Hospital, in Atlanta, in a statement. “GPOs are a major, if not the primary, contributor to the market distortions in the health care industry in the United States,” added S. Prakash Sethi, PhD, university distinguished professor at Baruch College, in New York City. “Through exclusive contracting, which has given GPOs effective monopolistic control of this industry, they have contributed to product shortages and disincentives for legitimate producers to manufacture and stock essential drugs. At the same time, they have given rise to unscrupulous manufacturers to produce and market substandard drugs and thereby expose the patient population to serious health risks.” But Thomas G. Moore, president of Hospira Inc., blamed shortages of injectable drugs on manufacturing problems and disputes any link between drug shortages and the meningitis outbreak or between drug shortages and GPOs. “The practice of hospitals contracting with a GPO in order to aggregate their purchasing power is not a factor in drug shortages,” Mr. Moore wrote in a Nov. 19, 2012, letter to the lawmakers. “It has been Hospira’s experience that GPOs do not limit the manufacturers who can contract with the GPO, especially in the circumstance of a drug shortage.” ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Golimumab Approved To Treat Ulcerative Colitis The FDA recently approved golimumab (Simponi, Janssen Biotech Inc.) to treat adults with moderate to severe ulcerative colitis (UC). Golimumab works by blocking tumor necrosis factor (TNF). The drug is approved to treat moderate to severe UC that is resistant to prior treatment or requires continuous steroid therapy, according to a press release from Janssen. For the treatment of UC, golimumab 200 mg is injected subcutaneously at week 0, followed by 100 mg at week 2 and then 100 mg every four weeks thereafter. “Simponi is an important new treatment option for patients with moderate to severe ulcerative colitis,” said Andrew E. Mulberg, MD, deputy director of the Division of Gastroenterology and Inborn Errors Products at the Center for Drug Evaluation and Research at the FDA. “It is critical that patients suffering from the serious and painful symptoms of UC have additional treatment options, since patients experience the effects of the disease and respond to treatments differently.” The safety and effectiveness of golimumab were established in two clinical studies. Evaluations of patients included measures of stool frequency and rectal bleeding. In the first study, 513 patients with moderate to severe UC who could not tolerate or failed to respond to other therapies, were randomly assigned to received golimumab or a placebo. Results showed that a greater proportion of patients treated with golimumab achieved clinical response and clinical remission, and had improved appearance of the colon after six weeks compared with the placebo group. In the second study, 310 patients with moderate to severe UC, who did respond to golimumab, were randomly assigned to receive golimumab or a placebo. A greater proportion of golimumab-treated patients maintained clinical response through week 54, had clinical remission at weeks 30 and 54, and also had improved appearance of the colon at both weeks 30 and 54 compared with the placebo group. The most common side effects of golimumab are upper respiratory infection and redness at the injection site. Patients treated with golimumab are at increased risk for developing serious fungal infections, lymphoma,

heart failure, nervous system disorders and allergic reactions. Golimumab also is approved by the FDA to treat moderately to severely active rheumatoid arthritis with the medicine methotrexate, active psoriatic arthritis alone or with methotrexate, and active ankylosing spondylitis. —Based on a press release from Janssen Biotech Inc.

Golimumab (Simponi) is administered as a subcutaneous injection. Photo courtesy of Janssen Biotech Inc.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Belviq for Chronic Weight Management in Adults Now Available in Pharmacies said Lonnel Coats, president and CEO at Eisai. The company said that Belviq will be available in U.S. pharmacies only, and that patients should not buy Belviq from sources offering the drug without a valid prescription from their doctor. Eisai will market and distribute Belviq in the United States, and Arena Pharmaceuticals will manufacture

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

35th Anniversary — 2013

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

Guidance Equivocal On HCV Screening Of Baby Boomers

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

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

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

see NAFLD, page 14

see Income, page 28

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

NAFLD Threatening Public Health BY KATE O’ROURKE

and supply the finished commercial product from its facility in Switzerland. The safety and effectiveness of Belviq in combination with prescription, over-the-counter and herbal weight loss products are not known. It also is not known if Belviq changes the risk for, or death due to, heart problems or stroke. For more information about Belviq, visit www.belviq.com. —Based on a press release from Eisai Inc.

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

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

BY MONICA J. SMITH

tor

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

Photo courtesy of Eisai Inc.

kg/m2 or greater or 27 kg/m2 or greater with at least one weightrelated medical condition, such as high blood pressure, high cholesterol or type 2 diabetes. “Belviq is a new treatment option for the medical management of patients who are obese and who have not been able to sustain longterm weight loss by altering their diets or increasing exercise alone,”

In June, Eisai Inc., announced the availability of Belviq (lorcaserin HCl) CIV tablets to eligible patients by prescription in the United States. Belviq was approved by the FDA in June 2012, in conjunction with a reduced-calorie diet and increased physical activity, for chronic weight management in adults who have a body mass index (BMI) of 30

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

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

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

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

CLINICAL REVIEW see insert between pages 20 and 21

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

PRODUCT ANNOUNCEMENT

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

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

BRIAN BOSWORTH, MD

see page 63 for product information

he e greatest ch hallenge for clinicians who

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

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

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

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

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

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

2013

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

Gastroenterology & Endoscopy News’

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

Please send product news to:

cgordon@mcmahonmed.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

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Pentax Medical Launches High-Resolution HD+ Imaging Technology For Flexible Endoscopy Pentax Medical has announced the launch of the EPK-i5010 video processor with Pentax i-SCAN which, according to the company, is the industry’s highest-resolution HD+ imaging technology for flexible endoscopy. “From our experience, the EPK-i5010 with Pentax i-SCAN has the potential to help physicians improve the characterization and detection of colon disease during surveillance procedures,” said Sharmila Anandasabapathy, MD, associate professor of medicine, gastroenterology, Mount Sinai Hospital School of Medicine in New York City, in a company press release. “The simplicity of the three i-SCAN settings also makes this technology extremely easy to use.” In a statement, Pentax Medical noted that studies have shown that EPK-i5010 with Pentax i-SCAN may improve detection and

characterization of disease by digitally enhancing blood vessels and mucosal surfaces. The Pentax i-SCAN has a quick, singlebutton control to cycle through all three preprogrammed settings. “The EPK-i5010 with Pentax i-SCAN is a remarkable blend of advanced features that combine to offer a clinically relevant and cost-effective solution,” said David Woods, president of Pentax Medical, Americas. “The device, The EPK-i5010 video processor with Pentax i-SCAN paired with our 90i series endo- image enhancement technology scopes, will offer endoscopists Photo courtesy of Pentax Medical an excellent level of visual clarity that may lead to improved detection, better treatment decisions, if treatment is necessary.” use of health care resources and highly informed —Based on a press release from Pentax Medical

Olympus Announces Next-Generation Ultrasound Processor To Power Ultrasound Endoscopes Olympus Medical Systems has announced that the nextgeneration ProSound F75 ultrasound processor will power the company’s ultrasound endoscopes. Developed in partnership with Hitachi Aloka Medical Ltd., the ProSound F75 ultrasound processor provides physicians with the highestquality imaging that aids in the more accurate diagnosis of diseases of the gastrointestinal (GI) tract and surrounding organs such as the pancreas, bile duct, liver and spleen. It also helps to assess various types of cancer. The newly introduced platform improves workflow for pre- and post-examination procedures for better data management and provides improved visualization for more accurate blood flow information. The ProSound F75 ultrasound processor “The ProSound F75 enables offers unique ergonomic capabilities for physicians to realize clini- conducting quick tasks and examinations cal efficacy through premier in every clinical setting, and its forward and backward scope compatibility allows it to imaging and helps health care work with most GI and endobronchial facilities to achieve efficient ultrasound endoscopes. asset management through Photo courtesy of Olympus Medical Systems forward and backward scope compatibility of the platform,” said The ProSound F75 ultrasound Luke Calcraft, president of the processor offers unique ergonomic Medical Systems Group at Olym- capabilities for conducting quick pus Corporation of the Americas, in tasks and examinations in every a company statement. clinical setting, and its forward

endobronchial ultrasound endoscopes, the company said. For more information, visit Olympus at www.olympusamerica.com.

and backward scope compatibility allows it to work with most GI and

—Based on a press release from Olympus Medical Systems

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

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and enter keyword “MN125” Release date: December 1, 2012 Expiration date: December 1, 2013

Chair

Learning Objectives

Jon Gould, MD

1 Review the pathophysiology and complications of postoperative adhesion formation.

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

2 Summarize current strategies used to prevent postoperative adhesion formation. 3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Faculty

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

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

FDA Grants 510(k) Clearance for Cook Medical’s Biliary Stent The FDA has granted 510(k) clearance for the Evolution Biliary Controlled-Release Uncovered Stent manufactured by Cook Medical. The stent adds to Cook’s line of Evolution controlledrelease stents for the gastrointestinal (GI) tract. According to the company’s press release, the woven construction of the Evolution biliary stent is designed to maintain patency and to aid specifically in preventing stent migration after placement. Cook’s family of Evolution stents has a delivery system that allows a physician to deploy or recapture the stent in equal increments by squeezing the trigger on the handle. A “pointof-no-return” mark alerts the physician when

The Evolution Biliary Controlled-Release Uncovered Stent Photo courtesy of Cook Medical

Sandoz Issues Voluntary Recall Of Methotrexate Sodium Injectable Product In May, the FDA announced that Sandoz US is conducting a voluntary, nationwide recall to the hospital/user level of two lots of its methotrexate sodium, USP, 25-mg/mL, 40-mL vial injectable product due to the discovery of particulate matter in vials during routine quality examination of retention samples at the manufacturer. Parenteral injection of the drug from the affected lots could lead to microembolization in areas where the particles lodge. Clinical symptoms are not expected from these microemboli, and Sandoz is not aware of any reports of related adverse events. The lot numbers and expiration dates of the two recalled lots are CL0996 (expiration date 12/2013) and CJ4948 (expiration date 05/2013). These lots were distributed across the United States and to a single foreign country, Poland. In the event that a patient experiences an adverse reaction or quality problem involving this product, he or she should immediately contact his or her health care professional, as well as Sandoz, to report the finding. The Sandoz drug information line is (800) 525-2492, and is open 24/7. Reports also can be made via email at qa.druginfo@sandoz.com. —Based on a press release from the FDA

the stent is deployed too far to be recaptured. The system also features Cook’s Flexor Plus technology (patent pending) and is flexible yet firm enough to be navigated through difficult paths in the anatomy. “We are thrilled with this addition to the Evolution family,” said Barry

Slowey, global leader of Cook Medical’s Endoscopy Division. “Now clinicians can experience the same precision and control throughout the entire GI tract, from the esophagus to the colon.” At press time, Cook Medical stated that the Evolution biliary stent will be available across the United States in July. —Based on a press release from Cook Medical

Some Covidien Surgical Stapler Reloads Unsterilized, FDA Warns In May, the FDA notified health care professionals that Covidien’s Endo GIA Articulating 60-3.5 Surgical Stapler Reloads (lot number N3B0165LX) were stolen from the manufacturer before they were sterilized. Although these devices were packaged and labeled as sterile, they are not sterile and their use could increase the risk for infection in surgical patients, the FDA said. The Covidien surgical repair reloads are used in abdominal, gynecologic, pediatric and thoracic surgery. The FDA is aware that some of these stolen and unsterile products have been offered for sale. At press time, the FDA Office of Criminal Investigation was in contact with Covidien regarding the situation. The only way to identify the stolen, unsterile products is to check the reference code and the lot number on every box of Covidien surgical

stapler reloads before use. The FDA also advised checking current inventory. Covidien Endo GIA Articulating 60-3.5 Surgical Stapler Reloads labeled with reference code 030458 and lot number N3B0165LX should not be used. If the surgical stapler reloads in question are found, health care professionals should quarantine the products and contact Covidien at (800) 522-0263 (option 5) for more information. The FDA advises that products should be purchased from trusted and reliable sources, such as the manufacturer or authorized distributors. Do not purchase products from online auction sites. Anyone with information regarding these stolen devices should contact the FDA Office of Criminal Investigation (OCI) at (800) 5513989, or visit the OCI website at www.fda.gov/ICECI/criminalInvestigations/default.htm. —Based on a press release from the FDA

™

Find what traditional endoscopes are missing. Colonoscopy py is widelyy accepted p as the g gold standard for screening, g, surveillance,, and diagnosis g of

How was this achieved? Traditional endoscopes p p provide no more than

lower GI diseases. However, endoscopy technology has not changed significantly in decades and

a 170° field of view. Fuse Full Spectrum Endoscopy provides a 330°

interval cancers still occur1. In a tandem study using traditional forward viewing (TFV) endoscopes,

field of view, allowing the endoscopist to see nearly twice as much

Rex et al. found they missed 24% of the adenomas in the first colonoscopy. Since that landmark

anatomy as traditional endoscopes.

study, other technologies have shown the miss rate for TFV to be 31%2. In another multi-center tandem trial, the Fuse™ endoscope system demonstrated the miss rate on adenomas with TFV was 42%. Out of 88 patients, a total of 48 adenomas were observed. TFV identified 28 adenomas. Fuse observed an additional 20 adenomas. This means an additional 71% more adenomas were detected by Fuse that traditional forward viewing endoscopes missed3. Conversely, when the patient received a colonoscopy with Fuse first, followed by TFV, the

Traditional Endoscope

researchers had an adenoma miss rate of only 8%.

TFV Gralnek et al.

42%

Adenoma Miss Rate

TFV Siersema et al.

TFV

31%

Limited 170° Field of View

42 % Miss Rate with TFV endoscope 8% Miss Rate with Fuse endoscope ™

Fuse™ Endoscope

Full 330° Field of View

Rex et al.

24%

™

Incremental adenoma find rate with Fuse

CE Marked, FDA 510(k) cleared

Gralnek et al.

8% 1997

2012

2013

To schedule a Fuse experience, call your EndoChoice sales representative, or the EndoChoice Headquarters, at 888.682.3636 x.5, or email fuse@endochoice.com. EndoChoice.com/Fuse (1) Rex et al. Gastroenterology 1997; (2) Siersema et al. World Journal of Gastroenterology, 2012; (3) Gralnek et al. 2013 DDW AGA/ASGE Plenary

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

FDA Clears Magpix Instrument To Aid in Testing for Causes of Infectious Gastroenteritis On April 15, Luminex Corporation announced the FDA clearance of its Magpix instrument with its xTAG gastrointestinal pathogen panel (xTAG GPP). This is the first clinical assay to be cleared on Magpix. â&#x20AC;&#x153;Receiving FDA clearance of Magpix opens the door for clinical laboratories of all sizes to use xTAG GPP on this innovative instrument,â&#x20AC;? said Patrick J. Balthrop, president and chief executive officer of Luminex. â&#x20AC;&#x153;By bringing a compact, cost-effective, easy-to-deploy multiplexing solution to the clinical market, Magpix makes molecular testing more accessible to all laboratories.â&#x20AC;? Based on Luminexâ&#x20AC;&#x2122;s MAP Technology, the Magpix instrument is a versatile, multiplexing platform capable of performing quantitative and qualitative analysis of proteins and nucleic acids in a variety of simple matrices. The instrument can perform up to 50 different tests in a single reaction volume, greatly reducing sample input, reagents and labor while improving productivity. According to Luminex, Magpix is easy to install out of the box, weighs less than 40 pounds and features an innovative and robust detection mechanism that uses high-performing light-emitting diodes. The xTAG GPP is a multiplexed, nucleic acid test that can simultaneously detect 11 common

viral, bacterial and parassitic causes of infectious gas-troenteritis from a single patient sample, including Campylobacter, Clostridium difficile toxin A/B, Escherichia colii O157, enterotoxigenic E. coli LT/ST, Salmonella, Shigella and Shiga toxinproducing E. colii Stx-1/ Stx-2. The test also can detect norovirus and rotavirus A, and the parasites Cryptosporidium and Giardia. xTAG GPP is capable of o delivering multiple resu ults within five hours. Simu ultaneous molecular testing g on a single sample within a single shift provides significant benefits to laboratories in terms of workflow and resource utilization, Luminex said. According to the Centers for Disease Control and Prevention, the number of people who died of gastroenteritis in the United States more than doubled between 1999 and 2007. During the eight-year study period,

Magpix with xTAG gastrointestinal pathogen panel and monitor Photo courtesy of Luminex Corporation

gastroenteritis-associated deaths from all causes increased from nearly 7,000 to more than 17,000 per year. â&#x20AC;&#x201D;Based on a press release from Luminex Corporation

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For classified advertising: contact Alina Dasgupta 212-957-5300 x338 adasgupta@mcmahonmed.com

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2013

Lighthouse Imaging Launches EndoBenchXT2 Endoscope Tester Lighthouse Imaging LLC has added an updated version of its EndoBench endoscope tester to its line of portable endoscope-testing equipment. The EndoBenchXT2 enables hospitals to quantitatively measure the optical quality of both rigid and flexible endoscopes before surgery to ensure patient safety and contain costs. The new EndoBenchXT2 includes a number of new features, such as an extended direction-of-view-measurement range, improved data interface and updated system software. It also includes a new modulation transfer function (MTF) weighted average measurement. The EndobenchXT2 quantitatively measures MTF—the image resolution or sharpness of endoscope optics—by using a backlit optical target, calibrated camera system and custom software. The EndoBench line of products also meets new Joint Commission standards for tracking rigid and flexible scopes in a medical equipment inventory, according to a press release from the manufacturer. As part of its research, Lighthouse Imaging recently used EndoBench to test the entire laparoscope endoscope inventory at a major midwestern hospital and discovered deficiencies in approximately 10% of the hospital’s rigid endoscopes, including deteriorated image quality and improperly repaired scopes, which had not been readily discovered during normal use. “These results are not surprising. They are typical of what any medical facility would discover when using the EndoBench to

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test its inventory of endoscopes,” said Mark Waite, CEO, Lighthouse Imaging. “Endoscope image quality is a hidden problem that, left unresolved, can pose significant problems for surgeons and clinical staff in the operating room.” —Based on a press release from Lighthouse Imaging LLC

EndoBenchXT2 Endoscope Tester Photo courtesy of Lighthouse Imaging LLC

BRIEF SUMMARY Please consult package insert for full prescribing information. INDICATIONS AND USAGE APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. DOSAGE AND ADMINISTRATION The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO. CONTRAINDICATIONS APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules. WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. In animal studies, the kidney was the principal organ for toxicity. Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. ADVERSE REACTIONS APRISO was studied in two placebo-controlled trials (n=367 treated with APRISO) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study. In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%). The most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/ kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. 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. Mesalamine is known to cross the placental barrier. Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman. Pediatric Use Safety and effectiveness of APRISO capsules in pediatric patients have not been established. Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. (see WARNING AND PRECAUTIONS) Phenylketonuria Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 0.56 mg of phenylalanine. CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity. Patients were randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six months. In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for placebo. In study 1 (N=305), 68% of subjects taking APRISO were relapse-free at 6 months EOT vs 51% with placebo (P<0.001). In study 2 (N=257), 71% of subjects in the APRISO group were relapse-free at 6 months EOT vs 59% for placebo (P=0.046). HOW SUPPLIED APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule. NDC 65649-103-02 NDC 65649-103-01

Bottles of 120 capsules Bottles of 4 capsules

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature. Reference: 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987;92:1894-1898.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GM 08/22-1

MANUFACTURED FOR:

WARNER CHILCOTT RECENTLY DISCONTINUED DISTRIBUTION OF ASACOL 400 MG IN THE UNITED STATES ®

CONSIDER APRISO AS AN OPTION FOR YOUR UC PATIENTS IN REMISSION LOW COST

Average co-pay of less than $35 (all tiers)* and on formulary for ~90% covered lives†

APRISO SAVINGS PROGRAM

ONCE-DAILY

* CO-PAY ON YOUR

FIRST PRESCRIPTION OF APRISO

1.5-g once-daily dose provides protection throughout the colon2

*Maximum beneﬁt of $110 off the ﬁrst use.

EFFECTIVE

BIN: 610020

In a combined analysis of 2 controlled clinical trials, 78% of adult UC patients who transitioned to once-daily APRISO from other 5-ASAs maintained remission for up to 6 months3 The most common adverse reactions (incidence ≥3% and >placebo) with APRISO in clinical trials were headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, inﬂuenza and inﬂuenza-like illness, and sinusitis2

PAY NO MORE THAN FOR ALL FUTURE APRISO PRESCRIPTIONS

Group: 99992236

*Maximum beneﬁt of $100 off each subsequent use.

ID: XXXXXXXXXXX

Card is valid for one use per month. Offer expires 12/31/2013. See reverse side of APRISO Card for eligibility criteria. For help processing this card, call 1-855-740-3034.

Please see printed card for complete program details.

APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials. APRISO® (mesalamine) extended-release capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates (sulfasalazine), or to any of the components of APRISO capsules.

MAINTAIN THEM ON

References: 1. Warner Chilcott Investment Call. Feb 8, 2013. 2. APRISO [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 3. Lichtenstein GR, Zakko S, Gordon GL, et al. Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials. Aliment Pharmacol Ther. 2012;36(2):126-134.

Please see brief summary of complete Prescribing Information on adjacent page. Please see complete Prescribing Information available at AprisoRx.com. Asacol® is a registered trademark of Warner Chilcott, Inc. *Average co-pay (all payers), Wolters Kluwer Health, March 2013. †

Patient savings and support at AprisoRx.com/UCan