August 2014

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 65, Number 8 • August 2014

HEPATOLOGY

I N

Fecal Transplants for IBD Show Mixed Results in Trials

F O C U S

Probiotics Could Prevent Hepatic Encephalopathy

BY DAVID WILD

BY DAVID WILD Probiotics may be associated with a reduced risk for hepatic encephalopathy, researchers in India have found. But at least one expert questioned the strength of the findings. see Probiotics, page 7

Studies Challenge Conventional Wisdom In Biliary Stent Cost

BY TED BOSWORTH Chicago—Two randomized trials of metal versus plastic stents for drainage of biliary duct obstruction have reached the same conclusion: Self-expanding metal stents, although they carry higher acquisition costs, are no more expensive than plastic stents because they see Stents, page 9

Chicago—Fecal transplant has reached a critical milestone: testing in the first randomized controlled trial of the therapy to treat inflammatory bowel disease.

Although this step might be good for science, the news was not quite so encouraging for patients. The treatment did not appear to be better than placebo transplant at alleviating symptoms of ulcerative colitis (UC), according to the researchers.

“Although we did not find a statistically significant effect of FMT [fecal microbiota transplantation] in active UC, there is the possibility that FMT may be effective when administered longer than six weeks,” the researchers said, noting that there were no major adverse events.

The study, led by Paul Moayyedi, MBChB, PhD, MPH, acting director of the Farncombe Family Digestive Health Research Institute and director

of the Division of Gastroenterology at McMaster University, in Hamilton, Ontario, Canada, was one of several trials of FMT whose results were presented at Digestive Disease Week (DDW) 2014.

In the trial, the researchers randomized 27 patients with mild to moderate UC to receive an FMT enema and 26 patients to receive a placebo

EXPERT ROUNDTABLE

I N S I D E EXPERTS’ PICKS

Inside the Electronic Health Record

The Best of Digestive Disease Week (DDW): Part 2

It’s a common co complaint: Many physicians who find themselves plugging data into elecctr ctronic health records (EHRs) feel like transcriptionists, not doctors. After all, th heyy say, “I didn’t go to medical school to become a medical journalist” (not, we h w hasten to add, that anything is wrong with that profession). But the world has changed, c and EHRs are here to stay. We asked four individuals who use or aree fam miliar with the software systems in gastroenterology practices how they’ve adapteed d to the new reality—and how those in the specialty who are just making the leap can n lland successfully. see Expert Roundtable, page 18

Faculty Prateek Sharma, MD, FACP, FACG Professor of Medicine, Section Chief Division of Gastroenterology & Hepatology University of Kansas School of Medicine Kansas City, Kansas Kansas City VA Medical Center Kansas City, Missouri

Amit Rastogi, MD, FASGE Associate Professor of Medicine University of Kansas Medical Center Kansas City VA Medical Center Kansas City, Kansas

Introduction

See page 26

Barrett’s esophagus (BE) is a complication that occurs in 10% to 15% of patients with chronic gastroesophageal reflux disease (GERD).1 In BE, the distal epithelium of the esophagus converts from squamous to columnar epithelium, which is confirmed by the presence of intestinal metaplasia (IM).2,3 In some patients, BE is a precursor to esophageal adenocarcinoma (EA); compared with the general population, patients with BE have a 30- to 40-fold increased risk for developing EA.1,4 The National Cancer Institute estimates that in 2014 there will be 18,170 new cases of esophageal cancer and

that 15,450 people will die of the disease, making this the 10th leading cause of cancer death in the United States.4 The 5-year survival rate for patients diagnosed with EA remains low at 17.5%.4 EA is particularly deadly because lymphatic vessels in the esophagus extend into even the most superficial layers of the esophageal mucosa, which favors early lymph node metastases in EA.3 Early detection of metaplasia and dysplasia may decrease mortality and morbidity significantly.5 In fact, survival rate is directly related to disease extent; the 5-year survival for patients with localized disease is 39.6%. However, only 21.3% of patients are diagnosed before cancer has spread (Figure 1).4 Thus, surveillance of patients with BE is vital, and the endoscopist has a responsibility to correctly diagnose dysplasia and EA in a timely manner.6 Staging of dysplasia in patients with BE determines the type of therapy most appropriate for each case.6 The appropriate treatment depends on accurate staging and determination of disease extent. Narrow band imaging (NBI) presents a new method of screening for changes in mucosal and vascular patterns related to BE. By restricting the wavelengths of light used in endoscopic imaging of these areas, NBI produces clearer images of tissue patterns resulting in more

Patients With Esophageal Cancer, %

Screening and Surveillance in Patients with BE Clinical care guidelines presently recommend a combination of examination by white light endoscopy (WLE), biopsy of any obvious lesions, and the Seattle protocol (random 4-quadrant sampling of the BE segment every 2 cm).8 However, these methods have limitations. The subtle changes of dysplasia and early EA may not be identifiable by WLE, and random sampling surveys only 4% to 6% of the BE segment.7 Additionally, adherence to the Seattle protocol is inconsistent. An analysis of 2,245 BE surveillance cases with linked endoscopy reports showed compliance to guidelines in only 51.2% of cases.9 The same study showed that decreased detection of dysplasia was significantly associated with nonadherence to the protocol. Furthermore, random biopsy may cause significant sampling error due to the patchy nature of dysplasia and the tendency among endoscopists to obtain fewer samples of large BE lesions.10 The current recommendation for surveillance in patients with BE is to perform 2 endoscopies with biopsy within 1 year of diagnosis and then surveillance endoscopy once every 3 years.2

Narrow Band Imaging Endoscopy using restricted wavelengths provides enhanced contrast in mucosal and vascular patterns.11 Conventional endoscopy instruments use white light to visualize esophageal tissue. However, NBI instruments restrict the wavelengths used to examine tissue to the blue-green range of light. The enhanced contrast produces clearer endoscopic images.12 Wavelength restriction has 3 important effects (Figure 2). First, tissue penetration distance is directly related to wavelength; shorter wavelengths result in reduced tissue penetration.1,12 Second, shorter wavelengths and less light result in less light scattering, and in some applications may produce clearer images.1 For example, NBI of epithelium mucosal pattern produces higher contrast images that are beneficial in evaluating diseases typified by mucosal pattern disruption.1,13 Third, NBI acts as a specific virtual biomarker for hemoglobin and aids in identifying vascular patterns in tissue.

Oxy- and deoxyhemoglobin have strong peaks of absorption from 400 to 600 nm (Figure 2). Restricting the endoscopic wavelength to this region optimizes visualization of hemoglobin and the imaging of blood vessels.14 NBI is suited to the identification of mucosal and vascular changes associated with dysplasia and metaplasia in patients with BE and has been used in screening and

Five-year survival

40

EDUCATIONAL REVIEW Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

Cases diagnosed at stage 35

See page 20

20 15 10

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

MOHAMMAD TITI, MD

NEIL GUPTA, MD

PRATEEK SHARMA, MD

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

Amy Foxx-Orenstein, DO

Division of Gastroenterology and Hepatology Loyola University Medical Center Maywood, Illinois

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

Gluten-free no boost to low-FODMAP diet for IBS ....page 3

Dr. Sharma has received grant support from CDX Labs, Cook Medical, NinePoint Medical, and Olympus Inc. Drs. Titi and Gupta report no relevant financial conflicts of interest.

C

olorectal

Bundled payments on the way—how to cope .........page 24

cancer

(CRC) is the second leading cause of

cancer-related in

the

mortality

Western

world.1

Screening colonoscopy and polypectomy have become widely accepted as the mostt effective available methods for for CRC and have shown a reduction iin mortality t lit within the screened population.2 However, colonoscopy remains imperfect and several studies have raised concerns about the miss rate of adenomatous polyps during screening.

5 0

Samir A. Shah, MD

early detection and prevention of

30 25

Localized

Regional

Distant

The overall miss rate is approximately 20%, and ranges from 6% for large (10 mm) adenomas to 26% for diminutive (<5 mm) lesions.3 Missing these adenomas is one of the proposed mechanisms in the development of interval colon cancers that occur within the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

Unstaged

Stage at Diagnosis

Figure 1. Survival and diagnosis of patients with esophageal cancer by stage.

Adapted from SEER Cancer Statistics Factsheets: Esophageal Cancer. National Cancer Institute.

22

efficient screening and surveillance, and a reduction in the number of biopsies needed during these procedures.1,7

Experts share their favorite abstracts from DDW 2014 ...................................................................page 28

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Extending Conventional Endoscopy in Barrett’s Esophagus Using Narrow Band Imaging

Extending Conventional Endoscopy in Barrett’s Esophagus Using Narrow Band Imaging

see Fecal, page 15

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Figure 2. Narrow band imaging optimizes visualization of hemoglobin by restricting light wavelengths to the blue-green range, resulting in reduced tissue penetration.

Image courtesy of Olympus.

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

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • AU G U ST 2 0 1 4

1

Rise in colectomy for constipation raises alarm ...... page 33

2

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Heard Here First See page 28

If this is proven to be

safe and accurate in larger studies, it could really change how we follow patients. Instead of requiring endoscopy, the sponge could simply be administered in an office-based setting, the sample sent to pathology and the results acted on

without the patient having the expense or risk of another endoscopic

A Sea Change in IBD Treattment?

BY MONICA SMITH A Florida immunologist and macrophage biolob gist recently received a substantial grant from the National Institutes of Health to investigate a possible role for chitin, an abundant compo onent of shrimp, crab and lobster shells, in treating inflammatory bowel disease.

Yoshimi Shibata, PhD, professor of biomedical science at the Charles E. Schmidt College of Medicine of Florida Atlantic University, in Boca Raton, has spent more than 20 years studying macrophages, an element of white blood cells that phagocytize bacteria. They also consume certain carbohydrates. Over the course of his career, Dr. Shibata has screened many carbohydrates in search of those that would appeal to macrophages.

“I found that only chitin could stimulate macrophage activation by phagocytosis. This results in the production of very unique inflammatory mediators,” he said.

To isolate these specific carbohydrates, Dr. Shibata and his colleagues removed the calcium and protein from crustacean shells. The remaining chitin microparticles are known as mimetic microbes; macrophages cannot

discriminate between them and bacteria.

“We can make many other forms of chitin, but only this form induces macrophage activation,” he said. “And we can make this fform easily.” il ” The form they developed is an orally administered dietary supplement. Earlier studies by Dr. Shibata and his team demonstrated the supplements reduced disease conditions of asthma, food allergies, colitis and foodborne infections in animal models, and seasonal allergies in humans. The new study, for which they received $380,552 from the National Institute of Complementary and Alternative Medicine, will investigate the effect chitin microparticles might have on intestinal macrophages.

“We want to know in more detail how orally administered chitin microparticles stay in the intestine and do something beneficial,” Dr. Shibata said. “We want to know in particular the interaction between microparticles and macrophages in the colon, perhaps shifting the balance toward a good bacterial environment.

That is our hope.”

procedure.

Vol. 65, No. 8 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, PHD

Farmington Hills, Michigan

Sacramento, California

FREDRIC DAUM, MD

PETER R. MCNALLY, DO

Mineola, New York

Fort Carson, Colorado

STEVEN M. FABER, MD

TARUN MULLICK, MD

Elizabeth City, North Carolina

St. Charles, Illinois

RONNIE FASS, MD

JOEL E. RICHTER, MD

Cleveland, Ohio

Tampa, Florida

BARBARA B. FRANK, MD

DAVID ROBBINS, MD

Philadelphia, Pennsylvania

New York, New York

FRANK G. GRESS, MD

ELLEN J. SCHERL, MD

New York, New York

New York, New York

CHRISTOPHER JOLLEY, MD

PRATEEK SHARMA, MD

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

August 2014

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3

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Nixing Gluten Offers No Added Benefit To Low-FODMAPs Diet for IBS

BY CAROLINE HELWICK Chicago—In the management of irritable bowel syndrome (IBS), the addition of gluten avoidance to a FODMAPs-restricted diet does not appear to offer any additional significant benefits, researchers have found.

FODMAPs are highly fermentable or poorly absorbable molecules, comprising four major classes: oligosaccharides (fructans, galacto-oligosaccharides), disaccharides (lactose), monosaccharides (fructose, in excess of glucose) and polyols (mannitol, maltitol, sorbitol and xylitol). The low-FODMAPs diet aims to alleviate gastrointestinal symptoms, such as abdominal bloating and pain, by eliminating a host of possible offenders. Among the banned foods are wheat, rye, barley, onions, garlic, artichokes, legumes, honey, apples, pears, watermelon, mango, stone fruits, mushrooms, cauliflower, sugar-free mints and gums, and sources of lactose.

“A low-FODMAPs diet has been suggested as a dietary therapeutic intervention for IBS,” said Daria Piacentino, MD, of Sapienza University, in Rome, who presented the findings at Digestive Disease Week 2014 (abstract 374). At least three studies have reported symptom improvement with low-FODMAPs diets in patients with IBS, he said.

Gluten also may play a role in IBS symptoms. “Many IBS patients autonomously reduce or eliminate gluten intake in their diet and report clinical benefit. In addition, a small subset of IBS patients is affected by non-celiac gluten sensitivity (NCGS). The overlap between IBS and NCGS is not infrequent,” Dr. Piacentino said. “But while the amount of gluten is undeniably reduced in low-FODMAPs diets, it is not known to what extent the benefits of low-FODMAPs diets are due to FODMAPs per se or to gluten reduction.”

The study examined the effect on bloating, abdominal distension and

Table. Diet-Related Median Percentage Reduction In Abdominal Symptoms Symptom

Low-FODMAPs/ Normal Gluten Diet (n=20)

Low-FODMAPs/ Gluten-Free Diet (n=20)

Normal FODMAPs/ Normal Gluten (Control) Diet (n=20)

Bloating: Self-reported VAS score, %

50.0a

33.3a

12.5

Bloating: Frequency over 2 wk, %

38.5

16.6

28.6

Pain: Frequency over 2 wk, %

42.6a

45.5a

28.6

VAS, visual analog scale a P<0.05

abdominal pain of three diets: low FODMAPs and no gluten; low FODMAPs and normal gluten; and normal FODMAPs and normal gluten (control). All diets were adjusted for patient weight, height and physical activity.

The study included 62 ROME III IBS patients (two of whom withdrew) with similar baseline clinical and sociodemographic hi characteristics. h i i At A enrollment, ll the h patients rated the severity of bloating on a visual analog scale (VAS), ranging from 0 (“no or mild bloating”) to 10 (“very severe bloating”). They also kept a two-week daily diary to calculate the number of days with abdominal distension or pain. At the end of the diary completion, the patients were

randomly and blindly assigned to one off the three dietary protocols, which they followed for four weeks.

During the last two weeks of the diet, the patients again rated the severity off bloating. Collected data were analyzed by an investigator blinded to the diett assignment.

After completion of the test diets, the h llow-FODMAPs/normal FODMAP / l gluten l and d the low-FODMAPs/gluten-free groups showed significant improvements in abdominal symptoms, whereas the normal-FODMAPs controls had a slight, but not statistically significant, improvement (Table).

“At baseline, the three groups reported

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a comparable severity of bloating and frequency of abdominal distension and pain, but differences in the same symptoms post-diet,” Dr. Piacentino said.

Symptoms of IBS improved significantly more in the two test diet groups than in the control diet group, with only a trend favoring the low-FODMAPs/normal gluten group versus the low-FODMAPs/gluten-free group.

Dr. Piacentino acknowledged that the study had a small sample size, consisted of highly motivated patients referred to a tertiary center and was of short duration.

But he noted that its strengths included a double-blind, randomized, parallel-group design and a highly compliant (85%) study population. He did question whether the effectiveness of a low-FODMAPs diet, regardless of gluten status, would last and whether compliance with such a restricted diet could be maintained over time.

Lin Chang, MD, co-director of the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress in the Division of Digestive Diseases at the David Geffen School of Medicine of the University of California, Los Angeles, said, “There are limited data on the effect of low FODMAPs in IBS; however, symptom improvement has been shown in IBS with and without self-reported gluten sensitivity. The beneficial effect of low FODMAPs does not appear to be predominantly due to gluten avoidance.”

Dr. Chang noted further that the lowFODMAPs diet can be “challenging to adhere to,” and that some patients can benefit from eliminating just some, and not necessarily all, of the high-FODMAPs foods. “Some IBS patients will benefit from low FODMAPs but others won’t,” she observed. “A [gastrointestinal] dietitian is key to the successful initiation and maintenance of [such a] diet.”

■ Dr. Piacentino reported no relevant disclosures. Dr. Chang has consulted for, served on advisory committees or review panels for, or received research support from Forest Laboratories, Ironwood Pharmaceuticals, Purdue Pharma, Salix Pharmaceuticals and Takeda Pharmaceutical Company.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Experts’ Picks:

Top Liver Abstracts From 2014 DDW and COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy News asked two hepatologists to share their insights on Digestive Disease Week 2014 and the 2014 annual meeting of the European Association for the Study of the Liver. Following are their selections of the top abstracts from the conference.

of a regimen including a oncee-daily single tablet containing 150 mg of ABT450 (AbbVie), a protease in nhibiChief of the Division of Gastroenterology and Hepatology tor, 100 mg of ritonavir and 25 Professor of Medicine mg of ABT-267 (ombitasviir, AbbVie). The regimen also Weill Cornell Medical College included ABT-333 (dasabuAttending Physician vir, AbbVie), a non-nucleNewYork-Presbyterian Hospital oside polymerase inhibitor, New York City administered twice daily in 250-mg tablets.

The momentum of research into the treatment of liver In the Phase 3, opendiseases is showing no signs of slowing. To provide a label PEARL-II study, 88 snapshot of some of the most exciting findings in the noncirrhotic patients with field, Gastroenterology & Endoscopy Newss asked Ira hepatitis C virus (HCV) Jacobson, MD, and Raymond Chung, MD, to share genotype 1b (GT1b) were their picks for the most clinically significant hepatol- randomized to receive the ogy abstracts presented at the 2014 International Liver regimen with 1,000 or 1,200 Congress and Digestive Disease Week 2014. mg of ribavirin (RBV) divided d Dr. Jacobson reported receiving research support into two daily doses; 79 patients from and serving as a consultant and advisor to AbbVie. received the regimen without RBV Dr. Chung reported receiving research funding from and with a placebo. Both grou ups were Gilead and Mass Biologics and having served as a con- treated for 12 weeks. sultant to AbbVie. All patients in PEARL-II had failed prior therapy with pegylated interferon (pegIFN)/RBV, including 35.2% who were prior null responders, 28.5% who had partially responded and 36.3% who responded ‘Results of the PEARL-II study provide and relapsed after the end of treatment.

A statistically similar 11% and 7.4% of compelling evidence that RBV is not needed in patients in the RBV and placebo-treatGT1b patients who are prior IFN nonresponders, ment arms, respectively, had the IL28B even in those with prior null response.’

CC genotype.

In an intent-to-treat analysis, find—Ira Jacobson, MD ings showed that rates of sustained virologic response 12 weeks after treatment cessation (SVR12) were 96.6% for RBV recipients and 100% for those not receiving RBV. SVR12 rates were similar regardless of prior response to pegIFN/RBV. All PEARL-II: Randomized Phase 3 Trial of patients in both groups experienced virologic response Interferon-Free, 12-Week Regimen of ABT-450/r/ while receiving treatment.

ABT-267, ABT-333 With or Without Ribavirin The most common adverse events (AEs) included in Hepatitis C Virus Genotype 1b-Infected, fatigue (31.9% vs. 15.8% for RBV and placebo groups, Treatment-Experienced Patients; and PEARL-IV: respectively; P P=0.015), headache (24.2% vs. 23.2%; A 12-Week Regimen of ABT-450/r/ABT-267 and P>0.05) and nausea (20.9% vs. 6.3%; P P=0.005). FortyABT-333, With or Without Ribavirin Achieves two percent of RBV recipients experienced a drop in SVR12 Rates ≥90% in Treatment-Naïve Adults hemoglobin below the lower limit of normal at the end Infected With Hepatitis C Virus Genotype 1A of treatment compared with 5.5% of placebo recipients The PEARL trials examined the safety and efficacy (P=0.001).

P Bilirubin rose beyond three times the upper

Ira Jacobson, MD

929e, Su1061.

limit of normal in 8.8% of RBV recipients but not in any of the individuals receiving placebo (P=0.01).

P Two patients receiving RBV discontinued treatment as a result of the AEs. PEARL-IV, a separate double-blind Phase 3 study of the same regimen, included 305 treatment-naive, noncirrhotic patients with chronic HCV GT1a infection.

One hundred individuals were randomized to receive the regimen with RBV, and 205 received the RBVfree regimen and a placebo, for 12 weeks. Approximately 31% of patients in each arm had the IL28B CC genotype.

In an intent-to-treat analysis, 97% and 90.2% of patients in the RBV and placebo groups, respectively, had SVR12.

The most common AEs included fatigue (46% and 35% for the RBV and placebo groups, respectively), headache (25% and 28%) and nausea (21% and 13%).

Two patients in the RBV group discontinued treatment due to AEs. There were two serious treatment-related AEs in the RBV group, including anemia and pancreatitis. In addition, 42% of RBV recipients experienced a hemoglobin drop below the lower limit of normal compared with 3.9% in the RBV-free group (P<0.001).

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST AUGUST 2014 2014

Dr. Jacobson: Results of the PEARL-II study provide compelling evidence that RBV is not needed in GT1b patients who are prior IFN nonresponders, even in those with prior null response. By inference, the same conclusion would be expected to apply in GT1b treatment-naive patients, and indeed this was the finding in the PEARL-III study, as yet reported only in a press release.

In contrast, although GT1a treatment-naive patients had excellent results without RBV, with SVR12 of 90%, this was exceeded by the 97% SVR12 rate in patients who received the drug. Barring strong contraindications to RBV, it is likely that most clinicians would not be willing to incur this degree of increased risk for failure for the sake of avoiding RBV. Rather, the preferable treatment approach would be to start with RBV and, should undue side effects such as significant anemia occur, reduce or even discontinue the RBV dose as needed, bearing in mind the large body of data from other studies on direct-acting antivirals (DAA) indicating that appropriately instituted RBV dose reductions do not adversely affect SVR [Poordad F, et al. Gastroenterology 2013;145:1035-1044].

The safety data from PEARL-II and -IV demonstrate incremental incidences of fatigue, nausea, hemoglobin reduction and hyperbilirubinemia with RBV, with very low rates of discontinuation for AEs, and are entirely consistent with historical experience.

475, 235.

SAPPHIRE I: Phase 3 PlaceboControlled Study of Interferon-Free, 12-Week Regimen of ABT-450/r/ ABT-267, ABT-333, and Ribavirin in 631 Treatment-Naïve Adults With Hepatitis C Virus Genotype 1 (Kowdley, KV, et al); and SAPPHIRE II: Phase 3 Placebo-Controlled Study of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333, and Ribavirin in 394 Treatment-Experienced Adults With Hepatitis C Virus Genotype 1 (Jacobson IM, et al.)

The double-blind, randomized placebo-controlled SAPPHIRE I and II trials examined the same treatment regimen as PEARL-II and PEARL-IV (ABT-450/r/ABT-267, ABT-333 with or without RBV).

In SAPPHIRE I, 473 noncirrhotic, treatment-naive patients with chronic HCV GT1 infection were randomized to receive the active treatment with

‘The preferable treatment approach would be to start with RBV and, should undue side effects such as significant anemia occur, reduce or even discontinue the RBV dose as needed.’

—Ira Jacobson, MD

5

1,000 or 1,200 mg RBV divided into two daily doses, and 158 received the regimen with placebo. Both regimens were administered for 12 weeks.

Most participants were white; approximately half were male; roughly 30% had the IL28B CC genotype; and approximately two-thirds of each group had HCV GT1a infection.

In an intent-to-treat analysis presented see Liver Picks, page 6

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6

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Liver Picks continued from page 5

at DDW, the researchers reported that 96.2% of patients who received the active treatment experienced SVR12, 0.2% experienced on-treatment failure and 1.5% relapsed following treatment. The researchers observed no significant differences in rates of SVR12 between HCV GT1a and GT1b patients.

Common AEs in the trial included fatigue (34.7% and 28.5% in the active treatment and placebo groups, respectively; P P=NS), headache (33% and 26%; P=NS), P nausea (23.7% vs. 13.3%; P<0.05), pruritus (16.9% vs.

3.8%; P<0.05), insomnia (14% vs. 7.6%; P<0.05), diarrhea (13.7% vs. 7%; P<0.05) and asthenia (12.1% vs.

3.8%; P<0.05), and rash (10.8% vs. 5.7%; P=NS).

P More serious side effects included elevations of alanine aminotransferase (ALT) greater than five to 20 times the upper limit of normal (0.9% vs. 4.4% in the active treatment and placebo groups, respectively; P<0.05) and total bilirubin beyond three to 10 times the upper limit of normal (2.8% vs. 0%; P<0.05).

Nearly 6% of patients in the treatment group experienced hemoglobin below 10 g/dL, compared with none of the patients in the placebo group. In each arm, 0.6% of patients discontinued treatment due to AEs. The double-blind, placebo-controlled SAPPHIRE II trial examined the same 12-week regimen of ABT-450/r/ ABT-267 and ABT-333 in 394 noncirrhotic, pegIFN/ RBV-experienced patients with HCV GT1 infection.

Researchers randomized 297 individuals to receive the regimen with RBV and 97 to receive the regimen with a placebo. Participants either had relapsed after previous pegIFN/RBV treatment or were partial or null responders (Table 1).

The investigators found that 96.3% of the RBV recipients experienced SVR12. SVR12 rates among patients taking RBV were similar regardless of prior null or partial pegIFN/RBV response (95.2% and 100%, respectively) or prior relapse (95.3%; Table 1 shows SVR12 by genotype).

In the active treatment group, 2.4% of patients experienced post-treatment relapse. Because those in the placebo arm in both SAPPHIRE studies received active treatment immediately after the 12-week blinded period, researchers did not record SVR12 rates.

There were no significant differences in rates of mild, moderate and severe AEs between the RBV and placebo groups, with the most common being headache (36.4% and 35.1% in RBV and placebo recipients, respectively) and fatigue (33.3% and 22.7%). One percent of patients in the RBV group discontinued treatment as a result of side effects, whereas none of the patients taking placebo stopped treatment.

Dr. Jacobson: Together with the TURQUOISE II study in cirrhotics, the SAPPHIRE I and II studies in noncirrhotic patients are the centerpiece of AbbVie’s Phase 3 program evaluating the three-drug regimen of ABT-450/low-dose ritonavir/ombitasvir—all coformulated—plus dasabuvir, along with RBV. The three-drug plus RBV regimen was chosen on the basis of the Phase II AVIATOR trial, which explored various durations of therapy and numbers of drug classes in this regimen and demonstrated SVR12 rates with 12 weeks of [active medication] plus RBV of 96% and 93% in GT1, treatment-naive and null responders, respectively (Kowdley KV, et al. N Engl J Med 2014;370:222-232).

Table 1. Baseline Characteristics and Efficacy in SAPPHIRE II Patient Factors

Treatment With RBV, n=297

Treatment With Placebo, n=97

Male, n (%)

167 (56.2)

60 (61.9)

White, n (%)

269 (90.6)

86 (88.7)

IL28B CC, n (%)

173 (58.2)

57 (58.8)

Fibrosis score >F2, n (%)

34 (11.4)

7 (7.2)

Prior relapser, n (%)

86 (29)

29 (29.9)

Prior partial responder, n (%)

65 (21.9)

21 (21.6)

Prior null responder, n (%)

146 (49.2)

47 (48.5)

SVR12 rate according to genotypea,b HCV GT1a, n/N (%)

166/173 (96)

—

HCV GT1b, n/N (%)

119/123 (96.7)

—

HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response a Data for one patient missing. b SVR12 for placebo recipients not recorded.

Notably, since the very first proof-of-concept study showing the curability of HCV infection with an IFNfree approach using a protease inhibitor (asunaprevir, Bristol-Myers Squibb) and an NS5A inhibitor (daclatasvir, Bristol-Myers Squibb), it has been recognized that the lower barrier to resistance of HCV GT1a to these classes of agents could make it more challenging to achieve SVR than in GT1b infection.

‘The virtual absence of on-treatment virologic failure in these two studies, with post-treatment relapse being the route to virologic failure in all but one patient among the small number who failed, further reflects on the regimen’s potency.’

—Ira Jacobson, MD

The SAPPHIRE I and II studies, conducted in treatment-naive and treatment-experienced patients, respectively, provide resounding affirmation of the high-level of potency and the high barrier to resistance cumulatively imposed by the three-drug plus RBV combination, resulting in very high SVR12 rates

that essentially level the playing field between GT1a and GT1b patients, and between treatment-naive and treatment-experienced patients. Both of these issues had threatened to result in outcome disparities with earlier antiviral regimens at the outset of the DAA investigational era, further underscoring the importance of the findings in these studies.

It is striking that null responders in SAPPHIRE I and II had the same SVR rates as prior relapsers, with the only signal of a possible effect of intrinsic IFN nonresponsiveness being the fact that six of the seven relapsers in SAPPHIRE II were prior null responders.

The virtual absence of on-treatment virologic failure in these two studies, with post-treatment relapse being the route to virologic failure in all but one patient among the small number who failed, further reflects on the regimen’s potency. The presence of resistance to at least two classes of agents among most of the relapsers leads to the question of salvage regimens, which may require a nucleotide in addition to other agents. This will be an important area for further study even though it fortunately bears on a small percentage of patients.

The placebo-controlled nature of these two studies also provides valuable insights into the safety and tolerability of the regimen, which in general was excellent with 1% or fewer discontinuations for AEs. Adverse events were quite common even in the placebo recipients, but more so with active treatment. There were several specific incremental side effects in the treatment-naive population, but only one, pruritus, attained statistical significance in the treatment-experienced see Liver Picks, page 8

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST AUGUST 2014 2014

Probiotics continued from page 1

The randomized controlled trial of 160 cirrhotic patients found that a threemonth course of probiotics was associated with a 50% reduction in the risk for overt hepatic encephalopathy (HE) over a 10-month period.

“Probiotics are effective in primary prophylaxis of HE,” the researchers, led

by Manish Kumar Lunia, MD, of the Department of Gastroenterology at G B Pan Hospital in New Delhi, reported in Clinical Gastroenterology and Hepatolology (2014;12:1003-1008).

But HE expert Jasmohan Bajaj, MD, associate professor of hepatology at Virginia Commonwealth University School of Medicine, in Richmond, who was not involved in the study, was more reserved about the findings.

“Further placebo-controlled studies using compounds with strict product integrity and adequate control of subjects’ diets are needed to say that probiotics are responsible for the preventive effect,” Dr. Bajaj said.

The rationale for probiotic prophylaxis of HE is based on prior research showing that small intestinal bacterial overgrowth (SIBO) and related buildup of potentially neurotoxic compounds are associated with the risk for liver damage (Gupta A, et al. J Hepatol 2010;53:849-855).

For the latest study, investigators randomized 86 patients, including 42 with minimal HE, to receive three months of thrice-daily VSL#3 (Sigma-Tau Pharmaceuticals), which includes 110 billion colony-forming units of several bacterial species and strains. Another 74 patients, including 33 with minimal HE, did not receive this intervention and were asked not to consume commercial probiotic yogurts during the study. At the time of enrollment, patients reported abstaining from alcohol and not taking antibiotics or lactulose therapy during the four to six weeks before study outset, as well as not using psychotropic drugs. No patients had neurologic or psychological illnesses at study outset.

Follow-up data from approximately 39 weeks for 149 of the 160 participants showed that seven probiotic recipients (8.8%) and 14 control patients (20.3%) developed overt HE (hazard ratio for controls vs. probiotic patients, 2.1; 95% confidence interval, 1.31-6.53; P<0.05).Three months after study outset, the number of individuals with minimal HE in the probiotics group fell from 42 at baseline to 18, whereas of the 33 control group participants with minimal HE at baseline, 25 had minimal HE after three months.

Researchers also found that the number of patients with SIBO fell from 33 to 14 in the probiotics group (P=0.006)

H E PAT O L O G Y I N F O C U S

‘The rationale for the efficacy of probiotics in preventing HE is sound, and further trials such as this one using clinically relevant end points such as HE prevention in cirrhotic patients are needed.’

—Jasmohan Bajaj, MD compared with a decrease from 26 to 21 cases in the control group (P=NS), supporting the posited association between SIBO and HE. As the researchers hypothesized, concentrations of arterial ammonia decreased in the probiotics

group but not in the control group (74.3 and 61.2 mmol/L of ammonia for treatment group at baseline and three months, respectively; vs. 78.4 and 81.3 mmol/L in controls at baseline and three months [P=0.04]).

7

Dr. Bajaj stressed that the researchers did not monitor probiotic intake from non-study sources, and that “this could introduce confounders into the study results and potentially reduce their generalizability. Nevertheless, the rationale for the efficacy of probiotics in preventing HE is sound, and further trials such as this one using clinically relevant end points such as HE prevention in cirrhotic patients are needed.”

■ Drs. Lunia and Bajaj reported no relevant conflicts of interest.

8

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Liver Picks continued from page 6

study. There was a low incidence of grade 3/4 ALT elevations, with only one patient in both studies combined stopping therapy for these. Hyperbilirubinemia also occurred, but was dissociated from ALT elevations and attributable to an interaction of the protease inhibitor with a bilirubin transporter. Roughly 5% of patients decreased RBV doses due to reduced hemoglobin levels, with no effect on SVR rates.

0109, 064, 056.

All Oral Fixed-Dose Combination Sofosbuvir/ Ledipasvir with or without Ribavirin for 12 or 24 Weeks in Treatment-Naïve Genotype 1 HCV-Infected Patients: the Phase 3 ION-1 Study (Mangia A, et al) and All Oral FixedDose Combination Sofosbuvir/Ledipasvir with or without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCVInfected Patients: the Phase 3 ION-2 Study (Afdhal N, et al) and Sofosbuvir/Ledipasvir with and without Ribavirin for 8 Weeks Compared to Sofosbuvir/Ledipasvir for 12 Weeks in Treatment-Naïve Non-Cirrhotic Genotype-1 HCV-Infected Patients: the Phase 3 ION-3 Study (Kowdley, KV, et al).

These three international, multicenter Phase 3 studies examined the efficacy and safety of a single tablet consisting of the nucleotide polymerase inhibitor sofosbuvir (SOF; Sovaldi, Gilead Sciences) and the NS5A inhibitor ledipasvir (LDV; Gilead Sciences) for the treatment of HCV GT1.

‘Regardless of how you analyze these data, it appears we’ve

groups, 8% of patients experienced hemoglobin below 10 g/dL compared with none given SOF/LDV alone.

In ION-2, researchers examined the same regimens in 440 treatment-experienced patients with HCV GT1.

They randomized 109 patients each to 12 and 24 weeks of SOF/LDV treatment and 111 patients each to 12 and 24 weeks of treatment with SOF/LDV+RBV. Fortyfour percent of patients had failed earlier treatment with pegIFN with RBV, and the remaining patients had either partial prior response or complete response followed by relapse.

Sixty-five percent of patients were male; most were white; 88% carried non-CC IL28B alleles; 79% had the HCV GT1a genotype; and 20% had compensated cirrhosis.

Researchers found 94% and 96% in the 12-week SOF/LDV and SOF/LDV+RBV groups, respectively, had SVR12, and 99% of both the 24-week SOF/LDV and SOF/LDV+RBV groups had SVR12. Rates and types of adverse events were similar to those reported in ION-1, and no patients discontinued treatment as a result of complications.

Finally, ION-3 compared an eight-week course of SOF/LDV, with or without RBV, to a 12-week course of SOF/LDV alone, in 657 noncirrhotic, treatment-naive patients with HCV GT1 infection. Seventy-eight percent of patients were white; 58% were male; 75% had non-CC IL28B alleles; and 80% had HCV GT1a infection.

Findings showed 94% and 93% of those who received eight weeks of SOF/LDV or SOF/LDV with RBV, respectively, had SVR12, compared with 95% of those in the 12-week SOF/LDV group.

The researchers found similar rates of AEs in the 12- and 24-week treatment groups. The most common were fatigue, headache, nausea, insomnia and irritability.

Additionally, asymptomatic lipase elevations and hyperglycemia occurred in up to 2% of SOF/LDV recipients.

found the holy grail of HCV treatment with the newer all-oral

Raymond Chung, MD

regimens. The ION, SAPPHIRE

Raymond Chung, MD Director of Hepatology and the Liver Center Massachusetts General Hospital Boston

and TURQUOISE studies simply help us tweak things and decide between several options, all of which are very attractive.’

—Raymond Chung, MD

ION-1 included 214 treatment-naive patients randomized to receive SOF/LDV once daily for 12 weeks and 217 who received the same regimen for 12 weeks along with a weight-based dose of RBV. Another 217 patients received SOF/LDV for 24 weeks and 217 received SOF/LDV+RBV for the same length of time.

Most patients were white; approximately two-thirds in each group had the HCV GT1a genotype; and more than half of all patients had the IL28B CT genotype.

Roughly 16% had cirrhosis.

Rates of SVR12 in the four groups ranged from 97% to 99%. Common AEs were fatigue, headache, insomnia and nausea, with fatigue and insomnia occurring in more patients in the SOF/LDV+RBV groups. In the RBV

Regardless of how you analyze these data, it appears we’ve found the holy grail of HCV treatment with the newer all-oral regimens. The ION, SAPPHIRE and TURQUOISE studies simply help us tweak things and decide between several options, all of which are very attractive.

Data from ION-1 were consistently excellent and we can conclude from this study that if given to treatmentnaive HCV GT1 patients for 12 weeks, this combination will produce excellent results without requiring RBV. Given the safety profile of RBV, obviating the need for that drug means AEs will now be less of an issue for HCV patients.

ION-2 yielded extremely encouraging results as well, again with the same combination, this time in treatment-experienced HCV GT1 patients. Virologic

‘It is impressive to see a Phase 3 study devoted to patients with HCV GT1 and compensated cirrhosis.’

—Raymond Chung, MD

response rates were impressive for all of the subgroups and, again, regardless of RBV use. However, a slightly closer look at the data reveals something of a splay in the performance of the regimen in the subgroup of cirrhotic treatment-experienced patients: 12 weeks of treatment led to SVR12 in 82% to 86% of cirrhotic patients compared with a 100% SVR12 rate with 24 weeks of treatment. So, it would appear that treatment duration makes a difference in treatment-experienced cirrhotics.

The ION-3 study asked whether we can further shave down treatment duration for noncirrhotics. The answer appears to be yes. These data support the notion that treatment-naive HCV GT1 patients can achieve equivalent rates of SVR with eight weeks of treatment as with 12 weeks.

The study is notable for being the first Phase 3 trial of an eight-week course, and we can expect additional studies to look at further shortening therapy with various combinations of other DAAs. Importantly, the ability to administer a shorter treatment course could lower the cost of treatment and may be associated with improved adherence.

TURQUOISE-II: SVR12 Rates of 92%-96% in 380 Hepatitis C Virus Genotype 1-infected Adults with Compensated Cirrhosis Treated with ABT450/R/ABT-267 and ABT-333 Plus Ribavirin (3D+RBV) (Poordad F, et al) An international group of researchers compared 12 and 24 weeks of open-label treatment with the same alloral, RBV-including regimen as the PEARL and SAPPHIRE trials, this time in 380 patients with HCV GT1 infection and Child-Pugh A cirrhosis.

Approximately 70% of patients in each group were male; more than 90% were white; and roughly 70% had HCV GT1a infection. Approximately 58% of patients in each group had previously received HCV treatment; roughly 62% of those individuals failed to respond to prior therapy.

At baseline, all participants had total bilirubin below 3 mg/dL, serum alpha-fetoprotein of at least 100 ng/ mL, median serum albumin of approximately 40 g/dL, international normalized ratio values of at least 2.3 and median platelet counts of roughly 140,000 cells/mL. The investigators randomized 208 individuals to 12 weeks of treatment and 172 to 24 weeks of treatment. In an intent-to-treat analysis, they found 91.8% and 95.9% of the 12- and 24-week treatment groups, respectively, had SVR12. Virologic response was not affected by prior treatment status (Table 2).

The rates and types of AEs were similar to those reported in the PEARL and SAPPHIRE studies, and approximately 2% of patients in each group discontinued treatment as a result of side effects.

0163.

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST AUGUST 2014 2014

9

Stents continued from page 1

are associated with significantly lower complication rates and fewer days of hospitalization.

The superiority of the metal stent for patency in both studies is not surprising.

It has long been recognized that plastic stents occlude within a few months. The question both studies asked was whether the better performance of metal stents, which are several times more expensive than plastic stents, is cost-effective. And in each, total procedural costs, including hospitalization, proved to be about the same between metal and plastic stents.

Although metal stents were more expensive, they were associated with fewer reinterventions and a shorter hospital stay.

The studies, both presented at Digestive Disease Week (DDW) 2014, evaluated somewhat different applications.

In one, the comparison was in patients requiring long-term palliation of common bile duct obstruction (abstract 606). Follow-up was up to 12 months. In the other, the comparison was conducted in patients requiring preoperative drainage for periampullary tumors scheduled for resection (abstract 372). Patients were followed for one month after resection of the tumor.

In the larger of the two studies, which looked at long-term palliation, 219 patients with common bile duct obstruction were randomized to receive a plastic stent, a partially covered self-expanding metal stent (pcSEMS) or an uncovered self-expanding metal stent (uSEMS). According to the lead author, Daisy Walter, MD, of the Department of Gastroenterology and Hepatology at the University of Utrecht, in The Netherlands, health care costs were initially evaluated at two weeks after the procedure and then monthly for one year.

Recurrent obstruction occurred in 43% of patients in the plastic stent group, 16% of those in the pcSEMS group and 15% of patients who received a uSEMS. The

‘For patients with a short survival, the total costs were the same for the metal and plastic stents. Since the clinical outcomes for metal stents are favorable and the total costs are not different, metal stents can be recommended for palliation in all patients with common bile duct obstruction.’

—Daisy Walter, MD

mean stent patency times were 172, 299 and 288 days, respectively. Overall survival did not differ.

As expected, the initial placement costs for the plastic stent were lower than those for either of the metal stent groups but hospitalization costs were higher, for a total cost over the course of follow-up of approximately $9,200 for plastic and $8,900 for metal stents. Perhaps most important, in the context of previous evidence that plastic stents have a shorter period of patency, there was no cost advantage even when the devices were compared at three months.

“For patients with a short survival, the total costs were the same for the metal and plastic stents,” Dr. Walter reported.

“Since the clinical outcomes for metal stents are favorable and the total costs are not different, metal stents can be

recommended for palliation in all patients with common bile duct obstruction.”

In the second study, 63 patients with biliary obstruction associated with a periampullary tumor scheduled for resection were randomized to receive a plastic stent or pcSEMS. Of these, 35 had pancreatic tumors, 11 had cholangiocarcinomas and 17 had ampullary carcinoma. The average stent-to-surgery interval in both groups was 37 days, although surgery ultimately was not performed in 13 of the patients.

The rate of complications involving the stents before resection, including recurrent obstruction, was 8.7% in the pcSEMS group and 25% in the plastic stent group (P=0.07) P on an intention-totreat basis. There were no differences in resection-related complications or in survival at one month.

Despite the lower acquisition costs of the plastic stent, the costs related to complications, including reinterventions and added hospital days, were higher, so that the total costs were comparable even over the short one-month follow-up of the study. Like Dr. Walter, the chief investigator of the study, Ferran Gonzalez-Huix Llado, MD, staff gastroenterologist at the Clinica Girona in Spain, concluded that metal stents should be the first option.

Todd H. Baron, MD, director of advanced therapeutic endoscopy at the University of North Carolina at Chapel Hill, said studies “done many years ago” created the impression that the cost-benefit of self-expanding metal stents for palliation was confined to patients with a life expectancy predicted to be longer than three months. Similarly, it has been shown and accepted that metal stents are superior to plastic stents in preoperative relief of jaundice only when the time to surgery is to be extended greatly, such as in patients receiving preoperative neoadjuvant therapy. The new studies challenge those standards.

“The first of these abstracts shows that costs are acceptable when metal stents are placed for palliation of malignant biliary obstruction, regardless of duration of survival,” Dr. Baron said.

“In the second abstract, it appears that metal stent placement is cost-effective even when the preoperative period is not markedly prolonged,” he added. However, “both of these studies were performed outside of the United States, and as in all cost-efficacy studies, cost savings depend on the payor.”

Dr. Baron said it is important to consider if societal and payor cost is “different from institutional cost.”

■ Drs. Walter and Gonzalez-Huix Llado reported no relevant financial conflicts of interest. Dr. Baron has received research support from Cook Endoscopy.

Table 2. SVR12 According to Prior Treatmenta Dr. Chung:

Treatment History

12 Wk, n=208 SVR12

24 Wk, n=172 SVR12

It is impressive to see a Phase 3 study devoted to patients with HCV GT1 and compensated cirrhosis, as was the case with TURQUOISE II. The study regimen performed excellently in the population as a whole, but a closer analysis shows that, for cirrhotic patients with a prior null response, as we saw with ION-2, duration of treatment appeared to have an impact—although not statistically significant.

So, the overall take-home message from TURQUOISE II is a strong one: Historically difficultto-treat treatment-naive or treatment-experienced cirrhotics will respond well to either 12 or 24 weeks of treatment.

■

Treatment-naive, n/N (%)

81/86 (94.2)

70/74 (94.6)

Prior null response, n/N (%)

65/75 (86.7)

59/62 (95.2)

Prior partial response, n/N (%)

17/18 (94.4)

13/13 (100)

Prior relapse, n/N (%)

28/29 (96.5)

23/23 (100)

Treatment-experienced

GT, genotype; HCV, hepatitis C virus; SVR, sustained virologic response a Table combines HCV GT1a/b.

INDICATION SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) as a component of a combination antiviral treatment regimen.

• SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Prescribing Considerations: • Monotherapy of SOVALDI is not recommended.

• Treatment regimen and duration are dependent on both viral genotype and patient population.

• Treatment response varies based on baseline host and viral factors.

SOVALDI OFFERS SIMPLE DOSING FOR PATIENTS WITH HCV GT 1, 2, 3 OR 41 A 12-week regimen for HCV GT 1 and 41 • SOVALDI is taken in combination with Peg-IFN + RBV for treatment-naïve or treatment-experienced patients with HCV GT 1 or 41 • SOVALDI in combination with RBV for 24 weeks can be considered as a therapeutic option for patients with GT 1 infection who are ineligible to receive an IFN-based regimen. The treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient1 An all-oral regimen for HCV GT 2 and 31 • SOVALDI + RBV is the first all-oral regimen for treatment-naïve and -experienced GT 2 patients (12 weeks of SOVALDI + RBV) and GT 3 patients (24 weeks of SOVALDI + RBV)1 Additional dosing considerations • The recommended dose of SOVALDI is one 400 mg tablet taken once daily with or without food in combination with RBV or Peg-IFN + RBV1 • No response-guided therapy is necessary with SOVALDI regimens1 • The recommended dosing is the same for both HCV mono-infected and HCV/HIV-1 co-infected patients1 • See next page for more dosing information

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS • SOVALDI combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to SOVALDI combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

WARNINGS AND PRECAUTIONS • Pregnancy: Use with Ribavirin or Peginterferon/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use 2 forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

• Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with SOVALDI as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Please see Brief Summary of full Prescribing Information on the following pages.

sovaldi.com/hcp

SIMPLE DOSING WITH SOVALDI (CONTINUED) • In patients with hepatocellular carcinoma (HCC) awaiting liver transplantation, SOVALDI in combination with RBV is recommended for up to 48 weeks or until the time of transplantation, whichever occurs first, to prevent post-transplant HCV reinfection1 • If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued1 • No SOVALDI dose adjustments are necessary based on advanced age, race, mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) or mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment, end stage renal disease (ESRD) or decompensated cirrhosis1 • If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose1

IMPORTANT SAFETY INFORMATION (CONTINUED) ADVERSE REACTIONS Most common (≥20%, all grades) adverse reactions for: • SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia • SOVALDI + ribavirin combination therapy were fatigue and headache

DRUG INTERACTIONS • In addition to rifampin and St. John’s wort, coadministration of SOVALDI is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

Please see Brief Summary of full Prescribing Information on the following pages.

Use with Potent P-gp Inducers: Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentration leading to reduced Brief summary of full Prescribing Information. Please see full Prescribing Information. therapeutic effect of SOVALDI. Rifampin and St. John’s wort should not be used with SOVALDI. Rx Only.

ADVERSE REACTIONS: Adverse Reactions from Clinical Trials Experience: SOVALDI should be

SOVALDI® (sofosbuvir)

INDICATIONS AND USAGE: SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) as a component of a combination antiviral treatment regimen.

• SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Prescribing considerations: • Monotherapy of SOVALDI is not recommended • Treatment regimen and duration are dependent on both viral genotype and patient population • Treatment response varies based on baseline host and viral factors DOSAGE AND ADMINISTRATION: Adult Dosage: one 400 mg tablet, taken orally, once daily with or without food. SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for treatment of CHC in adults.

administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use.

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 assessment of SOVALDI is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received SOVALDI + ribavirin combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, <1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks.

Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in Table 1. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

Recommended dose and treatment duration for SOVALDI combination therapy for patients with: genotype 1 or 4 CHC is SOVALDI + peginterferon alfa + ribavirin for 12 weeks; genotype 2 CHC is SOVALDI + ribavirin for 12 weeks; and genotype 3 CHC is SOVALDI + ribavirin for 24 weeks. See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC. Dose of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg).

Daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information.

Table 1 Treatment-Emergent Adverse Events (All Grades) Reported in ≥15% of Subjects in SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for Any Treatment Arm CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen.

Interferon-free Regimens Interferon-containing Regimens Treatment decision should be guided by assessment of potential benefits and risks for individual patient.

SOVALDI + Patients with Hepatocellular p Carcinoma Awaitingg Liver Transplantation: p SOVALDI in combination Peg-IFN alfa + PBO SOVALDI + SOVALDI + Peg-IFN alfa with ribavirin is recommended for up to 48 weeks or until time of liver transplantation to prevent RBV Va 12 RBV Va RBV Va + RBVb post-transplant HCV reinfection. weeks 12 weeks 24 weeks 24 weeks 12 weeks Dose Modification: Dose reduction of SOVALDI is not recommended.

Genotype yp 1 and 4: If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue peginterferon alfa and/or ribavirin dose.

Genotype yp 2 and 3: If a patient has a serious adverse reaction potentially related to ribavirin, ribavirin dose should be modified or discontinued, if appropriate, until adverse reaction abates or decreases in severity.

Ribavirin dose modification guideline for coadministration with SOVALDI: Reduce the ribavirin dose to 600 mg/daya in patients with no cardiac disease if hemoglobin is <10 g/dL and discontinue ribavirinb if it is <8.5 g/dL. Reduce the ribavirin dose to 600 mg/daya in patients with history of stable cardiac disease who have ≥2 g/dL decrease in hemoglobin during any 4 week treatment period and discontinue ribavirinb if it is <12 g/dL despite 4 weeks at reduced dose.a Daily dose of ribavirin is administered orally in two divided doses with food.b Once ribavirin has been withheld due to either laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase dose to 800 mg daily. It is not recommended that ribavirin be increased to original assigned dose (1000 mg to 1200 mg daily). Discontinuation of Dosing: If other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued.

Severe Renal Impairment and End Stage Renal Disease: No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.

N=71

N=650

N=250

N=243

N=327

Fatigue

24%

38%

30%

55%

59%

Headache

20%

24%

30%

44%

36%

Nausea

18%

22%

13%

29%

34%

Insomnia

4%

15%

16%

29%

25%

Pruritus

8%

11%

27%

17%

17%

Anemia

0%

10%

6%

12%

21%

Asthenia

3%

6%

21%

3%

5%

Rash

8%

8%

9%

18%

18%

Decreased Appetite

10%

6%

6%

18%

18%

Chills

1%

2%

2%

18%

17%

Influenza Like Illness

3%

3%

6%

18%

16%

Pyrexia

0%

4%

4%

14%

18%

Diarrhea

6%

9%

12%

17%

12%

Neutropenia

0%

<1%

<1%

12%

17%

Myalgia

0%

6%

9%

16%

14%

Irritability

1%

10%

10%

16%

13%

CONTRAINDICATIONS: When SOVALDI is used in combination with ribavirin or peginterferon alfa/ Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per ribavirin, contraindications applicable to those agents are applicable to combination therapies. Refer day if weighing ≥75 kg). to prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. b Subjects received 800 mg ribavirin per day regardless of weight.

SOVALDI combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant With the exception of anemia and neutropenia, the majority of events presented in Table 1 occurred because of the risks for birth defects and fetal death associated with ribavirin. at severity of grade 1 in SOVALDI-containing regimens.

WARNINGS AND PRECAUTIONS: Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin may cause birth defects Less Common Adverse Reactions Reported in Clinical Trials (<1%):: The following ADRs and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient occurred in <1% of subjects receiving SOVALDI in a combination regimen in any one trial. These effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of events have been included because of their seriousness or assessment of potential causal male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test relationship. Hematologic Effects:: pancytopenia (particularly in subjects receiving concomitant has been obtained immediately prior to initiation of therapy. When SOVALDI is used in combination pegylated interferon). with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners Psychiatric Disorders:: severe depression (particularly in subjects with pre-existing history of must use two forms of effective contraception during treatment and for at least 6 months after psychiatric illness), including suicidal ideation and suicide. treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 2.

There are no data on the effectiveness of systemic hormonal contraceptives in women taking A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be SOVALDI, therefore, two non-hormonal methods of contraception should be used during treatment made due to differing trial designs. with SOVALDI and concomitant ribavirin. Refer also to the prescribing information for ribavirin. a

Brief Summary (cont.)

Table 2 Percentage of Subjects Reporting Selected Hematological Parameters Interferon-free Regimens Hematological Parameters

Interferon-containing Regimens

PBO 12 weeks

SOVALDI + RBV Va 12 weeks

SOVALDI + RBV Va 24 weeks

Peg-IFN + RBVb 24 weeks

SOVALDI + Peg-IFN + RBV Va 12 weeks

N=71

N=647

N=250

N=242

N=327

Hemoglobin (g/dL) <10

0

8%

6%

14%

23%

<8.5

0

1%

<1%

2%

2%

Neutrophils (x109/L) ≥0.5 - <0.75 <0.5

1%

<1%

0

12%

15%

0

<1%

0

2%

5%

3%

<1%

1%

7%

<1%

0

0

0

0

0

9

Platelets (x10 /L) ≥25 - <50 <25 a

Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg). b Subjects received 800 mg ribavirin per day regardless of weight.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy g y Category g y X: Use with Ribavirin and/or Peginterferon g Alfa/Ribavirin: Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded.

There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI. Therefore, two effective non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin. In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263.

Animal Data: animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans.

Pregnancy g y Category g y B: SOVALDI: There are no adequate and well-controlled studies with SOVALDI in pregnant women.

Animal Data:: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5 to 10-fold and 12 to 28-fold the exposure in humans at the recommended clinical dose, respectively.

Nursing Mothers: It is not known whether SOVALDI and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing Bilirubin Elevations: Total bilirubin elevation of more than 2.5xULN was observed in none of the or discontinue treatment with ribavirin containing regimens, taking into account the importance of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of the therapy to the mother. See also the prescribing information for ribavirin. subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI Pediatric Use: Safety and effectiveness of SOVALDI in children less than 18 years of age have not treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. been established.

These bilirubin elevations were not associated with transaminase elevations.

Geriatric Use: Clinical studies of SOVALDI included 90 subjects aged 65 and over. The response Creatine Kinase Elevations: Creatine kinase was assessed in the FISSION and NEUTRINO trials. rates observed for subjects over 65 years of age were similar to that of younger subjects across Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed treatment groups. No dose adjustment of SOVALDI is warranted in geriatric patients. in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + Renal Impairment: No dose adjustment of SOVALDI is required for patients with mild or moderate peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively.

Lipase p Elevations: Isolated, asymptomatic lipase elevation of greater than 3xULN was observed renal impairment. The safety of SOVALDI has not been assessed in patients with severe renal 2 in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, impairment (eGFR <30 mL/min/1.73m ) or end stage renal disease (ESRD) requiring hemodialysis.

SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 Refer also to ribavirin prescribing information for patients with CrCl<50 mL/min. weeks groups, respectively.

DRUG INTERACTIONS: Potential for Drug Interactions: After oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS 331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and thus should not be used with SOVALDI. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors.

Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters. The intracellular metabolic and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs.

Based on Drug Interaction Studies or Predicted Interaction: Drug interaction information for SOVALDI with potential concomitant drugs is summarized as follows and the list is not inclusive. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. Anticonvulsants: Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital, oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not recommended. Antimycobacterials: Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not recommended. SOVALDI should not be used with rifampin, a potent intestinal P-gp. Herbal Supplements: SOVALDI should not be used with St. John’s wort (Hypericum perforatum), a potent intestinal P-gp inducer. HIV Protease Inhibitors: Coadministration of SOVALDI with tipranavir/ ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.

In addition to the drugs listed above, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

Hepatic Impairment: No dose adjustment of SOVALDI is required for patients with mild, moderate not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.

Patients with HCV/HIV-1 Co-infection: HCV/HIV-1 co-infected subjects. See Dosage and Administration for dosing recommendations in that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials.

Patients with Hepatocellular Carcinoma (HCC) Awaiting Liver Transplantation:: SOVALDI was studied in HCV-infected subjects with HCC prior to undergoing liver transplantation in an pre-transplant to prevent post-transplant HCV reinfection. See Dosage and Administration for dosing and ribavirin in HCV-infected subjects prior to liverr transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials.

Post-Liver Transplant Patients: post-liver transplant patients.

CHC Patients with Genotype 5 or 6 HCV Infection: Available data on subjects with genotype 5 or

Reference: 1. SOVALDI® (sofosbuvir). US Prescribing Information. Gilead Sciences, Inc. Foster City, CA. December 2013.

SOVALDI, the SOVALDI Logo, GILEAD and the GILEAD Logo are trademarks of Gilead Sciences, Inc., or its related companies. ©2014 Gilead Sciences, Inc. All rights reserved. SVDP0106 06/14

15

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Fecal continued from page 1

enema, both once weekly for six weeks (abstract 929c) c.

The patients had active disease, with Mayo scores of 4 or higher and endoscopic Mayo scores of 1 or greater. Subjects had not used antibiotics within the month before FMT and had tested negative for Clostridium difficile.

Roughly 45% in both groups had pancolitis. During the study, 42% of subjects received corticosteroids, 19% continued with immunosuppressive treatment and 9% continued with biologic therapy.

The findings showed that four FMT recipients (15%) and two placebo subjects (8%) achieved clinical remission, defined as a Mayo score of 2 or less and an endoscopic Mayo score of 0, a difference that was not statistically significant. Seven FMT patients (26%) and eight placebo recipients (31%) experienced improvements of at least 30% in their Mayo scores.

But FMT might be more effective with increasing treatment duration. In a subanalysis, 16 FMT recipients who reported subjective improvements after initial treatment, but did not achieve clinical and endoscopic remission, continued with six to 12 weeks of additional therapy. Five of these patients subsequently experienced clinical remission.

In a separate, open-label study, seven UC patients received a single FMT infusion colonoscopically (abstract Su1403). Scores on the Ulcerative Colitis Disease Activity Index (UCDAI) and histologic results of rectal biopsies were obtained before and one month after FMT. One patient experienced remission at one month, with a drop in UCDAI score from 8 to 2 and resolution of histologic inflammation, but did not maintain remission.

“Among all patients, there was a statistically significant drop in UCDAI scores at one month and a trend toward improvement in histologic scores,” the investigators said, adding that one patient experienced a colonoscopyrelated perforation and was excluded from the analysis.

The variation in responses in these studies points to the need to refine FMT protocols, said Lawrence J. Brandt, MD, professor of medicine and surgery at Albert Einstein College of Medicine and emeritus chief of the Division of Gastroenterology at Montefiore Medical Center, in New York City.

“These studies all show that FMT may have a therapeutic role in treating IBD, but the precise patients for whom it is best suited and the best approach to administering it need to be further studied,” said Dr. Brandt, who was not involved in the latest research.

Although Crohn’s disease “is overall less responsive to FMT,” as a recent review stated (Borody TJ, et al. J Clin Gastroenterol May 22, 2014 [Epub ahead of print]),

findings from a pair of studies presented at DDW help tip the balance in favor of a place for FMT in the treatment toolbox for the disease.

In one study, eight patients with active Crohn’s disease received a single FMT infusion colonoscopically in an open-label fashion (abstract Mo1228). The patients had a median score on the Harvey-Bradshaw Index (HBI) of 8 at baseline, indicating mild to moderate disease severity.

Before FMT, no patients received biologics, antibiotics, probiotics or steroids at a dose greater than 20 mg per day.

The investigators documented scores on the HBI, the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the short Inflammatory Bowel Disease Questionnaire (sIBDQ), which measures quality of life, at baseline and up to three months for some patients. They also documented levels of C-reactive protein (CRP), a marker of inflammation.

At the follow-up visit at four weeks, five patients (62%) achieved clinical remission, defined as an HBI score less than 5, and there were significant decreases in CRP levels and improvements in sIBDQ scores. Data from four patients monitored eight weeks after FMT and two patients monitored at 12 weeks showed that all of these individuals were in clinical remission. However, two patients required an increase in their Crohn’s medication within four weeks of FMT. Consistent with other FMT safety data presented at DDW, the researchers said there were no serious adverse events.

“These preliminary results suggest FMT is safe and can induce early improvements in symptoms in patients with active [Crohn’s disease],” the investigators told Gastroenterology & Endoscopy News. “Whether the improvements can be sustained, and whether they correlate with objective [endoscopic] measures of inflammation, still need to be determined.”

FMT was mostly effective in inducing remission in a group of nine children and teenagers with mild to moderate CD, who received a single transplant nasogastrically (abstract Tu1754). These patients, who were between 12 and 19 years old, received a three-day course of rifaximin before FMT as well as omeprazole the day before FMT.

The investigators found that mean scores on the Pediatric Crohn’s Disease Activity Index (PCDAI) dropped from 19.7 (±7.2) at baseline to 6.4 (±6.6) after two weeks, rising slightly to 8.6 (±4.9) at six weeks. That difference was not statistically significant. Moreover, seven patients (78%) were in clinical remission two weeks after FMT, defined as a PCDAI score of 10 or lower. Two of these patients relapsed six weeks after FMT, and five patients required maintenance drug therapy by that time.

“It’s the experience of the few researchers looking at FMT for IBD that, unlike the single administration of FMT that’s required for Clostridium difficile treatment, some IBD patients likely need several infusions to induce remission and most patients require ongoing maintenance FMT,” Dr. Brandt said. He noted that he has seen mixed results in his own Crohn’s patients to whom he has administered FMT. “The success of FMT in both Crohn’s disease and ulcerative colitis patients may have to do with disease characteristics, such as precipitating factors, genetics, age at onset, disease duration and severity, location of disease and perhaps the patient’s intestinal microbiota,” Dr, Brandt said. “It may be that we need to look at the patient’s unique bacterial composition and determine which organisms need to replaced, and formulate FMT accordingly.”

■ Dr. Brandt has served as an advisor for CIPAK.

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18

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY OPY NEWS • AUGUST 2014

EHR continued from page 1

Editor’s note: Dr. Nemec dictated ed his respon nses in Dragon, and we provide them m here unedite ed, along with an edited version below be to highligh ht the abilities—and room for improv ovement—in the voice recognition software.

GEN: The move to a pap perless system m seems like it has the pote tential to cause e serious growing pains. How ow easily did your group make the switch, and d what did you do to ease the transition?

Dr. Nemec (to Dragon): Transitioning from m paper to electronic systems is extraordinarily difficult. Not on only are all the records in paper prior to the transitiion, but once the transition to electronic records occurs, th he access to information the paper record is very limited d. Even if the records have been successfully scanned into the electronic healthcare system, skin copies lowed into the computer system and notoriously slow fashion (evven if it’s a current fax copy from another institution). Th herefore, it becomes essentially impossible to review any previous paper chart. Therefore, each and every established patient, becomes essentially a new patient for record pu urposes.

All the data needs to be loaded into the system to actually have an electronic healthcare record. However nor to make this data useful information, 3 glue the charrt needs to be reviewed in the salient features from each proocedure or note need to be extracted to allow a reasonable le rapid record review. For the first 6 months after we implemented electronic healthcare records, we had to add one medical record full-time equivalent forever he health care provider in order to meet the demands of this transition.

Richard Nemec, MD, FACG Managing Partner, Winchester Gastroenterology Associates Medical Director of Endoscopy Winchester Medical Center, Winchester, Virginia

Debbie Puccio, RN Chief Operating Officer Allied Digestive Health West Long Branch, New Jersey

Todd N. Witte, MD

Lawrence Kosinski, MD

Assistant Medical Director & IT Physician Champion Northwest Gastroenterology & Endoscopy, Bellingham, Washington

Managing Partner, Illinois Gastroenterology Group Elgin, Illinois President,SonarMD, LLC

GEN: Now that you’re all-electronic, how different is the day-to-day management of your practice?

training our staff to enter atypical plan based upon the endoscopic findings (this can be done in real-time).

Making M ki these h changes h has h allowed ll d the h physicians h i i in i our group to spend more time providing direct patient care in using the electronic record as a resource for reminders, information, and best practices. Therefore, with a transition to electronic healthcare record, a practice should strongly consider dividing the labor between the necessary functions of a physician and those they can be relegated other levels (Adams Smith would be proud with this divisional labor)

Dr. Nemec (to Dragon): Although I consider myself to be rather computer savvy, and I view the electronic healthcare record as a significant advance to ensure quality and consistency of care, considerable effort is expanded in order to enter all the necessary data into the electronic healthcare record. Over the past 50 years, healthcare records had transition from simple annotated reminders for the clinician to these extremely complex be hematemesis of medical data that do 9 communicate any useful information to the clinician, but it become necessary for payers, regulators and reviewers. Therefore, I anticipate the documentation requirements to be come even more extensive in the future. In my practice, we have developed a strategy known as GOMER-2014 [I had to type this!!!].

This acronym is for “get out of my electronic record.”

Our business goal has been to minimize the actual data entry made by physicians into the electronic healthcare record. To accomplish this goal, we use mid levels extensively for office visits. D attending physician oftentimes just supervises 4-5 mid levels in the delivery of office-based healthcare. During endoscopic procedures, we used scribes to record the findings and label images there have been obtained during the procedure.

Since most electronic healthcare records automatically generate impressions from the findings, we then

Edited answers: Dr. Nemec: Transitioning from paper to electronic systems is extraordinarily difficult. Not only are all the records in paper prior to the transition, but once the transition to electronic records occurs, the access to information in the paper record is very limited. Even if the records have been successfully scanned into the electronic health care system, scanned copies load into the computer system in a notoriously slow fashion (even if it’s a current fax copy from another institution). Therefore, it becomes essentially impossible to review any previous paper chart. Therefore, each and every established patient becomes essentially a new patient for record purposes. [Even though] the data needs to be loaded into the electronic health care record, this data is not e-useful information. The chart needs to be reviewed with salient features from each procedure or note abstracted and summarized to allow a reasonably rapid record review. For the first six months after we implemented electronic health care records, we had to add one medical record full-time equivalent for every health care provider in order to meet the demands of this transition.

Dr. Nemec: Although I consider myself to be rather computer savvy, and I view the electronic health care record as a significant advance to ensure quality and consistency of care, considerable effort

is expended in entering all the necessary data into the electronic health care record. Over the past 50 years, h health l h care records d h have transitioned ii d ffrom simple annotated reminders for the clinician, to these extremely complex behemoths of medical data that do not effectively communicate any useful information to the clinician. However, such data collection has become necessary to meet demands of payors, regulators and reviewers. Therefore, I anticipate that the documentation requirements will become even more extensive in the future.

In my practice, we have developed a strategy known as GOMER-2014. This acronym is for “Get Out of My Electronic Record.” Our business goal has been to minimize the actual data entry made by physicians into the electronic health care record. To accomplish this goal, we use mid-levels [providers] extensively for office visits. The attending physician oftentimes just supervises four to five mid-levels in the delivery of office-based health care by seeing patients briefly with mid-levels as need arises. During endoscopic procedures, we used scribes to record the findings and label images that have been obtained during the procedure.

Since most electronic health care records automatically generate impressions from the findings, we then train our staff to enter atypical plans based on the endoscopic findings (this can be done in real time). The physician simply reviews the record for accuracy. By making these changes, our physicians spend much more time providing direct patient care and using the electronic record as a resource for reminders, information and best practices. Therefore, with a transition to electronic health care records, a practice should strongly consider dividing the labor between the necessary functions of a physician and those that can be relegated to other employees. (Adam Smith would be proud of this division of labor.) see EHR, page 20

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EXPERT ROUNDTABLE

EHR continued from page 18

GEN: What should clinicians know when their group decides to purchase an EHR product?

Ms. Puccio: Be willing to embrace the change.

Clinicians, as well as every single staff member, must accept that there will be a learning curve. Everyone learns at their own pace and this area is no different.

The temporary drop in productivity during the implementation will end. The schedules will be back to where they were; and frequently more patients can be seen. The workflow willl change. There is no question in my mind that a digitized workflow dramatically improves patient care as a result of the availability and timeliness of information at the fingertips of each and every person caring for that patient in the practice.

Clinicians need to realize that they, as the physician, are a key factor in a successful implementation. Those physicians who insist on maintaining dual records, a hybrid of paper and electronic health records, or some other mishmash are a huge source of inefficiency—not only for themselves but for the health of the entire practice. Once clinicians decide to embrace the change, they become proficient at the EHR and can enjoy the full impact on their lives and time management.

Each practice needs to have a champion, a cheerleader, an enforcer. They need to identify which physician will be the one who works closely with the implementation team—making clinical workflow decisions, giving input on developing templates, etc. This is no small task, and some time really should be made for that doctor to perform these tasks during the workday.

In my experience, I have found that physicians learn best from other physicians. Site visits have always proven extremely helpful to me in the selection of an EHR. Be sure to have several members of your team visit practices that are currently using the system. Ask questions, observe their processes and realize what stumbling blocks were there.

Most workflows can be automated through the EHR; however, they cannot be automated to be provider-specific. This lack of specificity lends itself to standardized processes that may take some compromise on the part of the clinicians. But again, this is a culture change as well as technological advancement.

An interesting side note here is that anyone who is still in the market for an EHR either is not an early adopter or was an early adopter of an unsuccessful system. Seek out the market share for your specialty with the individual vendor that you are vetting. How many installs do they do? How many uninstalls did they do?

What was the reason? What percentage of the large specialty-specific groups use this EHR?

GEN: Are there any features clinicians should advocate for that will make their lives easier?

Ms. Puccio: As the market evolves, many EHRs are becoming quite competitive in the workflow features they offer. I would review the EHR from the perspective of your particular practice, and think through how certain processes would be done. A single system for practice management and EHR is ideal, although two separate systems certainly can be accommodated through appropriate interfacing.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

How the EHR you choose can mine your data will be critical in your ability to prove quality, improve outcomes and be successful in the future. Be comfortable that your EHR vendor can demonstrate this.

The mission-critical point is your confidence that the EHR vendor is forward thinking, is in for the long haul and has its priorities straight. Vendors that understand “meaningful use” and all of its implications understand the shifting payor climate toward quality and understand where our specific specialty is going should be your partner of choice. Although much tougher than meaningful use 1, I was thrilled with the ease that I was able to attest to MU2 due to the forethought and diligence of my EHR partner. The data was able to be mined; our progress and reports were always available at my fingertips; and monitoring our success was a breeze.

GEN: What are a few lessons you’ve learned about what not to do? Are there things you wish your group had done differently?

Ms. Puccio: The most important thing nott to do when purchasing an EHR is to skimp on the dollars you invest in the training and implementation. Everyone in your organization should go through every formal training process that is available for their job role. I have found repeatedly that when folks say their “EHR doesn’t work right,” it’s usually because they don’t know how to use it correctly. Appropriate, thorough training will prove to be one of the most important things you can do to ensure your success.

‘Be sure to have several members of your team visit practices that are currently using the system. Ask questions, observe their processes and realize what stumbling blocks were there.’

—Debbie Puccio, RN

Another area where I stress is not making a halfhearted commitment to the transitions. I have experience with a practice of four physicians, two of whom use EHRs exclusively, one is halfway there “if he has the time” and the other physician flat-out refuses to use the system. The workflow in that practice is disastrous, the staff is very frustrated and I am not confident that the information is getting where it needs to be in a timely fashion.

Finally, I now understand the complexities surrounding the ability, and actually sometimes the disadvantages, to “finding a workaround.” Finding a workaround very frequently can be interpreted as “I’d rather do it the way I want to do it instead of how the EHR is designed to function.”

We prided ourselves on being able to customize things to our workflow, but found that some of the modifications we made were preventing us from being able to collect the data appropriately. My suggestion is to try to fit your practice to the EHR of your choice, not to force the EHR to conform to your practice. Embrace

all that the system can do, engage your staff in the process and your workflow will only continue to improve.

GEN: Surveys suggest that many doctors are not fully documenting their patient visits using EHRs. What percentage of your group’s cases is documented? And how much transcription have you been able to eliminate with the system?

Dr. Witte: I’m surprised to hear that some practices aren’t fully documenting every case with their EHR systems. I guess some physicians feel it slows them down, but I would find it foolish not to document 100% of our cases. The whole concept is paying it forward.

Maybe your first visit is slow but your second visit is faster. We’ve tried to go paperless, which is hard to do, but part of the cost savings is not pulling charts.

Is everybody in love with it? No. I bet half of my doctors would switch overnight back to paper charting.

But I’m convinced it’s the right move. Of course, I’m the physician champion. I’m good with computers and I can troubleshoot them on my own. So it might be easier for me. But it’s important to make an effort to learn the software that your practice uses. For example, Dragon [the voice recognition program] meshes with the EHR but someone who hasn’t put in the time to understand how isn’t getting all the benefits of either system. It is very hard to get doctors to be willing to read a software manual or do software training, or to get them to appreciate that 15 minutes of training on software will save them far more time in the office later on. Clinicians need to get more involved on this level and champion the IT cause more. If they leave it up to their managers/staff, they often fall short because those folks, although well intentioned, often don’t really know the needs of the doctor; and doctors know other doctors’ needs best, and can best guide the needs of the practice as far as clinically focused software use and clinical EHR configuration.

I think most of the doctors in my group are still slower on the EHR than they were on paper, and their volume of patients has gone down. My volume in the office is unchanged, but I take home far more work than I used to, so it’s a trade-off. The positive is that before, I used to have to come into the office late at night or on weekends, but now I can sit at the kitchen table in my pajamas on a Saturday while my kids watch cartoons.

GEN: Although buying and setting up an EHR system involves substantial up-front costs, many practices run into the “nickeland-dime” effect of hidden and recurring expenditures that raise outlays even more. Did your practice experience such costs and what, if anything, did you do to mitigate them? What advice would you give to practices considering buying an EHR to make sure they have the most transparent picture of the true cost of the system?

Dr. Witte: It’s true many practices, including ours, encounter “added” costs when they purchase software systems. But I think this is part of a larger phenomenon and does not necessarily indicate that manufacturers are taking advantage of customers. One of the biggest

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

problems you’re dealing with is the “now” versus the “future.” Take a whole population of doctors, ranging in age from 30 to nearing retirement, and if you flip them over to an EHR, it’s going to be a big change for many of them. Now take my kids: They’re used to watching daddy on the computer, they’re going to go to medical school and expect to work on a computer. By that time, all of these software systems will be basically mature.

They won’t be evolving as rapidly as they are now, as they try to respond to the government pushing out regulations on meaningful use and other requirements.

It’s a moving target for vendors, who have to not only meet the regulations but also give customers a sleek product in the process. In other words, the product is always changing.

‘It’s like a takeout menu, and not everybody’s picking the same stuff, and you pay for what you pick.’

—Todd N. Witte, MD

We got into our EHR two years ago. At that time, patient access and portals weren’t required. But then the company had to build a portal, and the company charges extra for that. The same with a call-reminder system, which they designed after our go-live, and which we found we had to buy separately because it had not been included/available when we went live, and our prior system did not interact with our EHR system. (It shouldn’t come as a surprise that if the EHR company makes its own call-reminder system, then you can’t interface with other programs.) So, in a sense we have been sort of nickeled and dimed. It’s like a takeout menu, and not everybody’s picking the same stuff, and you pay for what you pick. If you compare that to the future, when all the government regulations hopefully cease, and they can finally design an all-inclusive product that meets not just government requirements but also more of our clinical needs, you’ll buy a product and it will be all-inclusive.

This is now available from our EHR vendor. If you buy the cloud version (we are server-based) that is now available, I understand it is all-inclusive.

GEN: How important is it for practices to select an EHR system that is designed with their specialty in mind?

Dr. Witte: We use G-MED, and as a gastroenterologist, it’s a phenomenal thing to go to a [user] conference where everyone has the same concerns about workflow, etc. The downside is that because it’s specialty-specific, it’s smaller than some of the larger products on the market and it has a harder time being as sleek. But their strength is that they [G-MED] know gastroenterologists and our business. They know what we do for work, they follow the meaningful use requirements and try to make it easier for us as gastroenterologists.

The company we use has a vested interest in helping private gastroenterologists stay private, so their product reflects this; and as we move toward an era of value and quality-driven [health care], our software will help us track and show this, specifically focused on what we do as gastroenterologists. That is well worth it for me to have that support.

GEN: How and when did your practice go about choosing an EHR system, and what

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have been the most noticeable changes in workflow, patient care and overall practice management since then?

Dr. Kosinski: Our practice, the Illinois Gastroenterology Group (IGG), was formed in 2010 as a merger of three moderately sized GI practices. We have since added two more and are in the process of adding another two, which will bring us to 48 physicians. Before that time, I practiced in an eight-physician see EHR, page 34

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Extending Conventional Endoscopy in Barrett’s Esophagus Using Narrow Band Imaging Faculty Prateek Sharma, MD, FACP, FACG Professor of Medicine, Section Chief Division of Gastroenterology & Hepatology University of Kansas School of Medicine Kansas City, Kansas Kansas City VA Medical Center Kansas City, Missouri

Amit Rastogi, MD, FASGE Associate Professor of Medicine University of Kansas Medical Center Kansas City VA Medical Center Kansas City, Kansas

Introduction Barrett’s esophagus (BE) is a complication that occurs in 10% to 15% of patients with chronic gastroesophageal reflux disease (GERD).1 In BE, the distal epithelium of the esophagus converts from squamous to columnar epithelium, which is confirmed by the presence of intestinal metaplasia (IM).2,3 In some patients, BE is a precursor to esophageal adenocarcinoma (EA); compared with the general population, patients with BE have a 30- to 40-fold increased risk for developing EA.1,4 The National Cancer Institute estimates that in 2014 there will be 18,170 new cases of esophageal cancer and

that 15,450 people will die of the disease, making this the 10th leading cause of cancer death in the United States.4 The 5-year survival rate for patients diagnosed with EA remains low at 17.5%.4 EA is particularly deadly because lymphatic vessels in the esophagus extend into even the most superficial layers of the esophageal mucosa, which favors early lymph node metastases in EA.3 Early detection of metaplasia and dysplasia may decrease mortality and morbidity significantly.5 In fact, survival rate is directly related to disease extent; the 5-year survival for patients with localized disease is 39.6%. However, only 21.3% of patients are diagnosed before cancer has spread (Figure 1).4 Thus, surveillance of patients with BE is vital, and the endoscopist has a responsibility to correctly diagnose dysplasia and EA in a timely manner.6 Staging of dysplasia in patients with BE determines the type of therapy most appropriate for each case.6 The appropriate treatment depends on accurate staging and determination of disease extent. Narrow band imaging (NBI) presents a new method of screening for changes in mucosal and vascular patterns related to BE. By restricting the wavelengths of light used in endoscopic imaging of these areas, NBI produces clearer images of tissue patterns resulting in more

Patients With Esophageal Cancer, %

Screening and Surveillance in Patients with BE Clinical care guidelines presently recommend a combination of examination by white light endoscopy (WLE), biopsy of any obvious lesions, and the Seattle protocol (random 4-quadrant sampling of the BE segment every 2 cm).8 However, these methods have limitations. The subtle changes of dysplasia and early EA may not be identifiable by WLE, and random sampling surveys only 4% to 6% of the BE segment.7 Additionally, adherence to the Seattle protocol is inconsistent. An analysis of 2,245 BE surveillance cases with linked endoscopy reports showed compliance to guidelines in only 51.2% of cases.9 The same study showed that decreased detection of dysplasia was significantly associated with nonadherence to the protocol. Furthermore, random biopsy may cause significant sampling error due to the patchy nature of dysplasia and the tendency among endoscopists to obtain fewer samples of large BE lesions.10 The current recommendation for surveillance in patients with BE is to perform 2 endoscopies with biopsy within 1 year of diagnosis and then surveillance endoscopy once every 3 years.2

Narrow Band Imaging Endoscopy using restricted wavelengths provides enhanced contrast in mucosal and vascular patterns.11 Conventional endoscopy instruments use white light to visualize esophageal tissue. However, NBI instruments restrict the wavelengths used to examine tissue to the blue-green range of light. The enhanced contrast produces clearer endoscopic images.12 Wavelength restriction has 3 important effects (Figure 2). First, tissue penetration distance is directly related to wavelength; shorter wavelengths result in reduced tissue penetration.1,12 Second, shorter wavelengths and less light result in less light scattering, and in some applications may produce clearer images.1 For example, NBI of epithelium mucosal pattern produces higher contrast images that are beneficial in evaluating diseases typified by mucosal pattern disruption.1,13 Third, NBI acts as a specific virtual biomarker for hemoglobin and aids in identifying vascular patterns in tissue.

Oxy- and deoxyhemoglobin have strong peaks of absorption from 400 to 600 nm (Figure 2). Restricting the endoscopic wavelength to this region optimizes visualization of hemoglobin and the imaging of blood vessels.14 NBI is suited to the identification of mucosal and vascular changes associated with dysplasia and metaplasia in patients with BE and has been used in screening and

Five-year survival

40

Cases diagnosed at stage 35 30 25 20 15 10 5 0

Localized

Regional

Distant

Unstaged

Stage at Diagnosis

Figure 1. Survival and diagnosis of patients with esophageal cancer by stage.

Adapted from SEER Cancer Statistics Factsheets: Esophageal Cancer. National Cancer Institute.

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efficient screening and surveillance, and a reduction in the number of biopsies needed during these procedures.1,7

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Figure 2. Narrow band imaging optimizes visualization of hemoglobin by restricting light wavelengths to the blue-green range, resulting in reduced tissue penetration.

Image courtesy of Olympus.

B

Figure 3. Endoscopic images obtained using narrow band imaging.

(A) Dark and light regions of the mucosa; blue and yellow arrows show the ridge/villous pattern.

(B) Irregular and distorted pattern of high-grade dysplasia.

Based on reference 1.

surveillance in the esophagus, stomach, colon, and bladder.1,13,15,16 High-definition NBI instruments such as the Olympus EVIS EXERA III provide more light and twice the viewable distance in the lumen than previous models.17

Screening With Narrow Band Imaging Advanced imaging techniques, such as NBI, present benefits over existing methods in the detection of dysplasia in patients with BE.18 Initial research assessed NBI endoscopy in patients with BE or suspected BE and identified mucosal and vascular patterns that coincided with IM or high-grade dysplasia (HGD).1 Two mucosal patterns were observed by NBI: a ridge/villous pattern and an irregular/distorted pattern (Figure 3). Histology of these areas verified that the ridge/ villous pattern was associated with IM (Figure 3, panel A) and that the irregular/distorted pattern signified HGD (Figure 3, panel B). Histology also confirmed that none of the ridge/villous samples exhibited HGD, demonstrating that the patterns were specific and not interchangeable. The sensitivity, specificity, and positive predictive value of ridge/villous areas representing IM without HGD were 93.5%, 85.7%, and 94.7%, respectively. The sensitivity, specificity, and positive predictive value of the distorted mucosal pattern representing HGD were 100%, 98.7%, and 95.3%, respectively. Review of vascular patterns by NBI similarly differentiated IM and HGD, but did not distinguish between IM and low-grade dysplasia. The research characterized that the distinct mucosal and vascular patterns observed by

NBI correlated histologically with IM or HGD with high sensitivity and specificity. The correspondence suggested that NBI could be a useful tool in the screening and surveillance of patients with BE and also could allow targeted and efficient sampling of BE mucosa.1 NBI endoscopy has several benefits: Relevant changes in mucosal structure are identified without the use of staining agents, very fine blood vessels that may be obscured by stain are visible, and it enhances the visualization of the capillary network and mucosal patterns during the endoscopy procedure itself. Additionally, NBI visualization of aberrant mucosal and vascular patterns during the procedure allows for targeted biopsies.

A recent meta-analysis reported on 8 studies (N=446) that used NBI endoscopy for patients with BE.18 The included studies measured the sensitivity and accuracy of detecting IM and dysplasia in patients with BE by NBI imaging of mucosal and vascular patterns.18 Additionally, a meta-analysis of 14 studies including 834 patients evaluated the potential of new endoscopic technologies compared with WLE and random biopsy for detecting esophageal dysplasia.19 Investigators found that the use of virtual chromoendoscopy (including NBI) increased the diagnostic yield of detecting dysplasia by 34% over that of WLE with random biopsies.19 NBI endoscopy has the potential to improve the screening and surveillance of patients with BE. A recent study directly compared NBI targeted biopsy with the standard Seattle protocol for screening patients with BE.7 This randomized, controlled crossover trial involved 123 patients from 3 medical centers. Biopsies obtained by WLE and

Conclusion

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

NBI is effective in imaging blood vessels in tissue and identifying surface features such as mucosal patterns. Many studies have shown the efficacy of NBI for detection of tissue metaplasia and dysplasia in patients with BE.1,7 Targeted biopsy using NBI has the potential to reduce the number of biopsies taken during screening and surveillance and to reduce the costs associated with these procedures. However, introduction of NBI into clinical care guidelines will require the endorsement of professional societies and the implementation of endoscopy training programs and testing standards.

15.

16.

17.

18.

References 1.

2.

3.

4.

Sharma P, Bansal A, Mathur S, et al. The utility of a novel narrow band imaging endoscopy system in patients with Barrett’s esophagus. Gastrointest Endosc. 2006;64(2):167-175.

Wang KK, Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus.

Am J Gastroenterol. 2008;103(3):788-797.

Falk GW. Current challenges in Barrett’s esophagus. Cleve Clin J Med. 2001;68(5):415-417, 422-424.

SEER Cancer Statistics Factsheets: Esophageal Cancer. Bethesda, MD: National Cancer Institute.

19.

2014. http://seer.cancer.gov/statfacts/html/esoph. html. Accessed July 7, 2014. van Sandick JW, van Lanschot JJ, Kulken BW, et al. Impact of endoscopic biopsy surveillance of Barrett’s esophagus on pathological stage and clinical outcome of Barrett’s carcinoma. Gut. 1998;43(2):216-222.

Aranda-Hernandez J, Cirocco M, Marcon N. Treatment of dysplasia in Barrett’s esophagus.

Clin Endosc. 2014;47(1):55-64.

Sharma P, Hawes RH, Bansal A, et al. Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett’s oesophagus: a prospective, international, randomised controlled trial. Gut. 2013;62(1):15-21.

Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological Association technical review on the management of Barrett’s esophagus.

Gastroenterology. 2011;140(3):e18-52.

Abrams JA, Kapel RC, Lindberg GM, et al. Adherence to biopsy guidelines for Barrett’s esophagus surveillance in the community setting in the United States. Clin Gastroenterol Hepatol.

2009;7(7):736-742.

Pohl H, Aschenbeck J, Drossel R, et al. Endoscopy in Barrett’s oesophagus: adherence to standards and neoplasia detection in the community practice versus hospital setting. J Intern Med. 2008;264(4):370-378.

Gono K, Obi T, Yamaguchi M, et al. Appearance of enhanced tissue features in narrow-band endoscopic imaging. J Biomed Opt. 2004;9(3):568-577.

Olympus. Narrow Band Imaging Fact Sheet.

Sumie H, Sumie S, Nakahara K, et al. Usefulness of magnifying endoscopy with narrow-band imaging for diagnosis of depressed gastric lesions.

Mol Clin Oncol. 2014;2(1):129-133.

Robles FE, Chowdhury S, Wax A. Assessing hemoglobin concentration using spectroscopic optical coherence tomography for feasibility of tissue diagnostics. Biomed Opt Express.

2010;1(1):310-317.

McGill SK, Evangelou E, Ioannidis JP, et al. Narrow band imaging to differentiate neoplastic and nonneoplastic colorectal polyps in real time: a metaanalysis of diagnostic operating characteristics.

Gut. 2013;62(12):1704-1713.

Zheng C, Lv Y, Zhong Q, et al. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis. BJU Int. 2012; 110(11 Pt B):E680-7.

EVIS EXERA III (CLV-190). http://m.medical.olympusamerica.com/products/light-source/evisexera-iii-clv-190. Accessed July 7, 2014.

Mannath J, Subramanian V, Hawkey CJ, et al.

Narrow band imaging for characterization of high grade dysplasia and specialized intestinal metaplasia in Barrett’s esophagus: a meta-analysis.

Endoscopy. 2010;42(5):351-359.

Qumesaya BJ, Wang H, Badie N, et al. Advanced imaging technologies increase detection of dysplasia and neoplasia in patients with Barrett’s esophagus: a meta-analysis and systematic review. Clin Gastroenterol Hepatol.

2013;11(12):1562-1570.e.1-2.

Disclosures: Dr. Sharma reported that he has received grant support from CDx Diagnostics, Cook Medical, Inc., NinePoint Medical, Inc., and Olympus, Inc. Dr. Rastogi reported that he has received grant support from and served as a consultant for Olympus, Inc.

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

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BB1415

A

NBI correctly identified 92% (104/113) of patients with IM. However, NBI examination involved significantly fewer biopsies (442 targeted biopsies during NBI examination vs 934 biopsies taken during WLE evaluation). On an average per-patient basis, the Seattle protocol required 7.6 biopsies, whereas targeted NBI biopsy averaged 3.6.

Thus, NBI produced the same findings with approximately half the number of biopsies.

With an average pathology cost per biopsy of $53.05, this amounts to $212 less expenditure per procedure. Therefore, reducing the number of biopsies shortens procedure duration and reduces the costs associated with screening and surveillance.7 Although identification of HGD was not a primary aim of the study, NBI detected 30% of neoplastic areas, whereas WLE detected 21%. All the areas of HGD or EA consistently displayed an irregular mucosal/vascular pattern as previously described. Perhaps more importantly, no lesions were found in areas where these patterns were absent, indicating that there may be no need to obtain biopsies from areas with a regular mucosal/vascular pattern. These results suggest that a targeted biopsy strategy has the potential to significantly reduce the number of biopsies during a procedure. Additionally, in some patients, biopsies may be avoided completely.7

SP1171V01

Supported by

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

New Non-Endoscopic Cell Sampling Tool Appears To Detect Eosinophilic Esophagitis

BY TED BOSWORTH Chicago—A cell sampling method that involves pulling a spongelike device up through the esophagus appears to be an effective diagnostic tool for eosinophilic esophagitis (EoE).

The device has been in development for several years for the diagnosis and monitoring of Barrett’s esophagus. Called Cytosponge, it may be at least as useful for detection and follow-up in patients with EoE, new research suggests.

“In our pilot study, [Cytosponge] detected a case of EoE missed with biopsy,” said David A. Katzka, MD, professor of medicine in the Division of Gastroenterology at Mayo Clinic, in Rochester, Minn. Dr. Katzka said the device was well tolerated and well accepted by patients, who generally preferred this method of evaluation to endoscopy. Dr. Katzka presented data on the device at Digestive Disease Week 2014 (abstract 56).

The Cytosponge comes as a gelatin pill on a string. The patient swallows the pill, the gelatin dissolves and the mildly abrasive sponge inside expands. The clinician pulls the sponge back up through the esophagus, collecting sufficient cells for a cytologic smear without causing significant injury or discomfort.

For a condition like EoE, which over the course of diagnosis and treatment may require multiple samples, the device

has the potential to be easier and more cost-effective than endoscopic biopsy, according to Dr. Katzka, who has not yet performed cost–benefit analyses with this technique.

In the study, 20 patients with active EoE or a history of EoE were evaluated with the sponge method, followed by endoscopy and biopsy. Endoscopy provided a control for the diagnostic accuracy of the device and permitted clinicians to evaluate the esophagus for injury after withdrawing the sponge. The goal of the study was to evaluate the device for diagnostic accuracy, acceptability to patients and potential for complications.

On biopsy, 16 patients had more than 15 eosinophils per high-power field

(HPF), which is a standard for the diagnosis of EoE. All of these patients had at least one eosinophil detected with the sponge and 10 had more than 15 HPF. Four of the patients had more eosinophils detected with the sponge than with the biopsy, and one patient was positive for EoE after specimen collection with the sponge but had a negative biopsy. Overall, good correlation was found between the sponge and biopsy, according to Dr. Katzka. The correlation between the sponge and biopsy for peak extracellular eosinophil-derived neurotoxin staining was statistically significant (P=0.0054).

P Mucosal abrasion scores were mild and no complications were associated

Bundled Payments for Colonoscopy Inevitable— But Maybe Not a Bad Thing

BY CAROLINE HELWICK Chicago—As the economics of medicine continues its move toward bundled payments, is it time gastroenterologists embrace the shift?

At least one expert believes the moment has come.

John Allen, MD, MBA, president of the American Gastroenterological Association Institute, said an increasingly unfavorable climate for reimbursement for colonoscopy means gastroenterologists (GIs) must begin to consider bundled payments in their negotiations with payors, hospitals and health systems.

“For a number of years, we have been demonstrating the quality and value of

colonoscopy in terms of cancer reduction, but now we are facing unprecedented pressures in terms of cost. We are getting to a tipping point where the unit payment is going to be below the unit cost for many of us,” said Dr. Allen, who also is professor of medicine and clinical chief of digestive disease at Yale University School of Medicine, in New Haven, Conn. “If we want to preserve this important lifesaving tool, we are going to have to start thinking about different ways of packaging it.”

The expense of colonoscopy has become a contentious issue, as studies show tremendous variation in cost among different providers. Virtually every large commercial payor now has a mechanism by which beneficiaries can examine their benefits and providers’ fees.

“The entry point for these programs is supposedly quality, but this threshold is relatively low,” Dr. Allen said. “Patients are really choosing based on price and site of service.”

Value and Risk Over the short term, Medicare is rapidly building an infrastructure to transition from volume-based to value-based reimbursement, with links between outcomes and payments. This change will have an immediate impact, Dr. Allen said.

The Physician Compare website is up and running. It will become richer with information, and fees and reimbursements will become more transparent. “We can assume that any interaction we have with Medicare in the future will become

with the sponge, said Dr. Katzka, who said every patient preferred the device to endoscopy and biopsy.

The next step will be larger studies to confirm the accuracy and safety of the sponge, Dr. Katzka said. The device was developed by Rebecca C. Fitzgerald, MD, a consultant gastroenterologist at the University of Cambridge, in England, as a relatively simple tool to evaluate patients for Barrett’s. In EoE, Dr. Katzka suggested that more work is needed to confirm that the optimal diagnostic cutoffs for eosinophil counts have been identified, but he said he was encouraged by its clinical potential.

Evan Dellon, MD, MPH, associate professor of medicine and epidemiology at the University of North Carolina at Chapel Hill, said the multiple biopsies required to diagnose EoE and judge response to treatment are a burden for patients. Dr. Dellon said the sponge looks promising enough that he plans to participate in the next set of clinical studies with this device.

“If this is proven to be safe and accurate in larger studies, it could really change how we follow patients,” Dr. Dellon said.

“Instead of requiring endoscopy, the sponge could simply be administered in an office-based setting, the sample sent to pathology and the results acted on without the patient having the expense or risk of another endoscopic procedure.”

■ Drs. Katzka and Dellon reported no relevant financial conflicts of interest.

public knowledge, and will be used by brokers and payors,” Dr. Allen said.

In the longer term, alternative payment models will emerge, especially bundled payments and multidisciplinary medical homes for high-risk patients, resulting in total cost of care as value-based reimbursement.

Both Medicare and private payors are developing infrastructures for bundling payments for colonoscopy. If GIs and their societies do not define the “risk corridors” within these bundles, payors will do that for them, Dr. Allen said.

Risk corridor describes the elements of a bundle, which can be narrow or wide depending on the amount of care. For example, Dr. Allen said, if GIs include post-polypectomy bleeding in their care bundle, the risk corridor would be broader than one that stopped when patients were discharged from the endoscopy unit.

“The wider the corridor, the greater the risk to the practice—but also the greater see Bundle, page 26

26

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Bundle continued from page 24

the reimbursement per procedure,” Dr. Allen explained. “A highly technical practice should be able to define the number of events in a particular component and then be able to ‘price’ that. Just like with stock or bond investments, the greater the risk, the greater the potential return—or loss.”

What a Colonoscopy Bundle Looks Like The Centers for Medicare & Medicaid

Services (CMS) is emphasizing two areas for the care of gastrointestinal disease: bundled payments for defined episodes and the specialty-based medical home.

For the bundled payment model, the provider’s payment is determined by the expected cost of the bundle for giving effective and efficient care. Within this model, screening colonoscopy is “high on the priority list,” Dr. Allen said, as it is easy to define, has predictable costs and complications, and yields itself to risk stratification.

Some experts have proposed a

colonoscopy bundle that looks like this: • Pre-procedure (three days): assessment for appropriateness, patient instruction and prep • Procedure (one day): professional fees, sedation, equipment and pathology • Post-procedure warranty (seven to 14 days): result reporting, complications, repeat procedure for poor prep, and imaging for incomplete procedure • Tie-in with granular quality metrics.

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An American Gastroenterological Association task force recently proposed a bundled payment framework for colonoscopy screening and surveillance based on data from Humana and McKesson. It includes a surgical warranty and allows individual practices to analyze their costs, processes and complications, to negotiate for bundled payment, and to choose their own risk corridors.

“We wanted to define an infrastructure of a bundle that we believe is medically definable and fair,” Dr. Allen said.

Gastroenterologists should not confuse bundled payments with reference pricing, another alternative payment model. With reference pricing, a set price exists for a specific service above which an employer will not pay, thus placing the member at full risk for this excess cost.

A bundled payment, also known as episode-based payment, involves a single payment to providers or facilities, or both, for all services to treat a given condition or to provide a given service, such as colonoscopy. The provider is at risk for costs above the bundle, including potentially preventable complications. This is the model being employed by Minnesota Gastroenterology for colonoscopy.

“These are important distinctions as you start being approved by ACOs [accountable care organizations] or managed care organizations,” Dr. Allen said.

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A notable example of reference pricing is the program at Safeway in the San Francisco area. The grocery chain is self-insured and can draw from its own claims and financial databases. Safeway sets its reference price for a colonoscopy at $1,250, a fee that is lower than those charged by the vast majority of the 40 or so area colonoscopists. Employees can choose more expensive providers, but it comes out of their pocket, whereas anything below $1,250 is fully covered.

Similarly, CalPERS, the nation’s second largest health care purchaser, set a reference pricing plan for joint replacement in 2011. The move triggered a market shift that reduced fees for the procedure at every facility in the area. CalPERS now is considering a combination of reference pricing and bundled payments, which will include some risk adjustment but also will increase provider risk, which Dr. Allen sees as an emerging trend.

The most startling example of bundled payments—labeled by Dr. Allen as “bundled payment on steroids”—is happening with Wal-Mart, which is offering free cardiac, spine and transplant surgery for employees who elect to be treated at one of six nationally regarded centers with which Wal-Mart contracts.

“Patients have no out-of-pocket costs

27

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

‘We are getting to a tipping point where the unit payment is going to be below the unit cost for many of us. If we want to preserve this important lifesaving tool, we are going to have to start thinking about different ways of packaging it.’

—John Allen, MD, MBA

I will provide quality,” he said. “That’s a strong argument that we need to lead with. With some innovation, I think we can thrive in the ACO world that is coming.”

John Vargo, MD, MPH, chair of gastroenterology and hepatology at Cleveland Clinic, in Ohio, said he has “sniffed around the country” to see whether sedation and pathology—two key services in colonoscopy—are being included in bundled payments, and has found that “for the most part, they are.”

Dr. Vargo cautioned that the inclusion

of sedation is a complex calculus, because there are many variables to consider: primarily, anesthesiologist- versus gastroenterologist-directed sedation and severity adjustments, which include sedation requirements; American Society of Anesthesiologists classification; presence of obstructive sleep apnea; and polypharmacy.

“I expect that we are going to see these bundles become more universal, and that variations of bundled parameters will standardize,” Dr. Vargo said. “They may undergo regionalization at first, but

ultimately we will see more of a homogenized nationally based product. And once these things get benchmarked, we are going to see further diminution in what we are getting paid.”

■ Dr. Allen reported financial relationships with gMed; consulting for Myriad, Olympus and Pentax; and participation in advisory committees or review panels for Ethicon Endo-Surgery. Dr. Vargo disclosed a financial relationship with Cook Medical, and participation in advisory committees or review panels for Boston Scientific, Ethicon Inc., and GEye Cue Ltd.

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and no travel expenses, or they can choose a different hospital and all their copays and deductibles kick in,” Dr. Allen said.

These programs clearly save the insurers money and they clearly shift the market to the lower-cost providers. “They also commoditize what we do, and that’s the danger,” he added.

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Reasons To Consider Bundled Payment in Your Practice Although market forces may be the stick, Dr. Allen said there are some carrots that make a colonoscopy bundle worthwhile. For starters, implementing one could offer a practice a marketing advantage. “If you are the first kid on the block, you will demonstrate to payors or ACOs that you understand the emerging payment models,” he said.

Bundled payments also are a hedge against falling fee-for-service rates. They provide a strong argument for maintaining the in-office Stark exemption— which allows for the in-house provision of anesthesiology and pathology services—and they allow a practice to control processes in ways that may not have been possible in a fee-for-service environment, with opportunities for innovation. They also move the conversation to value and quality.

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DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Experts’ Picks:

The Best of Digestive Disease Week 2014: Part 2 COMPILED AND WRITTEN BY DAVID WILD

In this second installment of our three-part series highlighting some of the most important studies presented at Digestive Disease Week 2014, two experts provide commentary on abstracts covering topics from infliximab dosing in ulcerative colitis patients to mindfulness meditation for irritable bowel syndrome.

Samir A. Shah, MD Clinical Professor of Medicine Alpert Medical School of Brown University Chief of Gastroenterology at The Miriam Hospital Providence, Rhode Island

Focus: the Future of Fecal Calprotectin Utility Study for the Diagnosis and Management of IBD (Rosenfeld G, et al) Fecal calprotectin correlates with endoscopic evidence of irritable bowel disease (IBD) activity. In this study, researchers set out to determine how best to incorporate testing of the marker into clinical practice.

In the prospective study, they sent 17 gastroenterologists at eight centers a total of 372 fecal calprotectin test kits. The clinicians used the kits in a total of 250 patients with established or suspected IBD, including 198 patients with Crohn’s disease, 55 patients with ulcerative colitis (UC) and six individuals with indeterminate colitis. Patients were aged 15 to 79 years old at the time of testing.

Physicians completed online surveys before sample collection and after receiving test results, indicating why they ordered the tests and what influence the results had on their treatment decisions.

Survey results showed that 118 tests were ordered to confirm suspected IBD, 113 were ordered to distinguish abdominal symptoms of irritable bowel syndrome (IBS) from IBD in patients with known IBD, and 141 were conducted to obtain an objective measure of IBD activity.

More than half (51.6%) of the test results led to changes in treatment. The most common changes were decisions to observe patients rather than take action (41.6%), initiate or modify therapy (31.5%) or conduct colonoscopic examination (16.1%). In cases where fecal calprotectin findings did not influence clinical management, treatment choices included proceeding with a watch-and-wait approach (68.5%), conducting an endoscopic examination (16.1%) and initiating or modifying therapy (15.3%).

Of 146 cases where clinicians said they had measured fecal calprotectin as an alternative to endoscopic examination, 18 proceeded to endoscopy despite the findings.

Approximately 98% of clinicians said they would conduct fecal calprotectin testing again in similar clinical scenarios.

Su1278.

Dr. Shah: Fecal calprotectin has been shown in previous studies to do three things: correlate with endoscopic disease severity in UC and Crohn’s colitis, distinguish between IBS and IBD symptoms, and correlate with response to anti–tumor necrosis factor therapy.

This real-world study showed that the test was useful in clinical practice, changing management in the majority of cases and reducing the use of colonoscopy to assess disease by 88%. It was felt to be useful in disease management nearly all of the time by physicians, who said they would order it again.

As insurance coverage for fecal calprotectin testing increases, it is likely to be used more often for monitoring disease in lieu of invasive colonoscopy, and it likely will be preferred over less accurate markers, such as C-reactive protein and sedimentation rate.

The Comparative Effectiveness of Biologics and Immunomodulators for the Treatment of Ulcerative Colitis (Shah ED, et al) To determine the relative safety and efficacy of immunosuppressive and biologic drugs in the treatment of UC, investigators conducted a systematic literature review and meta-analysis. They searched the PubMed and Cochrane databases for randomized, placebo-controlled trials of single immunomodulators or biologic drugs conducted between 1950 and 2013.

5.

‘As insurance coverage for fecal calprotectin testing increases, it is likely to be used more often for monitoring disease in lieu of invasive colonoscopy, and it likely will be preferred over less accurate markers, such as C-reactive protein and sedimentation rate.’

—Samir A. Shah, MD

The researchers used rates of drug discontinuation due to adverse events as a proxy measure of drugrelated harm, and they documented rates of complete clinical remission to define treatment efficacy. They calculated the relative risk (RR) for efficacy and harm, as well as the number needed to treat (NNT) and the number needed to harm (NNH).

The anaalysis consisted of 12 trials, including eight that studied infliximab, adalimumab b, golimumab or vedolizumab, and four that studied tacrolimus, 6-mercaptopurine or azathioprine.

Analyses off these studies showed thatt one of every 2.6 patients who receivved an immunomodulating agent for induction of remission achieved this outcome. One in every 5.7 patients who received an immunomodulator for remission maintenance experienced clinical remission.

One in every 4.6 patients who received biologics for remission induction achieved this treatment goal, and one in every 5.2 patients had sustained remission with maintenance biologic treatment.

Rates of treatment discontinuation were similar in the induction immunomodulator and placebo groups, the researchers found. In contrast, patients who received maintenance immunomodulator treatment were 2.8 times more likely than placebo recipients to discontinue treatment (RR, 2.8; 95% confidence interval, 0.7-10.5).

For both the induction and maintenance trials of biologics, rates of treatment discontinuation were similar in both the active treatment and placebo groups.

Dr. Shah: This critically important study found that in moderate to severe UC, biologics are safer than conventional immunomodulators, more effective as maintenance therapies, and due to the lower likelihood of treatment discontinuations with biologics, remission and response are more durable.

There are several caveats to the study. First, it was based on published rates of remission and adverse events instead of on an actual original comparative effectiveness trial, which would have been difficult and costly to perform. This somewhat limits the generalizability of the findings.

Second, the trials of immunomodulators included in the study were conducted before the trials of biologics, and they likely did not include more rigorous end points such as mucosal healing, which are now used in clinical research in IBD. Furthermore, the authors did not include important see Best of DDW, page 30

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Best of DDW

‘Despite the study’s limitations, it should change the

continued from page 28

discussion that we have with patients with moderate

combination treatment data from the UC-SUCCESS study, which looked at azathioprine with and without infliximab and found that although infliximab was superior to azathioprine, combination therapy using both agents was superior to either drug alone [Pannacione R, et al. Gastroenterology 2011;140:S134]. So, a comparative analysis including combination treatment safety and efficacy data would have been useful.

to severe UC who have not yet been treated with either immunomodulators or biologics.’

—Samir A. Shah, MD

Despite the study’s limitations, it should change the discussion that we have with patients with moderate to severe UC who have not yet been

treated with either immunomodulators or biologics. Based on the findings, we can advocate for a trial of biologic therapy as initial treatment, rather than considering either biologics or

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immunomodulators, or using a step-up approach with immunomodulators first and biologics second.

Accelerated Infliximab Rescue Reduces Early Colectomy Rate in Acute Severe Colitis (Gibson D, et al) These investigators reviewed prospectively collected data from 52 patients hospitalized for severe acute UC between 2005 and 2013, and who subsequently were treated with infliximab. Thirty-eight patients underwent a standard infliximab induction schedule, with initial infusion followed by an infusion after two and six weeks. Fourteen patients underwent “accelerated dosing” infliximab induction, receiving all three induction doses within a two-week period.

Patients in the two groups had similar levels of C-reactive protein, albumin, platelets and hemoglobin. The median disease duration before infliximab treatment was 11.8 years in the standard-dosing group and 5.3 years in the accelerateddosing group (P=NS).

P The researchers found that three months after initial infusion, 14 patients (36.8%) who received standard induction required colectomy, compared with one patient (7.1%) in the accelerated-dosing group (P=0.04).

P Six months after initial infusion, one additional patient in the accelerateddosing group required colectomy, and 12 months after initial infusion, two additional patients in this group required colectomy, raising the total colectomy rate within one year of initial infusion in the accelerated-dosing group to 29%.

In the standard-induction dosing group, one additional patient required colectomy within one year of initial infusion, raising the total one-year colectomy rate to 39% (P=0.53 P vs. accelerated dosing).

207.

Dr. Shah: This small retrospective study shows that accelerated-induction dosing is clearly superior to standard dosing in preventing colectomy at three months. The researchers hypothesized that severe UC shortens the half-life of infliximab, hence the need for accelerated or higher dosing, and the results support this hypothesis.

In light of these findings, we need to conduct further studies to determine the best dosing strategy for severe UC. Such a strategy may include evaluating clinical response and infliximab serum levels during induction treatment, and subsequently monitoring patients’ drug levels throughout treatment and making dose adjustments as necessary to ensure adequate drug levels and optimal outcomes.

Dr. Shah reported serving on the speakers’ bureau of AbbVie, Janssen, Salix Pharmaceuticals and Takeda Pharmaceuticals.

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Amy Foxx-Orenstein, DO Professor, Department of Gastroenterology and Hepatology Mayo Clinic Scottsdale, Arizona

High Sensitivity C-Reactive Protein as a Marker for Inflammation in Irritable Bowel Syndrome (Hod K, et al)

2046.

These investigators examined levels of high-sensitivity C-reactive protein (HSCRP) in 242 patients with IBS and 244 controls without IBS. They also administered the Functional Bowel Disorder Severity Index (FBDSI), measured IBSassociated pain and screened patients for psychological comorbidities. IBS patients met ROME III criteria and did not have evidence of other gastrointestinal disorders on colonoscopic examination.

The data revealed that patients with IBS had a mean HS-CRP level of 3.7±5.1 mg/L, compared with 2.8±4.3 mg/L among controls (P<0.006). HS-CRP levels were higher in patients with more severe IBS, and were further elevated in a subgroup of patients with severe diarrhea-predominant IBS (IBS-D; P≤ P 0.047 for both severe IBS and severe IBS-D vs. controls).

Multivariate analyses controlling for other potentially confounding variables confirmed that IBS was the only factor that was independently associated with higher HS-CRP levels (P=0.025).

P Dr. Foxx-Orenstein: HS-CRP has been used in conjunction with other inflammatory biomarkers to determine cardiac risk in asymptomatic patients (Best Prac Res Clin Endo Met 2014;28:281-294), but this is the first study to my knowledge that examined HS-CRP in the IBS population. The concept of HS-CRP as a biomarker of disease is intriguing, given that a subpopulation of IBS patients can have altered intestinal immunity and low-grade inflammation— a finding that could shed light on the pathophysiology of IBS. There are some challenges to using HS-CRP as a biomarker in IBS. One is that patients also may have asymptomatic and unknown heart disease or nonalcoholic fatty liver disease—two conditions that raise HS-CRP (Hepatogastroenterology 2014;61:422-425). Another is that medications can affect HS-CRP levels: Nonsteroidal anti-inflammatory drugs and statins reduce inflammation and HSCRP, and hormone replacement therapy

can raise HS-CRP. The lack of specificity of HS-CRP therefore may be a barrier to use in IBS. More studies are needed.

Mindfulness Meditation Has Long-Term Therapeutic Benefits in Women With Irritable Bowel Syndrome (IBS): Follow-Up Results From a Randomized Controlled Trial (Faurot KR, et al) This abstract presented follow-up data to a previously published trial of 75 women with IBS, randomized to participate in

715.

either eight weekly mindfulness meditation sessions or a support group (Gaylor SA, et al. Am J Gastroenterol 2011;106:16781688). That study showed that mindfulness participants had significantly greater improvements in symptoms than the support group patients one month after completing mindfulness training.

The new findings include six- and 12-month follow-up findings from 33 mindfulness-trained participants and 35 support group patients. The data included scores on the IBS Symptom Severity (IBS-SS) scale; the IBS Quality of Life

31

(IBS-QOL) scale; the Brief Symptom Inventory-18 (BSI-18); the Visceral Sensitivity Index (VSI), which measures gastrointestinal-specific anxiety; and the Five-Facet Mindfulness Questionnaire (FFMQ), which gauges mindfulnessrelated skills, such as sustained observation, descriptive detail and “acting with awareness.”

Scores on the IBS-SS were a mean of 284.1 and 287.5 before treatment in the mindfulness and support group patients, respectively, and dropped to a mean of 133 see Best of DDW, page 32

with the best-read gastroenterology publication.

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DDW 2014

Best of DDW continued from page 31

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

‘This is the first long-term, randomized controlled study evaluating the clinical effect of mindfulness training on

and 179.5 in the two groups, respectively, at six months (P<0.001 for mindfulness vs. support). At one year, mean IBS-SS scores were 169 and 259.5 in the two groups, respectively (P=0.004).

P Mean baseline IBS-QOL scores of 64.8 and 67.2 in the mindfulness and support group patients, respectively, increased to 81 and 74.6, respectively, at six months (P=0.04). At one year, mean IBS-QOL scores were 79.7 and 70.2 in

bowel and psychological symptoms in IBS patients. In the original randomized trial by these authors, patients were tested one month after completing eight weekly sessions of mindfulness, and were found to have lasting improvements in symptom severity.’

—Amy Foxx-Orenstein, MD

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the mindfulness and support groups, respectively (P=0.01).

Improvements in VSI scores were also significantly greater among mindfulness participants at both six and 12 months than among support group participants, the researchers found. Additionally, mindfulness participants had significantly higher scores than support group patients on the FFMQ at six months, although this difference was not seen at one year.

Dr. Foxx-Orenstein: When it comes to treating chronic pain, medications do not hold all the answers.

Mindfulness meditation incorporates mind–body exercises, awareness of the moment, meditation and sometimes yoga, to optimize one’s ability to reduce pain, stress and the immune response. It has become a popular treatment at many institutions, including ours, to enhance quality of life for patients with a variety of illnesses, including IBS (BMC Complement Altern Med 2013;13:248).

Although mindfulness appears to be effective for both short- and long-term management of chronic discomfort in patients with active IBS symptoms, as this study shows, there are factors that may be limiting the use of mindfulness in practice. These include lack of access to mindfulness trainers or therapists, limited insurance coverage and patient reluctance to participate in a mindfulness program.

Moreover, until now, longer-term evidence-based data have not been available to support meditation’s effectiveness.

This is the first long-term, randomized controlled study evaluating the clinical effect of mindfulness training on bowel and psychological symptoms in IBS patients. In the original randomized trial by these authors, patients were tested one month after completing eight weekly sessions of mindfulness, and were found to have lasting improvements in symptom severity. The current follow-up trial shows that the effect persists, although some benefits diminish with time. More data are needed on long-term results in this group of patients, including characteristics of which individuals might benefit from repeat treatments.

Dietary Restrictions Predict Worse Disease-Specific Quality of Life in Patients With Irritable Bowel Syndrome (Nojkov B, et al) Researchers administered the IBSQOL survey to 247 consecutive non-constipated patients with ROME-III–defined IBS. To determine the prevalence and effect of dietary restrictions, they grouped patients according to their responses on three food-related questions in the survey.

Sa1099.

see Best of DDW, page 35

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GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Colectomy for Chronic Constipation— A Rising Trend Causes Alarm

BY CAROLINE HELWICK Chicago—Colectomy as a treatment for chronic constipation is on the rise, but the surgery puts patients at risk for potentially serious perioperative complications with little evidence for long-term benefit, new research shows.

Anwar Dudekula, MD, of the University of Pittsburgh Medical Center, who helped conduct the study, said treatment guidelines include the use of surgical approaches, with subtotal colectomy and ileorectal anastomosis in patients with slow-transit constipation. However, he questioned whether surgical modalities are worth the associated risks, and suggested that the recommendations warranted reconsideration in light of the new findings.

“As a functional disorder, constipation may have a significant impact on quality of life, but it does not come with truly relevant morbidity or mortality,” Dr. Dudekula said. “Thus, the risks of more aggressive interventions need to be weighed against this generally benign prognosis.”

In Florida and California, the 181 colectomy patients in the databases logged 2,540 total health care visits, and they were followed for a median of 630 days before surgery and 446 afterward.

Visits to the emergency department and hospital admissions did not change appreciably after colectomy. Emergency department visits totaled 293 before colectomy and 223 afterward. Hospital

‘In my practice, I now very rarely advise surgery for chronic constipation because I am not convinced that, in most cases, the benefits outweigh the risks, and I have seen very poor outcomes.’

—Nicholas J. Talley, MD, PhD

Colectomies on the Rise Dr. Dudekula and his colleagues analyzed changing patterns in the use of colectomy for constipation and the rate of perioperative complications by examining the Nationwide Inpatient Sample for 1998 to 2011, as well as the State Inpatient Database and State Emergency Department Database for California and Florida for 2005 to 2011.

They included patients with diagnostic codes for total intraabdominal colectomy, either open or laparoscopic, and total abdominal colectomy of unspecified nature, as well as a primary diagnosis of constipation, slow-transit constipation and outlet dysfunction constipation.

They excluded patients with gastrointestinal hemorrhage or blood in stool, diverticulitis of the colon, diverticulosis with hemorrhage, lower gastrointestinal tract cancer and colitis.

The analysis identified 2,220 women and 157 men with these diagnoses; almost 90% were aged 25 to 64 years.

Nearly 90% of the procedures were elective, and most were performed in large, urban teaching hospitals in the South and Midwest. The analysis confirmed that while the numbers are still small, colectomy for constipation has increased dramatically since 1998—rising from 104 in 1998 to 311 in 2011.

Table 1. Emergency Department Visits—Top 5 Diagnoses (N=181)

admissions numbered 318 and 390, respectively.

“The longitudinal data demonstrated continuing use of health care resources, dominated by gastrointestinal complaints, and this suggests that the apparent risk of surgery is not offset by improved longterm outcomes [Tables 1 and 2]” Dr. Dudekula reported at Digestive Disease Week 2014 (abstract Sa2009). “Also, while surgery was mostly performed in the young [population], perioperative complications were common.”

Approximately 40% of patients developed a perioperative complication. Urinary and pulmonary problems together accounted for about 50% of these events, he said. The consequences of the complications were unclear.

“We came up with a very conservative estimate, excluding patients that may have had other, likely harmless problems, such as diverticulosis, and still the number of these radical operations performed doubled within about a decade,” Dr. Dudekula told Gastroenterology & Endoscopy News. “If indeed health care resource utilization goes up instead of down, it does not indicate true success and improved quality of life, which is the key target in managing functional disease. Thus, it is time to slow down and reassess these guidelines.”

Before Colectomy

Number of Cases (global)

After Colectomy

Number

‘Few Patients Will Pass This Evaluation’

Abdominal pain

127

Abdominal pain

132

Headache

77

Headache

98

Other gastrointestinal disorders

63

Nervous system disorders

33

Spondylosis, other back problems

49

Urinary tract infection

21

Nonspecific chest pain

34

Superficial injury, contusion

19

Nicholas J. Talley, MD, PhD, professor of medicine at the University of Newcastle, in Australia, and adjunct professor of epidemiology and medicine at Mayo Clinic, in Rochester, Minn., called the trend “disturbing.”

“Patients who might be surgical candidates after an appropriate evaluation should be very few, as it is essential to rule out pelvic floor dysfunction, confirm that colonic transit is very slow—two tests are recommended—and rule out small intestinal pseudo-obstruction,” he said.

Dr. Talley said significant psychiatric comorbidity and previous abdominal surgeries are contraindications to colectomy for patients with constipation and that evaluation at an expert center should be “routine.”

“Few patients will pass such an evaluation,” he observed. “In my practice, I now very rarely advise surgery for chronic constipation because I am not convinced that, in most cases, the benefits outweigh the risks, and I have seen very poor outcomes.”

■ Drs. Dudekula and Talley reported no relevant financial conflicts of interest.

Table 2. Hospital Admissions—Top 5 Diagnoses (N = 181) Before Colectomy

Number

After Colectomy

Number

Other gastrointestinal disorders

43

Complications of surgical procedures or medical care

64

Intestinal obstruction without hernia

42

Intestinal obstruction without hernia

45

Complications of surgical 21 procedures or medical care

Diabetes mellitus with complications

40

Spondylosis, other back problems

19

Other gastrointestinal disorders

31

Abdominal pain

17

Complication of device, implant or graft

24

34

EXPERT ROUNDTABLE

EHR continued from page 21

group, Elgin Gastroenterology. Because I have a passion for technology—and probably should be wearing a “geek button”—I wrote the electronic medical record software we used in our practice for six years. As a result, we had a very customized system that functioned extremely well for us, and I had a group of partners who were used to that customization.

The American Recovery and

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Reinvestment Act was passed in 2009 and along with it the birth of meaningful use (MU). This was a clear indication for me that my days of creating an EHR were over. The formation of IGG was a perfect time to move to a commercially produced EHR. It became my responsibility to research the available EHRs and assist the board of managers of IGG in their decision.

At the time, EHRs were a cottage industry with more than 300 vendors, most of which were small companies.

Because it was obvious that MU would

precipitate large-scale consolidation, we decided that it would be best to go with one of the market leaders.

We had the following core requirements: • The vendor needed to be a major player in the EHR space, preferably a pure player whose main focus was creating EHRs. • The vendor’s application needed to be certified for MU. • The application needed to be a complete one with integrated EHR and practice management.

Cases in Hyponatremia: Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com

Release Date: August 25, 2014

Expiration Date: August 25, 2015

Faculty

Goal

Juan Carlos Ayus, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor of Medicine Division of Nephrology University of Texas Health Science Center San Antonio, Texas

Michael L. Moritz, MD Associate Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Associate Professor Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia.

2 Describe the comorbidities and causes commonly associated with hyponatremia and their significance in treatment strategy.

3 Summarize current evidence and best practices in the management of hyponatremia.

4 Explain how to mitigate adverse events secondary to treatment of hyponatremia.

5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka.

Distributed via CMEZone

• The application needed to be user-friendly.

• The architecture needed to lend itself to Web-based access.

The software needed to be customizable. Gastroenterology is a specialty with specific needs and EHRs usually require being tailored to meet them.

Because we had plans to build clinical decision support tools into our EHR, the application needed to be flexible to accommodate this function. And because we also owned multiple ambulatory surgery centers (ASCs), we needed software for them as well.

We were able to find a vendor that fulfilled all of our requirements, and we have been fairly satisfied with our selection. That’s not to say that this was not a difficult and expensive endeavor. It has allowed us to accomplish the following: • Integrate our office practice with our ASCs; • Create a totally paperless work environment; • Have offices in multiple locations and function equally in all of them; • Create a set of clinical decision support tools; • Create an innovative patient engagement tool called Project Sonar that has allowed us to enter population health for patients with Crohn’s disease; and • Decrease the variability in the way we all practice as we are all using the same set of templates and tools.

GEN: Knowing what you know now about choosing an EHR system, what advice would you give your colleagues in gastroenterology practices that are in the process of doing so?

Dr. Kosinski: I would have the following advice: Analyze and know the needs of your practice. Although we all practice gastroenterology, we are all unique in some ways. Make sure your EHR allows you to maintain your uniqueness. Do you have multiple offices? Do you have an ASC? Do you do infusions?

Do you have pathology? Do you belong to an accountable care organization? These all bring issues to the table that require discussion with your vendor.

Do your homework! I can’t emphasize this enough. Every salesperson will try to make you believe that their EHR is the best of the best. This will require one or more of the physicians to be champions of the process. Make sure your vendor is poised to keep you positioned for MU as well as Physician Quality Reporting System and other registry-related endeavors like the American College of Gastroenterology’s GI Quality Improvement

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • AUGUST 2014

Best of DDW continued from page 32

One group consisted of patients who reported following moderate to severe dietary restrictions, and the second group included patients who reported following no or minimal restrictions. Study participants were a mean of 42.6 years old; 73% were female; and 92% were white.

Nearly two-thirds of patients (62.4%) said they moderately restricted the amount of food they ate; 73.6% moderately restricted the type of foods they ate; and 51.2% felt at least moderately frustrated that they could not eat when they wanted to because of their bowel symptoms.

Patients who moderately restricted the quantity of food they ate had a mean total IBS-QOL score of 52.52±21.55, compared with a mean score of 76.43±15.05 among those who did not limit the amount of food they ate or did so minimally, according to the researchers (P=0.0001).

P Patients who reported at least moderately restricting the types of foods they ate had lower IBS-QOL scores than those who did not do so or did so minimally. Patients who reported feeling at least moderately frustrated with not being able to eat when they wanted to had a mean IBS-QOL score of 47.63±19.75, compared with 76.45±14.3 among those who reported minimal or no frustration (P=0.0001).

P Compared with those who reported minimal to no dietary restrictions,

Consortium and the American Gastroenterological Association’s Digestive Health Recognition Program.

Assess the doctors around you. Is there a dominant EHR vendor that has captured the great majority of your referral sources? Is there a hospital system that is dominant in your area and is trying to capture the data from your primary care physicians? You may need to limit your choices to only a few EHRs as a result.

Keep a forward-thinking mindset.

Don’t look to the past. I always remember the Tom Cruise movie, “Minority Report,” and how I was blown away by the computer interface. Steven Spielberg tried to create the computer interface of the future. The EHR of the future will be a user interface that communicates with a health information exchange. Tools will be built into the EHR to promote highquality care.

Don’t sign until you have what you want. Remember, you don’t get what you deserve; you only get what you negotiate.

■

patients indicating at least moderately restricted diets were more likely to report dysphoria and also had a greater degree of disease interference in daily activity, more body image concerns, greater worry about their health, and lower-quality sexual and social relationships (P<0.05 for all). Statistical analyses controlling for age, gender, marital status, alcohol and tobacco consumption, and educational level did not affect the strength of the association between dietary restrictions and lower IBS-QOL scores, the investigators reported.

1978

—

Dr. Foxx-Orenstein: This prospective study found that patients with non-constipated IBS who reported more self-imposed dietary restrictions had greater symptom severity and a poorer quality of life.

Patients who impose greater dietary restrictions for long periods of time may have a higher anxiety/distress quotient driving those restrictions, so these types of dietary restrictions provide early cues of case complexity and can help clinicians adjust their management approach accordingly. Anecdotally, many patients

35

who follow restrictive diets are keen to continue with these diets even when the diets are not effective. In these cases, patients may benefit from a multidisciplinary approach to care, including psychological assessment, mindfulness techniques, dietary counseling and behavioral modification. Patients who gain a broad understanding of the many factors that influence IBS and symptom severity have a greater likelihood of improving their quality of life.

■ Dr. Foxx-Orenstein reported no relevant financial conflicts of interest.

36th Anniversary — 2 0 1 4 2014

The Independ Independent Monthly Newspaper for Gastroenterologists

For almost four decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician.

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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Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

MOHAMMAD TITI, MD

NEIL GUPTA, MD

PRATEEK SHARMA, MD

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

Division of Gastroenterology and Hepatology Loyola University Medical Center Maywood, Illinois

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

Dr. Sharma has received grant support from CDX Labs, Cook Medical, NinePoint Medical, and Olympus Inc. Drs. Titi and Gupta report no relevant financial conflicts of interest.

C

olorectal

cancer

(CRC) is the second leading cause of

cancer-related in

the

mortality

Western

world.1

Screening colonoscopy and polypectomy have become widely accepted as the mostt effective available methods for early detection and prevention of CRC and have shown a reduction in i mortality t lit within the screened population.2 However, colonoscopy remains imperfect and several studies have raised concerns about the miss rate of adenomatous polyps during screening.

The overall miss rate is approximately 20%, and ranges from 6% for large (10 mm) adenomas to 26% for diminutive (<5 mm) lesions.3 Missing these adenomas is one of the proposed mechanisms in the development of interval colon cancers that occur within the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

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Several elements can influence the detection of adenomas during colonoscopy, including improving the quality of bowel preparation to facilitate visualization of the mucosa and enhancing the endoscopistâ&#x20AC;&#x2122;s skills to perform the procedure. For the latter, careful inspection behind the folds, mucosal washing, adequate insufflation, and recognition of subtle mucosal changes or flat polyps are critical factors. These factors are of particular importance when dealing with flat polyps, especially those in the right colon, which may harbor a higher risk for colon cancer.5 The recent recognition of sessile serrated polyps as precursors to right-sided colon cancer emphasizes that these polyps usually are subtle and flat and can easily be missed or incompletely resected, resulting in the risk for an interval colon cancer.5-7 Standard-definition white-light (SDWL) colonoscopy has shown limitations in recognizing such subtle or flat changes and in detecting small polyps behind the folds. Accordingly,

the past several years have witnessed a growing interest in enhancing the imaging and endoscopic technology used during colonoscopy beyond SDWL and traditional forward-viewing angles. This article summarizes the advances made so far in the colonoscopy technology used during screening for CRC and the clinical evidence for their efficacy in improving adenoma detection (Table).

High-Definition Endoscopy And Wide-Angle Views

Chromoendoscopy

The higher resolution provided with the high-definition white-light (HDWL) scopes allows for more detailed imaging of the colonic mucosa. This feature, along with the fact that some HDWL scopes provide wider-angle views (170 degrees; OLYMPUS CF-HQ190) compared with 140 degrees with older scopes, suggest that these new devices may improve the detection of neoplasias. However, studies using HDWL scopes have found a small increase in the adenoma detection rate (ADR) compared with SDWL, mainly by improving the detection of small polyps with no benefit in the detection of large or advanced lesions.8-10 Three randomized trials comparing HDWLs with SDWLs found a small trend toward greater adenoma detection with HDWL scopes that did not reach statistical significance.8-10 The majority of published data comes from nonrandomized trials that involved sufficiently large sample sizes and comparable groups of patients. These studies found a small increase in ADRs with HDWL scopes.11-13 A recent metaanalysis found that HDWL colonoscopy has improved the ADR by 3.5% (95% confidence interval [CI], 0.9%6.1%), largely as a result of increased detection of diminutive adenomas.14

Methylene blue-assisted colonoscopy

Water-Infused Colonoscopy

Table.

Advances in Colonoscopy White-Light Endoscopy Fuse High-definition colonoscopy Standard definition colonoscop Water-immersion colonoscopy Dye-Based Endoscopy (White Light)

Virtual Chromoendoscopy Autofluoresence imaging Blue light imaging i-SCAN Narrow band imaging Accessory-Assisted Endoscopy Balloon-assisted colonoscopy Cap colonoscopy Endocuff-assisted colonoscopy Third Eye Retroscope colonoscopy

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The initial goal of using water infusion instead of air insufflation during colonoscopy was to facilitate cecal intubation and reduce patient discomfort.15,16 Early attempts at the water-immersion method combined water infusion and air insufflation during insertion. In this technique, infused water and any residual stool material are suctioned during withdrawal but the contaminated water obscures visibility and raises concern about reducing polyp detection. A recent systematic review, however, reported no differences in ADR between waterimmersion and air-insufflation colonoscopy.17 An alternative technique, the water-exchange method, has emerged. Air insufflation during insertion is replaced completely by water infusion with the contaminated water suctioned and exchanged for clean water. This approach results in a cleaner colon during withdrawal, facilitating mucosal inspection, and is proposed to increase ADR. Initial nonrandomized data do

indicate a significant increase in ADR, by 11% to 15% over air-insufflation colonoscopy.18-20 The 2 published randomized controlled trials (RCTs) showed a higher ADR with the water-exchange method, but this difference was not statistically significant.21,22 In an attempt to further improve the water-exchange method, an observational study added indigo carmine to the infused water during colonoscopy. The ADR was significantly higher in the indigo carmine group than in a historical cohort of patients who had undergone standard water-exchange (62% vs 40%; P<0.05) or air-insufflation colonoscopy (62% vs 36%; P<0.05).23 In another attempt to improve the water-exchange method, a pilot study compared the water-exchange technique plus cap-assisted colonoscopy (CAC) with air-insufflation colonoscopy alone. The mean number of adenomas was higher with the water-exchange CAC method (n=50) than in the group that received air-insufflation colonoscopy (n=101), although the ADR was not statistically significantly higher (70% vs 59.4%; P=0.22).24

Full-Spectrum Endoscopy The recently developed Fuse system (EndoChoice) allows for full-spectrum views of the colon lumen, comprising 330 degrees. The colonoscope in the Fuse system has 2 additional cameras, one on each side of the scope’s tip, to supplement the front camera. The video images transmitted from the cameras are displayed on 3 contiguous monitors corresponding to each camera. This array provides a comprehensive view of the total colonic lumen, including imaging of the traditionally encountered blind spots at the flexures or proximal edges of the mucosal folds.

The Fuse system was first studied in a model of simulated colonic polyps. Thirty-seven endoscopists performed colonoscopies with a forward-viewing colonoscope followed by the Fuse system. The investigators found a significant increase in polyp detection with the Fuse: 85.7% versus 52.9% with the conventional scope (P<0.0001). The difference was particularly pronounced for detection of polyps at flexures or behind folds.25 The safety and feasibility of the Fuse system was reported in a pilot study of 50 patients. The investigators found a rate of cecal intubation of 100% with a mean time of 3.1 minutes (SD=1.5 minutes).26 A randomized, multicenter, back-to-back study with sameday colonoscopies using Fuse and forward-viewing colonoscopy was performed in 185 patients.27 In those who underwent standard colonoscopy first (n=88), the Fuse system detected 39 additional polyps, including 20 adenomas, corresponding to an increase in detection of polyps and adenomas of 78% and 71.4%, respectively. In those patients who underwent screening with the Fuse system first (n=97), standard forward-viewing

colonoscopy detected 11 additional polyps, including 5 adenomas, corresponding to an increase in detection of polyps and adenomas of 10.8% and 8.2%, respectively (P<0.01). The adenoma miss rate with Fuse was considerably lower than with forward-viewing colonoscopy (7.5% vs 40.8%; P<0.0001). However, the median withdrawal time was approximately 30 seconds longer with Fuse colonoscopy (5.6 vs 6.2 minutes; P<0.01), a difference that may have biased the results. More studies are required before definitive conclusions can be made.

Chromoendoscopy Dye-spray chromoendoscopy (CE) has shown some benefit in increasing detection of neoplastic lesions in high-risk populations, such as patients with inflammatory bowel disease or hereditary syndromes that cause colonic polyps.28 However, the yield of such techniques in populations with average risk for colon cancer is uncertain; some small randomized trials found a higher ADR,29 whereas a large randomized trial comparing CE plus HDWL with HDWL colonoscopy found only a marginal increase in ADR (patients with at least 1 adenoma: 55.5% vs 48.4%, respectively; absolute difference: 7.1%; 95% CI, 0.5%-14.7%; P=0.07) and the number of adenomas per patient: 1.3±2.4 versus 1.1±1.8, respectively (P=0.07).30 These discouraging results, along with the fact that dye-spray CE is time-consuming and carries a prolonged withdrawal time, have limited the adoption of this technique in routine screening of patients at average risk for colon cancer. However, a new technique has been described in which the dye is incorporated within the bowel preparation using methylene blue (MB). MB MMX (Cosmo Technologies) tablets are an oral modified-release formulation manufactured using a multimatrix structure that ensures colonic drug delivery. MB tends to be absorbed by the normal columnar epithelial cells of the colonic mucosa, which results in mucosal staining, but is less absorbed by neoplastic lesions, resulting in unstained areas when these lesions are present. A preliminary study on the efficacy of MB MMX 25 mg for the detection of polyps involved 96 patients undergoing routine colonoscopy. Polyps were detected in 61 patients, resulting in a 63.5% polyp detection rate.31 More clinical trials are needed to evaluate this technique.

Virtual Chromoendoscopy Several systems have been developed that can enhance the contrast of the image by selecting specific light wavelength. The Narrow Band Imaging (NBI) system (Olympus Medical Systems) filters light before image processing to the narrow bands of the blue and green wavelengths (Figure 1). In contrast, the Fujinon Intelligence Chromoendoscopy (FICE, Fujinon Inc) and i-Scan (Pentax) systems manipulate light using post-processing

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Figure 1. Narrow band imaging of a tubular adenoma in the colon.

computer algorithms. These selective demonstrations of specific wavelengths result in a different color image resembling CE. The Autofluorescence imaging (AFI) system (Olympus Medical Systems) is based on the fact that tissue has naturally fluorescent molecules that, upon activation by the absorbed light energy, emit different light wavelengths depending on characteristics such as thickness, glandular density, and distribution of collagen.

Endoscopes that are capable of recognizing autofluorescence can produce a different colored image resembling CE; colorectal neoplastic lesions usually are shown as purple in contrast to normal colonic mucosa, which appears green.

Studies of virtual CEâ&#x20AC;&#x201D;chiefly NBIâ&#x20AC;&#x201D;overall found limited benefit of virtual CE in improving ADR compared with HDWL colonoscopy.32 More than 11 RCTs evaluated

4

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NBI and ADR in a screening population of average- and higher-risk individuals and found limited benefit compared with HDWL colonoscopy. These results were supported by a recent Cochrane review of 3,673 patients in 8 randomized trials (relative risk [RR], 0.94; 95% CI, 0.87-1.02). However, on pooled analysis, HDWL and NBI had higher ADRs than SDWL colonoscopy alone (RR, 0.87; 95% CI, 0.78-0.97).32-35 Three large RCTs comparing FICE with HDWL colonoscopy found that the techniques appear to have virtually identical ADRs.36,37 The published RCTs comparing HDWL with i-Scan38,39 or AFI40-42 had small sample sizes and showed conflicting results. No final conclusion on these modalities can be made at this point. Although larger trials may provide more accurate information, the lack of substantial benefit with

Figure 2. Recognition of colon polyp using cap-assisted colonoscopy.

virtual CE devices makes it less likely that the technology in its current form improves the detection of adenomas.

Technical issues inherent to virtual CE likely are responsible for the disappointing results. Insufficient brightness of the virtual CE image during colonoscopy produces suboptimal visualization of the colonic mucosa when used in a large-diameter colon lumen.

Furthermore, inadequate preparation of the colon leaves behind residual fluid or stool that appears red and dark in virtual CE images, hindering an optimal view of the mucosa.

Cap-Assisted Colonoscopy Putting a 4-mm clear cap on the end of the colonoscope was intended to improve visualization during

mucosal resection procedures by flattening the mucosal folds (Figure 2). However, randomized trials of CAC versus conventional colonoscopy have produced conflicting results. Although CAC may shorten cecal intubation time, it appears to have limited or no benefit in improving the ADR.43-45 A meta-analysis of 16 RCTs found a marginal increase in the number of individuals with polyps detected (RR, 1.08; 95% CI, 1.00-1.17) but no statistically significant difference in ADR.46

Third Eye Retroscope The Third Eye Retroscope (Avantis Medical Systems) has a 3.5-mm flexible single-use catheter with a camera and light source at the tip that is retroflexed 180 degrees after being advanced through the working channel of the colonoscope to provide a 135-degree

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retrograde view of the colon. Investigators who studied the device said the Third Eye Retroscope improves visualization of the colonic surface area from 87% with standard 140-degree view colonoscopes to 99%.47 Two nonrandomized studies evaluated the additional diagnostic yield of the Third Eye Retroscope and found an approximately 14% increase in polyp detection and an 11% to 16% increase in ADR.48,49 In the only randomized trial, the TERRACE (Third Eye Retroscope Randomized Clinical Evaluation) study, investigators reported net additional polyp and adenoma detection rates with the device of 29.8% and 23.2%, respectively.50 Although withdrawal time was nearly 2 minutes longer for patients in the Third Eye Retroscope group, post hoc analysis showed this did not significantly affect polyp detection.

Despite the reported increase in polyp detection, the Third Eye Retroscope system has several limitations that may hinder widespread adoption. In addition to costing more than conventional colonoscopy, reduced suction while using the scope means residual materials must be suctioned during insertion or the device must be removed intermittently during withdrawal. Furthermore, the scope must be removed from the working channel if any device, such as forceps or a snare, is needed for polyp removal. These factors may prolong withdrawal time and limit the use of this device in daily practice. Modifications that leave the suction channel free may help resolve some of the difficulties associated with this system.

Balloon- and Endocuff-Assisted Colonoscopy A new endoscopic cuff (Endocuff AEC120 or AEC140; Arc Medical) has been introduced as a means of enhancing visualization and scope stability during endoscopic mucosal resection of large or flat polyps of the sigmoid colon.51 The Endocuff (EC) is a 2-cm long, flexible cuff with 2 rows of small flexible, hinged wings that help flatten large mucosal folds during withdrawal of the instrument (Figure 3). Because the wings fall flush with the colonoscope, they do not interfere during insertion. EC-assisted colonoscopy was found to have good procedural success rates in terms of cecal intubation and time, as well as a good safety profile, with no associated complications.52 A prospective randomized trial in 498 patients undergoing screening colonoscopy in Germany showed EC-assisted colonoscopy increased the absolute rate of polyp detection by 14% over unassisted colonoscopy from 42% to 56% (P=0.001). The increase was particularly marked for polyps in the sigmoid colon—32% versus 15% (P<0.0001)—and cecum— 14% versus 7% (P=0.019).53 Balloon-assisted colonoscopy is similar in concept to the endoscopic cuff. The NaviAid G-EYE colonoscope (SMART Medical Systems) permanently integrates an inflatable, reusable balloon onto the flexible tip of a

6

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Figure 3. The Endocuff slips over the tip of an endoscope; during withdrawal, its flexible arms open the bowel for inspection to improve views of mucosa previously difficult to visualize. standard colonoscope. The balloon can be reprocessed and reinflated by the endoscopist upon withdrawal of the scope. The mechanical flattening and straightening of haustral folds with the inflated balloon permit visualization of hidden anatomic areas, thus increasing the ADR. In a prospective cohort study, 50 gastroenterologists performed back-to-back conventional (non–balloon-assisted) colonoscopy followed by balloon-assisted colonoscopy in a model of simulated colonic polyps. The median rate of polyp detection for all simulated polyps was significantly higher with balloon-assisted colonoscopy than with unassisted colonoscopy: 91.7% versus 45.8%, respectively (P<0.0001).54 The significantly higher rate of polyp detection with balloon-assisted colonoscopy was observed for both nonobscured and obscured lesions (P<0.0001 for both).

Clinical studies in humans are needed to further evaluate this new technology.

Conclusion One of the major advances in colonoscopy in recent years has been the development and adoption of HDWL. However, new technologies are still being investigated, and one of these approaches may increase adenoma detection to a degree that would result in reductions in the rate of interval cancers for all endoscopists and at a negligible incremental cost. Until then, endoscopists with low ADRs should review the existing technologies and consider whether and to what extent these devices may help their clinical practice.

20. Ramirez FC, Leung FW. A head-to-head comparison of the water vs. air method in patients undergoing screening colonoscopy.

J Interv Gastroenterol. 2011;1(3):130-135.

References 1.

Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer.

2010;127(12):2893-2917.

2. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths.

N Engl J Med. 2012;366(8):687-696.

21. Leung J, Mann S, Siao-Salera R, et al. A randomized, controlled trial to confirm the beneficial effects of the water method on U.S. veterans undergoing colonoscopy with the option of on-demand sedation. Gastrointest Endosc. 2011;73(1):103-110.

3. Van Rijn JC, Reitsma JB, Stoker J, et al. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol.

2006;101(2):343-350.

22. Leung FW, Harker JO, Jackson G, et al. A proof-of-principle, prospective, randomized, controlled trial demonstrating improved outcomes in scheduled unsedated colonoscopy by the water method. Gastrointest Endosc. 2010;72(4):693-700.

4. Pohl H, Robertson DJ. Colorectal cancers detected after colonoscopy frequently result from missed lesions. Clin Gastroenterol Hepatol. 2010;8(10):858-864.

23. Leung J, Mann S, Siao-Salera R, et al. Indigocarmine added to the water exchange method enhances adenoma detection—a RCT. J Interv Gastroenterol. 2012;2(3):106-111.

5. Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010;138(6):2088-2100.

24. Yen AW, Leung JW, Leung FW. A novel method with significant impact on adenoma detection: combined waterexchange and cap-assisted colonoscopy. Gastrointest Endosc.

2013;77(6):944-948.

6. Hetzel JT, Huang CS, Coukos JA, et al. Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort. Am J Gastroenterol. 2010;105(12):2656-2664.

7. Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 2012;107(9):1315-1329.

8. Pellise M, Fernandez-Esparrach G, Cardenas A, et al. Impact of wide-angle, high-definition endoscopy in the diagnosis of colorectal neoplasia: a randomized controlled trial. Gastroenterology.

2008;135(4):1062-1068.

26. Gralnek IM, Segol O, Suissa A, et al. A prospective cohort study evaluating a novel colonoscopy platform featuring full-spectrum endoscopy. Endoscopy. 2013;45(9):697-702.

27. Gralnek IM, Siersema PD, Halpern Z, et al. Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial. Lancet Oncol.

2014;15(3):353-360.

9. Tribonias G, Theodoropoulou A, Konstantinidis K, et al. Comparison of standard vs high-definition, wide-angle colonoscopy for polyp detection: a randomized controlled trial. Colorectal Dis. 2010;12:e260-e266.

10. Rastogi A, Early DS, Gupta N, et al. Randomized, controlled trial of standard definition white-light, high-definition white-light, and narrow-band imaging colonoscopy for the detection of colon polyps and prediction of polyp histology. Gastrointest Endosc.

2011;74(3):593-602.

11. Buchner AM, Shahid MW, Heckman MG, et al. High-definition colonoscopy detects colorectal polyps at a higher rate than standard white-light colonoscopy. Clin Gastroenterol Hepatol. 2010; 8(4):364-370.

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