Special Edition 2014 by McMahon Group

gastroendonews.com

@=206.9 216A6<; Annual Supplement to Gastroenterology & Endoscopy News • October 2014

Expert Roundtable: Inside the Electronic Health Record Richard Nemec, MD, FACG • Debbie Puccio, RN Todd N. Witte, MD • Lawrence Kosinski, MD

Overview of the Management Of Clostridium difﬁcile Infections Julia Garcia-Diaz, MD, MSc • Arnab Ray, MD • Karla Rivera Rivera, MD

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection? Mohammad Titi, MD • Neil Gupta, MD • Prateek Sharma, MD

The Changing HCV Landscape: Update on Diagnosis and Treatment Sonal Kumar, MD, MPH • Ira M. Jacobson, MD

A Review of Gastrointestinal Stenting Abraham Kalikstein, BS • Yvette Lam-Tsai, MD Pierre Hindy, MD • Frank Gress, MD

Endoscopic Eradication Therapy For Barrett’s Esophagus Shreyas Saligram, MD, MRCP • Prashanth Vennalaganti, MD Prateek Sharma, MD

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

First-Line Treatment Strategies For Helicobacter pylori Infection Richard J Saad, MD • William D. Chey, MD

Approach to Hemorrhoids: A Primer for Gastroenterologists Harry Sarles Jr, MD

@=206.9 216A6<; Annual Supplement to Gastroenterology & Endoscopy News

Expert Roundtable: Inside the Electronic Health Record

Richard Nemec, MD, FACG • Debbie Puccio, RN Todd N. Witte, MD • Lawrence Kosinski, MD

Overview of the Management Of Clostridium difﬁcile Infections

Julia Garcia-Diaz, MD, MSc • Arnab Ray, MD • Karla Rivera Rivera, MD

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

Mohammad Titi, MD • Neil Gupta, MD • Prateek Sharma, MD

The Changing HCV Landscape: Update on Diagnosis and Treatment

Sonal Kumar, MD, MPH • Ira M. Jacobson, MD

A Review of Gastrointestinal Stenting Abraham Kalikstein, BS • Yvette Lam-Tsai, MD Pierre Hindy, MD • Frank Gress, MD

Endoscopic Eradication Therapy For Barrett’s Esophagus

51 67

Shreyas Saligram, MD, MRCP • Prashanth Vennalaganti, MD Prateek Sharma, MD

Bowel Preparation for Colonoscopy: Maximizing Efﬁcacy, Minimizing Risk

Lawrence B. Cohen, MD

First-Line Treatment Strategies For Helicobacter pylori Infection

Richard J Saad, MD • William D. Chey, MD

Approach to Hemorrhoids: A Primer for Gastroenterologists Harry Sarles Jr, MD

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EDITORIAL STAFF

Professor of Medicine Department of Gastroenterology, Hepatology & Nutrition University of Texas MD Anderson Cancer Center Houston, Texas

Clinical Professor of Medicine University of Colorado Health Sciences Center Denver, Colorado

Adam Marcus, Managing Editor amarcus@mcmahonmed.com

Tarun Mullick, MD

Donald M. Pizzi, Editorial Director

James Prudden, Group Editorial Director

Clinical Associate Professor of Medicine Wayne State University Detroit, Michigan

Clinical Faculty, Rush-Copley Clinical Staff, Delnor and Provena-Mercy Hospital Gastrointestinal Health Specialists LLC Chicago, Illinois

Fredric Daum, MD

Joel E. Richter, MD

SALES

Chief, Department of Pediatric Gastroenterology, Hepatology and Nutrition Winthrop University Hospital Mineola, New York

Hugh Culverhouse Professor of Medicine Director, Division of Gastroenterology and Nutrition Director, Joy M. Culverhouse Center for Esophageal Diseases University of South Florida Tampa, Florida

Brian J. Higginson, Publication Director bhigginson@mcmahonmed.com

Alan F. Cutler, MD

Steven M. Faber, MD Albemarle Gastroenterology Associates Elizabeth City, North Carolina

Ronnie Fass, MD Director, Gastroenterology and Hepatology Department Head, Esophageal and Swallowing Center MetroHealth Medical Center Cleveland, Ohio

Barbara B. Frank, MD Clinical Professor of Medicine Division of Gastroenterology and Hepatology Drexel University College of Medicine Philadelphia, Pennsylvania

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

Christopher Jolley, MD

David Robbins, MD Associate Director Center for Advanced Therapeutic Endoscopy Lenox Hill Hospital New York, New York

Ellen J. Scherl, MD Director, Jill Roberts Center for Inflammatory Bowel Disease Jill Roberts Center for Inflammatory Bowel Disease Director of Research Professor of Clinical Medicine Jill Roberts Professor of Inflammatory Bowel Disease NewYork-Presbyterian Hospital/ Weill Cornell Medical Center Adjunct Professor of Medicine Columbia University College of Physicians and Surgeons New York, New York

Associate Professor of Pediatrics Chief of Pediatric Gastroenterology University of Florida College of Medicine Gainesville, Florida

Prateek Sharma, MD

Myron Lewis, MD

Jerome H. Siegel, MD

Associate Professor of Medicine University of Tennessee Vice-Chairman Memphis Gastroenterology Group, PC Memphis, Tennessee

Attending Physician, Gastroenterology Co-Director, Advanced Fellowship in Therapeutic Endoscopy Beth Israel Medical Center New York, New York Clinical Professor of Medicine Albert Einstein College of Medicine Bronx, New York

Gary R. Lichtenstein, MD Professor of Medicine University of Pennsylvania School of Medicine Director, Center for Inﬂammatory Bowel Diseases Hospital of the University of Pennsylvania Gastroenterology Division, Department of Medicine Philadelphia, Pennsylvania

Professor of Medicine University of Kansas School of Medicine Kansas City, Kansas

Nirmal S. Mann, MD, PhD, DSc Professor of Medicine and Gastroenterology Senior Consultant, Gastroenterology– Hepatology UCDMC—Sacramento Director, Gastroenterology–Hepatology UCDMC—Folsom Campus Folsom, California

DISCLAIMER—The reviews in this issue are designed to be a summary of information, and they represent the opinions of the authors. Although detailed, the reviews are not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of these reviews, and the absence of typographical errors is not guaranteed. Copyright © 2014, McMahon Publishing Group, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

Matthew Spoto, Senior Account Manager mspoto@mcmahonmed.com Craig Wilson, Classiﬁed Advertising Sales cwilson@mcmahonmed.com ART & PRODUCTION STAFF Jeanette Mooney, Senior Art Director Dan Radebaugh, Director, Production and Technical Operations Brandy Wilson, Circulation Coordinator MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael P. McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

McMahon Publishing is a 42-year-old, family-owned medical publisher of clinical newspapers and specialty periodicals. McMAHON PUBLISHING Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor New York, NY 10036 Telephone: (212) 957-5300 Subscription: $70 for 1 year ($90 outside USA); Single Copies $15 ($20 outside USA) Copyright © 2014 McMahon Publishing, New York, NY 10036. All rights reserved. Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to: Gastroenterology & Endoscopy News 545 West 45th Street, 8th Floor New York, NY 10036.

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Expert Roundtable:

Inside the Electronic 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 LC

t’s a common complaint: Many physicians who find themselves plugging data into electronic health records (EHRs) feel like transcriptionists, not doctors. After all, they say, “I didn’t go to medical school to become a

medical journalist” (not, we hasten to add, that anything is wrong with that profession). But the world has changed, and EHRs are here to stay. We asked 4 individuals who use or are familiar with the software systems in gastroenterology practices how they have adapted to the new reality—and how those in the specialty who are just making the leap can land successfully.

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Editor’s note: Dr. Nemec dictated his responses in Dragon, and we provide them here unedited, along with an edited version below to highlight the abilities of—and room for improvement in— the voice recognition software.

GEN: The move to a paperless system seems like it has the potential to cause serious growing pains. How easily did your group make the switch, and what did you do to ease the transition? Dr. Nemec (to Dragon): 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 the paper record is very limited. Even if the records have been successfully scanned into the electronic healthcare system, skin copies lowed into the computer system and 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. 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 chart needs to be reviewed in the salient features from each procedure or note need to be extracted to allow a reasonable 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.

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

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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 training our staff to enter atypical plan based upon the endoscopic findings (this can be done in real-time). Making these changes has allowed the physicians in 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) 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 6 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, health care records have transitioned from 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 midlevels [providers] extensively for office visits. The attending physician often just supervises 4 to 5 midlevels in the delivery of office-based health care by seeing patients briefly with midlevels 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.)

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 EHRs, 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 2 separate systems certainly can be accommodated through appropriate interfacing. 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. A vendor that understands “meaningful use” (MU) and all of its implications, the shifting payor climate toward quality, and where our specific specialty is going should be your partner of choice. Although much tougher than MU1, 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

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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. Another area I stress is not making a half-hearted commitment to the transitions. I have experience with a practice of 4 physicians, 2 of whom use EHRs exclusively, 1 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.

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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 “nickel-and-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 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. We got into our EHR 2 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 MU 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 valueand 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 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 3 moderately sized GI practices. We have since added 2 and are in the process of adding 2 more, which will bring us to 48 physicians. Before that time, I practiced in an 8-physician 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 6 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 Reinvestment Act was passed in 2009 and along with it the birth of 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. • The application needed to be user-friendly. • The architecture needed to lend itself to Webbased 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:

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• 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.

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

DIFICID ® (fidaxomicin) tablets, for oral use BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for Full Prescribing Information. INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID® and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile. Clostridium difficile-Associated Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). CONTRAINDICATIONS Hypersensitivity to fidaxomicin. WARNINGS AND PRECAUTIONS Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections. Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions. Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficilee infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials DIFICID (N=564)

Vancomycin (N=583)

n (%)

Anemia

14 (2%)

12 (2%)

Neutropenia

14 (2%)

6 (1%)

System Organ Class Preferred Term

Metabolism and Nutrition Disorders:: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders:: drug eruption, pruritus, rash Post Marketing Experience Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible. Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman. Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established. Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects. In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients. OVERDOSAGE No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin. Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay. Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells. Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC0-t) was approximately 100 times that in humans.

Blood and Lymphatic System Disorders

Distributed by:

Gastrointestinal Disorders Nausea

62 (11%)

66 (11%)

Vomiting

41 (7%)

37 (6%)

Abdominal Pain

33 (6%)

23 (4%)

Gastrointestinal Hemorrhage

20 (4%)

12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders:: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, ﬂatulence, intestinal obstruction, megacolon Investigations:: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count

Cubist Pharmaceuticals U.S. Lexington, MA 02421 USA Made in Canada. DIFICID® is a registered trademark of Cubist Pharmaceuticals in the United States. ©2014 Cubist Pharmaceuticals. All rights reserved. Revised: April 2014 DIF-0161-1

In adult patients with Clostridium difficile-associated diarrhea (CDAD)

DIFICID® (fidaxomicin) tablets demonstrated comparable clinical response at 10 days and superior sustained clinical response through 25 days beyond the end of treatment vs vancomycin1* DIFICID (n=542) was studied vs vancomycin (n=563) in two large Phase 3 CDAD trials (N=1105)1 Outcomes of treatment with DIFICID1 100

88% 86%

DIFICID 200 mg twice daily (n=542) vancomycin 125 mg four times daily (n=563)

PATIENTS (%)

71% 57%

CLINICAL RESPONSE

SUSTAINED CLINICAL RESPONSE

Primary endpoint: clinical response at the end of 10-day treatment.1 Sustained clinical response: initial clinical response at 10 days + survival without proven or suspected CDAD recurrence at 25 days post treatment end.1 Study description: two Phase 3, randomized, double-blind, non-inferiority studies (N=1105) comparing the efficacy and safety of oral DIFICID 200 mg twice daily versus oral vancomycin 125 mg four times daily for 10 days in the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements in the 24 hours before randomization and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization). Enrolled patients received no more than 24 hours of pretreatment with vancomycin or metronidazole and had either no prior CDAD history or only one prior CDAD episode in the past 3 months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.1

Efficacy measured only at days 10 and 35.1

DIFICID was associated with a lower rate of CDAD recurrence vs vancomycin at 25 days post treatment end as measured by sustained clinical response (14% [67/474] vs 26% [127/488])2,3 Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients1 In patients infected with a BI isolate, DIFICID did not demonstrate superiority in sustained clinical response when compared with vancomycin1

Indications and Usage DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficileassociated diarrhea (CDAD) To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile

Important Safety Information DIFICID is contraindicated in patients with hypersensitivity to fidaxomicin DIFICID should not be used for systemic infections Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. In the event of a severe reaction, discontinue DIFICID Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%)

Please see brief summary of full Prescribing Information for DIFICID on adjacent page. For more information about DIFICID and the AccessDIFICID™ patient access support program, please visit DIFICID.com or call 844-CUBIST-CARES (844 -282-4782) (M-F, 8 AM-8 PM; SAT, 9 AM-1 PM, ET) *Confidence interval was derived using Wilson’s score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response data and were imputed using a multiple imputation method.1 References: 1. DIFICID [package insert]. Lexington, MA: Cubist Pharmaceuticals; April 2014. 2. Data on file. A multinational, multicenter, double-blind, randomized, parallel-group study to compare the safety and efficacy of 200 mg PAR-101 taken q12h with 125 mg vancomycin taken q6h for ten days in subjects with Clostridium difficile-associated diarrhea. Clinical study report 101.1.C.003. June 17, 2010. Optimer Pharmaceuticals, Inc. 3. Data on file. A multinational, multicenter, double-blind, randomized, parallel-group study to compare the safety and efficacy of 200 mg PAR-101 taken q12h with 125 mg vancomycin taken q6h for ten days in subjects with Clostridium difficile-associated diarrhea. Clinical study report 101.1.C.004. June 4, 2010. Optimer Pharmaceuticals, Inc.

PRINTER-FRIENDLY VERSION AVA AILABLE AT GASTROENDONEWS.COM

Overview of the Man Of Clostridium diffic Infections JULIA GARCIA-DIAZ, MD, D, MSC Program Director, Infectiouss Disease D Fellowship Program Ochsner Clinic Associate Professor University of Queensland/Och Ochsne sner School Clinical Associate Professo sor of Medic dicine Tulane University New Orleans, Louisia siana

ARNAB RAY Y, MD Gastroenterolog ogist Ochsner Clinic New Orleans, Louisian iana

KARLA RIVERA RIVER ERA, MD Infectious Disease Fellow Ochsner Clinic New Orleans, Louisiana

lostridium difficile infecti in ion (CD DII) D I), a common cause of infectious diarrhea, has as becom come inc the acute care setting.1 CDI is associat

morbidity and more recently with increased mort rtality,2,3 and it has reus (MRSA) surpassed methicillin-resistant Staphylococcus aure as the leading cause of hospital-acquired infections (H (HAIs).2,4

CDI also increases hospital length of stay (LOS) and care costs. A well-known cause of antibiotic-associated diarrhea, it is estimated to account for 15% to 25% of all diarrheal episodes.2 No longer only associated with health care facilities, C. difficile infections are now an emerging threat in the community.

Epidemiology C. difficile is responsible for 12% of all HAIs in 10 geographically diverse states (Figure 1). This translates to an estimated 80,400 cases of hospital-onset infections.5,6 The Centers for Disease Control and Prevention (CDC) national and state HAI progress report

estimated that there nationwide in 2011 (th 4 from 2012 showed a 2% Once thought to have a low recent data has estimated CDI mortality to be 6.9% at 30 days after diagnosis and 16.7 6.7% at 1 year.6 The inf nfection accounts for approximately 14,000 deaths an annually, and there was a 400% increase in n CDI-related CDI-relate deaths from 2000 to 2007, with most deaths occ occurring in older individuals.7,8 It is estimated that half of all CDIs occur in people younger than age 65 years. However, 90% of CDIrelated deaths occur in those who are 65 and older.

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Barrier precautions and environmental cleaning

STOP ACQUISITION OF TOXIGENIC C. DIFFICILE STRAIN (ingestion of spores)

UNNECESSARY ANTIMICROBIAL USE ACQUISITION OF C. DIFFICILE

C. DIFFICILE E INFECTION (community-acquired)

ASYMPTOMATIC C. DIFFICILE COLONIZATION

Vaccines (if risk factors), monoclonal antibodies

HOSPITALIZATION

ANTIMICROBIALS (alter the gut microbiome)

Restore gut flora or colonize with nontoxigenic C. difficile

ANTIBIOTIC TREATMENT (minimize disruption of gut flora) ± • Vaccines (boost immunity) • Monoclonal antibodies (passive immunity) • Nontoxigenic C. difficile

CDI (mild, moderate, severe; first episode, recurrence)

FECAL MICROBIOTA TRANSPLANTATION

Figure 1. Overview of current hospital epidemiology and management strategies to prevent and treat CDI. CDI, Clostridium difficile infection Note: Prevention and treatment strategies are designated by green arrows. Adapted from Gerding DN, Johnson S. Management of Clostridium difficile infection: thinking inside and outside the box. Clin Infect Dis. 2010;51(11):1306-1313.

Furthermore, about 25% show initial symptoms in the hospital versus 75% in nursing homes, doctors’ offices, and clinics; hence, 94% of all CDIs are linked to medical care.8 Not only is this a concern for patient safety, it is also a concern for health care costs nationwide, which indirectly affect patient care. Scott demonstrated an average attributable per-patient cost of $9,124 for CDI, higher than catheter-associated urinary tract infections, which occurred at a higher rate at the time of the study.9 This translates to approximately $1 billion in extra health care costs annually. Yet, others have estimated the cost for CDI treatment to be as high as $4.9 billion in the acute care setting.10 Although once thought to be strictly an HAI, there is an increasing number of community-acquired C. difficile infections (CaCDI). Some reports estimate that 30% to 40% of all CDI cases are CaCDI.11,12 Of note, Khanna et al demonstrated that 22% of patients had no antibiotic exposure in the 90 days before the onset of CaCDI.12

Pathogenesis of Hypervirulent Strains As the rates of CDI increased in 2000, the North American Pulsed Field type 1 strain (NAP1), or PCR ribotype 027 emerged; this strain was responsible for the Pittsburgh, Atlanta, and Montreal CDI outbreaks.2 This strain has increased production of the classic A (enterotoxin; 16-fold) and B (cytotoxin; 23-fold) toxins, and also an additional binary toxin currently under study; the latter is associated with a more severe diarrheal illness. It is also inherently resistant to fluoroquinolone (FQ) antibiotics, likely secondary to their increasing and widespread use. Although FQs are not recommended for the treatment of CDI, their use is an important epidemiologic risk factor for the spread within health care facilities. Metronidazole (various) is the current recommended choice for mild to moderate disease and those with NAP1 infections see high failure rates,13 thought to be secondary to the severity of the disease, low concentration levels in the fecal material, and poor tolerance. The NAP1 or

Table 1. Treatment Options for Clostridium difficile Infection FDA-Approved

Off-Label Options

New Drugs in Development

Biotherapeutics

Metronidazole

Rifaximin (Xifaxan, Salix)

LFF571 (Novartis)

Fecal microbiota transplantation

Vancomycin

Nitazoxanide

Surotomycin (CB-183, 315, Cubist)

VP20621 (ViroPharma)

Fidaxomicin (Dificid, Cubist)

Tigecycline (Tygacil, Pfizer)

SMT 19969 (Summit)

Probiotics

Cadazolid (ACT-179811, Actelion) Oritavancin (LY333328, The Medicines Company) Cholate meta-benzene sulfonic derivative

ribotype 027 strains were associated with an increase in recurrences and a more complicated clinical course, therefore higher morbidity and mortality rates.14 Another strain sharing hypervirulence is C. difficile PCR ribotype 078. Keel et al demonstrated that this was the most commonly isolated strain in swine and calves.15 Also frequently found in meat products, ribotype 078 is a possible risk factor for animal-to-human transmission, as well as a source for CaCDI.15 In the United States, ribotype 078 is reported to be the third most commonly isolated strain in CaCDI.16 It shares toxin A and B production as well as a binary toxin. In general, CaCDI may present with a more severe infection; patients are less likely to receive antibiotics and more likely to be younger and have a greater proportion of PCR ribotype 078 than those with CDI acquired in a hospital setting.17 More vigilance is required to detect these cases in the community which may not present with the traditional predisposing factors.

also had higher rates of infection in patients age 65 years and older who had been admitted to an inpatient hospital setting, had any underlying disorder, and had a history of exposure to antibiotic therapy.14 However, although Brown et al found use of tetracyclines and penicillins related to lower risk for CDI,18 Keessen et al found that clindamycin (various) exposure was also a major risk factor, in addition to exposure to cephalosporins and FQs, specifically for CDI due to ribotype 078.19 Yet another study showed that in addition to the aforementioned risk factors, hospital LOS was a risk factor for colonization with C. difficile leading to CDI.20 Additional studies have highlighted treatment with PPIs as a novel risk factor for CaCDI in military active duty personnel (this study also revealed higher morbidity and mortality rates among older individuals plus those once considered low-risk groups for CaCDI, including community dwellers, pregnant women, and children).21

Risk Factors

Treatment Approaches

As the leading cause of HAIs, there is a need for understanding risk factors associated with CDI. The CDC has confirmed advanced age (≥65) and antibiotic exposure as risk factors for CDI and CaCDI primary and recurrent infections.8 Multiple meta-analyses have confirmed older age, continued antibiotic exposure, and concomitant use of H2 blockers and proton pump inhibitors (PPIs) as risk factors for recurrent CDI as well as comorbid conditions, previous CDI recurrence, CDI acquired in the hospital setting, and prolonged hospital LOS.18 Although it is generally agreed that exposure to certain antibiotics (particularly FQs) increases the risk for CDIs, there has been some conflicting data as to what classes of drugs yield the greatest risk. Goorhuis et al, for example, found FQ treatment to be an independent risk factor for CDI due to ribotype 078. Ribotype 027

In general, strategies for treatment should be tailored according to the patient’s age and underlying comorbidities (Table 1).

FDA-Approved Options METRONIDAZOLE

AND

VANCOMYCIN

Metronidazole is a nitroimidazole with broad activity against anaerobic bacteria, including C. difficile. It is currently recommended as the drug of choice for mild to moderate CDI.22 Vancomycin is a glycopeptide that is not absorbed when given orally. Vancomycin is currently recommended for the first episode of moderate to severe CDI or in cases of metronidazole therapy failure or potentially life-threatening CDI.22 Although early studies demonstrated similar efficacy between the 2 agents,23 studies since 2004 have shown

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an increased rate of treatment failures associated with metronidazole (16%-38%), whereas vancomycin failures remained the same (1%-6%).24 A study by Zar et al was the first to compare the drugs directly, in a prospective manner, in the treatment of C. difficile-associated diarrhea (CDAD). Among the patients with mild CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 90% and 98%, respectively (P=0.36). The critical results from this study were that among the patients with severe CDAD, clinical cure was 76% for metronidazole and 97% for vancomycin (P=0.02). Recurrence rates were similar (15% and 14%) between the 2 groups.24 Oral metronidazole is completely absorbed in the gastrointestinal tract but fecal penetration is poor, leading to low luminal concentrations (range 0.8-24 mcg/g; the susceptible range is 0.2-2.0 mcg/mL). Additionally, IV metronidazole has been shown inferior (P<0.001) to both oral metronidazole and oral vancomycin.25

FIDAXOMICIN Fidaxomicin (FDX; Dificid, Cubist) is the most recent CDI treatment to receive FDA approval. It is a macrocyclic antibiotic that is highly active against C. difficile (MIC90, 0.25 mcg/mL), including the epidemic strain. Results from 8 in vitro studies comprising 1,323 C. difficile isolates showed the minimum inhibitory concentration (MIC) range of FDX to be greater than 0.001 to 1 mcg/mL, with a MIC90 of 0.5 mcg/mL. No resistant isolate has been reported, although a single strain was recovered from a cured patient who had an elevated MIC of 16 mcg/mL at the time of recurrence.26 In the pivotal trial of FDX versus vancomycin, clinical cure rates were similar and FDX was noninferior to vancomycin (92.1% and 89.8%, respectively). However, patients treated with FDX had lower recurrence (13.3% vs 24%; P=0.004).27 Additionally, data from the 2 Phase III trials showed that FDX, when administered concomitantly with other antibiotics, has a higher cure rate (46 of 51 [90.2%]) than vancomycin (33 of 45 [73.3%]; P=0.031) and that overall treatment with FDX compared with vancomycin was associated with lower recurrence rates (16.9% vs 29.2%; P=0.048).28 The lower recurrence rates associated with FDX may be due to the drug’s ability to preserve the normal gut microbiome and completely resolve the underlying CDI pathogen, or both. A randomized clinical trial assessed the microflora-sparing properties of FDX by examining fecal samples for quantitative cultures for C. difficile and cytotoxin B fecal filtrate concentrations against normal microbiota. FDX and vancomycin rapidly killed C. difficile and neutralized toxin; however, FDX preserved the microbiome during and after CDI treatment.27

Other Options Because results with currently available treatments have been suboptimal—with high rates of recurrence— new modalities and treatments have been pursued.

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RIFAXIMIN Rifaximin (Xifaxan, Salix) is a semisynthetic derivative of rifamycin approved for the treatment of travelers’ diarrhea; it is also used off-label for irritable bowel syndrome and hepatic encephalopathy. It has in vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria. After 3 days of therapy, the fecal level of the drug reaches 8,000 mcg/g.29 C. difficile resistance to rifampin (a surrogate for rifaximin) has been observed in several studies. The prevalence of rifampin resistance among 470 C. difficile isolates from a large teaching hospital was analyzed and was observed in 173 patients (36.8%), including 167 of 205 (81.5%) with epidemic clone (BI/ NAP1) isolates (P<0.001). Of 8 patients who were exposed to rifamycin, 7 had rifampin-resistant C. difficile compared with 166 of 462 unexposed patients (relative risk, 2.4).30 In an open-label trial, 8 of 13 enrolled patients received rifaximin; all patients reported symptom resolution; 7 had no relapse at follow-up (median 162 days).31 Overall, more attention has been given to use of rifaximin as a “chaser” rather than as first-line therapy. In one study, for example, patients were given rifaximin or placebo immediately after finishing standard anti-CDI antibiotics. CDI recurrence was lower in the rifaximin arm than in the placebo group (15% vs 31%; P=0.11).32 A randomized placebo-controlled trial testing the hypothesis that rifaximin given in a decreasing dose over 4 weeks after successful CDI treatment will reduce relapse is ongoing.

NITAZOXANIDE Nitazoxanide (NTZ) is a synthetic nitrothiazole benzamide approved for the treatment of Cryptosporidium and Giardia species. It has excellent in vitro activity against C. difficile with an MIC90 of 0.125 mcg/ mL. A prospective, randomized, double-blind study compared NTZ (7 and 10 days) with metronidazole (10 days) in hospitalized patients with C. difficile colitis. Response rate at 1 month for metronidazole was 57.6% compared with 65.8% (7 days) and 74.3% (10 days; P=0.34) for NTZ.33 In another study, patients who had failed metronidazole treatment were given NTZ; 74% responded, although 7 later had recurrent disease (54% cure rate). Three who initially failed and 1 who had recurrent disease were retreated with NTZ and responded, yielding an aggregate cure rate of 66% in this difficult-to-treat patient population.34 No clinical trials are currently ongoing.

TIGECYCLINE Tigecycline (Tygacil, Pfizer) has activity against a broad spectrum of gram-positive and gram-negative aerobes and anaerobes, including C. difficile (MIC90 of 0.06-0.25 mcg/mL).35 Multiple case reports and small case series using IV tigecycline as adjunctive therapy to other treatment options for severe, refractory CDI in

critically ill patients have reported some success. A prospective clinical trial assessing the safety of tigecycline added to standard oral therapy (vancomycin or metronidazole) was completed recently and results are pending.

New Drugs in Development LFF571 LFF571 (Novartis) is a novel semisynthetic thiopeptide antibiotic with potent activity against a variety of gram-positive pathogens, including C. difficile. In a hamster model, LFF571 was more efficacious and had fewer recurrences than vancomycin.36 A study investigating the safety and pharmacokinetics of single- and multiple-ascending oral doses in healthy individuals reported that the drug was generally safe and well tolerated.37 A Phase II study of the safety and efficacy of multiple daily dosing of oral LFF571 in patients with moderate CDIs was completed recently and data is pending.

SUROTOMYCIN Surotomycin (CB-183,315, Cubist) is an orally available lipopeptide antibiotic that is structurally related to daptomycin.38 Surotomycin has shown good potency against C. difficile isolates (including 027/NAP1/BI isolates) as well as those with high MICs to metronidazole, moxifloxacin, and vancomycin. It lacks activity against Enterobacteriaceae and species of the Bacteroides group (MIC90 >8,192 mcg/mL); this suggests that this compound will minimize disruption and lead to rapid recovery of the normal gut flora.39,40 Surotomycin has successfully completed a Phase II trial in patients with CDI. It also showed better sustained cure rates than vancomycin as well as reduction and delay in recurrence (17% for surotomycin vs 36% vancomycin) of CDAD episodes.38 Phase III trials are ongoing.

SMT 19969 SMT 19969 (Summit) is a bis-benzimidazole tetrahydrate compound that has demonstrated potent activity against C. difficile isolates with MIC90 values 2-, 8-, and 16-fold lower than FDX, metronidazole, and vancomycin, respectively. SMT 19969 has shown limited activity against gram-positive and gram-negative anaerobes, including Bacteroides species, Bifidobacterium species, and others (with the exception of Clostridia). This suggests that SMT 19969 would have minimal disruption in the gut flora and preservation of the normal gut microbiome.41,42 SMT 19969 was safe and well tolerated at all dosages in the recent Phase I trial.41 A Phase II trial is ongoing.

CADAZOLID Cadazolid (CDZ; ACT-179811, Actelion) is a new quinolonyl-oxazolidinone with structural elements of the oxazolidinone as well as the quinolone class. It is a strong inhibitor of C. difficile protein synthesis that leads to the suppression of toxin and spore formation.

A recent study showed CDZ was active against all (including linezolid- and moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The CDZ geometric mean MIC was 152-, 16-, 9-, and 7-fold lower than those of moxifloxacin, linezolid, metronidazole, and vancomycin, respectively. CDZ levels persisted at 50- to 100-fold supra MIC for 14 days after dosing. Inhibition of gut microflora was limited with the exception of bifidobacteria; Bacteroides fragilis group and Lactobacillus species counts were not affected.43 In Phase I trials, CDZ was well tolerated and systemic exposure was low. Most of the compound was recovered unchanged in the feces, resulting in high concentrations in the colon.44 A Phase II study evaluated the efficacy, safety, and tolerability of CDZ in patients with CDAD. The results of this study indicate that the cure rates for all twice-daily doses of CDZ (76.5% [250 mg]; 80% [500 mg]; 68.4% [1,000 mg]) were similar to or better than those for vancomycin (68.2%). Recurrence rates were lower for all twice-daily doses of CDZ (18.2% [250 mg]; 25% [500 mg]; 22.2% [1,000 mg]) compared with vancomycin (50%).45 Phase III clinical trials are underway.

ORITAVANCIN Oritavancin (ORI; LY333328, The Medicines Company) is a lipoglycopeptide with activity against C. difficile. In vitro, it was found to be at least 4-fold more potent than vancomycin against C. difficile strains tested.46 When tested for the treatment of PCR ribotype 027 in a human gut model, it was found that both ORI and vancomycin were effective in treating CDI, but only ORI appeared active against spore forms of C. difficile. Overall, ORI therapy may be more effective in treating CDI than vancomycin because it may prevent recrudescence of C. difficile spores.47 In a simulated CDI human gut model, Chilton et al demonstrated that ORI short-course therapy (4-day) might be an effective CDI treatment.48 More recently this same group showed that ORI might adhere to spores, potentially causing early inhibition of germinated cells and preventing subsequent vegetative outgrowth and spore recovery. Again, this may prevent some recurrences of CDI that are due to germination of residual spores after antibiotic therapy.49 Despite all the information thus far available, no clinical trials are ongoing.

CAMSA Cholate meta-benzene sulfonic derivative (CamSA) is a bile salt analog that inhibits C. difficile spore germination in vitro. Howerton et al infected mice with massive inocula of C. difficile spores and treated them with different concentrations of CamSA. A single 50-mg/ kg dose of CamSA prevented CDI without any toxicity. This is a novel approach and would add to the treatment of CDI without compromising the microbiota in these patients.50 CamSAâ&#x20AC;&#x2122;s in vitro stability, distribution, and cytotoxicity are currently being characterized.

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MONOCLONAL ANTIBODIES

Biotherapeutics

250 Simpson’s Reciprocal Index

MK-3415A (Merck) is a combination of monoclonal antibodies (mAbs) to C. difficile toxin A (MK-3415) and toxin B (MK-6072). A Phase II study showed favorable results when C. difficile human mAbs were administered to patients with C. difficile infection after being treated with metronidazole or vancomycin. This clinical trial showed significant reduction in the rate of recurrence of C. difficile among patients treated with the mAbs (7% vs 25%; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006).51 Phase III trials are ongoing.

200

150

100

0 Donors

FECAL MICROBIOTA TRANSPLANTATION There has been a lot of attention surrounding the success of fecal microbiota transplantation (FMT) in the treatment of recurrent CDI. To date, numerous studies have shown superior efficacy of FMT over traditional antibiotics. The landmark study published by van Nood et al randomized patients with recurrent CDI to FMT via nasoduodenal infusion, vancomycin, and vancomycin with bowel lavage. The study was halted at interim analysis because the FMT arm showed a superior success rate (81%) compared with the vancomycin (31%) and vancomycin with bowel lavage arms (23%). Two of the 3 treatment failures in the FMT arm resolved with a second infusion from a different donor, bringing the overall success rate to 93.75%.52 This is consistent with meta-analyses of the success rate of FMT for CDI worldwide, which is 91%, regardless of the route of administration.53 Additionally, after the donor-feces infusion, patients showed an increased fecal bacterial diversity very much similar to the donors (Figure 2). In 8 patients from whom samples were available, the diversity of fecal microbiota could not be distinguished from that of the donors during the follow-up period.52 Although concerns have been raised regarding the safety of FMT, numerous literature reviews have reported no serious adverse events (AEs) or infectious transmissions directly attributable to FMT.54 There are, however, legitimate concerns regarding the safety of FMT in patients with compromised immune systems. Immunocompromised patients seem to be at increased risk for developing recurrent CDI due to repeated antibiotic treatment, prolonged hospital LOS, and decreased ability to eradicate the infection. A multicenter retrospective study of FMT in 75 immunocompromised adults found similar efficacy (89%) to other studies and no infectious complications directly attributable to FMT, with follow-up to 11 months. Patients included were solid organ transplants, HIV/AIDS, patients undergoing chemotherapy, and those receiving immunosuppressive

G AST R O E N D O N E WS .CO M

Patients before Patients after infusion infusion

Figure 2. Microbial diversity in patients before and after infusion of donor feces compared with diversity in healthy donors. Adapted from reference 52.

treatment for inflammatory bowel disease.55 Cost is also an issue with FMT. An analysis of FMT versus vancomycin for recurrent CDI found that FMT had an incremental cost-effectiveness ratio of $17,016 relative to vancomycin. More specifically, FMT via colonoscopy was felt to be the most cost-effective route of administration compared with duodenal infusion or enema.56 FMT has proven to be safe and efficacious, but it remains a time-consuming and nonstandard process. Although the major gastrointestinal societies and the Infectious Diseases Society of America released a joint statement on donor screening guidelines in July 2013, the recommendations are not evidence-based.57 Finding and screening a donor can be a time-consuming, expensive, and embarrassing process for the patient. In the inpatient setting with a critically ill patient, there is not always time to properly identify and screen a donor. Multiple techniques have been developed to try to work around these inherent difficulties in an attempt to standardize and speed up treatment, including frozen stool protocols and open-access stool banks. In frozen stool protocols, donor stool is blended, filtered, and then processed with glycerol before freezing at –80°C for later usage. Before use in FMT, the frozen slurry is thawed in an ice bath. A series of 43 patients treated with the frozen protocol showed an 86% treatment success rate, but it should be noted that 30% of the patients had underlying inflammatory bowel disease.58 More recently, Youngster et al conducted an open-label, randomized controlled pilot study using

Table 2. C. difficile Vaccines and Immunologics Product

Antigen

Formulation

Clinically trials

ACAM-CDIFF Vaccine (Sanofi Pasteur)

Formalin inactivated toxins A and B from VPI 10463

± alum-adjuvant IM injections 0, 7, and 28-30

Phase I volunteer safety and immune response Phase II for CDI Phase II for CDI prevention (ongoing)

Intercell IC84 Vaccine

Recombinant fusion protein of toxin A- and B-binding regions

± aluminum salt adjuvant IM injection days 0, 7, and 21

Phase I volunteer safety and immune response

Clostridium difficile vaccine (Pfizer)

Molecularly and chemically inactivated toxins A and B

Vaccine ± unnamed adjuvant, 3 ascending doses

Phase I volunteer safety and immune response

Monoclonal antibodies: MK-6072 & MK-3415A (Merck)

Monoclonals targeting toxin-binding epitopes

Human monoclonal antibody Two Phase III clinical trials IV

frozen inoculum from unrelated donors.59 Overall cure rate was 90% at 8 weeks. North York General Hospital in Toronto, Canada, has begun offering patients the option to bank their own stool before hospital admission in the event they become infected with hospital-acquired CDI. This approach offers the advantages of not requiring a donor or screening testing. This program is a pilot study and no efficacy data is available yet.60 Open Biome, meanwhile, is a nonprofit “stool bank” developed at Massachusetts Institute of Technology in Cambridge. A selected few “healthy donors” have undergone extensive screening for common infectious diseases beyond the consensus screening guidelines, and serially collected and frozen the stool, making it commercially available for hospitals. Anecdotal reports thus far have been positive, and data collection is currently underway to publish safety and efficacy data. There is concern from the FDA regarding oversight and regulation of “stool banks,” although Open Biome operates under an institutional review board. The goal is to remove the “fecal” from FMT, and this may be accomplished via stool substitute transplant therapy. Queen’s University in Canada has successfully reproduced 33 purified intestinal bacterial cultures under anaerobic conditions into a synthetic mixture, which was then instilled into the colons of 2 patients with recurrent CDI due to a hypervirulent ribotype 078 strain. Both patients had resumption of normal bowel habits within 3 days with durability of cure at 6 months.61 The “holy grail” of FMT is to develop a pill that would reconstitute the colonic microbiome and eradicate C. difficile. Louie presented a pilot series of 31 patients treated with 24 to 34 pills of fecally derived bacteria covered in gelatin to survive gastric acid and deliver the contents to the colon; 30 of 31 patients enrolled were cured with no significant AEs noted.62

VP20621 VP20621 (ViroPharma), spores of nontoxigenic C. difficile (NTCD) strain M3, have been shown to be protective against challenge with toxigenic strains in hamsters.63 Human administration and colonization by VP20621 may prevent primary CDI or recurrent CDI. Phase I clinical safety testing was completed in 2010. Healthy adults received single or multiple doses of an oral suspension of VP20621 or placebo. All doses were well tolerated, and no serious AEs were reported and no discontinuation due to AEs occurred. Participants did not experience diarrhea or change in bowel habits. Persistent colonization with VP20621 was detected in stools on days 21 to 28 in 44% of participants. VP20621 was able to colonize the gastrointestinal tracts of those pretreated with vancomycin.64 A Phase II clinical trial in recurrent CDI is underway.

PROBIOTICS A Cochrane meta-analysis of 31 randomized studies and 4,492 participants concluded that taking probiotics with antibiotics reduced the risk for developing CDAD by 64%. The use of probiotics appeared to be safe and effective in patients who were not immunocompromised.65 There are a number of clinical trials currently ongoing to determine the role of probiotics in the prevention of CDI and/or CDI recurrence.

Vaccines The only currently available antibody treatment for CDI is pooled intravenous immunoglobulin (IVIG); IVIG preparations contain neutralizing levels of IgG antibody to toxin A and B. To date, no studies have provided conclusive evidence for any clinical benefit of IVIG. Active immunization rather than passive is appealing, as this would confer durable protection against CDI. Vaccines for CDI have been in development for more than 2 decades. Torres et al showed that a formalin-inactivated

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C. difficile culture filtrate protected hamsters when given by nasal, intraperitoneal, and subcutaneous routes.66 Currently there are 3 vaccines in clinical development. ACAM-CDIFF (Sanofi-Pasteur) is a mixture of formalin-inactivated toxin A and B that is given 3 times IM. The vaccine has been shown to be safe, well tolerated, and immunogenic in healthy adults. Phase II trials have been completed in the therapeutic setting and additional trials in the prophylactic setting are ongoing. Due to the fact that the vaccine addresses an important unmet medical need, ACAM-CDIFF has been fasttracked by the FDA.67 A second injectable vaccine, IC84, is a subunit recombinant protein vaccine consisting of 2 truncated toxins A and B from C. difficile. IC84 has undergone Phase I safety and immunogenicity testing in volunteer subjects and also has been shown to be highly immunogenic in elderly subjects.68 In addition, a vaccine derived from molecularly and chemically inactivated toxins A and B is currently undergoing Phase I clinical trials.

Conclusion The incidence of CDI has increased dramatically over the past 2 decades and we have seen the emergence of epidemic strains with new resistance patterns, which have resulted in high morbidity and mortality. Despite the treatment advances in recent years, several challenges are still present: appropriate treatment of severe complicated/fulminant CDI; the management of CDI recurrence; proper management of repeat episodes and the BI/NAP1/027 strain; and, lastly, the role of vaccines, immunologics, and other biotherapeutics. The use of biotherapeutics to restore normal flora seems a novel and successful approach. There is a great need to continue to explore and develop new agents in the antimicrobial arena that spare the normal flora and perhaps most of all, avoid using antimicrobials altogether, whenever possible.

References 1.

Centers for Disease Control and Prevention. MMWR quickstats: rates of Clostridium difficile infection among hospitalized patients aged >65 years by age group—National Hospital Discharge Survey, United States, 1996-2009. CDC. 2011;60(34):1153-1185.

2. Centers for Disease Control and Prevention. Clostridium difficile FAQs (online). http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_ faqs_HCP.html. Accessed July 1, 2014. 3. Virginia Department of Health. Clostridium difficile (C. difficile) infections. http://www.vdh.virginia.gov/epidemiology/surveillance/ hai/cdiff.htm#Citation2. 4. Arnold K, Avery L, Bennett R, et al. National and state healthcareassociated infections progress report. http://www.cdc.gov/HAI/ pdfs/progress-report/hai-progress-report.pdf. 5. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014:370(13):1198-1208.

program—healthcare-associated infections community interface activity. http://www.cdc.gov/hai/eip/pdf/Cdiff-factsheet.pdf. 8. Centers for Disease Control and Prevention. CDC vitalsigns. http:// www.cdc.gov/vitalsigns/pdf/2012-03-vitalsigns.pdf. 9. Scott RD. The direct medical costs of healthcare-associated infections in US hospitals and the benefits of prevention. http://www.cdc.gov/hai/pdfs/hai/scott_costpaper.pdf. 10. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis. 2012;55(suppl 2):S88-S92. 11. Leffler DA, Lamont JT. Editorial: not so nosocomial anymore: the growing threat of community-acquired Clostridium difficile. Am J Gastroenterol. 2012;107(1):96-98. 12. Khanna S, Pardi DS, Aronson SL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol. 2012;107(1):89-95. 13. Kuijper EJ, Wilcox MH. Decreased effectiveness of metronidazole for the treatment of Clostridium difficile infection. Clin Infect Dis. 2008;47(1):63-65. 14. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014;58(10):1394-1400. 15. Keel K, Brazier JS, Post KW, et al. Prevalence of PCR ribotypes among Clostridium difficile isolates from pigs, calves, and other species. J Clin Microbiol. 2007;45(6):1963-1964. 16. Goorhuis A, Debast S, van Leengoed L, et al. Clostridium difficile PCR ribotype 078: an emerging strain in humans and pigs? J Clin Microbiol. 2008;46(3):1157. 17. Rupnik M, Widmer A, Zimmermann O, et al. Clostridium difficile toxinotype V, ribotype 078, in animals and humans. J Clin Microbiol. 2008;46(6):2146. 18. Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57(5):2326-2332. 19. Keessen E, Hensgens M, Spigaglia P. Antimicrobial susceptibility profiles of human and piglet Clostridium difficile PCR-ribotype 078. Antimicrob Resist Infect Control. 2013;2:14. 20. Eyre DW, Walker AS, Wyllie D, et al. Predictors of first recurrence of Clostridium difficile infection: implications for initial management. Clin Infect Dis. 2012;55(suppl 2):S77-S87. 21. Gutiérrez R, Riddle M, Porter K. Epidemiology of Clostridium difficile infection among active duty United States military personnel (1998-2010). BMC Infect Dis. 2013;13:609. 22. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. 23. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficileassociated diarrhoea and colitis. Lancet. 1983;2(8358):1043-1046. 24. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307. 25. Wenisch C, Parschalk B, Hasenhündl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22(5):813-818. 26. Goldstein EJ, Citron DM, Tyrrell KL, et al. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. Antimicrob Agents Chemother. 2013;57(10):4872-4876. 27. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

6. Dubberke ER. Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2014;35(6):628-645.

28. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis. 2011;53(5):440-447.

7. Centers for Disease Control and Prevention. Investigating Clostridium difficile infections across the US—emerging infections

29. Adachi JA, DuPont HL. Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis. 2006;42(4):541-547.

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30. Curry SR, Marsh JW, Shutt KA, et al. High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clin Infect Dis. 2009;48(4):425-429. 31. Rubin DT, Sohi S, Glathar M, et al. Rifaximin Is effective for the treatment of Clostridium difficile-associated diarrhea: results of an open-label pilot study. Gastroenterol Res Pract. 2011;2011:106978. 32. Garey KW, Ghantoji SS, Shah DN, et al. A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother. 2011;66(12):2850-2855. 33. Musher DM, Logan N, Bressler AM, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis. 2009;48(4):e41-e46. 34. Musher DM, Logan N, Mehendiratta V, et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother. 2007;59(4):705-710. 35. Hecht DW, Galang MA, Sambol SP, et al. In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother. 2007;51(8):2716-2719. 36. Trzasko A, Leeds JA, Praestgaard J, et al. Efficacy of LFF571 in a hamster model of Clostridium difficile infection. Antimicrob Agents Chemother. 2012;56(8):4459-4462. 37. Ting LS, Praestgaard J, Grunenberg N, et al. A first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers. Antimicrob Agents Chemother. 2012;56(11):5946-5951. 38. Mascio CT, Chesnel L, Thorne G, et al. Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium. Antimicrob Agents Chemother. 2014;58(7):3976-3982.

Clostridium difficile infection using a human gut model. J Antimicrob Chemother. 2012;67(10):2434-2437. 49. Chilton CH, Freeman J, Baines SD, et al. Evaluation of the effect of oritavancin on Clostridium difficile spore germination, outgrowth and recovery. J Antimicrob Chemother. 2013;68(9):2078-2082. 50. Howerton A, Patra M, Abel-Santos E. A new strategy for the prevention of Clostridium difficile infection. J Infect Dis. 2013;207(10):1498-1504. 51. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362(3):197-205. 52. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415. 53. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(7):1079-1087. 54. Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508. 55. Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jun 3. [Epub ahead of print]. 56. Konijeti GG, Sauk J, Shrime MG, et al. Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis. Clin Infect Dis. 2014;58(11):1507-1514. 57. ACG, AGA, ASGE, IDSA, NASPGHAN. Current consensus guidance on donor screening and stool testing for FMT. http://www.gastro. org/research/Joint_Society_FMT_Guidance.pdf.

39. Citron DM, Tyrrell KL, Merriam CV, et al. In vitro activities of CB-183,315, vancomycin, and metronidazole against 556 strains of Clostridium difficile, 445 other intestinal anaerobes, and 56 Enterobacteriaceae species. Antimicrob Agents Chemother. 2012;56(3):1613-1615.

58. Hamilton MJ, Weingarden AR, Unno T, et al. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013;4(2):125-135.

40. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of surotomycin in an in vitro gut model of Clostridium difficile infection. J Antimicrob Chemother. 2014 May 9. [Epub ahead of print].

59. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58(11):1515-1522.

41. Vickers R, Robinson N, Best E, et al. SMT19969 for Clostridium difficile infection (CDI): Phase I study investigating safety and pharmacokinetics in healthy male subjects. Presented at the 53rd Interscience Conference Antimicrobial Agents and Chemotherapy. Denver, CO: September 10-13, 2013. Abstract F-626. 42. Vickers R, Tinsley J, Storer R, et al. SMT-19969–a novel antibiotic for C. difficile infection: C. difficile growth inhibition, spectrum and resistance development. Presented at the 51st Interscience Conference Antimicrobial Agents and Chemotherapy. Chicago, IL: September 17-20, 2011. Abstract B-1194. 43. Chilton CH, Crowther GS, Baines SD, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother. 2014;69(3):697-705. 44. Baldoni D, Gutierrez M, Timmer W, et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses. J Antimicrob Chemother. 2014;69(3):706-714. 45. Locher HH, Seiler P, Chen X, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014;58(2):892-900. 46. O’Connor R, Baines SD, Freeman J, et al. In vitro susceptibility of genotypically distinct and clonal Clostridium difficile strains to oritavancin. J Antimicrob Chemother. 2008;62(4):762-765. 47. Baines SD, O’Connor R, Saxton K, et al. Comparison of oritavancin versus vancomycin as treatments for clindamycin-induced Clostridium difficile PCR ribotype 027 infection in a human gut model. J Antimicrob Chemother. 2008;62(5):1078-1085. 48. Chilton CH, Freeman J, Crowther GS, et al. Effectiveness of a short (4 day) course of oritavancin in the treatment of simulated

60. North York General Hospital. Spotlight on research: Sumit Raybardhan, infectious diseases pharmacy practitioner. http://www.nygh. on.ca/Default.aspx?cid=2492&lang=1. Accessed July 1, 2014. 61. Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology. 2014;146(6):1573-1582. 62. Louie T, Cannon K, O’Grady H, et al. Fecal microbiome transplantation (FMT) via oral fecal microbial capsules for recurrent Clostridium difficile infection (rCDI). Presented at IDWeek; San Francisco, CA: October 2-6, 2013. Abstract 89. 63. Merrigan MM, Sambol SP, Johnson S, et al. New approach to the management of Clostridium difficile infection: colonisation with non-toxigenic C. difficile during daily ampicillin or ceftriaxone administration. Int J Antimicrob Agents. 2009;33(suppl 1):S46-S50. 64. Villano SA, Seiberling M, Tatarowicz W, et al. Evaluation of an oral suspension of VP20621, spores of nontoxigenic Clostridium difficile strain M3, in healthy subjects. Antimicrob Agents Chemother. 2012;56(10):5224-5229. 65. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:CD006095. 66. Torres JF, Lyerly DM, Hill JE, et al. Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters. Infect Immun. 1995;63(12):4619-4627. 67. Leuzzi R, Adamo R, Scarselli M. Vaccines against Clostridium difficile. Hum Vaccin Immunother. 2014;10(6). 68. Valneva website. http://www.valneva.com/?page=85. Accessed June 28, 2014.

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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.

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 preve ention of CRC and have shown a reduction d ti in i mortality in 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 in the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 4

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 colonoscopy 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

G AST R O E N D O N E WS .CO M

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 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

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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; distributed in the United States by Medivators) 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

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Figure 3. The Endocuff slips over the tip th ti off an endoscope; d during d i withdrawal, its flexible arms open the bowel for inspection to improve views of mucosa previously difficult to visualize. (SMART Medical Systems) permanently integrates an inflatable, reusable balloon onto the flexible tip of a 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.

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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. 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.

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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. 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. 12. Burke CA, Choure AG, Sanaka MR, et al. A comparison of highdefinition versus conventional colonoscopes for polyp detection. Dig Dis Sci. 2010;55(6):1716-1720. 13. Erim T, Rivas JM, Velis E, et al. Role of high definition colonoscopy in colorectal adenomatous polyp detection. World J Gastroenterol. 2011;17(35):4001-4006. 14. Subramanian V, Mannath J, Hawkey CJ, et al. High definition colonoscopy vs. standard video endoscopy for the detection of colonic polyps: a meta-analysis. Endoscopy. 2011;43(6):499-505. 15. Church JM. Warm water irrigation for dealing with spasm during colonoscopy: simple, inexpensive, and effective. Gastrointest Endosc. 2002;56(5):672-674. 16. Baumann UA. Water intubation of the sigmoid colon: water instillation speeds up left-sided colonoscopy. Endoscopy. 1999;31(4):314-317. 17. Leung FW, Amato A, Ell C, et al. Water-aided colonoscopy: a systematic review. Gastrointest Endosc. 2012;76(3):657-666. 18. Leung FW, Aharonian HS, Leung JW, et al. Impact of a novel water method on scheduled unsedated colonoscopy in U.S. veterans. Gastrointest Endosc. 2009;69(3 Pt 1):546-550. 19. Leung JW, Do LD, Siao-Salera RM, et al. Retrospective analysis showing the water method increased adenoma detection rate— a hypothesis generating observation. J Interv Gastroenterol. 2011;1(1):3-7.

25. Gralnek IM, Carr-Locke DL, Segol O, et al. Comparison of standard forward-viewing mode versus ultrawide-viewing mode of a novel colonoscopy platform: a prospective, multicenter study in the detection of simulated polyps in an in vitro colon model (with video). Gastrointest Endosc. 2013;77(3):472-479. 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. 28. Kiesslich R, von Bergh M, Hahn M, et al. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy. 2001;33(12):1001-1006. 29. Brooker JC, Saunders BP, Shah SG, et al. Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial. Gastrointest Endosc. 2002;56(3):333-338. 30. Kahi CJ, Anderson JC, Waxman I, et al. High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening. Am J Gastroenterol. 2010;105(6):1301-1307. 31. Repici A, Di Stefano AF, Radicioni MM, et al. Methylene blue MMX tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers. Contemp Clin Trials. 2012;33(2):260-267. 32. Sabbagh LC, Reveiz L, Aponte D, et al. Narrow-band imaging does not improve detection of colorectal polyps when compared to conventional colonoscopy: a randomized controlled trial and metaanalysis of published studies. BMC Gastroenterol. 2011;11:100. 33. Inoue T, Murano M, Murano N, et al. Comparative study of conventional colonoscopy and pan-colonic narrow-band imaging system in the detection of neoplastic colonic polyps: a randomized, controlled trial. J Gastroenterol. 2008;43(1):45-50. 34. Adler A, Aschenbeck J, Yenerim T, et al. Narrow-band versus white-light high definition television endoscopic imaging for screening colonoscopy: a prospective randomized trial. Gastroenterology. 2009;136(2):410-416. 35. Nagorni A, Bjelakovic G, Petrovic B. Narrow band imaging versus conventional white light colonoscopy for the detection of colorectal polyps. Cochrane Database Syst Rev. 2012;1:CD008361. 36. Aminalai A, Rösch T, Aschenbeck J, et al. Live image processing does not increase adenoma detection rate during colonoscopy: a randomized comparison between FICE and conventional imaging (Berlin Colonoscopy Project 5, BECOP-5). Am J Gastroenterol. 2010;105(11):2383-2388.

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37. Pohl J, Ell C. Impact of virtual chromoendoscopy at colonoscopy: the final requiem for conventional histopathology? Gastrointest Endosc. 2009;69(3 Pt 2):723-725. 38. Hoffman A, Sar F, Goetz M, et al. High definition colonoscopy combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized controlled trial. Endoscopy. 2010;42(10):827-833.

analysis of randomized controlled trials. Am J Gastroenterol. 2012; 107(8):1165-1173. 47. East JE, Saunders BP, Burling D, et al. Surface visualization at CT colonography simulated colonoscopy: effect of varying field of view and retrograde view. Am J Gastroenterol. 2007;102(11): 2529-2535.

39. Hong SN, Choe WH, Lee JH, et al. Prospective, randomized, backto-back trial evaluating the usefulness of i-SCAN in screening colonoscopy. Gastrointest Endosc. 2012;75(5):1011-1021.

48. Waye JD, Heigh RI, Fleischer DE, et al. A retrograde-viewing device improves detection of adenomas in the colon: a prospective efficacy evaluation (with videos). Gastrointest Endosc. 2010;71(3):551-556.

40. Ramsoekh D, Haringsma J, Poley JW, et al. A back-to-back comparison of white light video endoscopy with autofluorescence endoscopy for adenoma detection in high-risk subjects. Gut. 2010; 59(6):785-793.

49. DeMarco DC, Odstrcil E, Lara LF, et al. Impact of experience with a retrograde-viewing device on adenoma detection rates and withdrawal times during colonoscopy: the Third Eye Retroscope study group. Gastrointest Endosc. 2010;71(3):542-550.

41. van den Broek FJ, Fockens P, Van Eeden S, et al. Clinical evaluation of endoscopic trimodal imaging for the detection and differentiation of colonic polyps. Clin Gastroenterol Hepatol. 2009;7(3):288-295.

50. Leufkens AM, DeMarco DC, Rastogi A, et al. Effect of a retrogradeviewing device on adenoma detection rate during colonoscopy: the TERRACE study. Gastrointest Endosc. 2011;73(3):480-489.

42. Kuiper T, van den Broek FJ, Naber AH, et al. Endoscopic trimodal imaging detects colonic neoplasia as well as standard video endoscopy. Gastroenterology. 2011;140(7):1887-1894. 43. Kondo S, Yamaji Y, Watabe H, et al. A randomized controlled trial evaluating the usefulness of a transparent hood attached to the tip of the colonoscope. Am J Gastroenterol. 2007;102(1):75-81. 44. de Wijkerslooth TR, Stoop EM, Bossuyt PM, et al. Adenoma detection with cap-assisted colonoscopy versus regular colonoscopy: a randomised controlled trial. Gut. 2012;61(10):1426-1434. 45. Rastogi A, Bansal A, Rao DS, et al. Higher adenoma detection rates with cap-assisted colonoscopy: a randomised controlled trial. Gut. 2012;61(3):402-408. 46. Ng SC, Tsoi KK, Hirai HW, et al. The efficacy of cap-assisted colonoscopy in polyp detection and cecal intubation: a meta-

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51. Tsiamoulos ZP, Saunders BP. A new accessory, endoscopic cuff, improves colonoscopic access for complex polyp resection and scar assessment in the sigmoid colon (with video). Gastrointest Endosc. 2012;76(6):1242-1245. 52. Lenze F, Beyna T, Lenz P, et al. Endocuff-assisted colonoscopy: a new accessory to improve adenoma detection rate? Technical aspects and first clinical experiences. Endoscopy. 2014;46(7):610-614. 53. Biecker E, Floer M, Heinecke A, et al. Novel Endocuff-assisted colonoscopy significantly increases the polyp detection rate: a randomized controlled trial. J Clin Gastroenterol. 2014 Jun 11. [Epub ahead of print] 54. Hasan N, Gross SA, Gralnek IM, et al. A novel balloon colonoscope detects significantly more simulated polyps than a standard colonoscope in a colon model. Gastrointest Endosc. 2014 Jun 11. [Epub ahead of print]

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SONAL KUMAR, MD, MPH

IRA M. JACOBSON, MD

Assistant Professor of Medicine Weill Medical College of Cornell University New York, New York

Chief of the Division of Gastroenterology and Hepatology Vincent Astor Distinguished Professor of Medicine Weill Medical College of Cornell University New York, New York

Dr. Kumar has served as an advisor to Gilead. Dr. Jacobson has received grant or research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Janssen, Merck, Novartis, and Vertex. He has served on the speakersâ&#x20AC;&#x2122; bureaus of Bristol-Myers Squibb, Genentech, Gilead, Janssen, and Vertex. He has been a consultant or advisor to AbbVie, Achillion, Boehringer Ingelheim, BristolMyers Squibb, Genentech, Gilead, Idenix, Janssen, Merck, and Vertex

ith more than 170 million people worldwide infected with the hepatitis C virus (HCV), the burden of the disease

is indisputably significant.1-4 In 2010, there were an estimated 2.7 to 3.9 million cases of chronic HCV in the United States alone, with up to 75% of individuals unaware of their diagnosis (Table 1).5

Due to the high prevalence and underdiagnosis of disease, the Centers for Disease Control and Prevention in 2012 and the U.S. Preventive Services Task Force in 2013 modified their guidelines to recommend a one-time screening of adults born between 1945 and 1965.5 G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 4

The goal of identifying undiagnosed adults is to eradicate the virus and avoid the development of cirrhosis and its life-threatening complications (Table 2). Pegylated interferon (PegIFN) and ribavirin (RBV) have served as the foundations of HCV therapy for years, but are accompanied by suboptimal rates of sustained virologic response (SVR) and significant adverse events (AEs). The lack of ideal treatment options was the impetus for further study of HCV and the development of novel therapies.

Hitting the Target (Molecule) Stages of the HCV life cycle have become targets of newer direct-acting antivirals (DAAs) that target several molecules required for HCV infection, such as the NS3/4a protease, NS5B RNA-dependent RNA polymerase, or the NS5A protein.6,7 The NS3/4A serine protease is a noncovalent heterodimer with a catalytic subunit (the NS3 N terminal) and an activating cofactor (NS4A protein), which plays an important role in viral replication through cleavage of 4 sites of the HCV polyprotein.8 The HCV NS5A phosphoprotein is also essential for viral RNA synthesis and virion assembly and secretion. The exact mechanism of action of NS5A inhibitors is unknown, but one route is through inhibition of hyperphosphorylation, which has an essential role in replication.9 The NS5B polymerase is another enzyme involved in viral replication. Inhibitors of this enzyme are classified as either nucleoside/nucleotide or non-nucleoside inhibitors. Non-nucleoside/nucleotide inhibitors bind to sites away from the active site of the polymerase and cause conformational changes in the protein. Nucleoside/nucleotide analogs mimic the natural substrate of the NS5B protein, leading to RNA chain termination.10 In 2011, the protease inhibitors (PIs) telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck) became the

Table 1. HCV Infection (AntibodyPositive Only or RNA-Positive), 2011 Site

Site Population

Rate per 100,000

Colorado

2,901

5,116,796

56.7

New Mexico

3,188

2,082,224

153.1

San Francisco

1,944

812,826

239.2

Minnesota

1,925

5,344,861

36.0

New York state

7,047

11,220,287

62.8

Oregon

5,464

3,871,859

141.1

Connecticut

2,898

3,580,709

80.9

New York City

8,749

8,244,910

106.1

Total

33,919

40,274,472

84.7

Source: Sou ce Centers Ce te s for o Disease sease Co Control o to a and d Prevention eve t o

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first approved DAAs to be combined with PegIFN/RBV for the treatment of genotype 1 (G1) HCV. The regimens significantly increased SVR rates, serving as a major advance in the treatment of HCV and opening the door for DAA therapy. However, the incremental adverse reactions were significant, and the regimen was not well tolerated by many patients.11-13 In late 2013, the FDA approved sofosbuvir (SOF; Sovaldi, Gilead), an NS5B nucleotide polymerase inhibitor, and simeprevir (Olysio, Janssen), a second-wave PI, used with PegIFN/RBV. Simeprevir was studied extensively with PegIFN/RBV before its approval. The QUEST-1 and QUEST-2 studies randomized G1, treatment-naive patients to receive simeprevir combined with PegIFN/RB V for 24 or 48 weeks based on response-guided therapy. In QUEST-1, the overall SVR at 12 weeks (SVR12) after therapy with simeprevir was 80% versus 50% in controls; 85% were able to shorten therapy to 24 weeks and 91% of these patients achieved SVR.14 In QUEST-2, therapy was shortened in 91% of patients, of whom 86% achieved SVR12 after treatment.15 The PROMISE trial had a similar study design except study patients had relapsed after prior IFN-based therapy.16 Results also were similar, reporting SVR rates of 80%. All of these studies showed lower SVR rates in patients with advanced fibrosis and in patients with IL28B non-CC genotype. Adverse events associated with simeprevir included hyperbilirubinemia related to interactions with transporters but no actual hepatotoxicity; a slight increase in photosensitivity; and in one study, mild pruritus. No additional hemoglobin decline was noted. Based on these studies, the FDA approved simeprevir for use in G1 patients, as a regimen consisting of 12 weeks of triple therapy and 12 to 36 weeks of PegIFN/RBV for treatment-naive or relapsed patients and prior nonresponders, respectively, with or without cirrhosis. Response-guided therapy is not a component of the approved regimen but parameters of viral response must be met at 4 weeks (HCV RNA <25 IU/mL) for treatment to continue. Sofosbuvir also has been studied comprehensively, leading to its approval nearly simultaneously with simeprevir. The Phase II trials initially demonstrated promising results in G1 patients treated with PegIFN/ RBV and SOF with SVR rates of 87% to 92%,17,18 which led to the Phase III NEUTRINO study of 12 weeks with the same regimen in patients with HCV genotypes 1, 4, 5, or 6.19 Most of the study population consisted of G1 patients, who overall achieved 89% SVR. The study also included a significant number of patients with compensated cirrhosis, with an SVR of 80% in patients with cirrhosis compared with 92% without cirrhosis. No incremental AEs were ascribed to SOF compared with those historically attributed to PegIFN/RBV alone, and only 2% of patients discontinued treatment due to AEs. The shortened treatment duration, higher success rate, and superior tolerability compared with the previous standard of care with PIs took IFN-based therapy to a new plateau, the utility of which has only been limited by the even greater paradigm shift to IFN-free regimens.

New Backbones of Therapy The high barrier to resistance imposed on viral replication by nucleotide polymerase inhibitors, related to the highly conserved structure of the polymeraseâ&#x20AC;&#x2122;s active binding site, makes potent nucleotide analogs like SOF highly attractive as a backbone of regimens consisting of DAA agents. One of the first trials demonstrating success with SOF and RBV was the ELECTRON trial, revealing SVR in 84% of 25 treatment-naive patients. Subsequent studies with the same drugs given for 12 to 24 weeks yielded SVR12 rates of 52% to 68% after therapy.20,21 Although promising, this regimen was unsuccessful in the few study patients with cirrhosis, as well in null responders in a separate arm, with only a 10% SVR (1 out of 10),22 signaling an inability of the regimen to overcome undefined factors linking IFN nonresponsiveness to impaired clearance of virus with SOF as the sole active agent in 12 weeks. The PHOTON study was the only Phase III study of this regimen in treatment-naive, mainly non-cirrhotic G1 patients, which resulted in 76% SVR in patients with HIVHCV coinfection.23 This accounts for the stipulation in the US labeling that SOF and RBV for 24 weeks could be an option for IFN-ineligible patients with G1 infection. Other regimens of DAAs combined with a nucleoside polymerase inhibitor have shown additional advances in oral treatment relative to the regimen of SOF and RBV alone. For example, the potent pangenotypic activity of the NS5A inhibitor daclatasvir complements the broad genotypic activity and high barrier to resistance of SOF.24 This was demonstrated in a Phase II trial in which non-cirrhotic treatment-naive patients and patients who had previously failed treatment with a PI received daclatasvir and SOF, with or without RBV.25 Treatmentnaive patients were treated for 12 or 24 weeks, and the previously treated patients were treated for 24 weeks. Collectively, there was a 98% SVR12 after therapy, with all 3 treatment failures being due to loss to followup. Two had documented SVR24 after treatment. No patient had virologic breakthrough during treatment, and rates of virologic response were similar across subgroups, including genotype subtypes, IL28B genotype, race, RBV treatment, and PI resistance. Ledipasvir (LDV) is another NS5A inhibitor that has yielded similar results in combination with SOF and RBV. In additional arms of the ELECTRON trial, treatment-naive patients and previous null responders, which included those who failed prior treatment with PIs, had an SVR of 100%.26 The Phase II LONESTAR study substantiated these results with SVR rates of 95% to 100% in both treatment-naive patients and those who had previously failed treatment with a PI, including cirrhotics and prior nonresponders.27 Notably, similarly high rates of SVR were seen in treatment arms with only 8 weeks of therapy, raising the possibility of even shorter regimens. More recent Phase III studies involving 1,952 patients treated with LDV/SOF have focused on optimizing duration, need for RBV, and treatment in subpopulations. ION-1 randomized patients to receive the fixed-dose LDV/SOF for 12 or 24 weeks. All treatment arms had 97%

to 99% SVR12 after treatment.28 Even in patients with cirrhosis, SVR was 94% to 100%. ION-2 used the same regimen in patients who had previously failed IFN-based treatment with or without a PI. Again, SVR rates were high: 96% and 94% with and without RBV, respectively, in the 12-week treatment arm and 99% in both 24-week arms.29 Baseline PI resistance did not affect treatment outcome, but prior treatment failures with cirrhosis had a higher rate of relapse, resulting in SVR of 82% to 86%. Still, with such high overall SVR12 and the results of the LONESTAR trial, the ION-3 trial evaluated 8 weeks of treatment in treatment-naive, non-cirrhotic patients. There was no difference based on the use of RBV with SVR 93% to 94% in the 8-week arm, and SVR was 95% in the 12-week arm.30 Although the frequency of relapse in patients treated for 8 weeks was somewhat higher, these findings introduced the possibility of highly successful treatment with an 8-week regimen. Patients with characteristics historically associated with poorer response, including cirrhosis, G1a subtype, non-CC IL28B allele, and race, all still had SVR rates higher than 90%. Mild AEs were common, including fatigue and insomnia, and were incrementally observed in treatment arms containing RBV. Anemia generally was only seen in RBV recipients. Given that RBV did not improve efficacy, collectively, the data from these trials support the absence of RBV from this regimen. Of note, deep-sequencing analyses revealed that most of the patients who failed to achieve SVR in these studies had NS5A-resistant variants, some at baseline. Conversely, however, the SVR rates in patients with baseline NS5A-resistant variants were very high.

Interferon-Free Regimens The FDA has not approved simeprevir and SOF for use in combination, but this regimen has been studied as part of Phase II trials. Its success has motivated clinicians to treat selected G1 patients with an IFN-free regimen. Moreover, the new online guidance from the American Association for the Study of Liver Diseases/Infectious Diseases Society of America has recommended the regimen in IFN-ineligible treatment-naive patients, as well as treatment-experienced patients, whether IFN eligible or not, as long as they have not previously received a PI. The COSMOS trial evaluated the 2 drugs, with or without RBV, for 12 or 24 weeks in G1 patients. There were 2 cohorts, the first of which enrolled previous null responders with METAVIR F0-F2 fibrosis.31 In this group, SVR12 post-therapy ranged between 79% and 93% by intent-to-treat analysis with 4 patients with nonvirologic failure clustered in the group receiving 24 weeks of therapy, including RBV. The second cohort included treatment-naive and prior null responders (without prior PI exposure) with METAVIR F3-F4 fibrosis.32 Overall SVR12 ranged from 93% to 100%; 3 patients who relapsed were in the 12-week arm. Of the 6 patients who relapsed in the entire study, 4 had G1a with the Q80K polymorphism, leaving open the possibility of a small effect of this polymorphism, but with insufficient numbers to definitively address the issue until the completion of ongoing Phase III trials.

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Although regimens without a nucleotide polymerase inhibitor lack a single class that has the high barrier to resistance of a nucleotide polymerase inhibitor, potent combinations of other classes cumulatively impose the high barrier to resistance needed to attain SVR rates similar to those seen with the nucleotides. One emerging regimen is the combination of the PIs ABT-450/r boosted with low-dose ritonavir and ombitasvir (ABT257, NS5A inhibitor), coformulated in a single-daily pill, with twice-daily ABT-333 (non-nucleoside NS5B inhibitor) and RBV. This regimen was studied initially in the AVIATOR trial for 12 weeks, yielding SVR rates in non-cirrhotic, treatment-naive patients and prior null responders of 96% and 93%, respectively.33 With these SVR rates comparing favorably to those obtained with 24 weeks of therapy or to regimens containing 3 of the 4 components previously outlined, the “3D plus RBV” regimen was chosen as the foundation of a robust Phase III program. SAPPHIRE-1 studied the 3D plus RBV regimen for 12 weeks in non-cirrhotic, treatment-naive patients.34 Of the 473 patients, 96% achieved SVR12 after therapy, 95% in G1a and 98% in G1b, with no difference in outcome due to baseline characteristics including HCV RNA, gender, race, age, fibrosis, and IL28B genotype. In SAPPHIRE-2, the same regimen was evaluated in treatment-experienced patients, with the same overall SVR12 rate of 96% (96% and 97% in genotypes 1a and 1b, respectively).35 TURQUOISE-II included both treatmentnaive and treatment-experienced patients with compensated cirrhosis.36 SVR12 after therapy was 92% in patients treated for 12 weeks and 96% in those treated for 24 weeks. With subgroup analysis, it became evident that G1a null responders were the treatment population that drove the difference in SVR based on treatment duration. SVR12 post-therapy was achieved in 93% of the group that was treated for 24 weeks but only 80% in those who were treated for 12 weeks, suggesting a continued effect of prior IFN response, as well as a difference between G1a and G1b patients. SAPPHIRE-1 and SAPPHIRE-2 were both placebo-controlled trials, allowing for a true assessment of safety and tolerability of the regimen. Patients receiving active treatment experienced more AEs, although the overall rate of such events was high even among patients who received placebo (88%-91% in treatment arms compared with 73%-83% with placebo). Adverse events were generally mild but included fatigue, headache, nausea, and pruritus. Elevations in alanine transaminase, through which most patients were able to continue treatment, occurred in about 1% of patients. No patient discontinued treatment as a result of laboratory abnormalities. Some patients required a lower dose of RBV; however, the outcome of treatment was not affected. Baseline resistance data were unavailable; however, most patients who failed treatment had 2 or 3 class drug-resistant variants after treatment. Additional studies include PEARL-4 in G1a treatment-naive patients without cirrhosis who received the 3D regimen for 12 weeks, with or without RBV. In this group, RBV did appear to have an added benefit,

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with SVR12 after treatment of 97% compared with 90% without RBV.37 RBV appears to have no effect with G1b infection as demonstrated in the PEARL-2 and PEARL-3 studies in treatment-experienced and treatment-naive patients, respectively (all without cirrhosis).37,38 In PEARL-2, 97% of patients achieved SVR with RBV and 100% achieved SVR without RBV. In PEARL-3, SVR was 99% in both groups. Other non-nucleotide–containing regimens being studied include daclatasvir combined with the PI asunaprevir and BMS-791325, a non-nucleoside inhibitor. This treatment was evaluated in 166 treatment-naive G1 patients for 12 weeks.39 There was 3% viral breakthrough, all in G1a, and 3.6% viral relapse, also restricted to G1a, resulting in an overall SVR of 92%. This regimen also was well tolerated, with treatment discontinuation as a result of AEs of only 1.2%. The HALLMARK study looked at asunaprevir and daclatasvir in G1b patients. Patients received 24 weeks of treatment and the study included cirrhotics. SVR ranged from 80% to 90% based on prior treatment history, with the highest SVR rates in treatment-naive patients.49

Efficacy Across Genotypes? The effectiveness of HCV treatment varies with nature of the infection. Genotype 2 and 3 HCV had been more successfully treated with IFN and RBV, with SVR rates of 70% to 85%, compared with the lower rates in G1 infection.41 Some of the newer DAAs have demonstrated efficacy across genotypes, allowing for IFN-free regimens to be formulated in this population as well. With 100% SVR in G2 and G3 patients treated for 12 weeks with SOF and RBV as part of the original arms of the ELECTRON trial,22 Phase III studies sought to corroborate the results. The FISSION trial compared 12 weeks of SOF and RBV with the standard of care.19 The trial demonstrated that G2 and G3 patients could no longer be grouped together appropriately, as 97% of G2 patients achieved SVR compared with only 56% of G3 patients (78% and 63%, respectively, in the standard-of-care arm). Cirrhosis was a strong predictor of poor outcome in G3 patients, with SVRs of 61% without and 34% with cirrhosis. Similar outcomes were seen with the POSITRON trial, which studied the SOF and RBV regimen for 12 weeks in G2 and G3 patients who were IFN intolerant to the drugs, or ineligible or unwilling to take them.42 SVR was 93% in G2 and 61% in G3. Cirrhosis again predicted poorer outcome, with SVR of 94% in G2 and 21% in G3. The FUSION trial evaluated the effect of extending treatment to 16 weeks instead of 12 for patients who had failed prior therapy.42 SVR increased from 86% to 94% with longer treatment in G2 patients, and from 30% to 62% in G3 patients. The additional benefit was seen in cirrhotic patients as well, with SVR increased to 78% from 60% with the additional 4 weeks of treatment in G2 and 61% from 19% in G3. However, the number of G2 patients with cirrhosis was too small to draw meaningful comparisons.

Table 2. Interpretation of Results of Tests for HCV Infection And Further Actions Test Outcome

Interpretation

Further Action

HCV antibody nonreactive

No HCV antiSample can be reported as nonreactive for HCV antibody. No further body detected action required. If recent HCV exposure in person tested is suspected, test for HCV RNA.a

HCV antibody reactive

Presumptive HCV infection

A repeatedly reactive result is consistent with current HCV infection, or past HCV infection that has resolved, or biologic false positivity for HCV antibody. Test for HCV RNA to identify current infection.

HCV antibody reactive, HCV RNA detected

Current HCV infection

Provide person tested with appropriate counseling and refer person tested to medical care and treatment.b

HCV antibody reactive, HCV RNA not detected

No current HCV infection

No further action required in most cases. If distinction between true positivity and biologic false positivity for HCV antibody is desired, and if sample is repeatedly reactive in the initial test, test with another HCV antibody assay. In certain situations,c follow up with HCV RNA testing and appropriate counseling.

HCV, hepatitis C virus a

If HCV RNA testing is not feasible and person tested is not immunocompromised, do follow-up testing for HCV antibody to demonstrate seroconversion. If the person tested is immunocompromised, consider testing for HCV RNA.

It is recommended before initiating antiviral therapy to retest for HCV RNA in a subsequent blood sample to confirm HCV RNA positivity.

If the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Source: Centers for Disea Disease ase Control and Preve Prevention ention

In the VALENCE trial, G2 treatment-naive patients treated for 12 weeks had 97% to 100% SVR, as did 78% of G2 treatment-experienced patients with cirrhosis, and 94% of G2 treatment-experienced patients without cirrhosis.43 Treatment was extended to 24 weeks in G3 treatment-naive patients, with 95% of patients without cirrhosis achieving SVR compared with 92% in the cirrhotic population. Those who had failed prior therapy had SVR rates of 87% in the non-cirrhotic population and 62% in patients with cirrhosis. These results led to the approval of SOF and RBV for 24 weeks in G3 and 12 weeks in G2 patients. With still suboptimal results, especially in G3 patients, LONESTAR-2 evaluated the addition of PegIFN to the regimen for treatment-experienced G2 and G3 patients with or without compensated cirrhosis.44 G2 patients had an overall SVR of 96%. G3 patients, including both cirrhotics and non-cirrhotics, had an SVR of 83%, supporting the concept of an ongoing role of PegIFN at least in treatment-experienced cirrhotic patients. Recent data also show that among patients with G3 who had failed a 12- to 16-week regimen of SOF and RBV, a 12-week retreatment regimen of PegIFN/RBV and SOF can act as a salvage regimen, even in patients with cirrhosis, with higher SVR rates than patients retreated with 24 weeks of SOF and RBV alone.45 Collectively, analysis from the NEUTRINO, FUSION, FISSION, POSITRON, and VALENCE trials has shown

that no single AE led to discontinuation in more than 1 patient receiving SOF and RBV, and anemia was the only AE leading to discontinuation of treatment in more than 1 patient receiving IFN, RBV, and SOF.46 However, the use of IFN likely will be unnecessary in the future, as regimens combining SOF with other DAAs, including pan-genotypic NS5A inhibitors, currently in development appear to have high rates of SVR.47 Although limited data exist on treatment in other genotypes, the NEUTRINO trial did include G4, G5, and G6 patients, all of whom had more than 95% SVR, most notably 27 of 28 (96%) G4 patients.19 A small study of G4 Egyptian patients in the United States provided data for the use of SOF and RBV only. In treatment-naive patients, the highest rate of SVR24 was 100%, compared with SVR12 of 79%. In treatment-experienced patients, SVR was 59% with 12 weeks and 87% with 24 weeks of treatment.48 The combination of ABT-450/ritonavir and ombitasvir also was studied in G4 patients in the PEARL-1 trial.49 Treatmentnaive patients received the combination, with or without RBV, for 12 weeks. The RBV-free arm had SVR of 91%, and 100% in the RBV-containing arm. In this study, the 2-drug regimen with RBV added was given to 49 treatment-experienced patients, all of whom achieved SVR.

The Most Difficult Patient The treatment of HCV historically has been the most difficult in patients who need it most urgently, especially

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 4

those with decompensated cirrhosis. In addition to success rates being dismal, treatment regimens, particularly those containing IFN and RBV, have been intolerable for most of these patients. A safe, well-tolerated oral DAA regimen would be ground-breaking for this population. The initial report of SOF and RBV in patients on the transplant list showed that longer duration of undetectable HCV RNA before transplant (>30 days) predicted prevention, although this study included only patients listed because of hepatocellular carcinoma who were otherwise well compensated.50 An arm of the ELECTRON-2 trial administered LDV/SOF for 12 weeks in patients with decompensated cirrhosis. Of the 20 patients, 13 achieved SVR (65%). Seven of the 13 relapsed.51 Ongoing studies are evaluating additional regimens in the decompensated population. Sofosbuvir also has been studied as a regimen for recurrent HCV in patients who have undergone liver transplantation. As part of a compassionate-use program, 104 patients with severe recurrent hepatitis or fibrosing cholestatic hepatitis were treated with SOF and RBV for 24 to 48 weeks.52 Physicians could add PegIFN at their discretion, which was done in about 25% of patients. Of the patients for whom there are data, 62% achieved SVR. Most patients also had improved liver function tests and clinical outcomes with treatment, including resolution of ascites, even in the absence of SVR. The 3D/RBV regimen also has been studied in the post-transplant population.53 Thirty-four patients received the regimen for 24 weeks. Data so far have shown a 96% (25 of 26) SVR, although patients with more aggressive liver disease were excluded. Importantly, there were no major interactions or apparent effects of immunosuppression, no organ rejections, and no serious AEs associated with the regimen.

Conclusion With the global burden of HCV, the need for effective, well-tolerated treatment regimens is great. Elucidation of the HCV life cycle has allowed for newer drugs to be developed, overcoming some of the major disadvantages of prior standard of care with IFN-based therapy. The DAAs are anticipated to completely replace IFN as the foundation of HCV treatment. Among the major advantages of these oral regimens, beyond their increased efficacy, has been their relatively clean safety profile. Although AEs are common, they generally are mild, including headache, fatigue, and insomnia, and trivial relative to those of telaprevir and boceprevir.46 The low rate of discontinuation in all the trials further attests to the tolerability of the regimens, even in those containing RBV. In addition, the once-daily dosing and limited drug窶電rug interactions have minimized the AEs of treatment for most patients. As newer medications and regimens are approved, the next dilemma will be to determine the ideal combination of medications and treatment duration for each patient. Ideally, predictors of response to treatment would aid in the decision making, but none has consistently been identified. Although one study has suggested that early

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viral kinetics may identify those with a higher risk for relapse,21 such predictive value has not been gleaned from the Phase III databases. Importantly, these new regimens also have been able to overcome baseline factors previously associated with poorer outcomes, including G1a subtype, race, non-CC IL28B allele, and prior treatment history. Although rates of treatment failure now appear to be minimal and routes to treatment failure have all but eliminated nonresponse and viral breakthrough, some patients will relapse. SOF has been associated in vitro with a S282T T signature mutation, but it is replicatively unfit54 and rarely found in samples from SOF-treated relapsers, providing a foundation for retreatment with a SOF-containing regimen in these failures. Now that the fundamental paradigm shift toward IFN-free regimens is imminent, further research will be needed to identify effective salvage therapies for patients who have failed both nucleotide-containing and nucleotide-free combination regimens.

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16. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology. 2014;146(7):1669-1679. 17. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381(9883):2100-2107. 18. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-408. 19. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887. 20. Lalezari JP, Nelson DR, Hyland RH, et al. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naive patients with HCV infection: the QUANTUM study. J Hepatol. 2013;58(1):S346. 21. Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310(8):804-811. 22. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44. 23. Sulkowski MS, Rodriguez-Torres M, Lalezari J, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology. 2013;58:313A–314A. 24. Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci USA. 2013;110(10):3991-3996. 25. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-221. 26. Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J Hepatol. 2013;58:S6–S7. 27. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatmentnaive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014;383(9916):515-523. 28. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014:370(20):1889-1898.

36. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(20):1973-1982. 37. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(20):1983-1992. 38. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology. 2014;147(2):359-365. 39. Everson GT, Sims KD, Rodriguez-Torres M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014;146(2):420-429. 40. Manns M, Pol S, Jacobson IM, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: Phase 3 HALLMARK-DUAL study results. J Hepatol. 2014;60:O166. 41. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374. 42. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. 43. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993-2001. 44. Lawitz E, Poordad F, Brainard D, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Presented at: AASLD: The Liver Meeting; November 2013; Washington, DC. Abstract LB-4. 45. Esteban R, Nyberg L, Lalezari J, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. J Hepatol. 2014;60:S4-S5. 46. Gordon SC, Towner W, Aggarwal A, et al. Integrated safety analysis of sofosbuvir-based HCV treatment regimens from phase 3 studies. Gastroenterology. 2014;146:S921. 47. Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with the interferon-free, ribavirin-free combination of sofosbuvir + GS-5816 for 12 weeks in treatment naive patients with genotype 1-6 HCV infection. J Hepatol. 2014;60:S46. 48. Ruane PJ, Ain D, Meshrekey R, et al. Sofosbuvir plus ribavirin, an interferon-free regimen, in the treatment of treatment-naive and treatment-experienced patients with chronic genotype 4 HCV infection. J Hepatol. 2014;60:S503-S504.

29. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1483-1493.

49. Hezode C, Marcellin P, Pol S, et al. Results from the phase 2 PearlI study: Interferon-free regimens of Abt-450/R + Abt-267 with or without ribavirin in patients with HCV genotype 4 Infection. J Hepatol. 2014;60:S24.

30. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.

50. Curry MP, Forns X, Chung R, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58:314A-315A.

31. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. Hepatology. 2013;58:LB3.

51. Gane EJ, Hyland RH, An D, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience. J Hepatol. 2014;60:S3-S4.

32. Lawitz EJ, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior nullresponder/treatment-naive patients (COSMOS study): primary endpoint (SVR12) results in patients with Metavir F3-4 (cohort 2). Presented at: International Liver Congress 2014; April 2014; London, UK.

52. Forns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation. J Hepatol. 2014;60:S26.

33. Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370(3):222-232.

53. Kwo P, Mantry P, Coakley E, et al. Results of the phase 2 study M12999: Interferon-free regimen of Abt-450/R/Abt-267 + Abt-333 + ribavirin in liver transplant recipients with recurrent HCV genotype 1 infection. Presented at: International Liver Congress 2014; April 2014; London, UK.

34. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(20):1594-1603.

54. Mariño Z, van Bömmel F, Forns X, et al. New concepts of sofosbuvir-based treatment regimens in patients with hepatitis C. Gut. 2014;63(2):207-215.

35. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(20):1604-1614.

55. Osinusi A, Marti M, Townsend K, et al. Retreatment of relapsers to sofosbuvir/ribavirin with sofosbuvir/ledipasvir: complete and rapid virologic suppression by week 4. J Hepatol. 2014;60:S5–S6.

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

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 REGIMENS WERE STUDIED ACROSS MANY TYPES OF HCV-INFECTED SUBJECTS Treatment-naïve and -experienced subjects1 • Treatment-naïve GT 1, 4, 5 and 6 subjects achieved an overall SVR12 of 90% (N=327), with GT 1 subjects achieving an SVR12 of 89% (n=292) and GT 4 subjects achieving an SVR12 of 96% (n=28), with SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin (RBV) for 12 weeks in NEUTRINO1,a • Treatment-experienced GT 1 patients can be treated with SOVALDI + Peg-IFN + RBV for 12 weeks, with an estimated SVR of 71%1,b • An all-oral regimen of SOVALDI + RBV for 12 weeks (GT 2) and 24 weeks (GT 3) demonstrated efficacy in treatment-naïve and treatment-experienced subjects1 Subjects with traditionally lower rates of response to treatment2 • SOVALDI delivered high SVR rates in GT 1, 4, 5 and 6 subjects with compensated cirrhosis (80%; n=54) and without cirrhosis (92%; n=273)1 • SVR12 was comparable in subjects with HCV GT 1a and 1b, IL28B C/C and non-C/C alleles, high and low baseline viral load and in Black and non-Black subjects1,3,4 HCV/HIV-1 co-infected subjects1 • SOVALDI is indicated for the treatment of HCV in HCV/HIV-1 co-infected patients. Treatment regimens recommended for co-infected patients are the same as those for HCV mono-infected patients1 NEUTRINO—GT 1 and 4 treatment-naïve adult subjects1 An open-label, single-arm trial evaluating 12 weeks of treatment with SOVALDI in combination with peginterferon (Peg-IFN) alfa 2a and ribavirin (RBV) in treatment-naïve subjects (N=327) with genotype 1, 4, 5 or 6 HCV infection, compared to a pre-specified historical control. In each of the phase 3 studies, sustained virologic response (SVR) was the primary endpoint, which was defined as HCV RNA <25 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR is considered a virologic cure.2 b The response rate in treatment-naïve subjects with difficult-to-treat factors in NEUTRINO (n=52) may approximate the response rate in patients who previously failed pegylated interferon and ribavirin therapy. (Difficult-to-treat factors include GT 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis.)1 a

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 Alfa/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.

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

sovaldi.com/hcp

ADDITIONAL SUBJECTS STUDIED WITH SOVALDI REGIMENS IFN-unable subjects1 • SOVALDI + RBV was evaluated in GT 2 and GT 3 subjects who were IFN-intolerant, -unwilling, or –ineligible1 • An IFN-free regimen of SOVALDI + RBV is the recommended regimen for GT 2 and 3 patients and can be considered as a therapeutic option for GT 1 patients who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient1 Patients with HCC awaiting liver transplant1 • SOVALDI + RBV is the first approved, all-oral regimen for HCV-infected subjects with HCC meeting the Milan criteria who are awaiting liver transplantation. Recommended treatment duration is up to 48 weeks or until the time of transplantation, whichever comes first, to prevent post-transplant HCV reinfection1 • The safety and efficacy of SOVALDI have not been established in post-liver transplant patients1

IMPORTANT SAFETY INFORMATION (CONTINUED) WARNINGS AND PRECAUTIONS (CONTINUED) • 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.

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.

SOVALDI (sofosbuvir) ®

Brief summary of full Prescribing Information. Please see full Prescribing Information. Rx Only. 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. 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. SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by assessment of potential benefits and risks for individual patient. Patients with Hepatocellular p Carcinoma Awaitingg Liver Transplantation: p SOVALDI in combination with ribavirin is recommended for up to 48 weeks or until time of liver transplantation to prevent post-transplant HCV reinfection. 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.

ADVERSE REACTIONS: Adverse Reactions from Clinical Trials Experience: SOVALDI should be 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. Table 1 Treatment-Emergent Adverse Events (All Grades) Reported in ≥15% of Subjects in Any Treatment Arm Interferon-free Regimens

Interferon-containing Regimens

PBO 12 weeks

SOVALDI + RBV Va 12 weeks

SOVALDI + RBV Va 24 weeks

Peg-IFN alfa + RBVb 24 weeks

SOVALDI + Peg-IFN alfa + RBV Va 12 weeks

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

15%

16%

29%

25%

Pruritus

11%

27%

17%

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.

Anemia

10%

12%

21%

Asthenia

21%

Rash

18%

Decreased Appetite

10%

18%

Chills

18%

17%

Influenza Like Illness

18%

16%

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.

Pyrexia

14%

18%

Diarrhea

12%

17%

12%

Neutropenia

<1%

12%

17%

CONTRAINDICATIONS: When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, contraindications applicable to those agents are applicable to combination therapies. Refer to prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. 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 because of the risks for birth defects and fetal death associated with ribavirin.

Myalgia

16%

14%

Irritability

10%

16%

13%

WARNINGS AND PRECAUTIONS: Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI, therefore, two non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin. Refer also to the prescribing information for ribavirin. 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 therapeutic effect of SOVALDI. Rifampin and St. John’s wort should not be used with SOVALDI.

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. With the exception of anemia and neutropenia, the majority of events presented in Table 1 occurred at severity of grade 1 in SOVALDI-containing regimens. Less Common Adverse Reactions Reported in Clinical Trials (<1%): The following ADRs occurred in <1% of subjects receiving SOVALDI in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. Hematologic Effects:: pancytopenia (particularly in subjects receiving concomitant pegylated interferon). Psychiatric Disorders:: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide. Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 2. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

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

14%

23%

<8.5

<1%

12%

15%

<1%

Neutrophils (x10 /L) ≥0.5 - <0.75 <0.5 Platelets (x109/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. Bilirubin Elevations: Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations. Creatine Kinase Elevations: Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + 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 in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.

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 or discontinue treatment with ribavirin containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin. Pediatric Use: Safety and effectiveness of SOVALDI in children less than 18 years of age have not been established. Geriatric Use: Clinical studies of SOVALDI included 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of SOVALDI is warranted in geriatric patients. Renal Impairment: No dose adjustment of SOVALDI is required for patients with mild or moderate renal impairment. The safety of SOVALDI has not been assessed in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. Refer also to ribavirin prescribing information for patients with CrCl<50 mL/min. Hepatic Impairment: No dose adjustment of SOVALDI is required for patients with mild,

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 activation pathway of

of SOVALDI have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.

phosphorylation pathways that are unlikely to be affected by concomitant drugs.

pre-transplant to prevent post-transplant HCV reinfection. See Dosage and Administration for

Recommended 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), m 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.

Patients with HCV/HIV-1 Co-infection: in 223 HCV/HIV-1 co-infected subjects. See Dosage and Administration for dosing co-infected subjects was similar to 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 b with HCC prior to undergoing liver transplantation in an

of SOVALDI and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials. Post-Liver Transplant Patients: in post-liver transplant patients. CHC Patients with Genotype 5 or 6 HCV Infection: Available data on subjects with genotype References: 1. SOVALDI® (sofosbuvir). US Prescribing Information. Gilead Sciences, Inc. Foster City, CA. December 2013. 2. US Department of Health and Human Services, Center for Drug Evaluation and Research. Draft Guidance for Industry. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf. Published October 2013. Accessed May 6, 2014. 3. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. d 2013;368(20):1878-1887. 4. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. d 2013;368(20)[suppl]. 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. SVDP0021 07/14

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A Review of Gastrointestinal Stenting

ABRAHAM KALIKSTEIN, BS YVETTE LAM-TSAI, MD PIERRE HINDY, MD FRANK GRESS, MD Division of Gastroenterology and Hepatology State University of New York Downstate Medical Center Brooklyn, New York The authors report no relevant financial conflicts of interest.

Esophageal Stenting

tents are used as a safe and effective alternative to surgery or repeated endoscopic

procedures to improve quality of life for patients with various gastrointestinal (GI) diseases and disorders. This article reviews the use of stents in the GI tract, including esophageal, gastroduodenal, and biliary stents, as well as stents for the colon and rectum.

Historically, esophageal stents were used to palliate patients with dysphagia or obstruction from malignancy. Placement of rigid plastic esophageal stents was associated with high complication rates and morbidity. Today, the esophageal stent has been improved. It is constructed from metal alloy compounds and durable polymers and designed for the treatment of a variety of benign and malignant esophageal diseases. Benign causes of disease include refractory strictures (eg, peptic, anastomotic, radiation-induced), tracheoesophageal fistulas, iatrogenic perforations, and leaks. More common uses for metal esophageal stents are for palliative treatment of inoperable esophageal, gastroesophageal junction, and gastric cardia cancer. With the recent development of self-expanding plastic stents (SEPS) and self-expanding metal stents (SEMS), stent placement for esophageal pathology can be safe and cost-effective.

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Table 1. An Overview of Esophageal Stents Available in the United States Manufacturer and Product Name

Material and Design

Outer Diameter (mm)

Length, cm (covered length)

Introducer Diameter (mm)

Other Features

Boston Scientific Polyflex Esophageal Stent

Polyester/silicone

16 (proximal flare, 20) 18 (proximal flare, 23) 21 (proximal flare, 25)

9, 12, 15

12, 14

Indicated for removal from refractory benign strictures

Ultraflex Covered Esophageal NG Stent System

Nitinol (polyurethane)

18 (proximal flare, 23) 23 (proximal flare, 28)

10 (7) 12 (9) 15 (12)

Available in proximal release

Ultraflex Non-covered Esophageal NG Stent System

Nitinol

18 (proximal flare, 23)

7, 10, 12, 15

Available in proximal release

WallFlex Partially Covered Esophageal Stent

Nitinol (silicone-coated; wire-braided; removal suture)

18 (proximal flare, 23) 23 (proximal flare, 28)

10 (7) 12 (9) 15 (12)

Reconstrainable up to 75% of deployment

Wallstent II Esophageal Stent

Elgiloy

20 (ends, 28)

10 (8) 15 (13)

Esophageal Z-Stent (Fully Coated)

Stainless steel

18 (proximal flare, 25)

8, 10, 12, 14

Esophageal Z-Stent (Uncoated Flange)

Stainless steel

18 (proximal flare, 25)

8, 10, 12, 14

Evolution Esophageal Fully Covered ControlledRelease Stent

Nitinol (internal and external silicone coating)

18 (flange, 23) 20 (flange, 25)

8, 10, 12

Can be recaptured to reposition

Evolution Esophageal Partially Covered ControlledRelease Stent

Nitinol (internal and external silicone coating)

20 (flange, 25)

8, 10, 12.5, 15

Can be recaptured to reposition

Nitinol (silicone coating)

6, 8, 10, 12, 14, 16

Nitinol (covered completely with polymer membrane)

18 or 22 (proximal end, 3 mm larger; distal end, 5 mm larger)

7, 10, 12

Cook Medical

EndoChoice Bonastent Esophageal

Merit Medical Systems, Inc. ALIMAXX-ES Fully Covered Esophageal Stent

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Types of Esophageal Stents A variety of SEPS and SEMS are available in the United States, including those manufactured by Boston Scientific, Cook Medical, EndoChoice, and Merit Medical Systems, Inc (Table 1). Each company has created stents that impart stronger radial forces to maintain stent patency and positioning, no or minimal foreshortening on stent deployment, silicone or polymer stent coating to decrease tissue ingrowth, and improved fluoroscopic visibility for accurate placement.

Challenges in Esophageal Stent Placement Potential complications of esophageal stenting include perforation, globus sensation, tracheal compression, hemorrhage, stent migration (eg, patients being treated with chemoradiation therapy [CRT]), obstruction from tumor ingrowth or overgrowth, and food impaction. High-Grade Strictures If the stricture is very tight or difficult to traverse with the standard endoscope, a 0.035-inch guidewire can be passed through a biliary or balloon catheter to cross the stricture, followed by dilation with Savary-Gilliard dilators before stent placement. The gastroscope can then traverse the stricture and the length of the stricture can be determined. Placement of radiopaque markers on the patientâ&#x20AC;&#x2122;s skin can mark the proximal and distal ends of the stricture to improve the accuracy of final stent position under fluoroscopy. Upper Esophagus or Cervical Esophageal Strictures Careful examination should be made to determine if there is at least 3 to 4 cm from the proximal end of an upper esophageal or cervical esophageal stricture before deciding the feasibility of stent placement. Complications that may accompany stent placement in this region include globus sensation, chest pain, and stent migration. Distal Esophageal Strictures and Gastroesophageal/Cardia Cancers Stent placement across the gastroesophageal junction can lead to problems such as reflux and aspiration. A modified esophageal stent with an antireflux valve has not been shown to prevent these complications.

Benign Esophageal Diseases Baron et al studied 30 patients with benign esophageal disease treated with SEPS. They performed 83 successful placements of SEPS. Patients complained mostly of chest pain, neck discomfort, and dysphagia. The researchers found that migration occurred most frequently with the stents placed in the proximal and distal esophagus. Only 5 of 83 (6%) interventions resulted in long-term improvement after removal of the stent. The authors concluded that there was no significant

difference in migration rates based on stent size, procedure indication, or pre-stent dilation. Plastic stents appeared to be safe for use, associated with minimal tissue trauma, and less costly compared with metal stents. SEPS are useful in alleviating dysphagia associated with benign esophageal stenoses and for the treatment of esophageal leaks, fistulas, and perforations. However, their use is still limited by stent migration and poor longterm outcomes for benign disease. Langer et al described the use of SEPS in the treatment of postoperative esophageal anastomotic leaks. Nearly 90% of treated patients had successful initial closure with SEPS, enabling early oral feeding. Late stent dislocation requiring reintervention occurred in 37.5% of patients. Median hospital length of stay was 8 days, shorter than in other studies. Eloubeidi et al recently reported their experience on the use of fully covered SEMS (FCSEMS) for benign esophageal diseases in 35 patients. They found that dysphagia scores improved 1 month after placement. Additionally, 31% of patients had successful long-term outcomes without requiring reintervention after stent removal (21% of patients with refractory strictures and 44% of patients with fistulas/leaks). Stents remained functional for approximately 60 days for all patients. However, this success was short-lived for most patients, with 49% requiring reintervention for stent migration, recurrent symptoms (chest pain, dysphagia, globus sensation), stent dysfunction, and other minor complications. Stricture is not completely resolved but can be treated repeatedly without major complications in benign diseases. Buscaglia et al looked at 41 FCSEMS placed in 31 patients with benign esophageal conditions. Complications occurred in 11 of 31 patients. Stent migration was the most common complication, with a migration rate of 25.6%. Approximately 90% of patients (28 of 31) experienced relief of dysphagia or resolution of fistulas/leaks; 3 patients who did not experience symptom relief had a fistula or leak. This study showed a higher rate of success with early treatment and a lower rate of stent migration compared with earlier studies (eg, Eloubeidi et al). The investigators attributed this finding to either the newer design of stents with flared flanges (dog-bone design) or an underestimation of retrospective data collection. Further studies, preferably prospective randomized trials with longterm data collection, are needed to determine the role of SEMS in the management of benign esophageal disease.

Malignant Esophageal Diseases Costamagna et al described the use of the Polyflex Esophageal Stent in the management of 16 patients (15 males, 1 female) with inoperable esophageal strictures. They showed that patients had a significant improvement in dysphagia scores during the follow-up course until death, with repeat interventions needed in 4 patients,

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1 because of tumor ingrowth, at a mean duration of 19.5 days. The most common complication was stent migration in 2 patients. Didden et al studied the safety and efficacy of stent placement in 13 patients who had received definitive CRT. They observed 8 major and 1 minor complications among 8 patients. Within the first month after placement of the stent, 3 patients developed pneumonia; 1 patient died, and 2 patients were treated with antibiotics and recovered. Two patients developed tracheoesophageal fistulas at long-term follow-up, and 1 patient experienced a massive, fatal GI hemorrhage 257 days after stent placement. Also, there were 4 cases of recurrent dysphagia in 3 patients due to stent migration, tumor overgrowth, or food impaction. The authors concluded that stent placement was effective in treating dysphagia; however, patients are susceptible to early development of pulmonary infections, and patients with invasive (T4) cancer are at high risk for fistula formation. More recently, Ji et al designed and reported on a new FCSEMS (Hanarostent Skidproof, M.I.Tech Co Ltd.). This stent has multiple protuberances on the body of the stent. In a canine study, there were significantly lower stent migration rates compared with conventional SEMS (55% vs 100%, respectively). Further clinical trials are anticipated. Choi et al studied the use of a retrievable FCSEMS (Niti-S, Taewoong Medical) in 100 patients. This stent is equipped with a drawstring to allow removal when necessary. Stent placement was successful in 100% of patients, and endoscopic stent removal was successful in all 17 patients in whom it was attempted. All patients experienced relief of dysphagia at 4 weeks after stent placement. Ninety-seven patients died during follow-up; median survival time was 74 days and was due to advanced-stage malignancies. Complications included 7 stent occlusions due to tumor overgrowth, 6 stent migrations, and 6 food impactions. This stent showed similar or lower migration rates compared with currently available FCSEMS and partially covered SEMS (PCSEMS). The authors attributed the low rates of migration and overgrowth to the dog-bone shape, flange, and fully covered design. Covered stents are commonly used in patients with esophageal cancer to prevent the tumor ingrowth that occurs in more than 25% of patients with uncovered stents; however, covered stents are associated with high migration rates. The Niti-S overcomes this limitation with its double-flared ends (dogbone design) and double-layered configuration, with an outer, uncovered nitinol wire tube, which allows the stent to adhere to the esophageal wall. Verschuur et al studied the Niti-S double-layered stent in 42 patients. Five patients developed recurrent dysphagia, 2 (5%) because of overgrowth and 3 (7%) because of stent migration. These rates are low compared with other fully covered stents. The investigators believe the low migration rates they observed are because of friction

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exerted by the outside wire of this stent. Eleven patients in this study experienced complications, with 5 major complications, a similar rate to what has been observed with other currently available stents.

The Future of Esophageal Stents: Biodegradable Stents A prospective study was conducted at 2 European centers of 21 patients with placement of the Ella stent (ELLA-CS, s.r.o.), a biodegradable stent composed of polydioxanone absorbable surgical suture. The mean stricture length was 3 cm, and stents were placed mainly in the mid- to distal esophagus. After 7 weeks, stent migration occurred in only 2 patients (9.5%). The median dysphagia score decreased by 2 points and lasted up to median follow-up of 53 weeks. By 6 weeks, the stent was completely dissolved in all cases. Nine of 20 patients (45%) no longer experienced dysphagia at the end of follow-up. However, the remaining 11 patients (55%) suffered symptom recurrence, 10 with stricture recurrence and 1 with obstruction from tissue ingrowth. In 3 patients, post-stenting pain was severe, and minor bleeding occurred in 1 patient. Similar difficulties have been reported with high migration rates (62%), poor long-term outcomes, and symptom recurrence. van Boeckel et al compared the use of SEPS and biodegradable stents in patients with refractory benign esophageal strictures. The Polyflex (SEPS) and the Ella BD stents were used in 20 and 18 patients, respectively. Polyflex stents were successfully placed in 19 of 20 patients, and Ella BD stents were successfully placed in 16 of 18 patients; Polyflex stents were removed in 16 cases. Six of 16 patients (37.5%) with SEPS were dysphagia-free after a median follow-up of 385 days. Six of 18 patients (33%) with BD stents were dysphagia-free after a median follow-up of 166 days. Major complications occurred in 4 patients with BD stents and 2 patients with SEPS. Stentrelated complications occurred more often (but nonsignificantly) in patients with BD stents (complications, 8 patients [44%]; migration, 4 patients; food obstruction, 2 patients; tissue ingrowth, 2 patients) compared with SEPS patients (complications, 5 patients [31.5%]; migration, 5 patients; P=0.21). Significantly more interventions were performed after SEPS placement (P=0.03). Patients with SEPS underwent 21 re-interventions; scheduled removal was performed in 11 patients, complications occurred in 5 patients, and recurrent stricture occurred in 5 patients. Patients with BD stents underwent 16 re-interventions; complications occurred in 10 patients, and recurrent strictures occurred in 6 patients. There was a lower success rate with SEPS in this study compared with other studies. The lower success rate may be because the data were analyzed on an intention-to-treat basis. Also, the feasibility of SEPS removal after only 6 weeks is yet to be determined. The primary advantage of BD stents is that they do not require removal; however, repeat BD stent

placement is indicated when the stent dissolves and the stricture is still present.

Table 2. Gastroduodenal Stents Available in the United States

Conclusion The esophageal stent remains an important tool for the palliative therapy of inoperable esophageal and gastric cardia cancers. With the development of multiple SEPS and SEMS, clinicians have several choices for managing benign and malignant esophageal disease. This minimally invasive approach has improved the quality of life for these patients who would otherwise face the challenges of a possibly morbid surgical procedure or may have limited treatment options because of multiple medical comorbidities. Further innovations are being developed to improve stent patency and to mitigate stent-related complications.

Stent (Manufacturer)

Diameter (mm)

Length (mm)

Enteral Wallstent, TTS (Boston Scientific)

20, 22 (internal diameter)

60, 90

Enteral WallFlex TTS, (Boston Scientific)

27 (edges); 22 (center)

60, 90, 120

TTS, S, tthrough oug the t e scope

Suggested Reading Buscaglia JM, Ho S, Sethi A, et al. Fully covered self-expandable metal stents for benign esophageal disease: a multicenter retrospective case series of 31 patients. Gastrointest Endosc. 2011;74(1):207-211. Choi SJ, Kim JH, Choi JW, et al. Fully covered, retrievable selfexpanding metal stents (Niti-S) in palliation of malignant dysphagia: long-term results of a prospective study. Scand J Gastroenterol. 2011;46(7-8):875-880. Costamagna G, Shah SK, Tringali A, et al. Prospective evaluation of a new self-expanding plastic stent for inoperable esophageal strictures. Surg Endosc. 2003;17(6):891-895. Didden P, Spaander MC, Kuipers EJ, et al. Safety of stent placement in recurrent or persistent esophageal cancer after definitive chemoradiotherapy: a case series. Gastrointest Endosc. 2012;76(2):426-430. Eloubeidi MA, Talreja JP, Lopes TL, et al. Success and complications associated with placement of fully covered removable self-expandable metal stents for benign esophageal diseases (with videos). Gastrointest Endosc. 2011;73(4):673-681. Holm AN, de la Mora Levy JG, et al. Self-expanding plastic stents in treatment of benign esophageal conditions. Gastrointest Endosc. 2008;67(1):20-25. Ji JS, Lee BI, Kim HK, et al. Antimigration property of a newly designed covered metal stent for esophageal stricture: an in vivo animal study. Gastrointest Endosc. 2011;74(1):148-153. Langer FB, Wenzl E, Prager G, et al. Management of postoperative esophageal leaks with the Polyflex self-expanding covered plastic stent. Ann Thorac Surg. 2005;79(2):398-403. Repici A, Vleggaar FP, Hassan C, et al. Efficacy and safety of biodegradable stents for refractory benign esophageal strictures: the BEST (Biodegradable Esophageal Stent) study. Gastrointest Endosc. 2010;72(5):927-934. van Boeckel PG, Vleggaar FP, Siersema PD. A comparison of temporary self-expanding plastic and biodegradable stents for refractory benign esophageal strictures. Clin Gastroenterol Hepatol. 2011;9(8):653-659. Verschuur EM, Homs MY, Steyerberg EW, et al. A new esophageal stent design (Niti-S stent) for the prevention of migration: a prospective study in 42 patients. Gastrointest Endosc. 2006;63(1):134-140.

Gastroduodenal Stenting Gastroduodenal obstruction is a common presentation of patients with advanced malignancies of the stomach, pancreas, and duodenum. Most patients with gastroduodenal obstruction have very poor quality of life due to constant emesis and severe malnutrition. Surgical gastrojejunostomy has been the traditional palliative treatment, but is associated with various complications and morbidity.

Gastroduodenal stenting offers a reasonable alternative to surgical palliation in unresectable malignant tumors. Most of the data on enteral stenting are from case series, small comparative trials, and one randomized controlled trial (RCT). One would conclude that the main indications for placement of gastroduodenal stents are malignant obstructions caused by unresectable tumors (eg, stomach, duodenum, pancreas). Some patients who are not surgical candidates with benign gastroduodenal obstructions also may benefit from stenting, but the use of stents in benign diseases is still under investigation.

Equipment and Techniques Only 2 stents are available in the United States for gastroduodenal obstruction, both manufactured by Boston Scientific (Table 2), although esophageal stents have been used in some case studies. These stents can be deployed through the accessory channels of a therapeutic endoscope and are known as TTS, or “through the scope.” Gastroduodenal stents can be placed endoscopically with the aid of fluoroscopy. The patient should be placed in the left lateral decubitus or prone position to avoid the risk for aspiration. A prone position allows for a better anatomic view under fluoroscopy. In the case of a partially obstructing lesion, an attempt should be made to traverse the lesion with the endoscope, whereupon a guidewire should be inserted under fluoroscopic guidance. The length of the stricture should be assessed. If the scope cannot traverse the lesion, the stricture should be assessed with contrast injection under fluoroscopy. The stent should be passed over the guidewire to the level of the obstruction, then passed until its tip is proximal to the tumor. Ideally, 2 cm of the stent proximally and distally should be exposed after deployment so that a “waist” in the stent is seen when in the region of the tumor and a flare at the edges. It is recommended that deployment occur under fluoroscopic and endoscopic guidance. In the case of coexisting biliary obstruction, it is advisable to achieve biliary decompression before

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the placement of gastroduodenal stents, as biliary access would be difficult once an enteral stent has been placed.

Efficacy Technical success, defined as successful stent placement and deployment, is usually achieved in more than 95% of patients, and clinical success, achieving decompression, was reported to be approximately 90%, according to a systematic review of 44 studies that compared enteral stenting with gastrojejunostomy. Technical and clinical success rates ranged from 91% to 100% in prospective studies. Recurrent obstructive symptoms were more common after stent placement, and, despite initial success, up to 40% of patients required reintervention for recurrent symptoms or for biliary obstruction compared with almost no reintervention required in the gastrojejunostomy group. Similar conclusions were drawn in the only RCT to date that compared stent placement with palliative surgery for gastroduodenal obstruction. Initial success rates were better in the stent group; however, rates of long-term relief were lower in the stent group. More complications also were observed in the patients who underwent stenting. There were no differences regarding survival or quality-of-life scores between the 2 groups. On the other hand, observational studies suggest that enteral stenting is associated with less morbidity, no procedure-related mortality, and lower costs.

Complications No procedure-related mortality has been reported with enteral stent placement. A systematic review defined major and minor complications associated with enteral stenting. Major complications were categorized as early (â&#x2030;¤7 days after treatment) or late (>7 days after treatment) and were considered life-threatening or severe. Early major complications included intraprocedural complications, perforation, stent migration, hemorrhage, fever, jaundice, or severe pain requiring additional treatment and hospitalization. Late major complications included distal stent migration, bleeding, late perforation, stent obstruction, and fistula formation. Persistent obstructive symptoms after stent placement occurred in 8% of patients, and a reintervention for recurrent obstructive symptoms was performed 18% of the time. Causes of obstruction included stent occlusion by tumor ingrowth, tumor overgrowth, or food impaction. Minor complications were not life-threatening and included mild pain, wound infection, mild fever, or occasional vomiting without obstruction. A study of the double-layered ComVi stent showed a tumor ingrowth and overgrowth of 0% and 8%, respectively. These results are similar to or lower than what has been reported previously with other covered stents. Stent migration was 10% (4 of 5 migrations occurred within the first 2 weeks), which is slightly lower than

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previous studies with covered stents (10%-27.7%) but higher than with uncovered stents (0-6.1%). The rate of stent collapse was 10%, with a 28% rate of reintervention, much higher than what has been observed in other studies. When reintervention is taken into account, this stent does not appear to have any clear advantage. Isayama et al reported on the triple-layer covered metal M-ComVi stent (modified ComVi; Niti-S ComVi type; Taewoong Medical) in a prospective study of 50 patients. Stent occlusion occurred in 5 patients (10%) at the uncovered portion; the authors advised using longer stents to help prevent occlusion at the uncovered portion. No stent collapses occurred. Other complications were insufficient stent expansion (n=1), cholangitis (n=1), and mild pancreatitis (n=1). Asymptomatic stent migration occurred in 3 patients, at 95, 230, and 553 days, respectively, after placement. All 3 patients were receiving chemotherapy.

Conclusion Gastroduodenal stenting is evolving into an acceptable alternative to gastrojejunostomy in patients with malignant obstruction and short-term survival. It is a minimally invasive procedure with a high technical and clinical success rate. A significant number of patients will require reintervention for stent or biliary obstruction. Our knowledge of duodenal stenting comes from small case series and observations, with only one small RCT to date. More studies are needed to compare gastroduodenal stent placement with gastrojejunostomy.

Suggested Reading Isayama H, Sasaki T, Nakai Y, et al. Management of malignant gastric outlet obstruction with a modified triple-layer covered metal stent. Gastrointest Endosc. 2012;75(4):757-763. Kim YW, Choi CW, Kang DH, et al. A double-layered (comvi) self-expandable metal stent for malignant gastroduodenal obstruction: a prospective multicenter study. Dig Dis Sci. 2011;56(7):2030-2036.

Biliary Stenting Biliary endoprostheses have been used since the 1970s for the treatment of both malignant and benign conditions to provide biliary decompression. The main indication for emergent treatment is cholangitis. Other indications include patients with obstructive jaundice who are symptomatic (eg, pruritus) or patients who are candidates for chemotherapy. The most common indications for biliary stenting in benign conditions include large obstructing biliary stones, bile duct leaks, and benign biliary strictures. Short-term plastic stenting is a viable alternative in patients with irretrievable biliary stones. Biliary decompression with biliary stenting, particularly with metal stents, most often is used to treat unresectable GI malignancies, such as cholangiocarcinomas; gallbladder, pancreatic, and duodenal tumors; or ampullary tumors involving the biliary tree. In the past, surgical bypass

Table 3. Metal Stents for Biliary Indications Uncovered Metal Stents Manufacturer

Product

Features

Boston Scientific

WallFlex Biliary RX Stent

• • • •

ConMed

• • • • •

Shortwire or longwire compatible Platinol wire construction (nitinol plus platinum) Available in uncovered, partially covered, and fully covered Integrated retrieval loop in both partially and fully covered stents for repositioning or removal Closed-cell design with looped and flared ends Permalume covering (silicon plus proprietary materials) 8 Fr (uncovered) and 8.5 Fr (partially covered/fully covered) system and tapered tip 1:1 controlled deployment system, reconstrainable up to 80% MR conditional (static magnetic fields of 3 Tesla or less)

WALLSTENT

• • • • • •

Shortwire- or longwire-compatible Available in uncovered and partially covered Closed-cell design Permalume covering (silicon plus proprietary materials) 1:1 controlled deployment system, reconstrainable up to 80% MR conditional (static magnetic fields of 1.5 Tesla or less)

Flexxus Endoscopic Biliary Stent

• • • •

Made of nitinol Single-tube, laser-cut design For use with a 0.035-inch guidewire Designed with 4 radiopaque tantalum spoons at polished flared ends (when compressed within the delivery catheter, they appear as fluoroscopic markers) • The delivery system uses a pistol grip controller system • ConMed touts minimal shortening, short tapered catheter tip, and highest radial expansion force

Cook Medical Zilver • Nitinol design Biliary Self• Z-stent tube design Expanding Stent • For use with a 0.035-inch guidewire • Minimum accessory channel, 2.8 mm • Preloaded in a 7 Fr, 208-cm long introducer • Stent diameters ranging from 6 to 10 mm • Stent lengths ranging from 4 to 8 cm • 4 gold markers on each end of stent Zilver 635 • Includes all of the features of the original Zilver Biliary Self-Expanding Stent Biliary Selflisted above, and: Expanding Stent • A smaller 6 Fr, 200 cm introducer • MR conditional (up to 3 Tesla MR systems) Covered Metal Stents Manufacturer Product

Features

Boston Scientific

WallFlex RX Endoprosthesis

• • • •

ConMed

GORE Viabil Biliary Endoprosthesis (fully covered)

• Made of nitinol • Nonporous expanded polytetrafluoroethylene (ePTFE), fluorinated ethylene propylene stent lining to reduce bacterial buildup and bile occlusion, tissue ingrowth, and preserve stent patency • Pull-line deployment system: Pull of the deployment knob unknots a double-layered PTFE braid to release the stent from the catheter to allow precise positioning • Soft-wired ends • Flexible covered anchoring fins • Branch drainage side holes or no side holes • Geometric configuration • Curved tip catheter

Shortwire or longwire compatible 8 Fr catheter can pass through a 3.2-mm working channel Permalume (silicone) covering Closed-cell design with platinum core and nitinol encasing

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was necessary for management of biliary obstruction, which is associated with high morbidity and mortality. The advent of the biliary stent obviates the need for immediate surgical intervention in many scenarios, particularly for patients with multiple medical comorbidities and those who are poor candidates for surgery. The relative risk for all complications was found to be reduced by 40% in a meta-analysis of 308 patients.

Patients With Potentially Resectable Common Bile Duct Obstruction Two RCTs have shown that overall morbidity was increased when plastic biliary drains were placed preoperatively compared with direct surgery. Preoperative drainage is advised for patients who are candidates for neoadjuvant therapies, patients with acute cholangitis, or patients with intense pruritus and delayed surgery. When surgical status is uncertain, SEMS are as cost-effective as plastic stents for draining an obstruction related to pancreatic cancer. Some models of biliary SEMS (short intrapancreatic or covered) do not impede pancreatic resection and may be used for preoperative biliary drainage in patients with malignant obstruction of the common bile duct (CBD) when surgical status is unknown. In patients with uncertain diagnoses, plastic stents are generally preferred.

Palliation of Malignant CBD Obstruction Endoscopic drainage is effective in 80% of cases. A meta-analysis (3 RCTs, 308 patients) compared endoscopic versus surgical drainage and found no differences in overall survival, quality of life, or technical and therapeutic success. Compared with surgical drainage, relative risk for complications was reduced by 40%, there was a trend for lower 30-day mortality rates, and higher rates of biliary obstruction occurred in the endoscopic group (plastic stents were used). An RCT of 30 patients found no significant differences between SEMS and surgery, except for a better quality of life and lower cost in the endoscopy group. A meta-analysis including 7 RCTs (724 patients) showed that SEMS was associated with half of the risk for recurrent biliary obstruction at 4 months until death or end of study compared with biliary stents. (There was no difference in survival rates if patients were followed regularly.) Plastic stents appeared to be more cost-effective if life expectancy was less than 4 months, with SEMS more cost-effective if life expectancy was longer than 4 months. Among SEMS models measuring 10 mm in diameter, no difference has been clearly demonstrated, including between covered and uncovered models. Plastic stents with a 10-Fr diameter showed longer patency than smaller-caliber stents. In one nonrandomized study, the Tannenbaum stent (no side holes) was suggested to have longer patency; however, this was not confirmed in 2 RCTs. In an RCT, Tannenbaum stents modified with

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double-layer (Olympus) or with the addition of an antireflux valve (Wilson-Cook) were found to prolong patency compared with regular Tannenbaum stents. Further studies are needed.

Complications of Biliary Stenting Early complications were reported in 4.9% of 638 patients, including biliary infection (35%), pancreatitis (29%), bleeding (23%), perforation (6%), early stent migration (3%), and renal failure (3%). A meta-analysis found no difference in complication rates among stent models. Post-ERCP biliary infection, a serious complication that is fatal in 8% to 20% of cases, is best prevented by complete biliary drainage. Post-ERCP pancreatitis is usually mild but rarely may be fatal. Bleeding is associated with sphincterotomy but not with biliary stenting. Approximately 5% of plastic stents and partially covered SEMS migrate, whereas 1% of uncovered SEMS and 20% of FCSEMS migrate. After distal migration, most plastic stents are spontaneously eliminated. Migration of plastic stents is more frequent in benign strictures than in malignant biliary strictures, as well as with single compared with multiple stents. Endoscopic treatment of stent migration is feasible in more than 90% of cases, with low morbidity rates. In patients with stents that have migrated, ERCP is recommended for removing stents that have not been spontaneously eliminated and for stenting potentially persistent strictures. In cases of persistent biliary stricture, insertion of multiple plastic stents is recommended, or, if SEMS is indicated, an uncovered model. If SEMS cannot be extracted, in the case of distal migration its distal extremity can be trimmed; in the case of proximal migration with a persistent stricture, a second SEMS can be inserted within the first one. In cases of stent occlusion, endoscopic restoration is successful in more than 95% of patients. Plastic stents may be exchanged for plastic stents or SEMS. Mechanical SEMS cleaning does not appear to be very effective. Of 5 studies comparing SEMS and plastic stent insertion for occluded SEMS, 3 studies reported longer patency with SEMS (2 were statistically significant), and 1 study reported longer patency with plastic stents. Two recent studies found longer patency if 1 of the stents (initially or secondarily placed) was covered compared with 2 uncovered stents. SEMS-related acute cholecystitis has been reported in up to 10% of patients. Two large retrospective studies showed that tumor involvement of the cystic ductâ&#x20AC;&#x201D; plus the presence of gallbladder stone in one studyâ&#x20AC;&#x201D;but not the presence or absence of a covering on SEMS, is the main factor associated with post-ERCP cholecystitis. Hilar Strictures In the case of malignant hilar stricture, assessment of tumor resectability by computed tomography (CT)

or magnetic resonance imaging (MRI) may be affected by the presence of biliary stents. In cases of malignant hilar stricture of Bismuth-Corlette type II or greater, better biliary drainage may be achieved, with fewer infective complications, via the percutaneous compared with the endoscopic route. High-volume hospitals have higher ERCP success rates compared with low-volume hospitals. MRI is recommended over CT to assess malignant hilar stricture obstruction. Plastic and uncovered SEMS show similar short-term results, but SEMS offer longer patency and less need for reintervention, based on one RCT. Plastic stents are recommended, as long as no definitive decision about curative/palliative treatment has been made. If a decision for palliative treatment is made, insertion of SEMS is recommended in patients with a life expectancy of 3 months or longer, with biliary infection. If dysfunctional, plastic stents should be removed, ducts cleaned, and new stents inserted; with uncovered SEMS, stents are cleaned, and in the case of persistent stricture, new stents are inserted. Benign Strictures Temporary simultaneous placement of multiple plastic stents is technically feasible in more than 90% of patients. This endoscopic technique provides the highest long-term biliary patency rate (90% for postoperative biliary strictures; 65% in cases of complicating chronic pancreatitis). It requires a mean of approximately 4 ERCPs over a 12-month period. Possible stricture recurrences after this treatment are usually successfully retreated with ERCP. Temporary placement of a single plastic stent provides poorer patency rates. Treatment with uncovered SEMS is plagued by high long-term morbidity rates. Temporary placement of covered SEMS is an investigational option that needs to be carefully evaluated by long-term followup studies. Management of Common Duct Stones Cerefice et al reported on the temporary placement of covered SEMS (42 stents placed) in 36 patients with complex biliary stones and incomplete stone clearance after endoscopic retrograde cholangiography (ERC) with biliary sphincterotomy. Sixty percent of patients underwent mechanical and/or laser lithotripsy, and 38.8% of patients underwent endoscopic papillary balloon dilation during initial ERC before initial stent placement. Immediate short-term duct decompression was achieved in all patients. Four clinically insignificant stent migrations were discovered on the planned second ERC for stent removal and repeat attempt at duct clearance. Overall, 29 of 35 patients (83%; higher than reported in other studies) achieved complete biliary clearance during the repeat ERC with stent removal. Nineteen patients required balloon sweep extraction, while 10 patients had either 1 type of lithotripsy or a combination

of mechanical lithotripsy (n=9), laser lithotripsy (n=4), and biliary balloon dilation (n=6). Of the 6 patients with failed removal, stones were cleared with repeat endoscopic intervention (n=20), a second stent placement with clearance upon removal (n=3), or after removal of a fourth stent (n=1).

Types of Stents Plastic Biliary Stents The benefits of plastic stents include low cost and removability. They are durable for 3 to 5 months. Plastic biliary stents commonly become occluded with proteinaceous debris and bacterial biofilm. The common causes of benign intra- and extrahepatic strictures include postsurgical anastomosis (as a result of liver transplant, hepatic resection, or bile duct injury during cholecystectomy), chronic pancreatitis, autoimmune pancreatitis, primary sclerosing cholangitis, and choledocholithiasis. The treatment of choice in the past was surgical bypass. Today, strictures can be treated endoscopically by placing multiple large-caliber plastic stents side by side and exchanging them in multiple sessions for up to 1 year. The limitation is that this method for stricture resolution is only effective in 50% of patients. Plastic stents can be placed to divert the bile flow from the injured site down into the duodenum. There is still ongoing controversy about whether the placement of the stent across or below the leak is most effective for bile leak resolution. Pigtail Stents Nib Soehendra, MD, created the first single pigtail stent used for biliary drainage from an angiographic catheter in 1978. Since then, a variety of biliary stents have been created in different sizes, materials, and configurations. Pigtail stents are available in single and double pigtail types. They are made from polyethylene and are available in sizes 5 to 10 Fr. They have been used for pancreatic pseudocyst drainage, endoscopic transpapillary gallbladder drainage, and in the treatment of large obstructing bile duct stones. The single pigtail stent has a tapered tip at its proximal end and multiple side holes at both ends. The pigtail end is straightened over a guidewire to facilitate duct insertion and resumes its shape once the guidewire is withdrawn. This design anchors the stent in place and prevents stent migration. Straight Stents Cotton-Leung (Amsterdam): In 1984, Cook Medical Endoscopy collaborated with Joseph Leung, MD, and Peter Cotton, MD, to create a straight stent. The stent is made from polyethylene, a malleable material at lower temperatures. Its slightly C-curved design in mid-stent

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allows better conformity to the common bile duct. A single flap at each end also prevents stent migration. Its design overcame some limitations encountered with the pigtail stent: A 5-mm proximal end side hole allows better biliary drainage and flow, and a tapered proximal end permits easier passage across tight strictures. It has 3 side holes, 1 at the proximal end and 2 at the distal end. It is available in several diameters: 7, 8.5, 10, and 11.5 Fr, with variable lengths (measured between flaps), from 5 to 18 cm. This stent comes with a positioning sleeve to cover the distal flap as it is advanced through the working channel of the therapeutic endoscope (4.2 mm). The stent requires an introducer system for deployment. Soehendra-Tannenbaum: Made by Cook Medical Endoscopy, this stent is composed of Teflon. The material has a lower friction coefficient than polyethylene, which reduces accumulation of protein and debris in the stent. The absence of side holes also reduces turbulence within the stent to maintain longer stent patency. Its design is unique, with 4 anchoring flaps at each end. It is available in several diameters: 8.5, 10, and 11.5 Fr, with variable lengths (5-15 cm). It also requires an introducer system and comes with a positioning sleeve. Cotton-Huibregtse: This stent is similar to the CottonLeung stent, with the exception of the location of the C-curve near the distal end of the stent. It is available in several diameters (7, 8.5, 10, and 11.5 Fr), with variable lengths (5, 7, 9, 12, 15, and 18 cm). It also requires an introducer system and comes with a positioning sleeve. Advanix Biliary Stent With NaviFlex RX Delivery System: The Advanix Biliary Stent (Boston Scientific) is both shortand longwire-compatible. It has thin walls designed to maximize flow and extend patency. Its adjustable catheter length is designed for customized use. A preloaded stent system allows stent repositioning by attaching a suture at the distal end. The stent is available in diameters of 7, 8.5, and 10 Fr, and comes in several shapes, including the duodenal bend, center bend, and double pigtail. In 3 RCTs including 278 patients, Teflon-made stents had significantly lower short-term efficacy compared with polyethylene stents for benign obstruction. For benign CBD obstruction, temporary placements of multiple plastic stents have shown the highest clinical success rates with lower complication rates. For malignant CBD obstruction, plastic stents with a 10-Fr diameter have shown longer patency compared with smallercaliber stents. Metal Biliary Stents Table 3 outlines the features of uncovered and covered metal stents. Uncovered metal stents are indicated for permanent placement in patients with malignant biliary obstruction from unresectable cancer who have a short

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life expectancy. The stent embeds into tissue so that it cannot be removed. It typically becomes occluded from tissue ingrowth or hyperplasia. Metal stents are now being used for off-label indications, such as treatment of benign biliary strictures. The selection of metal stent type (uncovered, fully covered, or partially covered) remains dependent on the physician. Many studies have examined the differences and possible advantages of using one type over another. A review by Baron illustrates the multipurpose use and efficacy of covered metal stents for benign biliary diseases. The advantage of metal stents over plastic stents is durability, and in the case of covered metal stents, removability. In cases of malignant CBD obstruction, SEMS are more cost-effective if life expectancy is longer than 4 months. A study by Sangchan et al of unresectable complex hilar cholangiocarcinomas found SEMS to confer a greater survival benefit (median, 126 vs 49 days) with a higher rate of successful drainage (70.4% vs 46.3%). The covered metal biliary stent design is meant to overcome the limitations of plastic biliary stents: longer patency due to less tissue ingrowth and limited embedding into tissue. Several types of metal stents available in the United States are outlined in Table 3. All are compatible for MRI up to 1.5 Tesla, except where indicated. Early and late complications of covered SEMS placement include stent migration, perforation, pancreatitis, and cholecystitis. A retrospective study of 155 patients with malignant biliary obstruction showed that 9.7% developed cholecystitis after insertion of a covered metal stent, with cystic duct obstruction and presence of gallbladder stones being risk factors. Some studies have suggested that tissue ingrowth or occlusion of the cystic duct could be the possible reason for this complication. A randomized multicenter study by Telford et al compared uncovered versus partially covered SEMS for the palliative management of malignant biliary obstruction. Median time to recurrence of biliary obstruction and median survival times in the 2 groups did not differ significantly. However, 12% of patients in the group that received partially covered stents experienced migration, versus none of those who received uncovered devices. This rate of migration is much higher than that observed in previous studies, which found a 4% to 6% migration rate with the partially covered stent. With higher patient survival rates, the better removability of covered stents offers the advantage of allowing placement of a second stent. Kasher et al reported a 100% success rate in the removal of the Viabil FCSEMS in 37 patients. Some studies show no significant difference in patency rates and duration between initially placed and replacement stents after removal of initial stents. A study by Shah et al showed a novel use of covered SEMS. In 5 patients who underwent ERCP with biliary sphincterotomy complicated by difficult-to-control

post-sphincterotomy bleeding, complete hemostasis was achieved with temporary placement of a covered SEMS. Three patients had successful stent removal after 2 to 8 weeks. No complications occurred. However, 2 patients had a spontaneous stent migration noted on ERCP 4 weeks later, which may represent a significant risk to consider when using this method. Another study of 52 patients with unresectable malignant biliary obstruction evaluated the efficacy of a chemotherapeutic drugâ&#x20AC;&#x201C;eluting biliary stent for the treatment of unresectable malignant biliary obstruction. These advances will provide a variety of options for the interventional endoscopist to effectively treat hepatobiliary and pancreatic diseases.

Conclusion The evolution of biliary stents allows the endoscopist more versatility in treating benign and malignant conditions. Its application allows benign strictures to be treated endoscopically, whereas patients required a highly morbid surgical procedure in the past.

Suggested Reading Baron TH. Covered self-expandable metal stents for benign biliary tract diseases. Curr Opin Gastroenterol. 2011;27(3):262-267. Behm B, Brock A, Clarke BW, et al. Partially covered self-expandable metallic stents for benign biliary strictures due to chronic pancreatitis. Endoscopy. 2009;41(6):547-551. Chung MJ, Kim H, Kim KS, et al. Safety evaluation of self-expanding metallic biliary stents eluting gemcitabine in a porcine model. J Gastroenterol Hepatol. 2012;27(2):261-267. Classen M, Lightdale CJ, Tytgat G. Gastroenterological Endoscopy. New York, NY: Thieme Publishing Group; 2010:406-424. ConMed Corporation, www.conmed.com. Cook Medical, www.cookmedical.com. Costamagna G, Tringali A, Mutignani M, et al. Endotherapy of postoperative biliary strictures with multiple stents: results after more than 10 years of follow-up. Gastrointest Endosc. 2010;72(3):551-557. Dumonceau JM, Tringali A, Blero D, et al. Biliary stenting: indications, choice of stents and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy. 2012;44(3):277-298. Kahaleh M, Tokar J, Conaway MR, et al. Efficacy and complications of covered Wallstents in malignant distal biliary obstruction. Gastrointest Endosc. 2005;61(4):528-533. Kasher JA, Corasanti JG, Tarnasky PR, et al. A multicenter analysis of safety and outcome of removal of a fully covered self-expandable metal stent during ERCP. Gastrointest Endosc. 2011;73(6):1292-1297. Kim KO, Kim TN, Lee HC. Effectiveness of combined biliary and duodenal stenting in patients with malignant biliary and duodenal obstruction. Scand J Gastroenterol. 2012;8-9(47):962-967.

Sejpal D. Advancements in biliary stenting. J Clin Gastroenterol. 2012;46(3):191-196. Shah JN, Marson F, Binmoeller KF. Temporary self-expandable metal stent placement for treatment of post-sphincterotomy bleeding. Gastrointest Endosc. 2010;72(6):1274-1278. Song TJ, Lee SS, Yun SC, et al. Paclitaxel-eluting covered metal stents versus covered metal stents for distal malignant biliary obstruction: a prospective comparative pilot study. Gastrointest Endosc. 2011;73(4):727-733. Suk KT, Kim HS, Kim JW, et al. Risk factors for cholecystitis after metal stent placement in malignant biliary obstruction. Gastrointest Endosc. 2006;64(4):522-529. van Boeckel PG, Vleggaar FP, Siersema PD. Plastic or metal stents for benign extrahepatic biliary strictures: a systematic review. BMC Gastroenterol. 2009;9:96.

Colorectal Stenting Colorectal cancer can result in malignant obstruction. Therapies available for relieving obstruction are surgical resection and palliative colostomy. Emergent resections are usually associated with high morbidity and mortality, and stoma creation undermines patient psychological well-being and quality of life. Colorectal stenting offers a reasonable alternative to surgical intervention and provides long-term palliation in nonsurgical candidates.

Indications for Stenting in Colorectal Cancer Stenting can achieve long-term palliation in about 90% of patients who are not candidates for surgery. The role of palliative stenting for patients who are able to undergo surgery is less clear. Colonic stenting can convert a relatively emergent 2-step surgical procedure into an elective 1-step resection with a primary anastomosis. In patients with right-side obstructions, it is a 1-step emergent procedure to elective surgery. Patients who undergo the 1-step resection appear to have higher survival rates than those treated with tumor resection and subsequent reversal of colostomy. Other advantages include medical stabilization,

Table 4. Colonic Stents Available In the United States Manufacturer and Product Name

Diameter (mm)

Length (mm)

Boston Scientific WALLSTENT Colonic & Duodenal Endoprosthesis

20, 22 (internal diameter)

60, 90

WallFlex Colonic Stent

27, 30 (edges); 22, 25 (center)

60, 90, 120

Mahajan A, Ho H, Sauer B, et al. Temporary placement of fully covered self-expandable metal stents in benign biliary strictures: midterm evaluation (with video). Gastrointest Endosc. 2009;70(2):303-309.

Ultraflex Precision Colonic Stent System

30 (edges); 25 (center)

57, 87, 117

Sangchan A, Kongkasame W, Pugkhem A, et al. Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial. Gastrointest Endosc. 2012;76(1):93-99.

Cook Endoscopy 35 (edges); 25 (center)

40, 60, 80, 100, 120

Lawrence C, Romagnuolo J, Payne KM, et al. Low symptomatic premature stent occlusion of multiple plastic stents for benign biliary strictures: comparing standard and prolonged stent change intervals. Gastrointest Endosc. 2010;72(3):558-563.

Colonic Z-stent

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Table 5. Self-Expandable Metal Stents for Colorectal Obstruction Manufacturer and Model

Delivery System, diameter

Material

Deployed Diameter, mm/flares/flanges

Deployed Length, cm

Covering

Features

Boston Scientific WallFlex Colonic Stent

TTS, 10F

Nitinol

25 body/30-mm proximal flange; 22 body/27-mm proximal flange

6, 9, 12

Uncovered

Reconstrainable up to 70% of deployment; 39%-49% foreshortening during expansion

Ultraflex Precision Colonic Stent

Non-TTS, 16F

Nitinol

25 body/30-mm proximal flange

5.7, 8.7, 11.7

Uncovered

Nonreconstrainable; 23% foreshortening; string release closest to endoscope

Wallstent Colonic and Duodenal Endoprosthesis Stent

TTS, 10F

Stainless steel

20, 22/minimal to no flare

6, 9, 12

Uncovered

Reconstrainable up to 79% of deployment

Taewoong Medical Niti-S Enteral Colonic (D Type) Stent

TTS, 10F

Nitinol

18, 20, 22, 24/ no flare

6, 8, 10, 12 Uncovered

Reconstrainable up to one-third of deployment; 17% foreshortening during expansion

Niti-S Enteral Colonic (Head Type) Stent

TTS, 10F, 10.5F

Nitinol

18, 20/24-mm flanged ends

6, 8, 10, 12 Partially covered

Reconstrainable up to 70% of deployment; 50%-60% foreshortening during expansion

Nitinol (double layer)

18, 20/no flare

6, 8, 10, 12 Partially covered

Reconstrainable up to one third of deployment; 17% foreshortening during expansion

TTS, 10F

Nitinol

25, 30/both ends flanged

6, 8, 10

Uncovered

Controlled-release delivery system; reconstrainable up to 45% foreshortening during expansion

Hanarostent Colon/Rectum Stent

TTS, 10.2F, 10.5F; non-TTS, 24F

Nitinol

20, 22, 24/26, 28, 30, both ends flared/ available flanged and symmetric and asymmetric

6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16

Uncovered and fully covered

Reconstrainable up to 80% of deployment; 20%-35% foreshortening during expansion, with or without lasso

Choostent Colon/Rectum (CCC) Stent

Non-TTS

Nitinol

22, 24/30, 32, both ends flanged, available symmetric and asymmetric

6-17

Fully covered

20, 22, 25

8.2, 9, 11.3, 13.5

Uncovered and fully covered

ComVi Niti-S TTS, 10F, Enteral Colonic 10.5F Stent Cook Endoscopy Evolution Colonic Stent

M.I.Tech

ELLA-CS SX-ELLA Colorectal (Enterella) Stent

Non-TTS, Nitinol 15F (uncovered), 18F (covered)

35%-40% foreshortening during expansion

TTS, through the scope Source: Baron TH, Wong Kee Song LM, Repici A. Role of self-expandable stents for patients with colon cancer. Gastrointest Endosc. 2012;75(3):653-662.

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Table 5. Self-Expandable Metal Stents for Colorectal Obstruction (Continued) Material

Deployed Diameter, mm/flares/flanges

Deployed Length, cm

TTS, 10F and 12F

Nitinol

22, 24, 26 (f)

6, 8, 10

EGIS Colorectal Stent

TTS, 10F

Nitinol

20, 22

6, 8, 10, 12 Uncovered single or double; covered single or double

Hercules SP Colorectal Stent Dual Type

Non-TTS

Nitinol

28 outer, 18 inner

11, 13, 15, 17, 19 (outer)

Inner uncovered, outer partially covered

Nitinol

30/36, both ends flared

8, 10

Uncovered

8, 10, 12

Uncovered and partially covered

Manufacturer and Model

Delivery System, diameter

Covering

Features

EndoChoice BONASTENT

Uncovered Non-foreshortening and partially covered

S&G Biotech

Composed of 2 separate stents, sequentially deployed

Leufen Medizintechnik OHG Eco-stent

Non-TTS

MICRO-TECH Europe (Dusseldorf, Germany) MICRO-TECH Colon and Rectum Stent

TTS, non-TTS

Nitinol

30/36 25/30 (covered)

TTS, through the scope Source: Baron TH, Wong Kee Song LM, Repici A. Role of self-expandable stents for patients with colon cancer. Gastrointest Endosc. 2012;75(3):653-662.

assessment and management of underlying comorbidities, optimal staging through imaging, and the possibility of laparoscopic imaging. There is a controversial role for colonic stenting in benign causes of colonic obstruction, such as diverticulitis and benign inflammatory strictures. Stenting might only be considered in the setting of emergent decompression before planned elective surgery, as the rate of complications of stenting for benign disease is higher.

Equipment and Technique Stents used to treat colonic obstruction can be covered or uncovered. Colonic stents available in the United States are outlined in Table 4. A comprehensive list of colonic stents used to treat colonic obstruction in patients with colon cancer is presented in Table 5. Colonic stents can be placed endoscopically with or without the aid of fluoroscopy. Some argue that

fluoroscopic markings are not necessary because the tumor can be visualized endoscopically. Prior imaging, such as barium enema or CT with rectal contrast before stent placement, is ideal to assess stricture length and degree of obstruction. For partially obstructing lesions, an attempt should be made to traverse the lesion with the colonoscope; if not feasible, a guidewire should be inserted under fluoroscopic guidance. The length of the stricture should be assessed again with contrast injection under fluoroscopy. If not using TTS, the stent should be passed over the guidewire to the level of the obstruction, and the colonoscope should be reintroduced so that deployment under endoscopic visualization can be done. In both techniques, the stent should be passed until its tip is proximal to the tumor. Ideally, the stent should be exposed 2 cm proximally and distally so that a “waist” in the stent and a flare at the edges can be observed.

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Efficacy According to a systematic review, technical success, defined as successful stent placement and deployment, is achieved in more than 95% of the patients. A recent prospective study of SEMS placement for malignant colorectal obstruction in 447 patients reported a procedural success rate of 94.8% (439 of 463 cases) and clinical success rates of 90.5% and 71.6% assessed on a per-protocol basis and an intent-to-treat basis, respectively. Complications included 15 perforations (3.9%; 3 resulting in death), 7 migrations (1.8%), 7 cases of pain (1.8%), and 2 cases of bleeding (0.5%). Clinical success, achieving colonic decompression, is achieved in more than 90% of patients. Notably, the median duration of patency was 106 days and the median rate of reintervention was approximately 20%. However, these data are derived from case series and small trials. A recent randomized trial from the Netherlands revealed no clinical advantage of stenting over emergency surgery for acute left-sided malignant colonic obstruction. However, the study had a technical success rate of only 70% (lower than the 95% described in the literature) and a perforation rate of 13% (higher than the 4.5% risk known). In contrast, in a prospective study of 182 patients, the largest to date, Jiménez-Pérez et al demonstrated that SEMS is an effective bridge to surgery. Technical and clinical success rates were 97.8% and 94%, respectively. Elective surgery was performed in 89.8% of patients, with only a 6% stoma creation rate. The overall complication rate was 7.8%; perforation occurred in 3% of patients, migration in 1.2%, bleeding in 0.6%, persistent colonic obstruction in 1.8%, and fecal impaction in 1.2%. Most of the stents used in the major studies reviewed are uncovered. A randomized trial compared covered stents with uncovered ones; technical and clinical success rates were almost identical. There were higher rates of stent migration in the covered arm of the study and higher rates of tumor ingrowth in the uncovered stent arm of the study.

Complications Complications from colorectal stenting are classified as early or late and include abdominal pain, bleeding, and perforation (early and delayed); recurrence of obstruction, tumor invasion, ingrowth, and overgrowth (late); and stent migration.

Conclusion Colorectal stenting has been considered the procedure of choice for the treatment of acute malignant colonic obstructions in nonsurgical candidates. It also has an important role in the palliation of advanced disease. It is a minimally invasive technique with a high technical and clinical success rate and a relatively low complication rate. More studies are needed to assess long-term outcomes of colonic stents in colorectal cancer and the use of stents for nonmalignant obstructions.

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Suggested Reading Baron TH. Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med. 2001;344(22):1681. Baron TH, Wong Kee Song LM, Repici A. Role of self-expandable stents for patients with colon cancer (with videos). Gastrointest Endosc. 2012;75(3):653-662. Bonin EA, Baron TH. Update on the indication and use of colonic stents. Curr Gastroenterol Rep. 2010;12(5):374-382. Costamagna G, Shah SK, Tringali A, et al. Prospective evaluation of a new self-expanding plastic stent for inoperable esophageal strictures. Surg Endosc. 2003;17(6):891-895. Holm AN, de la Mora Levy JG, Gostout CJ, et al. Self-expanding plastic stents in treatment of benign esophageal conditions. Gastrointest Endosc. 2008;67(1):20-25. Jeurnink SM, Steyerberg EW, van Hooft JE, et al; Dutch SUSTENT Study Group. Surgical gastrojejunostomy or endoscopic stent placement for the palliation of malignant gastric outlet obstruction (SUSTENT study): a multicenter randomized trial. Gastrointest Endosc. 2010;71(3):490-499. Jeurnink SM, van Eijck CH, Steyerberg EW, et al. Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: a systematic review. BMC Gastroenterol. 2007;7:18. Jiménez-Pérez J, Casellas J, García-Cano J, et al. Colonic stenting as a bridge to surgery in malignant large-bowel obstruction: a report from two large multinational registries. Am J Gastroenterol. 2011;106(12):2174-2180. Khot UP, Wenk Lang A, et al. Systematic review of the efficacy and safety of colorectal stents. Br J Surg. 2002;89(9):1096-1102. Langer FB, Wenzi E, Prager G, et al. Management of postoperative esophageal leaks with the Polyflex self-expanding covered plastic stent. Ann Thorac Surg. 2005;79(2):398-403. Lopera JE, Brazzini A, Gonzales A, et al. Gastroduodenal stent placement: Current status. Radiographics. 2004;24(6):1561-1573. Meisner S, González-Huix F, Vandervoort JG, et al. Self-expandable metal stents for relieving malignant colorectal obstruction: short-term safety and efficacy within 30 days of stent procedure in 447 patients. Gastrointest Endosc. 2011;74(4):876-884. Repici A, Vleggaar FP, Hassan C, et al. Efficacy and safety of biodegradable stents for refractory benign esophageal strictures: the BEST (Biodegradable Esophageal Stent) study. Gastrointest Endosc. 2010;72(5):927-934. van Hooft JE, Bemelman WA, Oldenburg B, et al; collaborative Dutch Stent-In study group. Colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction: a multicentre randomised trial. Lancet Oncol. 2011;12(4):344-352. Watt AM, Faragher IG, Griffin TT, et al. Self-expanding metallic stents for relieving malignant colorectal obstruction: a systematic review. Ann Surg. 2007;246(1):24-30. Yoon JY, Jung YS, Hong SP, et al. Outcomes of secondary stent-in-stent self-expandable metal stent insertion for malignant colorectal obstruction. Gastrointest Endosc. 2011;74(3):625-633. Yoon JY, Jung YS, Hong SP, et al. Clinical outcomes and risk factors for technical and clinical failures of self-expandable metal stent insertion for malignant colorectal obstruction. Gastrointest Endosc. 2011;74(4):858-868.

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The Barrx™ Channel RFA Endoscopic Catheter offers the same ablation capabilities as the widely-accepted focal and balloon catheters, delivering controlled depth of coagulation for Barrett’s esophagus and other bleeding and non-bleeding conditions of the GI tract, but now through the working channel of a ﬂexible endoscope.1,2

References 1. P/N V-0234-02 (A), Report, Channel Design Veriﬁcation Testing. On ﬁle at Covidien, GI Solutions. 2. Barrx™ Channel RFA Endoscopic Catheter Instructions For Use (IFU). COVIDIEN, COVIDIEN with logo, Covidien logo and positive results for life are U.S. and internationally registered trademarks of Covidien AG. Other brands are trademarks of a Covidien company. ©2014 Covidien. 6.14 US130064

MCGEN2124.indd 1

13/06/14 4:42 PM

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Endoscopic Eradication Therapy for Barrett’s Esophagus SHREYAS SALIGRAM, MD, MRCPa,b PRASHANTH VENNALAGANTI, MDa PRATEEK SHARMA, MDa,b a

Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Kansas City, Kansas Dr. Sharma has received grant support from Barrx Medical, CDX Labs, Cook Medical, Ninepoint Medical, and Olympus Inc. Drs. Saligram and Vennalaganti reported no relevant financial conflicts of interest.

arrett’s esophagus (BE) is the precursor lesion to esophageal adenocarcinoma, which in an invasive stage causes significant morbidity and mortality. Surgery was the mainstay of treatment for patients with high-grade dysplasia (HGD) and adenocarcinoma associated with BE. However, surgery in itself carries i substantial b t ti l morbidity. There has been tremendous progress in the minimally invasive treatment of BE in the past decade.

The premise to be aggressive in treating dysplastic BE and early-stage adenocarcinoma is to prevent progression to an advanced-stage cancer. Most interventional endoscopists are comfortable treating dysplasia and intramucosal esophageal cancer, although recently there have been emerging data on the treatment of early submucosal cancer in BE. This article reviews the different modes of and strategies for endoscopic treatment of BE with emphasis on newer techniques.

Barrett’s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (IM; goblet cells) proximal to the gastroesophageal junction. The overall population prevalence is estimated at 1.6%1 with an annual incidence of 62 per 100,000.2 In patients with BE, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12% and 0.5%.3-6 Intestinal metaplasia can have a histologic transformation from no dysplasia to low-grade dysplasia (LGD),

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HGD, and eventually to esophageal adenocarcinoma.7 Patients with HGD have the highest tendency to progress to esophageal adenocarcinoma. Therefore, endoscopic eradication therapy increasingly is used to treat HGD and early esophageal adenocarcinoma to decrease the progression to invasive disease. Data from the US National Cancer Institute show a 6-fold increase in the incidence of esophageal adenocarcinoma in 2001; the disease now is considered the fastest rising cancer in the United States.8

Rationale for Endoscopic Eradication Barrettâ&#x20AC;&#x2122;s esophagus has the potential to transform into esophageal adenocarcinoma by genetic alteration of IM, where there is unregulated cell growth due to inactivation of tumor suppressor genes and activation of oncogenes. This genetic activity causes a morphologic change in the lining of the epithelium of the esophagus called dysplasia (cytologic atypia, architectural complexity due to nuclear pleomorphism and hyperchromatism confined to basement membrane).9,10 The aim of ablation/eradication therapy is to destroy this abnormal lining of the esophagus and reinstate the neosquamous epithelium.

Natural History of Dysplasia in BE Before embarking on endoscopic therapy for BE, it is important to understand the risks for dysplasia and cancer in these patients. Contemporary literature suggests that the reported rate of progression of cancer or dysplasia from IM, or nondysplastic BE, is low.6 Nondysplastic BE, which is the early stage of the condition, has the lowest incidence of transforming to dysplasia or esophageal adenocarcinoma. A retrospective study of 1,204 patients diagnosed with nondysplastic BE during index endoscopy and followed for a mean period of 5.52 years found that 98.6% and 97.1% were cancer free after 5 and 10 years, respectively. Per-year incidence of esophageal adenocarcinoma was reported to be 0.27%, 0.48% for HGD, and 3.6% for LGD.11 A recent meta-analysis, which included 11,434 patients diagnosed with nondysplastic BE and followed for 58,547 patient-years, reported a low annual incidence of cancer, at 0.3%.12 Similar findings were reported from a large population-based study from Denmark, which found that the risk for cancer in patients with nondysplastic BE was less than 0.2% per year. Low-grade dysplasia has a lower degree of dysplastic cells and is the initial stage of dysplasia. Several studies have shown varying results for LGD developing into HGD or cancer. A multicenter study including 210 patients with LGD followed for an average of 6.2 years reported a low incidence of esophageal adenocarcinoma (0.44% per year) and HGD (1.6% per year). Combined esophageal adenocarcinoma and HGD was 1.83% per year with a mean time of progression to esophageal adenocarcinoma of 4.41 years. Based on survival analysis, 97.4% of patients were cancer free after 5 years of

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follow-up.13 Based on this study, only 2.6% of patients developed cancer at the end of 5 years; overall, patients with LGD had a low risk for developing malignancies. However, other studies found a higher incidence (up to 13.6% per year) of combined HGD and esophageal adenocarcinoma developing from LGD.14-16 This inconsistent incidence in the rate of LGD that becomes HGD and cancer was long suspected to reflect a sampling error and significant interobserver variability among pathologists.13,17 The natural course of LGD thus appears to be highly variable. A recent multicenter randomized controlled trial from Europe suggested higher rates of progression of LGD to cancer. The study included 136 patients with LGD; 68 were randomized to undergo radiofrequency ablation (RFA) and 68 were monitored by surveillance endoscopy every 6 to 12 months. After 3 years of follow-up, 1.4% of patients undergoing RFA and 8.8% being followed without RFA developed esophageal adenocarcinoma.18 By comparison, a recent meta-analysis of cancer risk in patients with LGD (24 studies; 2,694 patients) showed a 0.5% risk for cancer.19 Clearly, LGD remains a difficult disease to diagnose. High-grade dysplasia has a greater prevalence of dysplastic cells and is the advanced stage of dysplasia. Timely treatment at this stage can prevent dysplasia from progressing to cancer. A 2008 meta-analysis found a high incidence of esophageal adenocarcinoma (6% per year) in patients with HGD who had not undergone ablation or surgery. Of the 236 patients who met the inclusion criteria for the study, 69 developed esophageal adenocarcinoma within 1.5 to 7 years of followup.20 A multicenter sham control trial in 2009 randomly assigned 63 patients with HGD to receive either RFA or sham procedure and followed them for 12 months. Although 19% of the patients in the control group experienced spontaneous regression of dysplasia, a significant proportion progressed to esophageal adenocarcinoma.21 These data and the meta-analysis show beyond doubt that untreated HGD has a significant risk for developing into cancer.

Endoscopic Eradication Esophagectomy is effective in treating early-stage esophageal adenocarcinoma but is a radical therapy and carries a significant morbidity (30%-40%) and mortality (1%-4%).22-27 Therefore, it is used for patients at a high risk for or with the presence of lymph node metastasis. A systematic review of 1,350 patients who underwent esophagectomy for intramucosal (T1a) esophageal adenocarcinoma showed that only 26 (1.39%) had lymph node metastasis in the final pathology.28 A retrospective review of 70 patients with T1a esophageal adenocarcinoma and 56 patients with submucosal (T1b) esophageal adenocarcinoma revealed lymph node metastasis in 1.3% and 22%, respectively. Lymphovascular invasion, tumor size of at least 2 cm in diameter, and poor differentiation

Table. Endoscopic Eradication Therapy for Barrettâ&#x20AC;&#x2122;s Esophagus Thermal ablation therapy

Argon plasma coagulation Laser therapy Multipolar electrocoagulation

Nonthermal ablation therapy

Cryotherapy Photodynamic therapy Radiofrequency ablation

Endoscopic resection

Endoscopic mucosal resection Endoscopic submucosal dissection

were associated with an increased risk for lymph node metastasis.29 All T1b lesions, regardless of the depth of T1b (SM1 indicates invasion into the superficial third of the submucosa, SM2 invasion into the middle third, and SM3 invasion into the deepest third of the submucosa), were associated with significant lymph node metastasis (12.9%-20.4%).30 The risk for lymph node metastasis in early esophageal adenocarcinoma therefore is low and endoscopic eradication therapy can be attempted in the vast majority of patients with T1a lesions. However, endoscopic eradication therapy typically is precluded in patients with T1b esophageal adenocarcinoma because of the higher risk for metastasis to the lymph node. To obtain accurate tumor staging of visible lesions and patients with esophageal cancer, endoscopic mucosal resection (EMR) is performed to assess depth of the lesion. In patients with known cancer on biopsies, the accuracy of TNM staging is enhanced when endoscopic ultrasound is combined with EMR.31 After accurate staging and resection of early esophageal adenocarcinoma, it is important to ensure that the rest of the BE is eradicated completely to prevent recurrence of cancer. A retrospective study of 349 patients treated with ablation therapy for BE found occurrence of metachronous lesions in 21.5% of patients at a median of 15 months. The metachronous lesions were not found in the group that had undergone complete eradication of IM (CE-IM).32 The current practice for endoscopic eradication therapy of BE is resection of any visible lesions by EMR, ablation of residual BE to prevent metachronous lesions or recurrent neoplasm, and follow-up surveillance. Multimodal endoscopic eradication therapy with EMR and RFA commonly is used. Visible or flat lesions are described by Paris classification33 and endoscopic inspection for visible or flat lesions is performed under white light endoscopy.

Advanced imaging techniques including chromoendoscopy and virtual chromoendoscopy; optical frequency domain imaging; or confocal laser endomicroscopy are available but underused. A recent meta-analysis showed that detection of HGD or cancer increased by 34% when clinicians used advanced imaging techniques.34 Based on the available evidence, the American Gastroenterology Association issued guidelines for endoscopic surveillance and eradication therapy of BE. Endoscopic surveillance should be performed every 3 to 5 years for nondysplastic BE, every 6 to 12 months for LGD, and every 3 months for HGD if endoscopic eradication therapy is not performed. All patients with dysplasia should have the diagnosis confirmed by at least 2 experienced gastrointestinal pathologists. The treatment of early-stage dysplastic lesions is controversial given the variability in the diagnosis and natural history. In a recently concluded multicenter study, which classified LGD as inflammatory and dysplastic, interobserver agreement among expert pathologists was poor, with kappa values for inflammatory and dysplastic lesions of 0.03 and 0.04, respectively. The overall kappa value for LGD was 0.2.35 The aim of endoscopic eradication therapy should be to eradicate BE completely once dysplasia has been eradicated to prevent the progression of residual IM to recurrent or metachronous neoplasia.36

Modalities of Endoscopic Eradication The different modalities of endoscopic eradication therapy are listed in Table. The advent of RFA as primary therapy has displaced some of the older therapies like thermal (multipolar electrocoagulation, argon plasma coagulation, Yag laser) and nonthermal (photodynamic therapy) methods.37 Argon plasma coagulation for eradication of residual BE tissue after use of EMR and/or RFA is still used for the treatment of focal areas. Endoscopic resection consists of 2 approaches, EMR and endoscopic submucosal dissection (ESD), depending on the depth of the tissue removed. Endoscopic Mucosal Resection The 2 types of EMR that can be performed are focal and radical, or wide area.38 Focal EMR is a technique used to excise visible polypoid, flat, or nodular lesions of esophageal mucosa suspected to be harboring cancer. It serves both as a diagnostic tool for tumor staging and also as a therapeutic tool for excising the neoplastic lesion. Two commonly used techniques are the multiband ligator and the cap-assisted device.39 The multiband ligator 40 uses suction to draw lesions into a cap and a rubber band is applied to create a pseudopolypoid lesion, which is then snared using electrocoagulation and the specimen is subsequently retrieved. The cap-assisted technique41 uses saline or diluted epinephrine (1:100,000) to lift the suspected lesion. A prelooping of the snare to the rim of the transparent cap

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 4

Figure 1. Barrett’s esophagus with visible lesion before and after endoscopic mucosal resection.

attached to the endoscope tip is performed after raising the suspected lesion. The raised lesion is then sucked into a cap, creating a pseudopolyp, which is then snared by electrocoagulation before the specimen is retrieved (Figure 1). Radical EMR is used to remove larger areas of BE. Side-by-side resections can achieve complete eradication of the neoplastic and metaplastic tissue, and the procedure is repeated every 2 to 3 months until all visible BE has been removed. This technique frequently is used in patients with noncircumferential BE, and those with maximal extents of lesions up to 4 to 5 cm in diameter. Short-Term Results: Few studies have used EMR as the sole treatment for eradication of all BE tissue. The majority of studies have used a multimodal approach, such as initial focal EMR followed by ablation to evaluate the efficacy of EMR in treating HGD and early esophageal adenocarcinoma. A retrospective study of 49 patients (67% HGD and 33% T1a adenocarcinoma) who underwent radical EMR with a mean follow-up of 22.9 months reported CE-IM in 97% of cases. No recurrence of dysplasia or cancer was observed in the 32 patients who completed the eradication protocol. However, nearly one-third of patients developed symptomatic stenosis that was successfully dilated.42 A multicenter randomized clinical trial enrolled 25 patients in a radical EMR group and 22 patients in combined modality group (focal EMR with ablation therapy). During a mean follow-up of 24 months, 92% of patients in the radical EMR group achieved CE-IM compared with 96% in the combined modality group;

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similar high rates of CE-dysplasia or cancer were observed (all patients in the radical EMR group vs 96% in the group receiving combined modality).43 Based on these studies and several others, radical EMR appears to have good short-term efficacy in treating HGD and early esophageal adenocarcinoma.44,45 Long-Term Results: Robust data now exist for longterm efficacy of EMR in patients with HGD and early esophageal adenocarcinoma. A prospective study of 100 T1a patients who underwent EMR with a mean follow-up of 36.7 months revealed CE-dysplasia or cancer in 99%—with metachronous lesions noted in 11%—that was successfully retreated with EMR.46 A retrospective study of 132 T1a patients with a mean follow up of 43 months found that of the 75 patients who underwent EMR alone, 96% achieved CE-dysplasia or cancer, with 11% recurrences. All were successfully treated with a repeat EMR.47 Another recent retrospective study of 76 patients with HGD or T1a cancer who underwent radical EMR and were followed for a mean of 40.6 months reported a CE-IM rate of 71% and CE-dysplasia or cancer in 100%.48 Complications: Adverse events associated with EMR generally are uncommon. Dysphagia, strictures requiring dilation,43,49-53 bleeding—both immediate and delayed for more than 48 hours after the procedure42,53-56—chest pain, and perforation are among the reported complications.57 Resection of more than 50% of the esophageal circumference is associated with higher rates of strictures.50 Radical EMR has been linked to more complications than focal EMR, including a high rate of strictures.42,43,57-62

Figure 2. Barrettâ&#x20AC;&#x2122;s esophagus before and after radiofrequency ablation.

Endoscopic Submucosal Dissection This technique is used for en bloc resection of larger lesions. Pioneered in Japan mainly for early gastric lesions, the practitioner uses a coagulation tip to mark around the lesion. Diluted epinephrine with 10% glycerol (multiple other agents like hyaluronidate, mannitol, epinephrine, and indigo carmine can be used as well) is injected into submucosa to separate the lesion from the muscle layer. The mucosa initially is resected by needle knife and subsequently submucosal fibers and vessels by hook knife. The resected lesions are obtained for histopathology. The advantage of ESD over EMR is that larger lesions (7 cm) can be resected en bloc and more accurate information about depth of the lesion can be obtained.63,64 Short-Term Results: A single published study evaluated the outcome of ESD. The trial included 29 patients known to have large T1a cancers, with a median diameter of 2 cm, in the setting of BE. The patients underwent ESD. They were followed for a mean period of 17 months. An R0 resection was achieved in only 38.5% of the patients. CE-IM and neoplasia was achieved in 53.6% and 96.4% of patients, respectively. The CE-IM rate increased to 80% when additional treatment with RFA was performed.65 Long-Term Results: As ESD is relatively new, few studies have reported the long-term efficacy of the technique. One such study, of 25 patients (both T1a and T1b) who underwent the procedure with a mean follow-up of 30.6 months, showed that en bloc resection was achieved in 100% of patients but R0 resection was attained in only 72%. The mean size of

resected lesions was 1.6 cm. There were no reports of neoplasia recurrence among patients who achieved R0 resection.64 Complications: Although the data are limited, published reports suggest that complications in expert hands are minimal. Some of the known complications are delayed bleeding, sudden cardiac death, incomplete R0 resection, and strictures.64,65 Radiofrequency Ablation Radiofrequency ablation is the most commonly used and best studied ablative therapy currently available for the treatment of BE (Figure 2). RFA can be performed with either a circumferential or focal device. The circumferential ablation device has a 3-cm cylindrical balloon with circular electrodes delivering the preset energy to ablate in a circumferential fashion. The focal ablation device is placed over the tip of the endoscope to ablate smaller areas with preset energy. Short-Term Results: Several published studies have evaluated the short-term efficacy of RFA, which appears to be excellent. A retrospective registry study from 19 centers in the United Kingdom included 335 patients (HGD, 72%; T1a esophageal adenocarcinoma, 24%; and LGD, 4%) treated with either focal EMR and RFA (49%) or RFA alone (51%). After a mean of 2.5 treatments and 12 months of follow-up, CE-IM and CE-dysplasia were achieved in 62% and 81% patients, respectively. Invasive cancer developed in 3% of patients and the cumulative risk for cancer progression more than 5 years was 8%.66 Another retrospective study of a U.S. cohort of 54 patients with

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Figure 3. Barrett’s esophagus before and after cryotherapy.

T1a cancer who underwent focal EMR combined with ablation therapy (81%) with a mean follow-up of 23 months, reported CE-dysplasia/cancer in 96% and CE-IM in 59%.53 A recent meta-analysis that included 3,802 patients from 18 studies evaluated the efficacy of RFA in treatment of BE during a 20.5-month followup period. The overall rates of CE-IM and CE-dysplasia were 78% and 91%, respectively.67 A recent Cochrane review of 1,074 patients from 16 studies evaluated the efficacy of RFA in treatment of BE during a 12-month follow-up period. The overall rates of CE-IM and CEdysplasia were 82% and 94%, respectively.37 Thus, based on the available evidence, short-term efficacy for RFA for CE-IM has been reported to be 62% to 82%, and CE-dysplasia as 81% to 94%. Cancer recurrence was seen in 3% of patients at the end of 12 months. Long-Term Results: Several recent studies have focused on the long-term efficacy of RFA therapy after achieving initial successful eradication of BE. A multicenter analysis of 448 patients (HGD, 60%; T1a esophageal adenocarcinoma, 11%; LGD, 15%; and nondysplastic BE, 14%) who underwent EMR (55%) and RFA revealed that CE-IM was achieved in 26%, 56%, and 71% at 1, 2, and 3 years, respectively. Kaplan-Meier analysis showed that the incidence of recurrent IM at 1 and 2 years was 20% and 33%, respectively. Younger patients and those with short-segment BE responded much better to RFA.68 A single-center long-term retrospective study on BE was conducted of 72 patients (HGD, 49%; T1a esophageal adenocarcinoma, 22%; and LGD, 17%). All patients underwent RFA alone. After a mean of 2.3 treatments and 9.5 months of follow-up, CE-IM and CE-dysplasia were achieved in 79% and 89% of patients, respectively. Superficial adenocarcinoma persisted in 5% of patients requiring esophagectomy.

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Thirty-four patients who achieved CE-IM were followed for 3 years with no further recurrences noted. The overall rate of CE-IM was 73%.69 RFA therefore appears to have excellent short-term efficacy in achieving CE-IM (71%-93%) and CE-dysplasia (98%-100%). However, during long-term follow up, 15% to 30% of the patients can experience recurrence of IM within 2 to 3 years of achieving CE-IM, thereby requiring ongoing surveillance. Complications: RFA is generally well tolerated. Bleeding, mucosal tears, dysrhythmias, chest pain, buried metaplasia (IM buried under neosquamous epithelium),70 recurrent esophageal adenocarcinoma, and HGD66,71-75 are among the reported complications. A systematic review in 2011 showed that of 1,004 patients who underwent RFA, only 0.9% had buried metaplasia.70 Cryotherapy Cryotherapy is a relatively new technique to ablate BE, using an extremely low temperature—between –76°C and –158°C76—to target tissue for destruction and ablation (Figure 3). A repetitive cycle of rapidfreezing and slow-thawing results in the formation of extracellular and intracellular ice, which disrupts cell membranes and tissue ischemia through vascular thrombosis due to vascular stasis.76-78 Two types of cryotherapy devices are available: CSA Medical, Inc., with a modified cryo-decompression tube, delivers liquid nitrogen at –196°C, and GI Supply, with a suction catheter attached to the tip of the endoscope, uses high-pressure gas carbon dioxide at –78°C. The depth of the tissue injury depends on the duration of the freeze time. The technical advantage of cryotherapy over other

ablative therapies is that it is easy to spray over large areas of mucosa, causing destruction without precise close contact. Hence, it is particularly helpful in tortuous esophageal anatomy and at the area of the gastroesophageal junction. However, both robust short- and long-term results are lacking with this technique.

but more evidence regarding its long-term efficacy is required. Continued surveillance after achieving CE-IM is recommended due to risk for recurrence of intestinal metaplasia, buried metaplasia, and subsequent development of neoplasia.73,84

References Short-Term Results: Two small observational studies reported the short-term efficacy of cryotherapy. A retrospective study of 60 patients followed for a mean period of 10.5 months found that after a mean of 3.4 treatments of liquid nitrogen cryotherapy, CE-dysplasia was achieved in 87% and CE-IM in 57% of treated patients.79 In another small study, 30 patients with BE (HGD-25 and T1a-5) underwent liquid nitrogen cryotherapy and were followed up for a mean of 12 months. There was downgrading of pathology in 90% of the patients with a mean of 5 sessions. The reported rates of CE-IM, and CE-dysplasia/cancer were 3.3% and 60%, respectively.80 Finally, a trial of 23 patients treated with 6 treatments of carbon dioxide cryotherapy and followed for a mean of 11.5 months found CE-IM and CEdysplasia in 95.6% of patients. Twenty-five of these patients had failed earlier treatment with RFA, photodynamic therapy, and EMR.81

Wang KK, Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol. 2008;103(3):788-797.

Coleman HG, Bhat S, Murray LJ, et al. Eur J Epidemiol. 2011;26(9):739-745.

de Jonge PJ, van Blankenstein M, Looman CW, et al. Gut. 2010;59(8):1030-1036.

Shaheen NJ, Crosby MA, Bozymski EM, et al. Gastroenterology. 2000;119(2):333-338.

Bhat S, Coleman HG, Yousef F, et al. J Natl Cancer Inst. 2011;103(13):1049-1057.

Hvid-Jensen F, Pedersen L, Drewes AM, et al. N Engl J Med. 2011;365(15):1375-1383.

Schlemper RJ, Riddell RH, Kato Y, et al. Gut. 2000;47(2):251-255.

Pohl H, Welch HG. J Natl Cancer Inst. 2005;97(2):142-146.

Spechler SJ. Am J Gastroenterol. 2005;100(4):927-935.

10.

Goldblum JR. Mod Pathol. 2003;16(4):316-324.

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Wani S, Falk G, Hall M, et al. Clin Gastroenterol Hepatol. 2011;9(3):220-227.

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Desai TK, Krishnan K, Samala N, et al. Gut. 2012;61(7):970-976.

Long-Term Results: A single retrospective study including 32 patients with HGD evaluated the longterm efficacy of cyrotherapy. Patients underwent a mean of 4 treatments and were followed for a mean 37 months. In this study, CE-HGD was achieved in 96% and CE-IM in 81% of patients.82

13.

Wani S, Falk GW, Post J, et al. Gastroenterology. 2011;141(4):11791186.e1.

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Curvers WL, ten Kate FJ, Krishnadath KK, et al. Am J Gastroenterol. 2010;105(7):1523-1530.

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Montgomery E, Bronner MP, Goldblum JR, et al. Hum Pathol. 2001;32(4):368-378.

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Montgomery E, Goldblum JR, Greenson JK, et al. Hum Pathol. 2001;32(4):379-388.

Complications: Adverse effects reported with cryotherapy usually are self-limiting. Chest pain and dysphagia are the predominant complications with minimal stricture and rare perforation. Odynophagia and sore throat are some of the other known complications.79,80,83

17.

Sharma P. Gastroenterology. 2004;127(4):1233-1238.

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Phoa KN, van Vilsteren FG, Weusten BL, et al. JAMA. 2014;311(12):1209-1217.

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Singh S, Manickam P, Amin AV, et al. Gastrointest Endosc. 2014;79(6):897-909.

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Rastogi A, Puli S, El-Serag HB, et al. Gastrointest Endosc. 2008;67(3):394-398.

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Shaheen NJ, Sharma P, Overholt BF, et al. N Engl J Med. 2009;360(22):2277-2288.

Summary Current evidence suggests that multimodal endoscopic eradication therapy with focal EMR and RFA is the best therapy for treatment of BE with HGD and T1a esophageal adenocarcinoma and should be the preferred management option over surgery. Defining LGD continues to remain a challenge with poor interobserver agreement and wide variability rates in cancer progression reported in the literature (0.5% in a recent meta-analysis to 8.8% in a randomized controlled trial in Europe). Radical EMR is associated with more complicatio ns than focal EMR. Endoscopic submucosal dissection is technically challenging, with low R0 resection rates, making it less attractive. Therefore, the procedure is still in an incipient stage. Cryotherapy appears promising due to its low cost and the ease of the procedure,

22.

Altorki NK, Lee PC, Liss Y, et al. Ann Surg. 2008;247(3):434-439.

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Griffin SM, Burt AD, Jennings NA. Ann Surg. 2011;254(5):731-736.

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Zehetner J, DeMeester SR, Hagen JA, et al. J Thorac Cardiovasc Surg. 2011;141(1):39-47.

26.

Pech O, Bollschweiler E, Manner H, et al. Ann Surg. 2011;254(1):67-72.

27.

Tseng EE, Wu TT, Yeo CJ, et al. J Gastrointest Surg. 2003;7(2):164-170.

28.

Dunbar KB, Spechler SJ. Am J Gastroenterol. 2012;107(6):850-862.

29.

Leers JM, DeMeester SR, Oezcelik A, et al. Ann Surg. 2011;253(2):271-278.

30.

Badreddine RJ, Prasad GA, Lewis JT, et al. Clin Gastroenterol Hepatol. 2010;8(3):248-253.

31.

Larghi A, Lightdale CJ, Memeo L, et al. Gastrointest Endosc. 2005;62(1):16-23.

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32.

Pech O, Behrens A, May A, et al. Gut. 2008;57(9):1200-1206.

33.

Endoscopic Classification Review Group. Endoscopy. 2005;37(6):570-578.

34.

Qumseya BJ, Wang H, Badie N, et al. Clin Gastroenterol Hepatol. 2013 Jul 11. [Epub ahead of print]

61.

35.

Vennalaganti P, Kanakadandi V, Goldblum JR, et al. Gastroenterology. 2014;146(5):S-147.

Seewald S, Akaraviputh T, Seitz U, et al. Gastrointest Endosc. 2003;57(7):854-859.

62.

36.

Spechler SJ, Sharma P, Souza RF, et al. Gastroenterology. 2011;140(3):e18-e52.

Tomizawa Y, Iyer PG, Wong Kee Song LM, et al. Am J Gastroenterol. 2013;108(9):1440-1447.

63.

37.

Rees JR, Lao-Sirieix P, Wong A, et al. Cochrane Database Syst Rev. 2010;(1):CD004060.

Oyama T, Kikuch Y. Min Invas Ther Allied Technol. 2002;11(5-6):291â&#x20AC;&#x201C;295.

64.

38.

Coron E, Robaszkiewicz M, Chatelain D, et al. Best Pract Res Clin Gastroenterol. 2013;27(2):187-204.

Yoshinaga S, Gotoda T, Kusano C, et al. Gastrointest Endosc. 2008;67(2):202-209.

65.

39.

Soetikno RM, Gotoda T, Nakanishi Y, et al. Gastrointest Endosc. 2003;57(4):567-579.

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66.

Haidry RJ, Dunn JM, Butt MA, et al. Gastroenterology. 2013;145(1):87-95.

40. Fleischer DE, Wang GQ, Dawsey S, et al. Gastrointest Endosc. 1996;44(1):68-72.

59.

Lopes CV, Hela M, Pesenti C, et al. Surg Endosc. 2007;21(5):820-824.

60. Peters FP, Kara MA, Rosmolen WD, et al. Am J Gastroenterol. 2006;101(7):1449-1457.

67.

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Inoue H, Takeshita K, Hori H, et al. Gastrointest Endosc. 1993;39(1):58-62.

Orman ES, Li N, Shaheen NJ. Clin Gastroenterol Hepatol. 2013;11(10):1245-1255.

68.

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Chennat J, Konda VJ, Ross AS, et al. Am J Gastroenterol. 2009;104(11):2684-2692.

Gupta M, Iyer PG, Lutzke L, et al. Gastroenterology. 2013;145:79-86.

69.

43.

van Vilsteren FG, Pouw RE, Seewald S, et al. Gut. 2011;60(6):765-773.

Dulai PS, Pohl H, Levenick JM, et al. Gastrointest Endosc. 2013;77(4):534-541.

70.

Gray NA, Odze RD, Spechler SJ. Am J Gastroenterol. 2011;106(11):1899-1908.

71.

Titi M, Overhiser A, Ulusarac O, et al. Gastroenterology. 2012;143(3):564-566.

72.

Phoa KN, Pouw RE, van Vilsteren FG, et al. Gastroenterology. 2013;145(1):96-104.

73.

Orman ES, Kim HP, Bulsiewicz WJ, et al. Intestinal metaplasia recurs infrequently in patients successfully treated for Barrettâ&#x20AC;&#x2122;s esophagus with radiofrequency ablation. Am J Gastroenterol. 2013;108(2):187-195.

74.

Kim MP, Brown KN, Schwartz MR, et al. Innovations (Phila). 2013;8(1):17-22.

75.

Shaheen NJ, Overholt BF, Sampliner RE, et al. Gastroenterology. 2011;141(2):460-468.

44. Pouw RE, Wirths K, Eisendrath P, et al. Clin Gastroenterol Hepatol. 2010;8(1):23-29. 45.

Herrero LA, van Vilsteren FG, Pouw RE, et al. Gastrointest Endosc. 2011;73(4):682-960.

46.

Ell C, May A, Pech O, et al. Gastrointest Endosc. 2007;65(1):3-10.

47.

Prasad GA, Wu TT, Wigle DA, et al. Gastroenterology. 2009;137(3):815-823.

48.

Konda VJ, Gonzalez Haba Ruiz M, Koons A, et al. Clin Gastroenterol Hepatol. 2014 April 13. [Epub ahead of print]

49.

Chung A, Bourke MJ, Hourigan LF, et al. Endoscopy. 2011;43(12):1025-1032.

50.

Lewis JJ, Rubenstein JH, Singal AG, et al. Gastrointest Endosc. 2011;74(4):753-760.

51.

Katada C, Muto M, Manabe T, et al. Gastrointest Endosc. 2003;57(2):165-169.

52. 53.

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77.

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78.

Saligram S, Chennat J, Hu H, et al. Gastrointest Endosc. 2013;77(6):872-876.

Greenwald BD, Dumot JA. Curr Opin Gastroenterol. 2011;27(4):363-367.

79.

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Ell C, May A, Gossner L, et al. Gastroenterology. 2000;118(4):670-677.

Shaheen NJ, Greenwald BD, Peery AF, et al. Gastrointest Endosc. 2010;71(4):680-685.

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May A, Gossner L, Pech O, et al. Eur J Gastroenterol Hepatol. 2002;14(10):1085-1091.

Dumot JA, Vargo JJ 2nd, Falk GW, et al. Gastrointest Endosc. 2009;70(4):635-644.

81.

56.

Peters FP, Kara MA, Rosmolen WD, et al. Gastrointest Endosc. 2005;61(4):506-514.

Canto MI, Gorospe EC, Shin EJ, et al. Gastrointest Endosc. 2009;69:AB341.

82.

57.

Gerke H, Siddiqui J, Nasr I, et al. Gastrointest Endosc. 2011;74(4):761-71.

Gosain S, Mercer K, Twaddell WS, et al. Gastrointest Endosc. 2013;78(2):260-265.

83.

58.

Larghi A, Lightdale CJ, Ross AS, et al. Endoscopy. 2007;39(12):1086-1091.

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84.

Gorospe EC, Sun G, Wang KK. Am J Gastroenterol. 2013;108(2):197-199.

G AST R O E N D O N E WS .CO M

SUPREP Bowel Prep ep Kit Kit. Beca Because se the q quality alit of cleansing matters. • Effective bowel cleansing2*, 3** in all bowel segments4* †

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

*Based on investigator grading. †This clinical trial was not included in the product labeling. References: 1. IMS Health, NPA Weekly, March 2014. 2. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2012. 3. Di Palma JA, Rodriguez R, McGowan J, Cleveland MvB. A randomized clinical study evaluating the safety and efﬁcacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenterol. 2009;104:2275-2284. 4. Rex DK, Di Palma JA, Rodriguez R, McGowan J, Cleveland M. A randomized clinical study comparing reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy. Gastrointest Endosc. 2010;72:328-336.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prep Kit is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 375 patients who took SUPREP Bowel Prep Kit in clinical trials, 94 (25%) were 65 years of age or older, while 25 (7%) were 75 years of age or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP may not be absorbed completely. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Split-Dose (Two-Day) Regimen: Early in the evening prior to the colonoscopy: Pour the contents of one bottle of SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume only a light breakfast or have only clear liquids on the day before colonoscopy. Day of Colonoscopy (10 to 12 hours after the evening dose): Pour the contents of the second SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least two hours prior to colonoscopy. Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F). Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185

SU-00406E

September 2014

#1 Most Prescribed Branded Bowel Prep1

Clean Freak

Effective cleansing2*,3* in all bowel segments, including the right colon4*† Percent of patients with NO RESIDUAL STOOL by colon segment4*† Colon Segment

Cecum Ascending Transverse Descending Sigmoid/Rectum

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

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

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

SUPREP Bowel Prep Kit achieved “excellent” bowel cleansing in patients based on investigator grading2*,3* • Split-dose regimens of SUPREP Bowel Prep Kit and MoviPrep®¶ were equivalent in colon cleansing3* • Significantly more patients had “excellent” bowel cleansing with SUPREP Bowel Prep Kit compared to MoviPrep (63% vs 53%, respectively; P=0.043#)3* P≤0.02 vs 4-Liter Prep. Statistically significant difference. MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies. # Statistically significant difference. ||

Important Safety Information SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. Please see Brief Summary of Prescribing Information on accompanying page. ©2014 Braintree Laboratories, Inc.

SU-00406E

September 2014

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

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

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

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

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

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

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

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

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

G AST R O E N D O N E WS .CO M

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

Oral Sodium Phosphate For many endoscopists, a new era in bowel cleansing for colonoscopy arrived on Dec. 11, 2008, when the FDA issued an alert about the safe use of oral sodium phosphate (OSP) products.19 The agency expressed its concern about the risks associated with the use of OSP at the higher doses typically used for bowel cleansing before colonoscopy, and it recommended that consumers not use the OTC OSP products designed specifically for bowel cleansing. The FDA said, however, that the available data continue to indicate the safety of OSP at the lower dose used for the laxative. In response to the FDA warning, CB Fleet immediately announced a voluntary recall of its OTC products, Fleet Phospho-soda and Fleet Phospho-soda EZ-Prep. The FDA alert also indicated that the manufacturer of prescription NaP tablets (OsmoPrep, Salix) would be required to put a black box warning on its product labels. The warning highlights several key concepts related to the use of NaP laxatives for bowel cleansing, including the following: 1) acute phosphate

Table. Commonly Used Purgatives for Colonoscopy Preparation Class Polyethylene glycol

Product

Recommended Usea

4-L PEG-ELS

GoLYTELY (Braintree)

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

Colyte (Schwarz Pharma)

Same as above

NuLYTELY (Braintree)

Same as above

TriLyte (Schwarz Pharma)

Same as above

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

HalfLytely (Braintree)

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

2-L PEG and bisacodyl delayed-release tablets

MiraLax (Schering-Plough)

Same as above

2-L PEG with ascorbate

MoviPrep (Salix)

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

OsmoPrep (Salix)

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

4-L SF-PEG

Sodium phosphate Tablet

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

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

Suprep (Braintree)

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

Sodium sulfate

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

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

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

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

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

G AST R O E N D O N E WS .CO M

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

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

Bowel Preparation: Flexibility Is Key Some endoscopists prefer to offer all patients a single method of bowel preparation. The benefits of such an approach include simplicity and economy of time, eliminating the need to discuss with the patient more than 1 regimen of bowel cleansing. Among the

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

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

The Role of Hydration Colon cleansing produces significant volume loss through the GI tract that can result in intravascular volume depletion. The fluid loss during bowel preparation may exceed 2 to 3 L, based on an assessment of hemodynamic parameters and indirect measures such as body weight, serum osmolality, and hematocrit.32 Significant differences in fluid loss between NaP and PEG formulations have been reported in some studies.33-36 Decreases in systolic blood pressure (>10 mm Hg from

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

Timing Is Everything The quality of colon preparation—especially in the ascending colon—is closely related to the length of time between completion of preparation and the examination.35,41 Despite diet restriction for 24 hours, optimal cleansing of the colon requires that at least part of the preparation be ingested within 4 to 6 hours of the examination. When more than 6 hours has elapsed, ileal contents begin to fill the right colon, coating the ascending colon with a thin film of chyme that obscures mucosal detail. The American College of Gastroenterology (ACG) supports the concept of split-dosing as a method for enhancing the efficacy of commercial bowel cleansing preparations.42 Split-dose regimens improve the efficacy of both NaP and PEG preparations.9 In a study of 3-L PEG plus bisacodyl, a split-dose regimen (including 1 L on the day of the procedure) increased the proportion of satisfactory preparations (75% vs 66%) and patient compliance, with lower rates of discontinuation.43 Another study sought to determine whether the quality of bowel preparation was better with a 2-L PEG solution administered on the day of (6-8 hours before) versus the evening before (13-16 hours before) the procedure.44 Colon preparation was better (93% vs 72%) and more lesions were detected (2.8 vs 1.9) in the patients who received same-day bowel cleansing than in the patients who received cleansing the evening before the examination. A randomized trial compared 2 dosing regimens of NaP, one consisting of two, 45-mL doses taken the evening before (3 and 8 PM) the procedure and the other consisting of the same 2 doses with the second

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

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

Special Patient Populations Elderly Patients. Individuals aged 65 years and older comprise at least 20% of the patient population undergoing routine colonoscopy and are more likely to have an incomplete preparation.1,53 The reasons for this are multifactorial and include an increased likelihood of constipation, reduced mobility, and difficulty completing the preparation. Elderly patients using NaP also are more likely to manifest hyperphosphatemia as a result of impaired renal function, comorbid illness, and concomitant medications.36 Several studies have evaluated the efficacy, safety, and tolerability of various purgatives in older individuals. A randomized controlled trial with octogenarians compared NaP with a 4-L PEG preparation.53 The quality of preparation was similar in the 2 groups, with a good or excellent rating in 77% to 81% of patients receiving NaP or PEG, respectively. As anticipated, PEG produced less change than NaP in the clinical parameters of dehydration and laboratory values. Fewer patients were unable to complete the NaP preparation than the PEG preparation, although the difference did not reach statistical significance. Overall, patients preferred NaP to PEG and were more willing to repeat this preparation in the future. A second study comparing NaP with PEG in elderly patients reported that the overall quality of colon cleansing was comparable for the 2 preparations.54 Furthermore, patients who received NaP tolerated the preparation better than those who received PEG, although the difference was not statistically significant. Patients With Inflammatory Bowel Disease. In general, patients with inflammatory bowel disease can prepare for colonoscopy with any of the standard bowel purgatives. An exception is the patient with moderate to severe diarrhea (>6-8 bowel movements per day); for this patient,

the dose of cathartic may be reduced or eliminated altogether. NaP preparations can produce aphthoid lesions in the colon, most prominently within the rectum and sigmoid. This endoscopic appearance is distinct and can be readily distinguished from the endoscopic appearances of Crohn’s disease and ulcerative colitis. Pediatric Patients. In children 12 years or older, an oral NaP solution at a dosage of 45 mL taken twice is probably the most widely used preparation.10 For children 6 to 11 years, the dosage often is reduced to 30 mL taken twice. NaP is not recommended for children aged 5 years and younger. A second method of preparation for children is a PEG-based formulation (MiraLax) administered at a dose of 1.25 to 1.5 g/kg daily for 4 days. In some instances, a laxative, such as bisacodyl, may be added to the regimen 1 day before colonoscopy. The least commonly used preparation is either a saline or a phosphate enema in combination with a senna laxative.10 In the pediatric population, the data assessing efficacy and safety are inadequate to recommend a particular regimen over another. The PEG-based preparations generally are effective but often are accompanied by abdominal bloating and vomiting.55 A modified PEG preparation that is administered over 4 days appears to be better tolerated but has the potential for disrupting a child’s ability to attend school and participate in other activities.56 Generally, children tolerate oral NaP better than PEG, although hyperphosphatemia often is observed. Practice recommendations for bowel preparation in children undergoing colonoscopy vary. A recent consensus statement prepared by a joint task force in the United States10 concluded that NaP, PEG, and phosphate enema/senna preparations all are “safe and will adequately prepare the child’s colon for colonoscopy.” The authors caution, however, that “in certain circumstances, such as bowel preparation in children … it may be advisable to adhere to PEG-based solutions because of the risks for occult physiologic disturbances that may potentially contraindicate the use of NaP-based regimens.” Regardless of the regimen selected, it is important to provide children with adequate hydration during the process of bowel preparation. A carbohydrate-electrolyte solution designed specifically for children often is helpful for this purpose. Patients With Lower Gastrointestinal Bleeding. In most circumstances, patients undergoing colonoscopy for hematochezia must be prepared quickly.57 Colon transit is hastened by the presence of blood, and in most cases, bowel cleansing can be completed within 2 to 3 hours by using 0.5 to 2 L of PEG solution. Patients who are unresponsive or mechanically ventilated may receive the PEG solution through a nasogastric tube. Patients With a History of Inadequate Preparation or Chronic Constipation. No studies are available to guide the clinician for preparation of the patient with chronic constipation or a history of inadequate bowel cleansing during a previous colonoscopy. Measures that have been recommended include the following: extending the period of diet modification from 24 to 48 hours; adding

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

oral bisacodyl or senna to a PEG or a NaP regimen; and increasing the total volume of PEG from 4 to 6 L, with administration split over 48 hours (usually 1-2 L on day 1, and 3-4 L on day 2). Adequate hydration also will help to improve the adequacy of cleansing.

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

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

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

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

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

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

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

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

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

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

11. Marmo R, Rotondano G, Riccio G, et al. Gastrointest Endosc. 2010;72(2):313-320.

42. Rex DK, Johnson DA, Anderson JC, et al. Am J Gastroenterol. 2009;104(3):739-750.

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

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

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

44. Chiu HM, Lin JT, Wang HP, et al. Am J Gastroenterol. 2006;101(12):2719-2725.

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

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

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

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

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

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

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

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

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Lowest volume of active prep solution— only 10 oz.

Superior

cleansing *

…that

patients preferred in clinical trials†

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

PATIENT PREFERENCE

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

reported in clinical trials†1-3

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

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

Colon segment

Prepopik

84%

Overall

(n=256/304)

Ascending Mid (Transverse and Descending) Rectosigmoid

90%

(n=272/304)

92%

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

74%

(n=221/297)

79%

10%

86%

(n=255/297)

92%

87%

Completed preparation

DIFFERENCE

(n=234/297)

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

Patient perspective

(n=259/297)

Prepopik

99%

(n=304/305)

96%

Would ask for the prep again in the future

(n=290/302)

Was very easy or easy to take

(n=270/302)

89%

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

91%

(n=267/292)

55%

(n=162/296)

29%

(n=86/296)

SPLIT-DOSE OR DAY-BEFORE REGIMEN 4

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

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

The SEE CLEAR I and SEE CLEAR II studies were phase 3, randomized, multicenter, assessor-blinded, noninferiority studies in patients preparing for colonoscopy. The primary endpoints were evaluation of overall colon cleansing with Prepopik vs a comparator using modified Aronchick and Ottawa scales. Patients were also required to complete a questionnaire, which included the questions: “How easy or difficult was it to consume the prescribed bowel preparation?” and “Would you ask your doctor for this preparation again if you needed another colonoscopy in the future?”1,3 ‡ The Ottawa bowel preparation scale assesses bowel cleanliness by section, based on numeric scores of 0-4. A score of 0 denotes “excellent” cleansing with ascending numbers denoting “good,” “fair,” “poor,” and “inadequate.” Additional numeric value is assigned based on the amount of fluid present (small, moderate, or large). [Prepopik: n=272/304; comparator: n=234/297].1,2

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

Aspiration Patients with impaired gag reÀex and patients prone to regurgitation or aspiration should be observed during the administration of PREPOPIK. Use with caution in these patients. Not for Direct Ingestion Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances. INDICATIONS AND USAGE PREPOPIK® (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, CONTRAINDICATIONS adverse reaction rates observed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: be directly compared to rates in clinical trials of another drug and may • Patients with severely reduced renal function (creatinine clearance not reÀect the rates observed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and vomiting were the most common adverse reactions (>1%) • Gastrointestinal obstruction or ileus following PREPOPIK administration. The patients were not blinded to • Bowel perforation the study drug. Since abdominal bloating, distension, pain/cramping, • Toxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing • Gastric retention preparations, these effects were documented as adverse events in • An allergy to any of the ingredients in PREPOPIK the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adverse event), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signi¿cant worsening during the study that was Advise patients to hydrate adequately before, during, and after the not in the frame of the usual clinical course, as determined by the use of PREPOPIK. Use caution in patients with congestive heart investigator. ffailure when replacing Àuids. If a patient develops signi¿cant vomiting PREPOPIK was compared for colon cleansing effectiveness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters (2L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all lab tests (electrolytes, creatinine, and BUN) and treat accordingly. administered the day before the procedure. Table 1 displays the most Approximately 20% of patients in both arms (PREPOPIK, 2L of PEG common adverse reactions in Study 1 and Study 2 for the PREPOPIK + E plus two x 5-mg bisacodyl tablets) of clinical trials of PREPOPIK Split-Dose and Day-Before dosing regimens, respectively, each as had orthostatic changes (changes in blood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy. Table 1: Treatment-Emergent Adverse Reactions observed in at Fluid and electrolyte disturbances can lead to serious adverse events Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte abnormalities should be corrected before treatment with PREPOPIK. In addition, use caution when prescribing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen ffor patients who have conditions or who are using medications that Reaction increase the risk for Àuid and electrolyte disturbances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adverse events of seizure, arrhythmia, and renal (N=305) with 2 x 5-mg (N=296) with 2 x impairment. n (% = n/N) bisacodyl n (% = n/N) 5-mg Seizures There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of Àuid and electrolyte abnormalities. Use caution when prescribing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia. Use in Patients with Renal Impairment As in other magnesium containing bowel preparations, use caution when prescribing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inÀammatory drugs). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before during and after the use of PREPOPIK. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

tablets (N=298) n (% = n/N)

bisacodyl tablets (N=302) n (% = n/N) Nausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) * 2L PEG + E = two liters polyethylene glycol plus electrolytes solution. **abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected

Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may be Àushed from the GI tract and the medication may not be absorbed. Tetracycline and Àuoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of PREPOPIK to avoid chelation with magnesium. Antibiotics Prior or concomitant use of antibiotics with PREPOPIK may reduce ef¿ f cacy of PREPOPIK as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with PREPOPIK have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to PREPOPIK. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREPOPIK should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PREPOPIK is administered to a nursing woman. Pediatric Use The safety and effectiveness of PREPOPIK in pediatric patients has not been established.

Geriatric Use In controlled clinical trials of PREPOPIK, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatmentemergent adverse events was similar among patients 65 years of age ( 3%) and patients <65 years of age ( 1%). Among all patients 65 years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group (81.1%) than in the comparator In general, PREPOPIK was associated with numerically higher rates group (70.9%). of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two x 5-mg bisacodyl Renal InsufÀ f ciency tablets. These shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant between treatment arms at the Day 30 visit. medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor Postmarketing Experience blockers, or non-steroidal anti-inÀammatory drugs) may be at The following foreign spontaneous reports have been identi¿ed during increased risk for further renal injury. Advise these patients of the use of formulations similar to PREPOPIK. Because these events are importance of adequate hydration before during and after the use reported voluntarily from a population of uncertain size, it is not always of PREPOPIK. Consider performing baseline and post-colonoscopy possible to reliably estimate their frequency or establish a causal laboratory tests (electrolytes, creatinine, and BUN) in these patients. relationship to drug exposure. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. The Allergic reactions signs and symptoms of hypermagnesemia may include, but are not Cases of hypersensitivity reactions including rash, urticaria, and limited to, diminished or absent deep tendon reÀexes, somnolence, purpura have been reported. hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest. Electrolyte abnormalities There have been reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation The patient who has taken an overdose should be monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing PREPOPIK for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal ECGs should be considered in patients at increased risk of serious Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. There have been isolated reports of reversible Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has been reported with the use Osmotic laxatives may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. However, a and there have been reports of more serious cases of ischemic colitis causal relationship between these ischemic colitis cases and the use requiring hospitalization. Concurrent use of additional stimulant of PREPOPIK has not been established. laxatives with PREPOPIK may increase this risk. The potential ffor mucosal ulcerations should be considered when interpreting Neurologic colonoscopy ¿ndings in patients with known or suspected inÀammatory There have been reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients. bowel disease. Use in Patients with SigniÀcant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering PREPOPIK. Use with caution in patients with severe active ulcerative colitis.

arrhythmias, and prolonged QT in the setting of Àuid and electrolyte abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inÀammatory drugs (NSAIDS) or drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate.

DRUG INTERACTIONS

Manufactured by: Ferring Pharmaceuticals (China) Co., Ltd. No. 6 HuiLing Lu (Ferring Road) National Health Technology Park Zhongshan City, Guangdong Province, CHINA Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, N.J. 07054

www.ferringusa.com 1-888-FERRING Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing PREPOPIK for patients with conditions ©2014 Ferring Pharmaceuticals Inc. or who are using medications that increase the risk for Àuid and All rights reserved. Printed in USA. electrolyte disturbances or may increase the risk of seizure, PK/069/2014/US

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

First-Line Treatment Strategies for

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

elicobacter pylori is a major cause of chronic gastritis and peptic ulcer

disease (PUD); it is closely linked with gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma; and it is causally associated with unexplained iron-deficiency anemia, primary immune thrombocytopenia

(formally

termed

idiopathic thrombocytopenic purpura), and vitamin B12 deficiency.

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

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 4

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

Maastricht/Florence Consensus Conference (2012)6

Established indications:

• PUD • Gastric MALT lymphoma • Following endoscopic resection of early gastric cancer • Uninvestigated dyspepsia (if H. pylori prevalence >20%) • Functional dyspepsia • Prior use of NSAIDs with a history of PUD • Long-term NSAID use or use of lowdose aspirin • Long-term PPI use (>1 y) Controversial indications: • Unexplained iron deficiency, ITP, or vitamin B12 deficiency • Functional dyspepsia • First-degree relative with gastric cancer • Use of NSAIDs (especially • Severe pan-gastritis, corpus-predomifor patients with a history nant gastritis, or severe mucosal atrophy of PUD or those initiating • Chronic gastric inhibition for more NSAID therapy) than 1 y • Unexplained iron • Environmental risk factors for gastric deficiency cancer (eg, heavy smoking or high • Populations at increased exposure to dust, coal, quartz, cement, risk for gastric cancer or quarry work) • Active PUD • Confirmed history of PUD but not previously treated for H. pylori • Gastric MALT lymphoma • Following endoscopic resection of early gastric cancer • Uninvestigated dyspepsia (if H. pylori prevalence >20%)

Asia-Pacific Consensus (2009)10 • PUD • MALT lymphoma • Atrophic gastritis • Following resection of gastric cancer • First-degree relative with gastric cancer • If desired by patient (following full consultation with physician) • Functional dyspepsia • NSAID-naive users • Before long-term aspirin use, if at high risk for PUD and PUDrelated complications • Long-term low-dose aspirin use, with a history of upper gastrointestinal bleeding or perforation • Screening strategy in communities with high incidence of gastric cancer • Unexplained iron deficiency or ITP

ITP, idiopathic thrombocytopenic purpura; MALT, mucosa-associated lymphoid tissue; NSAID, nonsteroidal anti-inflammatory drug; PPI,, p proton oto pump pu p inhibitor; b to ; PUD, U , pep peptic pt c ulcer u ce disease d sease

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

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

G AST R O E N D O N E WS .CO M

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

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

Treatment Duration, d

Practical Considerations

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

7-14

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

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

7-14

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

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

10-14

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

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

• Requires validation in North America

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

3-10

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

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

7-10

• Superior to standard triple therapy in US clinical trial

Emerging Therapies

bid, twice daily; PPI, proton pump inhibitor; qd, daily a

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

2,200 patients in 18 European countries.4 Another recent study identified an increased risk for antibiotic resistance based on the number of previous exposures to antibiotics (Table 3).5 International guidelines have presented similar recommendations for first-line eradication therapy, with some notable differences. The fourth Maastricht/Florence Consensus Conference, comprising 44 experts from 24 countries, presented its most recent H. pylori treatment recommendations, primarily for the European community, in 2012.6 In regions were resistance to clarithromycin is low, clarithromycin-based triple therapy was recommended as the initial therapy of choice, with bismuth quadruple therapy as an alternative. However, in regions where the rate of resistance to clarithromycin exceeded 15% to 20%, bismuth quadruple therapy was recommended as the initial therapy of choice. In 2004, 12.9% of H. pylorii strains in the United States were resistant to clarithromycin.7 Unfortunately, no

organized national surveillance of H. pylorii antimicrobial resistance in the United States has occurred since that time. In comparison, a recent large-scale, multicenter study involving 18 European countries found an overall clarithromycin resistance rate of 17.5%.4 Antibiotic-resistance rates varied widely in different regions of Europe, highlighting the difficulties of designing a “one-size-fits-all” approach to first-line therapy for any region or country (Table 4).4 Clarithromycin-resistance rates in Asia also are highly variable, ranging from 3.7% in Thailand to 85% in a population of children in Beijing.8,9 The Second Asia-Pacific Consensus published its expert panel recommendations in 2009 for Asian populations.10 The panel concluded that the use of high-dose, twice-daily PPI therapy increased the success of clarithromycin-based triple therapy, largely based on the results of a meta-analysis of randomized controlled trials (RCTs) that demonstrated a cure rate of 82% with twice-daily high-dose

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

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

Antibiotic Sensitivity

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

RRa (95% confidence interval)

0 Courses

1 Course

≥2 Courses

Levofloxacin

114 (4)

7 (14)

11 (27)

1.8 (1.24-2.49)

Metronidazole

114 (28)

13 (38)

5 (100)

1.6 (1.46-1.75)

Clarithromycin

103 (7)

21 (19)

8 (25)

1.5 (0.92-2.41)

Erythromycin

Clarithromycin

104 (8)

15 (20)

13 (15)

1.1 (0.82-1.59)

Ratio of the risk for resistance per unit increase in number of courses off therapy.

PPIs compared with 74% with twice-daily standard-dose PPI therapy. A 7-day course of clarithromycin-based triple therapy was recommended as the initial first-line therapy, despite the panel’s acknowledgment of rising clarithromycin resistance in Asian countries and its negative effect on eradication rates. The panel also recommended bismuth quadruple therapy as an alternative to clarithromycin-based triple therapy. (Because of production issues, the United States experienced a shortage of tetracycline that lasted from 2011 until March 2014. Limited clinical data suggested the possibility of substituting tetracycline with doxycycline at a dose of 100 mg twice daily.11-13)

EMERGING FIRST-LINE ERADICATION THERAPIES Sequential therapy was introduced in 2000 to address the diminishing efficacy of clarithromycin-based triple therapy.14 This treatment regimen—which consists of a PPI plus amoxicillin for 5 days, followed by a PPI, clarithromycin, and tinidazole for an additional 5 days—was associated with an eradication rate of 93.5% in a pooled analysis of 15 Italian studies including more than 1,800 patients.15 A subsequent systematic review and metaanalysis of 10 clinical trials totaling 3,006 patients, which directly compared sequential therapy with clarithromycin-based triple therapy for eradication of H. pylori, reported an odds ratio (OR) of 2.99 in favor of sequential therapy (95% confidence interval [CI], 2.47-3.62; number needed to treat, 7); in patients with clarithromycin resistance, the OR for eradication was 10.21 in favor of sequential therapy (95% CI, 3.01-34.58).16 However, 8 of these trials were performed in Italy, with the other 2 trials from Korea and China, calling into the question the generalizability of the results. Indeed, subsequent studies of sequential therapy

G AST R O E N D O N E WS .CO M

from other parts of the world have yielded differing results. For example, a recent multicenter trial comprising 1,463 adults from 6 Latin American countries found clarithromycin-based triple therapy marginally better than sequential therapy, with an eradication rate of 82.2% compared with 76.5%, respectively (difference, 5.6%; 95% CI, –0.04% to 11.6%).17 A recent Turkish trial reported a cumulative eradication rate of only 66.5% in 200 adults receiving 1 of 2, 14-day sequential therapies as first-line therapy for H. pylorii infection (either lansoprazole plus amoxicillin for 1 week, followed by a second week of lansoprazole, clarithromycin, and metronidazole, or lansoprazole, clarithromycin, and tetracycline).18 Furthermore, a large study from Taiwan found that preexisting clarithromycin resistance may reduce the efficacy of sequential therapy, and that eradication rates might be improved by extending therapy duration to 14 days (Table 5).19 A recent systematic review and metaanalysis of RCTs—totaling 46 trials and 13,532 patients, conducted through May 2013—compared sequential therapy with either preexisting or new therapy.20 In this study, the overall eradication rate of sequential therapy was 84.3% (95% CI, 82.1%-86.4%). Sequential therapy was superior to 7 days of clarithromycin-based triple therapy (relative risk [RR], 1.21; 95% CI, 1.17-1.25); however, sequential therapy was only marginally superior to 10 days of clarithromycin-based triple therapy (RR, 1.11; 95% CI, 1.04-1.19) and was not superior to 14 days of clarithromycin-based triple therapy (RR, 1.00; 95% CI, 0.94-1.06) or bismuth quadruple therapy (RR, 1.01; 95% CI, 0.95-1.06). Based on these data, the ACG guideline expressed cautious optimism for sequential therapy, and recommended formal validation in the United States.1 To date, no RCT has evaluated the efficacy of sequential

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

Number of Resistant Strains/ Total Number Tested

Resistance, % (95% confidence interval, %)

Northern Europea

31/401

7.7 (5.4-10.7)

Western/Central Europeb

136/725

18.7 (16.1-21.7)

165/767

21.5 (19.9-25.5)

Northern Europe

31/401

7.7 (5.4-10.7)

Western/Central Europe

135/725

18.6 (15.9-21.6)

Southern Europe

101/767

13.1 (11.0-15.8)

Northern Europe

115/401

28.6 (24.3-33.1)

Western/Central Europe

318/725

43.8 (40.2-47.3)

Southern Europe

228/767

29.7 (26.5-32.9)

Clarithromycin

Southern Europe

Levofloxacin

Metronidazole

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

therapy in this country. Because of the divergent results of international studies and a lack of US data, it is difficult to offer an unqualified endorsement of sequential therapy for the treatment of US patients with H. pylori infection. The Second Asia-Pacific Consensus also concluded that there were insufficient data to recommend sequential therapy as a first-line eradication therapy for H. pylori infection in Asian populations.10 Likewise, the fourth Maastricht/Florence Consensus Conference recommendation states: “In areas of low clarithromycin resistance, clarithromycin-containing treatments are recommended for ﬁrst-line empirical treatment.”6 A treatment regimen primarily developed to address the complexity of sequential therapy is non-bismuth quadruple therapy, or so-called “concomitant therapy.” This regimen consists of a PPI, amoxicillin, clarithromycin, and an imidazole given concomitantly for 3 to 10 days. The initial clinical trial, from Germany, reported an eradication rate of 91% in 46 patients receiving a 5-day concomitant first-line therapy consisting of omeprazole, clarithromycin, metronidazole, and amoxicillin.21 A meta-analysis of 19 clinical trials of concomitant

therapy for the treatment of 2,070 patients with H. pylorii infection revealed a mean cure rate of 88%.22 Furthermore, in the RCTs comparing concomitant therapy with clarithromycin-based triple therapy (984 patients), the cure rate was 90% versus 78%, respectively (OR, 2.36; 95% CI, 1.67-3.34).22 Nearly all of the trials evaluated were performed in Europe or Asia, with 1 study performed in Latin America. Treatment duration ranged from 3 to 10 days, with cure rates of 83% to 91%. Longer durations of therapy were associated with a trend toward higher cure rates. As with sequential therapy, no RCTs evaluating concomitant therapy in North American populations have been published. Given the lack of data from North America, the ACG guideline provides no recommendations for the use of concomitant therapy in the United States. A recent large, multicenter, randomized trial in Latin America found clarithromycin-based triple therapy superior to 5 days of concomitant therapy, with eradication rates of 82.2% and 73.6%, respectively (95% CI, 2.6%-14.5%).17 Given these data, if concomitant therapy is used, a duration of 7 to 10 days seems

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

14-Day Sequential Therapya

10-Day Sequential Therapy

14-Day Triple Therapyb

Cla-S, Met-S

116/117 (99)

123/129 (95)

98/109 (90)

Cla-S, Met-R

30/33 (91)

29/37 (78)

39/42 (93)

Cla-R, Met-S

10/14 (71)

7/10 (70)

9/16 (56)

Cla-R, Met-R

0/1 (0)

3/7 (43)

2/4 (50)

bid, twice daily; Cla, clarithromycin; Met, metronidazole; R, resistant; S, sensitive a Sequential therapy: lansoprazole 30 mg bid + amoxicillin 1 g bid for first 5 or 7 d, followed by lansoprazole 30 mg + clarithromycin 500 mg bid + metronidazole 500 mg bid for subsequent 5 or 7 d. b

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

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

ROLE

PROBIOTICS

There is growing interest in the use of probiotics as adjuvant therapy in the treatment of H. pylori infection. Emerging evidence suggests an inhibitory effect of Lactobacillus and Bifidobacterium species on H. pylori. Furthermore, these probiotic strains also may help to reduce the side effects of eradication therapies and improve compliance with therapy.24 A recent meta-analysis of 10 clinical trials of adjuvant probiotics in patients with H. pylorii infection demonstrated increased cure rates with probiotic supplementation (pooled OR, 2.066; 95% CI, 1.3983.055).24 Probiotics also reduced the incidence of total side effects (pooled OR, 0.305; 95% CI, 0.117-0.793).

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The majority of these studies were performed in China, and there was great variability in the probiotics used, as well as the treatment regimen employed. Although probiotic therapy for H. pylorii infection seems promising, many important questions remain, including the optimal dose, the time of dosing (before, during, or after eradication therapy), and the duration of therapy. Some evidence suggests that Lactobacillus may be a useful adjuvant therapy for treating H. pylori infection.25

Conclusion Clarithromycin-based triple therapy and bismuth quadruple therapy for 10 to 14 days remain the most universally recommended and most commonly prescribed first-line eradication regimens for H. pylori infection. Ten- to 14-day sequential, 7- to 10-day concomitant, and 10-day LOAD quadruple regimens are gaining popularity as alternative choices for first-line treatment. Evidence clearly indicates that the presence of clarithromycin-resistant H. pylori significantly reduces the efficacy of clarithromycin-based triple therapy, and to a lesser extent, sequential therapy. Although rates of antibiotic resistance are available for many parts of Europe and Asia, this information is lacking in the United States. Therefore, it is critical for clinicians to ask patients about previous exposure to macrolide agents. In regions where clarithromycin resistance is known to be greater than 15% to 20%, or if a patient has a history of more than 1 previous course of macrolide antibiotics, for any indication, clarithromycin-based triple therapy, and arguably sequential therapy, should be

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

(–) Penicillin (–) Macrolide

(–) Penicillin (+) Macrolide

(+) Penicillin (–) Macrolide

(+) Penicillin (+) Macrolide

Treatments:

Treatment:

Clarithromycin-based triple therapy

Bismuth quadruple therapy

Sequential therapy?

PCM

Sequential therapy

Concomitant therapy? LOAD therapy?

Concomitant therapy LOAD therapy?

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

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

avoided in favor of bismuth or LOAD quadruple therapies. Obtaining a complete medical history of allergy or intolerance to any of the commonly prescribed antibiotics also will assist in the most appropriate choice of treatment (Figure). Gone are the days when physicians can freely prescribe clarithromycin-based triple therapy for all patients with H. pylorii infection. Although this regimen

remains useful in specific circumstances, a strategy that uses information regarding previous antibiotic use, regional antibiotic susceptibility, and drug allergies will assist the clinician in making the best treatment choice for an individual patient.26 In this era of superbugs and epidemic Clostridium difficile infections, responsible care demands a fresh look at how we manage this common and important infection.

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References 1.

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

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

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

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Approach to Hemorrhoids A Primer for Gastroenterologists HARRY SARLES JR, MD Gastroenterologist Digestive Health Associates of Texas Dallas, Texas Dr. Sarles is a member of the advisory board of CRH Medical.

emorrhoids are normal vascular structures of the anal canal. Often, they are the source of a variety of troublesome symptoms, including bleeding, anal pruritus, prolapse, and pain due to thrombosis of external hemorrhoids. Patients often mistake other anal or perianal problems for hemorrhoids, such as anal fissures, skin tags, hypertrophied anal papillae, anal cancer, and anal condylomata and other infections.

A good medical history and physical examination, including anoscopy or office proctoscopy, should guide the physician to the correct diagnosis; in cases of bleeding, a colonoscopy or sigmoidoscopy in addition to anoscopy is necessary to verify the source of the bleeding. This article will provide gastroenterologists with a general introduction to the nonsurgical management of hemorrhoids.

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Anatomy Thomson, in his description of hemorrhoidal anatomy, noted a series of 3 cushions in the anal canal, located in the left lateral, right anterior, and right posterior positions. These hemorrhoidal cushions receive their blood supply primarily from the superior and middle hemorrhoidal arteries; the superior, middle, and inferior hemorrhoidal veins provide venous drainage. A sinusoidal pattern of arteriovenous communication is formed within the cushions, which explains why hemorrhoidal bleeding is arterial, rather than venous in nature.1 In addition to the vessels noted above, the hemorrhoidal cushions are also rich in muscular fibers arising from the internal sphincter and the conjoined longitudinal muscle. These fibers help to anchor the cushions to the underlying muscular layer of the anorectum, and it is the breakdown of these supporting fibers that eventually leads to the changes that can cause hemorrhoidal symptoms.1,2 The cushions play an important role in the maintenance of rectal continence, as they provide 15% to 20% of the resting pressure at the anal verge.3 The epithelial layer of the anorectum is characterized by the relatively insensate columnar epithelium, which covers the internal hemorrhoidal cushions (mucosa) and the extremely sensitive squamous epithelium, which extends up into the anus (anoderm). The junction of these 2 epithelial layers is known as the dentate line and is typically located approximately 3 cm inside the anal verge. This line marks the transition between the columnar epithelial–covered internal hemorrhoids and the squamous epithelial–covered external hemorrhoidal vessels.4-6

completely clear, but several factors, including lack of dietary fiber, constipation, straining on defecation, diarrhea, pregnancy, obesity, sedentary lifestyle, spending excess time on the commode, spinal cord injuries, and family history all have been suggested.8

Epidemiology It is difficult to quantify the incidence of hemorrhoidal disease, in large part because many patients do not seek medical care for their condition; moreover, some attribute almost any anorectal symptom to hemorrhoids. Estimates of the prevalence of hemorrhoidal disease in the United States range from 4.4% to 40%.9 Some research suggests that 75% of the population will experience symptomatic hemorrhoid disease at some point in their lives.10 Although these estimates vary widely, symptomatic hemorrhoids clearly have a significant effect on health and well-being.

Grading of Hemorrhoidal Disease Banov et al11 developed a grading system for internal hemorrhoids based on the degree of prolapse. The grade of hemorrhoidal disease has some bearing on the treatment options available to a patient with internal hemorrhoids: Grade I: nonprolapsing internal hemorrhoids Grade II: prolapse of internal hemorrhoids during defecation with spontaneous reduction Grade III: prolapse of internal hemorrhoids during defecation that requires manual reduction Grade IV: prolapse and incarceration of internal hemorrhoids; hemorrhoids cannot be reduced

Diagnosis Patient History

Pathophysiology There are a number of proposed mechanisms to explain the development of symptomatic hemorrhoids, including abnormal venous dilatation, abnormal distension of the arteriovenous anastomoses, downward displacement or prolapse of the hemorrhoidal tissue, or a breakdown of the connective tissue anchoring the hemorrhoidal cushions. Prolapse of hemorrhoidal tissue is what appears to lead to the development of symptoms. This prolapse allows for mucus deposition on the perianal skin, which causes itching and leads to tissue friability and bleeding. Other symptoms include swelling of associated external disease and fecal soiling when the prolapsing tissue precludes complete closure of the anal opening.1,7 Internal hemorrhoids are covered by the mucosa; they reside proximal to the dentate line and are generally painless. External hemorrhoids are located distal to the dentate line and are covered by squamous epithelium; patients who experience pain as a result of hemorrhoids often have a thrombosed external hemorrhoid or an anal fissure. The causes of symptomatic hemorrhoids are not

As previously stated, patients often attribute any anorectal symptom to hemorrhoidal disease, and although this may partly explain symptoms, it is important for the physician to determine if other issues also are involved.5,12 Internal hemorrhoids are associated with painless bleeding, prolapse, mucus discharge, soiling, and symptoms of pruritus ani; these symptoms rarely cause significant pain. External hemorrhoids usually are asymptomatic, unless they become thrombosed. Pain with defecation is commonly due to the presence of an anal fissure, which is found in up to 20% of patients with hemorrhoids.13 The relationship between symptoms, defecation habits, and bleeding, and a description of factors that might relieve or exacerbate a patient’s symptoms are important to consider in the medical history.

Physical Examination A visual inspection of the perianal area will allow for the discovery and description of rashes, tags, fissures, fistulae, abscesses, neoplasms, condylomata, some cases of prolapse, and so forth. The left lateral decubitus position is preferred for the examination, as this position

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seems to be better tolerated than the prone, “jack-knife” position.14 A digital rectal examination will identify such things as scars, small fissures, and origins of fistulae. These clinical findings will be important in formulating a comprehensive treatment plan for the symptomatic patient.15

Endoscopic Examination Anoscopy is an accurate, efficient, inexpensive way to evaluate the anal canal quickly, with minimal discomfort to the patient. Flexible endoscopy frequently is performed to evaluate patients with symptoms of hemorrhoids, however, it is not as accurate as anoscopy. A prospective study showed that anoscopy revealed 99% of anorectal lesions, whereas endoscopy revealed 78% when performed with straight withdrawal of the endoscope, and 54% with retroflexion.16 The limitations of flexible endoscopy, along with increased cost and inconvenience to the patient, underscore the need to consider anoscopy in the evaluation of hemorrhoidal disease.

Treatment Conservative Medical Treatment Several over-the-counter preparations are available to treat patients with symptomatic hemorrhoids. These compounds contain ingredients such as antiseptics, astringents, topical anesthetics, and corticosteroids. However, many of these products lack evidence to support their use, and the potential negative effects of the long-term use of topical steroids should be considered.17 Common dietary and behavioral recommendations for patients with hemorrhoids include increasing the intake of dietary fiber, minimizing the amount of time spent on the commode, avoiding straining during defecation, and taking sitz baths several times per day. Evidence supports these recommendations both for the treatment of symptomatic disease and in limiting the risk for recurrence.18 These measures are a reasonable firstline approach for patients with mild symptoms.

Nonsurgical Treatment Sclerotherapy Sclerotherapy uses the injection of a sclerosant into the submucosa, beneath the hemorrhoid, to create an inflammatory reaction in the soft tissue that affixes the loose hemorrhoidal mucosa back to the underlying musculature. The procedure dates back to the 1800s. Some research shows sclerotherapy to be beneficial in patients with grade I and II hemorrhoids,19 whereas other research shows it to be no more beneficial than bulk laxatives.20 Potential complications of sclerotherapy include pain, urinary retention, abscess, and impotence. Avoidance of these complications depends on precise placement of the injection.21 Rubber Band Ligation Rubber band ligation (RBL) is the most commonly performed nonsurgical procedure for the treatment of

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hemorrhoids; it is used in up to 80% of patients with hemorrhoids.22,23 Blaisdell first described a ligation technique using a silk suture in 1958,24 with Barron beginning to use rubber bands in 1963.25 Barron treated one column of hemorrhoids per session to minimize pain and post-banding complications. The process causes the banded tissue to necrose and slough, with the resultant inflammatory reaction causing refixation of the mucosa to the underlying tissue, eliminating hemorrhoidal prolapse. This mechanism of action is common among the nonsurgical treatments for hemorrhoids, stressing the importance of hemorrhoidal prolapse in the etiology of symptoms. RBL is a simple, inexpensive procedure, effective for grade I to III hemorrhoids.2 Patients undergoing RBL typically do not require bowel preparation, sedation, narcotics, or a significant recovery period; they are able to return to work immediately.5 One of the disadvantages of earlier RBL procedures was the need for 2 operators to perform the procedure, but this has since been overcome with the development of single-use, disposable devices that do not require an assistant.6,7 RBL leads to reconfiguration and reduction in the size of hemorrhoidal cushions, resulting in symptom resolution. Short-term success rates of up to 99% and longterm success rates of up to 80% have been described; however, the reported incidence of complications ranges widely. The predominant issue in patients undergoing RBL is significant pain, with incidence rates ranging from less than 1% to 50%, in some series.6,26 Other reported complications include bleeding, urinary retention, vasovagal reactions, and the very rare complication of sepsis. Based on the literature, the incidence of complications appears to be related to the techniques that are used to perform the banding. Endoscopic RBL has been shown to have excellent results, although the method is more expensive than the others and requires patient preparation as well as anesthesia.27 Endoscopic RBL also has been reported to be more painful than other banding techniques.28 Other common techniques use an anoscope to gain access to the hemorrhoids. There also is a procedure that allows for a “blind” placement of the band, obviating the need for an anoscope. The literature is conflicting when it comes to where the band should be placed, as descriptions vary from “a few millimeters” above the dentate line29 to “at least 2 cm proximal” to the dentate line.30,31 I prefer a technique that involves placing the band at least 2 cm above the dentate line, as this technique has been associated with less pain.6 Controversy exists regarding the number of hemorrhoids that can be treated during a single session. Since Barron published his original work,, most researchers have recommended treating only one column of hemorrhoids per session to minimize the rate of complications. Other authors have suggested banding 2 or more columns per session to minimize the number of patient

visits required; however, complication rates are higher when more bands are placed.32 I recommend banding a single hemorrhoid per session. Endoscopic band placement is effective but is more costly and is associated with higher rates of post-procedural pain compared with in-office band placement.24,33 I prefer the blind “touch” technique described by Cleator and Cleator.6 This technique allows placement of the band without an anoscope at 2 cm above the dentate line. Using this technique, the researchers demonstrated a 1% complication rate (primarily pain) and successful treatment of up to 99% of patients, with a recurrence rate of 5% at 2 years.5 Infrared Coagulation Neiger first described infrared coagulation (IRC) in 1979.34 The infrared coagulator is placed through an anoscope while infrared light is converted to heat in the hemorrhoidal tissue. The heat produces tissue destruction, protein coagulation, and inflammation, leading to scarring and tissue fixation. During the procedure, 3 to 4 pulses of energy are applied to the mucosa at the apex of the hemorrhoid, and 1 to 2 columns of hemorrhoids are treated at a time. Treatment is repeated every 2 to 4 weeks.24 Advantages of IRC include a relative lack of significant complications. Disadvantages include equipment costs, the need for repeated treatments, higher rates of recurrence, and ineffectiveness in patients with more advanced disease.24,34

associated with a higher overall rate of complications (11.9% vs 5.1%), including pain, bleeding, fissure formation, and spasm of the internal sphincter. Another study demonstrated symptomatic mucosal ulceration in 24% of patients treated with bipolar electrocoagulation, significant bleeding in 8%, and prolonged pain in 4%.36 Neither technology was able to reliably eliminate prolapsing tissue.29,36,37 Cryosurgery and Lord’s Stretch Procedure These techniques are mentioned for historical reference only, as neither is recommended. Cryosurgery is associated with significant post-procedure pain, along with foul-smelling discharge and prolonged recovery in several series.36 The “Lord’s Stretch,” a forceful dilatation of the anus in order to reduce elevated sphincter pressures results in incontinence in a significant number of patients.38 Some have recommended that the procedure be abandoned.39

Surgical Treatment Options This review is intended to discuss nonsurgical options available for the treatment of symptomatic hemorrhoidal disease, and these approaches have proven effective in 80% to 99% of patients. A number of surgical options are available as well, but because of increased cost, pain, disability, recuperation time, risk for complications, and so on, surgical options should be reserved only for nonresponders and for patients with grade IV hemorrhoids or hemorrhoids with both internal and external components.40

Direct Current Electrotherapy Direct current electrotherapy also uses a device that is inserted through an anoscope (Ultroid, Ultroid Technologies, Inc).35 This procedure uses direct current and rather than generating heat, it produces sodium hydroxide, creating the submucosal reaction that leads to scarring, which helps eliminate hemorrhoidal prolapse.7 Limitations of direct current electrotherapy include cost of the technology and amount of time required to treat the involved tissue. The length of the procedure depends on the grade of hemorrhoidal disease and the amount of current that the patient can tolerate, which ranges from 4:45 to 19:45.35 The procedure has been reported to cause significant pain in up to 20% of patients, resulting in termination of therapy; 16% of patients have prolonged post-procedural pain.36 Bipolar Diathermy and “Heater Probe” Coagulation These technologies may be used by way of anoscopy to control symptoms of chronic hemorrhoids. Both procedures generate heat, which causes coagulation of the target tissue leading to a fibrotic reaction with fixation of the treated tissue.32 The procedures have similar efficacy for the treatment of bleeding. In one study, the heater probe controlled the bleeding more quickly (76.5 vs 120.5 days) at the expense of more pain.37 The bipolar technology was

Conclusions Symptomatic hemorrhoids are common and patients frequently visit a gastroenterologist for diagnosis and treatment. A number of effective nonsurgical approaches are available for these patients. RBL is the most commonly used office-based hemorrhoidal therapy. Information is presented here to aid the gastroenterologist in the evaluation and definitive treatment of patients with hemorrhoidal disease.

References 1. 2. 3.

5. 6. 7. 8. 9.

Thomson WH. The nature of haemorrhoids. Br J Surg. 1975;62(7):542-552. Sardinha TC, Corman ML. Hemorrhoids. Surg Clin North Am. 2002; 82(6):1153-1167, vi. Lestar B, Penninckx F, Kerremans R. The composition of anal basal pressure. An in vivo and in vitro study in man. Int J Colorectal Dis. 1989;4(2):118-122. Wexner SD, Jorge JMN. Anatomy and embryology of the anus, rectum, and colon. In: Corman ML, ed. Colon and rectal surgery. 4th ed. Philadelphia, PA: Lippincott-Raven; 1998. Guttenplan M, Ganz RA. Hemorrhoids—office management and review for gastroenterologists. Touchgastroenterology.com; December 2011. Cleator IGM, Cleator MM. Banding hemorrhoids using the O’Regan disposable bander. US Gastroenterology Review. 2005:69-73. Corman ML. Hemorrhoids. In: Corman ML, ed. Colon and rectal surgery. 4th ed. Philadelphia, PA: Lippincott-Raven; 1998:147-205. Loder PB, Kamm MA, Nicholls RJ, et al. Haemorrhoids: pathology, pathophysiology and aetiology. Br J Surg. 1994;81(7):946-954. Ohning GV, Machicado GA, Jensen DM. Definitive therapy for internal hemorrhoids—new opportunities and options. Rev Gastroenterol Disord. 2009;9(1):16-26.

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10. Baker H. Hemorrhoids. In: Longe JL, ed. Gale encyclopedia of medicine. 3rd ed. Detroit: Gale; 2006:1766-1769.

26. Kumar N, Paulvannan S, Billings PJ. Rubber band ligation of haemorrhoids in the out-patient clinic. Ann R Coll Surg Engl. 2002;84(3):172-174.

11. Banov L Jr, Knoepp LF Jr, Erdman LH, et al. Management of hemorrhoidal disease. J S C Med Assoc. 1985;81(7):398-401. 12. Halverson A. Hemorrhoids. Clin Colon Rectal Surg. 2007;20(2):77-85.

27. Jutabha R, Jensen DM, Chavalitdhamrong D. Randomized prospective study of endoscopic rubber band ligation compared with bipolar coagulation for chronically bleeding internal hemorrhoids. Am J Gastroenterol. 2009;104(8):2057-2064.

13. Schubert MC, Sridhar S, Schade RR, et al. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009;15(26):3201-3209.

28. Cazemier M, Felt-Bersma RJ, Cuesta MA, et al. Elastic band ligation of hemorrhoids: flexible gastroscope or rigid proctoscope? World J Gastroenterol. 2007;13(4):585-587.

14. Alonso-Coello P, Castillejo MM. Office evaluation and treatment of hemorrhoids. J Fam Pract. 2003;52(5):366-374.

29. Daram SR, Lahr C, Tang SJ. Anorectal bleeding: etiology, evaluation and management (with videos). Gastrointest Endosc. 2012:76(2):406-417.

15. Beck DE. Evaluation of the anorectum during endoscopic examinations. Tech Gastro Endoscopy. 2004;6:2-5.

30. Madoff RD, Fleshman JW, Clinical Practice Committee, American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of hemorrhoids. Gastroenterology. 2004;126(5):1463-1473.

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