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

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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 5 • May 2012

gastroendonews.com ESA Retraction Triggers Backlash By Monica J. SMith Much to the chagrin of U.S. gastroenterologists who had praised the European Society of Anesthesiology (ESA) for its rigor and fairness, the society recently decided to retract its endorsement of guidelines for non–anesthesiologist-administered propofol (Pelosi P. Eur J Anaesthesiol 2012;29:208). see Retraction, page 32

From the Literature

Use, Cost of Anesthesia For Endoscopy Increasing By Monica J. SMith The authors of a study gauging the use of anesthesia services for endoscopy and colonoscopy say their research accomplished a couple of firsts, but to those familiar with the ongoing sedation saga, the main finding—that anesthesia services have

see Anesthesia, page 26

H e pat o l o g y

F o c u s

Experts Offer Guidance on Use of DAAs For Difficult-To-Treat Hep C Patients By chriStina Frangou San FranciSco—For several months, it has been one of the most pressing questions among clinicians who treat patients with hepatitis C: How well do the two FDA-approved direct-acting antivirals (DAAs) perform in the patients who are most in need of a new form of therapy? The answer, based on evidence presented at The Liver Meeting 2011, appears to be that these therapies improve sustained viral response (SVR) rates in hepatitis C patients with cirrhosis and those who have previously failed standard therapy, but these patients still lag far behind others, with SVR rates that dip below the 50% mark. Two factors—previous response to treatment and fibrosis stage—appear to be the most important

CMS Unveils Major Changes for ASCs Modest Pay Increases; Quality Reporting Mandate

predictors of achieving SVR. But experts have yet to reach a consensus on the best treatment for difficult-to-treat patients. see DAAs, page 10

I N S I D E H e pat o l o g y

i n

Focus

Surveillance of Patients at Risk for HCC Paltry, at 6% �� page 6 Expert Aims To Improve Sensitivity of Diagnostic Imaging for HCC Surveillance �� page 7

By chriStina Frangou Major changes are under way in the Centers for Medicare & Medicaid Services (CMS) system of payments to ambulatory surgical centers (ASCs) and hospital outpatient departments.

i n

The CMS 2012 final rule increased payment rates to ASCs by 1.6% this year, and rates under the Outpatient Prospective Payment System rose by 1.9%. see CMS, page 59 PRODUCT ANNOUNCEMENT

No Discernable Benefits of New Terms for Liver Transplantation �� page 8 Deaths Attributed to HCV on the Rise, Outstripping HIV Mortality �� page 12 Expert Reviews Data on Silymarin for NAFLD �� page 18

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Atlas of Clinical Gastrointestinal Endoscopy

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

Cecum Ascending Descending Transverse Sigmoid/Rectum

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

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

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

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

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

GastroenteroloGy & endoscopy news • May 2012

ACGME Rolls Out New Accreditation System for Medical Residents System in Place for Gastroenterology Programs by 2014 By chriStina Frangou The Accreditation Council for Graduate Medical Education (ACGME) is rolling out a new accreditation system for graduate medical education that will be implemented in seven programs by next year and in gastroenterology

programs by 2014, according to a plan recently announced in The New England Journal of Medicine (Nasca TJ et al. 2012;366:1051-1056). The new system, referred to as the Next Accreditation System (NAS) requires all programs to evaluate each of their trainees at six-month intervals using 30 to 36 educational milestones. The milestones

will be based on the six competencies: patient care, medical knowledge, professionalism, interpersonal and communications skills, practice-based learning and improvement and systems-based practice. “Over time, we envision that the NAS will allow the ACGME to create an accreditation system that focuses less on the identification of problems and more

on the success of programs and institutions in addressing them,” wrote Thomas J. Nasca, MD, CEO of the ACGME, and colleagues in the Feb. 22 edition of The New England Journal of Medicine. The NAS will be initiated by July 2013 in seven of the 26 ACGME-accredited core specialties: emergency medicine, internal medicine, neurologic surgery, orthopedic surgery, pediatrics, diagnostic radiology and urology. Over the following year, the residency review committees in each of these specialties will collect milestone data to create a baseline data set for the ACGME. By July 2014, all specialties will implement the new program. The NAS was created to help foster innovation, ease restriction and keep educational standards apace with delivery-system changes, said Dr. Nasca, a board-certified internist and nephrologist, in a statement.

‘Over time, we envision that the NAS will allow the ACGME to create an accreditation

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

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

References: 1. Rex DK, DiPalma JA, Rodriguez 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. 2. DiPalma 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. 3. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2010.

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 one hour 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 For additional information, please call 1-800-874-6756 or visit www.suprepkit.com ©2012 Braintree Laboratories, Inc.

SU-13280T

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system that focuses less on the identification of problems and more on the success of programs and institutions in addressing them.’ —Nasca TJ et al

The system moves the ACGME away from its old “episodic ‘biopsy’ model,” in which compliance was assessed every four to five years, to 10-year site visits, complemented by annual and semi-annual data collection. The data collected will include key educational milestones, resident and faculty surveys and operative and case-log data. “I think the idea of evidence-based training is excellent; this is a lofty goal and will not be easy to achieve,” said Avlin Imaeda, MD, PhD, assistant professor of medicine (digestive diseases), Yale School of Medicine, New Haven, Conn. “Overall, I think providing trend data on how trainees progress rather than simply having a folder full of paper evaluations represents significant progress in a program’s ability to understand a trainee’s skill set and the ACGME’s ability to follow program quality.” see ACGME, page 31

GastroenteroloGy & endoscopy news • May 2012

Clinical Trial Under Way To Investigate New Agent for PBC

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The Independent Monthly Newspaper for Gastroenterologists

Volume 62, Number 8 • August 2011

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

New C. diff Antibiotic Ignites Discussion BY ROSEMARY FREI, MSC Fidaxomicin (Dificid, Optimer Pharmaceuticals, Inc., and Cubist Pharmaceuticals, Inc.) is a new entrant into the thin field of agents that fight Clostridium difficile infection (CDI). Will the first antibiotic approved to treat CDI in the past 30 years live up to the promise set see Fidaxomicin, page 10

Preoperative Testing For Lynch Syndrome Yields ‘Huge’ Benefit BY CHRISTINA FRANGOU VANCOUVER, BRITISH COLUMBIA—Mayo Clinic researchers are calling for all young patients with colorectal cancer (CRC) to undergo preoperative testing for Lynch syndrome as the results can significantly alter

H E PAT O L O G Y

I N

FOCUS

Use of New HCV Protease Inhibitors ‘Not That Simple,’ Say Researchers Experts Espouse Training, Education for Doctors, Patients BY CHRISTINA FRANGOU On May 13, patients began phoning Donald Jensen, MD, at his office at the University of Chicago’s Center for Liver Diseases, as soon as the FDA announced its approval of boceprevir. The call frequency increased when the FDA gave the goahead for telaprevir several days later. Within two weeks, more than 115 patients had phoned the office asking about the much anticipated, direct-acting antivirals. Patients wanted to know if they were candidates for one of the new agents and if they could trade their pegylated interferon and ribavirin regimen for one of the new therapies. And, most

Web Comment

Give FMT a Chance

Re: “New Treatment Options for C. difficile Infection Raise More Questions,” by Christina Frangou. Gastroenterology & Endoscopy News. January 2012;63(1):1,12,13,19.

Re: “Investigational Agent Effective for Primary Biliary Cirrhosis,” by David Wild. Gastroenterology & Endoscopy News News. August 2011;62(8):32.

Since the current medical and usual surgical treatment options [for the treatment of Clostridium difficile infection] are performing rather poorly but FMT [fecal microbiota transplantation] is excelling, it may be time to simplify the access to stool samples from healthy donors and treat the patients with FMT as first-line therapy. If this is possible for blood donations, surely stool sampling could be organized in a similar fashion.

A Phase III study of obeticholic acid in patients with primary biliary cirrhosis has been initiated in North America and Europe. More information is available at www.PBC-Study.com.

often, they wanted to know when they could start. But it’s not that simple, said Dr. Jensen, professor of medicine and director of the center. “It’s not like giving pills to someone and saying here, ‘go home, take this for 10 days and let me know how you’re doing.’ These are much, much more see HCV, page 24

see Lynch Syndrome, page 20

I N S I D E

DDW 2011

Time Has Come for Gastros To Treat Diabetes, Expert Says

Best of Digestive Disease Week (DDW): Part 3 Experts share their favorite abstracts from this year’s DDW meeting ..........................................page 6

“jamee” Via Web site on Feb. 26, 2012

BY MONICA SMITH Endoscopic technologies geared toward treating both obesity and type 2 diabetes may become the new field of metabolic endoscopy, according to Ian Taylor, MD, PhD, who spoke on the subject at this year’s Digestive see Diabetes, page 14

Sheila E. Crowe, MD

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Ronnie Fass, MD

Ellen J. Scherl, MD

Clinical Review Pancreatic Enzyme Replacement Therapy for Pancreatic Enzyme Insufficiency By Jason Bratcher, MD, and Jerome H. Siegel, MD …see insert between pages 22 and 23

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM

Pancreatic Enzyme Replacement Therapy for Pancreatic Exocrine Insufficiency JASON BRATCHER, MD

JEROME H. SIEGEL, MD, RPH

Center for Digestive Health Beth Israel Medical Center New York, New York

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

ormal exocrine pancreatic function involves the secretion of enzyme-rich

fluid that is responsible for the breakdown of fats, starches and proteins, the

vital nutrients that are absorbed during transit through the intestinal lumen. A

disruption in this process by pancreatic ductal blockage, parenchymal destruction or

surgical removal of a significant portion of pancreatic tissue may lead to pancreatic exocrine insufficiency (PEI) and the inability to process and absorb these nutrients.

If a majority of the enzymatic secretion is lost, symptoms of progressive weight loss and steatorrhea may develop, leading to decreased quality of life, malnutrition and increased morbidity. Supplementation with oral replacement therapy can improve nutritional status,

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

reduce steatorrhea and improve the affected individual’s quality of life. This review will outline the major causes and diagnosis of PEI, the approach to treatment and monitoring of patients who require pancreatic enzyme replacement therapy (PERT).

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

Web Comment

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Volume 63, Number 1 • January 2012

gastroendonews.com Efficacy of H. pylori Therapies Equivocal BY DAVID WILD

New Treatment Options for C. difficile Infection Raise More Questions BY CHRISTINA FRANGOU

A growing body of research that has yielded conflicting findings on the efficacy of various Helicobacter pylori treatment regimens suggests that one size does not fit all when it comes to eradicating this bacterium. “It’s not easy to generalize the results of H. pylori treatments from one population to another,” said E. Robert see H. pylori, page 20

IBD Med Adherence There’s an App for That BY DAVID WILD HOLLYWOOD, FLA.—Nurses and nurse practitioners can play a critical role in increasing adherence among patients with inflammatory bowel disease (IBD) by forming strong alliances with patients, providing adequate information and making use of new technologies, according to experts who spoke at the Crohn’s & Colitis see Adherence, page 24

In the past six months, new surgical and medical options have become available to treat patients with Clostridium difficile. As the options for treating C. difficile have increased, so too have the questions about who should get what treatments and when. The ambiguity over how best to treat C. difficile became especially clear after fidaxomicin (Dificid, Optimer Pharmaceuticals Inc.) was approved by the FDA in May. Clinicians are now trying to determine whether fidaxomicin is as good or better than the two long-time standards, vancomycin and metronidazole. “The answer to that is not clear yet,” said Lawrence Brandt, MD, professor of medicine and surgery

at Albert Einstein College of Medicine of Yeshiva University, New York City. Two additional up-and-coming treatments also have been touted as possible game changers in the C. difficile realm. Fecal microbiota transplantation (FMT)—a procedure first reported in the medical literature in 1958—has been garnering attention as a highly successful therapy for C. difficile infection (CDI). One recently published report suggests FMT could be considered a firstline therapy for severe infection (Brandt LJ et al. J Clin Gastroenterol 2011;45:655-657). And on the surgical front, surgeons are reporting that a diverting ileostomy with colonic lavage for severe, complicated CDI could be used to spare patients from

Too Many Codes; Lack of EMR Systems To Support It BY CAROLINE HELWICK

“zigat” Via Web site on Jan. 28, 2012

NEW ORLEANS—At the 65th Interim Meeting of the American Medical Association (AMA) House of Delegates, delegates voted to “work vigorously to stop the implementation” of the International Classification of Diseases, Tenth see ICD-10, page 26

GARy R� LICHTENSTEIN, MD

ALAN F� CuTLER, MD

NIRMAL S� MANN, MD, BSC, MS, PhD, DSC

Houston, Texas

Farmington Hills, Michigan

FREDRIC DAuM, MD Mineola, New York

STEVEN M� FABER, MD

Elizabeth City, North Carolina

RONNIE FASS, MD Tucson, Arizona

Philadelphia, Pennsylvania

Sacramento, California

PETER R� MCNALLy, DO Fort Carson, Colorado

TARuN MuLLICK, MD St. Charles, Illinois

JOEL E� RICHTER, MD

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Gastroenterology & Endoscopy News Medical Advisory Board Members share their favorite abstracts from the 2011 ACG Annual Scientific Meeting .................................................... page 6

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Sandhill Scientific and IntroMedic introduce EG Scan™

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FROM THE BENCH TO THE BEDSIDE

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Bowel Preparation for Colonoscopy: Eschewing the One-Prep-Fits-All Approach

Acing the GI Board Exam : The Ultimate Crunch-Time Resource

Vol. 63, No. 5

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Best of the American College of Gastroenterology (ACG) Meeting: Part 1

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see C. difficile, page 12

I N S I D E

AMA Delegates Balk at ICD-10

May 2012

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Focus GastroenteroloGy & endoscopy news • May 2012

Surveillance of Patients at Risk for HCC Paltry, at 6% By chriStina Frangou San FranciSco—For patients at highest risk for hepatocellular carcinoma (HCC), the careful surveillance that can lead to early diagnosis is simply not happening, according to a recent study (Singal AG et al. J Gen Intern Med 2012 Jan 4 [Epub ahead of print]). Investigators found that only 6% of patients who are considered at risk for HCC undergo consistent surveillance in accordance with national guidelines. Another 20% receive inconsistent surveillance and the remainder is not monitored at all.

‘We found multiple points in the process of care where the system is failing. The most common reason for lack of surveillance is simply a failure to order surveillance in those with cirrhosis.’ —Amit Singal, MD

“We found multiple points in the process of care where the system is failing. The most common reason for lack of surveillance is simply a failure to order surveillance in those with cirrhosis,” said lead author Amit Singal, MD, assistant professor of medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas. Dr. Singal presented the study at The Liver Meeting 2011. Previous research has shown that HCC surveillance in patients with cirrhosis markedly improves outcomes. In a study of 270 American patients, researchers found that three-year survival for HCC was 12% among cirrhotics who had received no surveillance, compared with 39% among those who received the standard of care (Stravitz RT et al. Am J Med 2008;121:119-126). The authors concluded that, “the quality of surveillance has a direct impact on hepatocellular carcinoma stage at diagnosis, access to liver transplantation and survival.” Despite this clear relationship, surveillance remains problematic throughout the United States. Even at Veterans Affairs

hospitals, where an extensive system for surveillance is in place, rates are “in the 60% to 70% range,” said David B. Ross, MD, PhD, National Clinical Public Health Program, U.S. Department of Veterans Affairs. In the current retrospective cohort study, the research team collected data on all patients with cirrhosis diagnosed with HCC between January 2005 and July 2011 at the Parkland Health and Hospital System in Dallas. This is the safety net hospital system for Dallas County and receives patients from a broad mix of ethic backgrounds who have limited access to insurance. All patients with no primary care or liver clinic visits in the two years prior to their HCC diagnosis were excluded from the study. Two authors independently extracted data on demographics, clinical, laboratory and tumor data for all patients. The research team then studied surveillance for the two years prior to the HCC diagnosis, examining whether patients with cirrhosis had regular ultrasounds, with or without α-fetoprotein, every six months, as is recommended by the American Association for the Study of Liver Diseases. The investigators also examined where the failure occurred in the process of care. Of 178 patients studied, only nine (6%) had regular surveillance in the two years prior to the HCC diagnosis. Another 36 (20.2%) had inconsistent surveillance, meaning they had had ultrasounds but not on a regular basis. Failures to properly carry out surveillance occurred at every point in the process of care, the study showed, from identifying liver disease, diagnosing cirrhosis and following through with consistent surveillance. Nearly 40% of patients were not recognized as having liver disease and/or cirrhosis prior to presenting with HCC. Without acknowledging this underlying risk factor, physicians were not aware that HCC surveillance was necessary in these patients. The investigators found, however, that the surveillance process most often broke down somewhere after diagnosing

‘The majority of patients with cirrhosis in the United States are cared for by primary care doctors, not subspecialists. … Really, I think our job as hepatologists is to educate the primary care providers how to care for cirrhotics with things like HCC surveillance.’ —Amit Singal, MD

cirrhosis and before ordering surveillance tests. Only 38% of diagnosed cirrhotics received any orders for surveillance. When the tests were ordered, they were not at regular intervals. Less often, the failure was because patients did not comply with surveillance orders. The study showed for the first time that individuals who were using alcohol on a daily basis were the least likely to receive surveillance (odds ratio [OR], 0.14; 95% confidence interval [CI],

0.03-0.65), a failing that was unrelated to patient compliance but occurs because the tests were not ordered. “This association may be related to multiple factors, including clinic time constraints if these patients had more active issues, provider beliefs regarding the benefits of surveillance in this subgroup or regarding the likelihood of adherence,” Dr. Singal said. The only factor that was associated see HCC Surveillance, page 16

Volume 1 • Issue 1 www.gitractexaminer.com

A diagnostic publication for gastroenterologists and radiologists

Enterography: Advances in IBD Imaging

he use of imaging modalities in the diagnosis and treatment of inflammatory bowel disease (IBD) has grown substantially in the past 2 decades. Crosssectional enterography is now considered an integral imaging technique in the diagnosis and treatment of Crohn’s disease (CD). Advances in the temporal and spatial resolution of computed tomographic (CT), magnetic resonance (MR) imaging, and the development of enteric agents to distend the bowel have made it possible for clinicians to detect inflammation in parts of the gastrointestinal tract that in the past have been difficult to reach, such as the small bowel.1,2 Enterography allows for visualization of the bowel wall and mesentery—supplementing the mucosal images of optical colonoscopy—and permits assessment of the small bowel proximal to the terminal ileum.3 “Clinically, we frequently use imaging to give us an idea of where there is inflammation, to help guide endoscopy and biopsies when we’re trying to confirm a diagnosis,” said Peter D. Higgins, MD, PhD, MSc, assistant professor of medicine in the Division of Gastroenterology at the University of Michigan Health System in Ann Arbor, Michigan. CT enterography (CTE), for example, can

detect active inflammation associated with CD with a sensitivity of about 82% and specificity of about 89%.4 “It can show you that you may need to do an upper endoscopy or a double-balloon enteroscopy to reach the areas of inflammation,” added Dr. Higgins. In 2007, Dr. Higgins and his colleagues published a landmark paper that established the diagnostic value of CTE, finding that it helped clinicians better assess the potential usefulness of steroid treatments and detect additional strictures in patients with small bowel CD.5 These days, Dr. Higgins uses enterography with almost every patient with strongly suspected or known IBD. He noted that in patients with ulcerative colitis, enterography only may be necessary once (because it usually only involves the colon) to confirm there is no evidence of small bowel disease. In patients with CD, however, enterography can be used more often to guide treatment; monitor inflammation; and look for evidence of strictures, abscesses, or fistulas. Bowel wall imaging findings in patients with active CD include mural hyperenhancement, bowel wall thickening, and stratification.3 “Cross-sectional enterography can often identify unsuspected penetrating complications of the

disease and assess the degree of inflammation associated with strictures—providing guidance about which therapy may be most helpful for individual patients,” said Joel G. Fletcher, MD, professor of radiolog y at Mayo Clinic in Rochester, Minnesota. Dr. Fletcher described CTE as involving a sizable volume

of neutral oral contrast media, IV contrast media, and images reconstructed in the horizontal and coronal planes on multidetector row scanners that can complete scans in seconds at high temporal and spatial resolutions. Adequate luminal distention of the small bowel is made possible by the oral intake of large see Enterography, page 2

Focus on an IBD Center

n a city rich with history lies a hospital on a mission to live up to Boston’s storied past by advancing the future of digestive health care. The Massachusetts General Hospital’s Crohn’s and Colitis Center is one of the few comprehensive, multidisciplinary programs in New England for the diagnosis and treatment of patients with Crohn’s disease (CD) and ulcerative colitis, 2 types of inflammatory bowel disease (IBD). The program, which earned Massachusetts General the No. 4 spot on this year’s U.S. News & World Report’s Best Hospitals list for gastroenterology,1 is part of the hospital’s Center for the Study of IBD, a multimillion-dollar National Institutes of Health–funded program for research on this set of digestive diseases.2 The Crohn’s and Colitis Center brings together a team of gastroenterologists, surgeons, radiologists, pathologists, nurse practitioners, psychiatrists, nutritionists, and enterostomal specialists to provide expert diagnosis and long-term care for patients with IBD. Gastroenterologists and radiologists at the center are especially congenial and share mutual respect as they work closely to treat patients, said Dushyant V. Sahani, MD, director of computed tomography see Mass General, page 3

ImagIng InsIghts

Enterography continued from page 1 

quantities of water and contrast agents, such as a low Hounsfield value barium sulfate, polyethylene glycol electrolyte solutions, sugar alcohols, or methylcellulose. 2 In studies, neutral oral contrast has been reported to be generally well tolerated by patients at large volumes. 2 Along with neutral oral contrast, radiologists administer IV iodinated contrast to visualize extraluminal structures, after which CT imaging is generally performed within 45 to 65 seconds and multiplanar, thin-slice (≤3 mm) images are reconstructed, noted Dr. Fletcher (Figure 1). Radiologists should carefully examine CTE findings and be aware that poorly distended bowel segments may falsely suggest CD by mimicking mucosal hyperenhancement or bowel wall thickening.2 Special attention should be paid when using intraluminal-positive oral contrast, as it can obscure pathologic mural enhancement of the small bowel by decreasing the attenuation difference between the lumen and the small bowel wall.2 For gastroenterologists, the indications for employing CTE and MR enterography (MRE) for IBD are similar for both modalities, Dr. Higgins said. “The questions are weighing the risks and benefits of the radiation with CT enterography. CT enterography is very quick if you have an emergent reason and you need information the same day. MRE is nice for follow-up when it’s not urgent and you don’t want to worry about radiation, but it has higher costs. Generally, depending on availability in your center, it may take a few days to a week to obtain one.” Although ionizing radiation from CTE has been dramatically reduced over the past few years, the exposure of patients with CD, especially those under the age of 35 years, still should be considered, as they may require a dozen or more scans in their lifetime, Dr. Higgins said. To avoid radiation, For more MRE may be used to follow patients through information on the use of treatment but cost and time (to obtain an exam enterography for slot and to complete a session) may present limIBD, please visit itations.1 The slower speed of MR imaging also the Enterography increases the chance of generating motion artiResource Center facts, which occasionally can reduce the value of at www. the exam, Dr. Higgins said. auntminnie.com. Both CTE and MRE require radiologists to consider how the patient is prepared and how Brought to you from the publishers of

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Figure 1. Patient with chronic Crohn’s disease. Computed tomographic enterography image from a 27-year-old man with chronic Crohn’s disease (A). Image from magnetic resonance enterography performed 15 months later to reduce radiation exposure (B). Each study provided mural hyperenhancement, bowel wall thickening, and mural stratification in the same mid-small bowel segment (arrows). Reprinted from Gastroenterology. 2011;140(6):1795-1806. Fletcher JG, Fidler JL, Bruining DH, Huprich JE. New concepts in intestinal imaging for inflammatory bowel diseases. Copyright ©2012, with permission from Elsevier.

the images are acquired, in addition to interpretation, Dr. Fletcher noted. “Patient preparation and attention to technical acquisition are key features that influence the quality of CT and MR enterography images. In CT, we seek to minimize the radiation dose for each patient, whereas in MR, we utilize motion-robust sequences and check coverage. These exams are more complicated than the routine but are not onerous to perform or interpret once critical features are understood,” concluded Dr. Fletcher.

References 1. Fidler JL, Guimaraes L, Einstein DM. MR imaging of the small bowel. Radiographics. 2009;29(6):1811-1825. 2. Paulsen SR, Huprich JE, Fletcher JG, et al. CT enterography as a diagnostic tool in evaluating small bowel disorders: review of clinical experience with over 700 cases. Radiographics. 2006;26(3):641-657. 3. Fletcher JG, Fidler JL, Bruining DH, Huprich JE. New concepts in intestinal imaging for inflammatory bowel diseases. Gastroenterology. 2011;140(6):17951806. 4. Solem CA, Loftus EV, Fletcher JG, et al. Small-bowel imaging in Crohn’s disease: a prospective, blinded, 4-way comparison trial. Gastrointest Endosc. 2008;68(2):255-266. 5. Higgins PD, Caoili E, Zimmermann M, et al. Computed tomographic enterography adds information to clinical management in small bowel Crohn’s disease. Inflamm Bowel Dis. 2007;13(3):262-268.

Volume 1 • Issue 1

PractIce ProfIle

Mass General continued from page 1 

(CT) at the center and associate professor of radiology at Harvard Medical School in Boston. “Crohn’s disease is a great model for a multidisciplinary collaborative effort to optimize patient care. Radiologists can advise gas15 troenterologists on the imaging services that are most appropriate, tailor the scan protocols to answer the clinical question at hand, mSv and also learn the nuances of the disease process,” he said. 10 Among other advanced diagnostic techniques for IBD, the center is leading the way in the use of CT enterography (CTE), which combines a CT scan with negative or neutral oral contrast, IV con5 trast, and thin-cut, multiplanar (horizontal, coronal, and sagittal) slices to image the small bowel. Use of CTE for IBD has grown rapidly over the past decade because of its high sensitivity and specificity, and its ability to detect both luminal and extraluminal dis0 ease.3 The imaging technique has overtaken barium small bowel follow-through as the modality of choice in evaluating IBD.3,4 “For the last at least 6 or 7 years, we’ve been using CT enterography to evaluate IBD, looking at the early lesions,” said Vijay Yajnik, MD, PhD, attending gastroenterologist at the center and “For the last at assistant professor of medicine at Harvard Medical School. least 6 or 7 years, He noted the role of CTE in we’ve been assisting in a diagnosis of CD. “It’s using [computed pretty much the standard of care. There is also colonoscopy to obtain tomographic] the biopsy and confirm the diagnoenterography to sis,” said Dr. Yajnik. Massachusetts General Hospievaluate IBD, looking tal continues to refine CTE for IBD. at the early lesions.” Dr. Sahani works with the acclaimed —Vijay Yajnik, MD, PhD team at the center to evaluate techniques and protocols, ensure that exams can be ordered easily online, are consistent across the organization, and are very safe. Researchers at the center study new and innovative ways to better evaluate changes in IBD using CTE. Some current projects examine dual-energy CT techniques and computer-aided algorithms to improve detection and assess the severity of IBD. “We’re not only early adopters of new technologies but we’re also making them safer and leading the efforts with other institutions to educate the rest,” said Dr. Sahani. CTE is relatively easy to perform, its acquisition parameters and interpretation can be standardized, and it also is a reliable test for imaging patients with known or suspected IBD and its complications. Nevertheless, radiation exposure to patients remains a concern with CTE, especially considering the relatively young age of some patients presenting with symptoms of IBD. However, in the past 10 years, Dr. Sahani and his colleagues have focused extensively on developing protocols and investing in technology and research that has enabled the group to lower the radiation exposure in CTE exams (Figure 2). “The radiation exposure from CT enterography has dropped substantially,” he said. “Our radiation doses are less than half of what has been reported in

Volume 1 • Issue 1

CT enterography (national average) Abdominal CT (national average) Abdominal CT at Mass General CT enterography at Mass General

18.5

(standard scanner)

15.0

CT enterography at Mass General (advanced scanner)

Background radiation (1 year at sea level)

7.0

7.0 5.5 3.1

Figure 2. Computed tomographic enterography radiation exposure. Average dose of CT enterography and abdominal CT enterography at Massachusetts General Hospital compared with national average. CT, computed tomography; mSv, millisieverts Image courtesy of Dushyant V. Sahani, MD; available at www.massgeneral.org/imaging/ about/reducing_radiation_exposure.aspx

several leading publications. Moreover, for smaller patients, who are considered more vulnerable to radiation risk, the doses are close to the background radiation we all get exposed to in a year.” As an alternative that does not involve ionizing radiation, the team at Massachusetts General also is investigating the use of magnetic resonance enterography, noted Dr. Sahani (Figure 3, page 4). At Massachusetts General Hospital, the teamwork between multiple disciplines plays a substantial role in its success in caring for patients with digestive diseases. “Management of IBD requires cooperation between surgeons, gastroenterologists, and radiologists. And there’s nutrition and nursing. We have phenomenal nurses,” said Dr. Yajnik. “I think the [radiologists at the center] are so easily accessible. Without them, I don’t think I’d be able to provide adequate care for my patients,” said Dr. Yajnik. “Centers like this can act as a portal to create a nucleus that will allow patients

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Mass General continued from page 3 

to come in and get world-class care in medicine. When the patient comes in, it’s very comprehensive care,” added Dr. Yajnik who estimates that 95% of his patients have CD and ulcerative colitis.

References 1. U.S. News & World Report’ Best Hospitals: Massachusetts General Hospital Rankings. http://health.usnews.com/ best-hospitals/massachusetts-general-hospital-6140430/ digestive-disorders. Accessed March 28, 2012. 2. Massachusetts General Hospital Digestive Healthcare Center: Treatment Programs. Crohn’s and Colitis Center (About This Program). http://www.massgeneral.org/digestive/services/treatmentprograms.aspx?id=1301. Accessed March 28, 2012. 3. Bruining DH. CT enterography: is it the current state-of-theart for small bowel diagnostics? Dig Dis. 2010;28(3):429-432. 4. Raptopoulos V, Schwartz RK, McNicholas, MM, Movson J, Pearlman J, Joffe N. Multiplanar helical CT enterography in patients with Crohn’s disease. AJR Am J Roentgenol. 1997;169(6):1545-1550.

Figure 3. Patient with Crohn’s disease. (Left to right:) Computed tomographic enterography and magnetic resonance enterography film images depicting the bowel of a patient with Crohn’s disease. Photo courtesy of Dushyant V. Sahani, MD.

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Expert Reviews Diagnostic Imaging for HCC Increased Sensitivity of Imaging Exams Could Help Improve Surveillance By caroline helwick San FranciSco—Patients at high risk for liver cancer should undergo surveillance with ultrasound at six-month intervals and any new lesions 1 cm or larger should be evaluated by computed tomography (CT) or magnetic resonance imaging (MRI). This recommendation was issued by the American Association for the Study of Liver Diseases (AASLD) in its latest guideline on the surveillance of hepatocellular carcinoma (HCC) and was reviewed in a lecture by Tae Kyoung Kim, MD, at the 2012 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. “Proper imaging techniques are crucial for achieving a successful screening program for hepatocellular carcinoma,” said Dr. Kim, of the University of Toronto, in Ontario. The AASLD practice guideline recommends ultrasound because it is inexpensive, noninvasive, well accepted by patients and can be repeated every six months without risk. Additionally, ultrasound shows high specificity—greater than 90%. However, sensitivity varies from 65% to 80%, Dr. Kim pointed out. “High sensitivity can be only achieved by imposing rigorous operator standards and using proper equipment,” he said. For new nodules smaller than 1 cm, a repeat ultrasound should be performed in three months. Any new nodule 1 cm or larger detected on the surveillance ultrasound should undergo diagnostic testing

according to the updated AASLD guidelines, Dr. Kim said. “For nodules larger than 2 cm, imaging diagnosis is reliable; for those 1 to 2 cm, imaging diagnosis may be challenging,” he added. Appropriate diagnostic tests include dynamic contrast-enhanced CT and MRI. If one imaging test is inconclusive, the other imaging test or a biopsy should be performed. Contrast-enhanced ultrasound has proven useful, but is not approved for liver imaging in the United States. A diagnosis of HCC can be made without biopsy if the imaging shows arterial-phase hyper-vascularity and later washout. “This is diagnostic of HCC,” Dr. Kim said. “With proper imaging techniques, there is no need for biopsy, and the MRI not only shows hypervascularity and washout but other things that can be useful in diagnosis.” Hemangiomas are frequently detected during HCC surveillance and can be confidently diagnosed by dynamic contrast-enhanced imaging, according to Dr. Kim. Peripheral nodular enhancement, progressive central fill-in and lack of washout are the signs. Biopsy is needed only if the imaging findings are indeterminate. The biopsy diagnosis of equivocal nodules, such as a high-grade dysplastic nodule or well differentiated HCC, remains a challenge, Dr. Kim said, noting that a small biopsy specimen may not contain portal tracts with stromal invasion and that other features and immunohistochemical markers are prone to sampling error.

Diagnostic imaging tests for HCC are highly specific. Theses tests have moderate sensitivity for small (1-2 cm) nodules. The requirement for two coincident positive imaging exams only decreases the sensitivity; a single exam shows comparable specificity, Dr. Kim noted. “Dynamic CT/MRI has a high specificity for diagnosing HCC, more than 95%; however, the sensitivity is moderate (50%-70%). Therefore, the development of new diagnostic criteria should focus primarily on improving sensitivity, while maintaining specificity,” he said.

Improving Diagnostic Sensitivity MRI with a liver-specific contrast agent, such as gadoxetic acid (GdEOB-DTPA) or gadobenate dimeglumine (Gd-BOPTA), has been shown to improve the sensitivity of HCC diagnostic imaging. Dr. Kim led a study of 96 patients evaluated with Gd-BOPTA MRI. Investigators identified 116 nodules of 1 to 2 cm in size; they found 43 HCCs and 73 benign nodules. The investigators assessed MRI findings for signal intensity at each sequence, and several diagnostic criteria were developed. A univariate analysis revealed four imaging features associated with HCC: arterial phase hyperintensity, portal or delayed phase hypointensity (washout), hyperintensity on T2-weighted images and hepatobiliary phase hypointensity. A multivariable analysis showed that arterial phase hyperintensity and washout were associated with HCC (adjusted

odds ratio [OR], 17.1 and 11.7, respectively). The use of these features (fitting AASLD criteria) or the existence of three or more of these findings was associated with a sensitivity of 77% and specificity of 95%. Dr. Kim concluded that the incorporation of these alternative MRI criteria can improve the sensitivity of HCC diagnosis compared with the use of the features recommended in the AASLD practice guideline alone. Dr. Kim suggested that Gd-EOBDTPA be added to the diagnostic algorithm for HCC, in particular, to be performed on patients with hypovascularity in the arterial phase or hypervascularity in the arterial phase and no washout. Norah Terrault, MD, MPH, of the University of California, San Francisco, commented on the need for more widespread surveillance of patients at risk for HCC. “Overall, surveillance is not done at a level we would like to see. At-risk patients are often not recognized as being at risk. “Much of the surveillance is dedicated to patients known to have cirrhosis, but a physician may be following a patient with hepatitis C without knowing if that patient has cirrhosis,” she continued. “We have to ask whether patients have cirrhosis, and if we can make that distinction we should initiate surveillance. Although the techniques described by Dr. Kim are not uniformly available, most community gastroenterologists who identify an area of concern can access these imaging studies through referral.” n Dr. Kim has received research funding from Bracco Diagnostics. Dr. Terrault reported no relevant conflicts of interest.

From the Literature

Studies Illustrate Role of HCV Infection as Risk Factor for HCC Researchers Stress Importance of Early Detection of HCV By george ochoa Two Mayo Clinic studies published earlier this year illustrate the role of chronic hepatitis C virus (HCV) infection in the rising trend of liver cancer� One study (yang JD et al� Mayo Clin Proc 2012;87:916) analyzed longitudinal trends in the incidence, etiology and treatment of hepatocellular carcinoma (HCC), and survival in community residents aged 20 years or older with newly diagnosed HCV infection between Jan� 1, 1976 and Dec� 31, 2008, in Olmsted County, Minn� The researchers found that in earlier periods (1976-1990 and 1991-2000), alcohol use was the most common risk factor associated with HCC, but, in 2001 to 2008, chronic HCV infection filled that role� At the same time, HCC incidence rose dramatically, from 3�5

per 100,000 person-years for the period from 1976 to 1990 to 6�9 per 100,000 person-years between 2001 and 2008� “The biggest and unique risk factor for HCC is underlying liver disease,” said the study’s senior author, W� Ray Kim, MD, associate professor of medicine, Mayo Clinic College of Medicine, Rochester, Minn� “Our data showed that previously alcohol, more recently HCV has become the underlying cause�” The second study (Shire AM et al� Mayo Clin Proc 2012;87:17-24) evaluated a cohort of Somali immigrants seen at Mayo Clinic from July 1, 1996 to Oct� 31, 2009� Non-Somali Olmsted County residents served as controls� Investigators calculated the frequencies of chronic hepatitis B virus (HBV) and HCV infection in these populations, and their associations with HCC� Both HBV and HCV occurred frequently in the Somali cohort, but HCV

was the major risk factor for HCC� There were significant differences in the HCV genotype distributions between Somalis and non-Somalis� The high prevalence of HCV in the Somali sample came as a surprise to the researchers� “We didn’t expect it,” said lead author Abdirashid M� Shire, PhD, assistant professor of medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine� The study, Dr� Shire said, supports the value of early detection of HCV� “It’s very important to screen for HCV,” he said� Dr� Kim said that his study also indirectly supports the value of early detection and treatment of HCV infection to improve outcomes� Drs. Kim and Shire had no relevant financial disclosures.

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No Discernable Benefits of New Terms for liver Transplantation Researchers Say Risk Aversion Limits Access to New Livers, Compromises Patient Care By chriStina Frangou San FranciSco—Transplant centers have stopped accepting as many highrisk donors and high-risk recipients after the Centers for Medicare & Medicaid Services (CMS) initiated its revised Conditions of Participation in June 2007, according to an abstract presented at The Liver Meeting 2011. Researchers behind the study are calling for changes to the CMS program, saying that it omits critical riskadjustment criteria in its formula. The program is leading to more risk aversion at transplant centers, which could limit access to liver transplantation and reduce the pool of already limited organs, the researchers said. “While quality improvement initiatives aim to enhance post-transplant outcomes, the inadequately risk-adjusted criteria implemented by CMS might act as a disincentive [for physicians] to perform lifesaving liver transplantation in high cardiovascular risk patients and

limit the use of valuable donor organs of perceived lower quality,” said study coauthor Edward Wang, PhD, research associate professor in surgery at Northwestern University in Chicago. In 2007, the CMS implemented new conditions of participation for organ transplant programs in order to improve quality, performance and transparency. The regulations mandated that transplant-specific survival meet risk-adjusted expected outcomes, and that centers deviating from these metrics in two successive program reports would be flagged for decertification. When the program was first proposed, some transplant surgeons expressed concern that the model did not include all the risk-adjusted factors that affect outcomes, such as immunosuppression protocols, organs from extended criteria donors and those who died from cardiac arrest, as well as donors with steatosis. Critics were concerned that transplant centers would be penalized for using organs from high-risk donors or for highrisk recipients. They also feared centers

would deny access to high-risk patients in order to meet the expected outcomes. Dr. Wang and colleagues set out to measure the effect of these conditions on liver transplant recipients and donors. They retrospectively examined the records of 65,601 adult recipients of deceased donor livers in transplantations

following the implementation of the CMS Conditions of Participation. The majority of transplant centers (n=75; 71%) demonstrated some degree of increased risk aversion. Half reduced their use of organs for recipients with high cardiovascular risk scores; 41% limited receipt of livers from donors

‘The inadequately risk-adjusted criteria implemented by CMS might act as a disincentive [for physicians] to perform lifesaving liver transplantation in high cardiovascular risk patients and limit the use of valuable donor organs of perceived lower quality.’ —Edward Wang, PhD

documented in the Organ Procurement and Transplant Network (OPTN) of the United Network of Organ Sharing between 1995 and 2010. Analysis showed that access to liver transplantation for patients with high cardiovascular risk dropped immediately

with a high-risk index; 19% showed risk aversion on both the donor and recipient ends. Overall, the recipient cardiovascular risk index fell from 0.76 in 2006 to 0.65 in June 2007, a significant drop; however, the overall risk was still higher than

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Risk aversion would be justified if outcomes improved. But that’s not the case. The data suggest that certain centers provide consistently excellent outcomes even for high-risk patients.

before 2004. The donor risk index leveled off in June 2007, marking it the first time in a decade that the risk index did not increase. Survival rates remained relatively unchanged after the policy launched, the investigators found. One-year patient survival dropped 1%, from 87% to 86%. Graft survival was similar, falling from 83.3% to 83.05%. The data are, however, limited with only two years of follow-up, the authors noted. Even before the CMS ruling, transplant centers were reluctant to offer transplantation to recipients with a high cardiac risk. The vast majority of the transplants performed before 2007 involved patients with no or only one cardiac risk factor, the study showed. Additionally, the size of the transplant center did not appear to have any bearing on risk aversion, according to the results. Centers that performed more than 1,000 transplants were just as likely to have a decline in recipient cardiovascular risk index and donor risk index as centers that performed less than 200.

Dr. Skaro added that the team focused on cardiac variables because they are an important element of risk adjustment, but their findings suggest that the

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registry does not appropriately capture cardiac risk. “Perhaps covariates like diabetes severity or angiographic coronary artery disease burden or hemodynamic parameters that one can collect from echocardiography would be more helpful in predicting outcomes,” said Dr. Skaro. He and colleagues believe the OPTN should reduce the number of variables collected by dropping those that don’t affect outcome and adding others that could potentially predict outcomes. Their study has been submitted to the CMS for

consideration. However, Robert M. Merion, MD, pointed out that reducing the acceptable recipient cardiovascular risk index could potentially be beneficial by sparing a limited resource for the patients most likely to survive. It might not be a “bad thing” to reduce the number of patients who receive liver transplants but are at proven high cardiac risk for subsequent mortality, said Dr. Merion, professor of surgery, University of Michigan Transplant Center, Ann Arbor.

see Transplantation, page 16

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Analysis showed that access to liver transplantation for patients with high cardiovascular risk dropped immediately following the implementation of the CMS Conditions of Participation. But survival rates remained relatively unchanged after the new policy launched.

At this point, the study identified no measurable benefits to the Conditions of Participation, the authors said. “There don’t seem to be any strata that demonstrate improved survival as a consequence of the reduced risk,” said study co-author Anton Skaro, MD, assistant professor of surgery transplant, Comprehensive Transplant Center, Northwestern Feinberg School of Medicine, Chicago, who presented the study at The Liver Meeting.

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Focus GastroenteroloGy & endoscopy news • May 2012

DAAs continued from page 1

In a crowded plenary session called “HCV: Refining the Use of DirectActing Antivirals,” researchers presented three new subanalyses from the Phase III trials that led to the approval of boceprevir and telaprevir. Overall, the new reports revealed the following: • Cirrhotic patients who previously received the standard two-drug therapy and then received telaprevir in combination with pegylated interferon (Peg-IFN) and ribavirin had improved SVR compared with patients who received Peg-IFN and ribavirin alone. However, among those with cirrhosis, SVR rates peaked at 47% in previous responders and were lower for previous null responders. The study also found that cirrhotic patients with several baseline factors—high baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels—were more likely to achieve SVR following telaprevir triple therapy. • HCV genotype 1–infected patients who previously failed Peg-IFN and ribavirin treatment had significant improvements in SVR rates when telaprevir was added to their therapy. But the strongest predictor of achieving SVR with a telaprevir-based regimen was the patient’s previous response to Peg-IFN and ribavirin. In other words, patients who did not respond to standard therapy had a reduced likelihood of responding to telaprevir. Prior relapsers had the greatest chance of achieving SVR, followed by previous partial responders. The lowest SVR rates were among previous null responders. Patients’ baseline factors also changed the odds for achieving SVR, particularly baseline low-density lipoprotein (LDL) levels and fibrosis stage. • Among poor IFN responders who received boceprevir in Phase III trials, 28% to 34% achieved SVR compared with 0% to 4% of those who received Peg-IFN and ribavirin alone. Poor IFN responders were much more likely to achieve SVR if they were infected with HCV subtype 1b rather than subtype 1a, and had fibrosis stages 0 to 2 rather than 3 to 4. This research suggests that patients’ prior experience with Peg-IFN and ribavirin has the strongest value in predicting their likelihood of responding to the new DAAs, investigators said. There are other factors at play as well, including fibrosis stage, baseline LDL and AST levels, as well as HCV genotype subtype. SVR rates for previous nonresponders

or partial responders improve with the addition of a DAA but, still, response rates remain far below that expected for other hepatitis C patients. That leaves many questions about who should be treated with these new therapies, said session moderator Anna Lok, MD, professor in the Department of Internal Medicine and Alice Lohrman Andrews Research Professor in Liver Disease, University of Michigan, Ann Arbor. “You can tell these patients that they have a 30% chance of responding. But, there’s the flip side to that—a 70% chance of resistance. All of a sudden, the equation becomes very different,” she said.

Previous response to Peg-IFN and ribavirin therapy was a key predictive factor for all patients. Even among noncirrhotic patients who had previously not responded to Peg-IFN and ribavirin, the SVR was low, at only 41%. The rate was similarly low (42%) among previous null responders with mild fibrosis.

Rash, pruritus and anemia (hemoglobin <10 g/dL) were more frequent in cirrhotic patients receiving triple therapy (43%, 55% and 44%, respectively) than in those who received PegIFN and ribavirin alone (27%, 35% and 27%, respectively). Adverse events led to telaprevir discontinuation in 15% of

‘You can tell these patients that they have a 30% chance of responding. But, there’s the flip side to that—a 70% chance of resistance. All of a sudden, the equation becomes very different.’ —Anna Lok, MD

Telaprevir-based Regimen: Patients With Cirrhosis In the first study presented during the session, Stanislas Pol, MD, PhD, professor of hepatology at Université Paris V (René Descartes), and head of the Hepatology Unit at Cochin Hospital, Paris, and colleagues conducted a subanalysis of the Phase III REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial (presentation 31). The study was designed to gauge the effect of triple therapy including telaprevir on patients with Child class A cirrhosis who previously responded poorly to the Peg-IFN and ribavirin regimen. The REALIZE study compared telaprevir in combination with Peg-IFN and ribavirin in patients with HCV genotype 1 who had a previous null or partial response or who relapsed after treatment with Peg-IFN and ribavirin. The study included one treatment arm of Peg-IFN and ribavirin alone and two telaprevir treatment arms, which were pooled together for this analysis. Of 662 randomized patients, 578 with complete baseline information were included in the study. There were 169 patients with cirrhosis and 493 without. Cirrhotic patients were slightly older and more likely to be prior null responders but, otherwise, the two groups were similar in demographics. Results showed that SVR was achieved in 75% of patients who underwent triple therapy and had no, minimum or intermediate fibrosis. However, the SVR rate decreased to 67% in patients with bridging fibrosis and dropped to 47% in cirrhotics. SVR rates were even lower among cirrhotics who were previous partial responders, at 34%, and cirrhotics who were previous null responders, who had the lowest SVR rate reported, at 14%.

‘For some people, a 30% chance is valid. That’s the best thing they’ve heard in years. For others, it just isn’t good enough.’ —Bruce R. Bacon, MD

The study showed that a relationship exists between fibrosis stage, prior response and SVR but the association with fibrosis stage is not singularly incremental. Patients who relapsed after prior Peg-IFN and ribavirin therapy still achieved high rapid viral response rates and low virologic failure rates, irrespective of the fibrosis stage. However, for prior null and partial responders, fibrosis stage had a significant impact on SVR.

cirrhotic patients compared with 11% of non-cirrhotics. Anemia and neutropenia were significantly more common in cirrhotics (42% and 25%) than noncirrhotics (34% and 27%). After hearing the study presentation, Paul Pockros, MD, division head of gastroenterology/hepatology and director of the Center for Liver Diseases at Scripps Clinic in La Jolla, Calif., said that many of his cirrhotic patients

GastroenteroloGy & endoscopy news • May 2012

become anemic “rather rapidly,” a finding not borne out in Dr. Pol’s study of Child class A patients. The condition is difficult to manage because it begins soon after DAA treatment is initiated. Making it worse, according to FDA recommendations, cirrhotic patients are required to undergo a 48-week course of therapy and are not eligible for a shortened course of therapy. Dr. Pol noted that anemia occurs in approximately 50% of patients in his group’s unpublished experience with more advanced cirrhotics and “indeed” appears very early. However, he cautioned that, for the moment, the recom-

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Telaprevir-based Regimen: Patients With HCV Genotype 1 In a second study, researchers again analyzed data from the Phase III REALIZE study (Berg T et al, presentation 32). This time, they focused on the predictors of SVR in HCV genotype 1 patients with prior Peg-IFN and ribavirin treatment failure. And again, the study showed that patients’ prior response to treatment predicted their response to DAA therapy. The study, presented by Thomas Berg, MD, professor of medicine, University Hospital, Leipzig, Germany, included

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response to standard Peg-IFN and ribavirin therapy, high LDL concentration, HCV subtype 1b and maximum AST/ ALT. A patient’s viral load and stage of fibrosis had only borderline value in predicting SVR. Of all factors, prior response to therapy was the most significant. There was one other valuable clue as to a patient’s odds of achieving SVR, the researchers found. The on-treatment response—or viral detectability at weeks 4 and 12—was a strong predictor of SVR (odds ratio, 7.8). “In summary, prior response and ontreatment response appear to be the main predictive factors in terms of likelihood of response. Other baseline parameters, although statistically significant, do not appear to add much prognostic value,” said Dr. Berg. “Further investigation is needed to examine how baseline LDL is associated with treatment response.”

Boceprevir-based Regimen: Prior Poor Responders

Should patients who have poor baseline predictions be started on a DAA regimen? ‘That’s a good question … and one that has been batted about in multiple conversations… . I don’t think we have an answer.’

mendation remains to treat cirrhotics with 48 weeks of treatment, irrespective of extended rapid viral response. Logistic regression analysis defined the predictors of response to the telaprevir-based regimen in cirrhotic patients. The only factors that were significantly associated with SVR across all groups were low baseline AST levels and prior relapse following Peg-IFN and ribavirin therapy.

—Bruce R. Bacon, MD 578 patients of the 662 who were originally randomized. Of these, 28% were prior null responders, 19% were partial responders and 53% were prior relapsers. For the entire cohort, median age was 51 years, 69% were male, 88% had HCV RNA levels of 800,000 IU/mL or less and 25% had cirrhosis. On multivariate analysis, the following factors were independent predictors of treatment outcome: patients’ prior

In a third study, investigators looked at factors that appear to increase the chance of SVR in patients who are poor IFN responders and then received boceprevir (Bacon BR et al, presentation 33). In this study, patients’ HCV genotype and fibrosis stage appeared to carry the greatest weight in predicting patients who will attain SVR after a poor response to the Peg-IFN and ribavirin lead-in. Investigators studied boceprevirtreatment outcomes in patients who were poorly responsive to interferon during the four-week Peg-IFN and ribavirin lead-in during the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) and SPRINT-2 (Serine Protease Inhibitor Therapy 2) Phase III trials (Bacon BR et al. N Engl J Med 2011;364:1207-1217 and Poordad F. N Engl J Med 2011;364:1195-1206, respectively). Of the more than 1,000 patients in the two trials, 28% to 34% responded poorly to IFN, and patients’ response to the lead-in was the strongest predictor of SVR response. In the follow-up study, investigators focused on 282 poor IFN responders. Of these, 93 patients achieved an SVR. Analysis showed that the baseline factors that were associated with SVR were HCV subtype 1b not 1a, minimal not advanced fibrosis and a low baseline viral load, defined as HCV RNA less than 400,000 IU/mL. “HCV subtype and fibrosis level may differentiate between responders and nonresponders in poorly interferonresponsive patients,” said Bruce R. Bacon, MD, the study’s lead author and

the James F. King Endowed Chair in Gastroenterology, Saint Louis University School of Medicine, St. Louis. Viral load decline after eight weeks of treatment with boceprevir also was shown to be highly predictive of SVR. No patient studied who had a less than 3 log10 decline in HCV RNA levels after eight weeks of boceprevir went on to achieve SVR.

Still No Consensus It’s still unclear what these findings mean in terms of best treatment practice for poorly responsive patients. Dr. Lok questioned whether patients should be stopped on boceprevir after eight weeks if they don’t have a significant early response. But, Dr. Bacon replied that there is no well-defined course of action other than detailed conversation with patients. “If your patient wasn’t doing very well, it’s reasonable to consider stopping,” Dr. Bacon said. “Still, it’s a relatively small group of patients and it hasn’t been prospectively vetted. With those caveats, nonetheless, the data are pretty strong.” But should patients who have poor baseline predictions even be started on a DAA regimen? “That’s a good question,” Dr. Bacon said. “And one that has been batted about in multiple conversations that I’ve been in over the last couple of days. I don’t think we have an answer.” Dr. Bacon noted that new medications are in the pipeline, although they are still several years away. It’s important to consider, too, that any patient who is started on a DAA is at risk for developing resistance. In some groups of patients— cirrhotics and poor IFN responders, specifically—that risk comes without a strong likelihood of a SVR, he said. Physicians and patients must discuss all these issues. “Each practitioner and their patients are going to have to address that question. You have to know the data and you have to present it to your patients and let them participate in the decision,” Dr. Bacon said. “For some people, a 30% chance is valid. That’s the best thing they’ve heard in years. For others, it just isn’t good n enough.” Dr. Lok has served on the advisory committee or review panel for Abbott Laboratories, Bayer, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck & Co. and Roche; she has received grant or research support from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck & Co., and Roche. Dr. Pol has served as a board memsee DAAs, page 16

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Deaths Attributed to HCV on the Rise, Outstripping HIV Mortality By chriStina Frangou San FranciSco—The annual death toll from hepatitis C virus (HCV) is rising and has now surpassed HIV-related mortality in the United States, according to data originally presented at The Liver Meeting 2011. An analysis of death certificate data showed that between 1999 and 2007 recorded deaths associated with HCV

rose to 15,106, while deaths associated with HIV dropped to 12,734 in 2007 (Ly KN et al. Ann Intern Med 2012;156:271-278). However, the difference in mortality between these two diseases is likely greater than these figures suggest. HCV infection may only be diagnosed in 50% or even fewer people before their death so the actual affect of HCV may be even larger, the study authors said. Moreover, middle-aged Americans account for

the majority of deaths from HCV and hepatitis B virus (HBV), which strongly suggests that the “silent epidemic” of hepatitis, as it is often called, will continue to worsen, said researchers. “Hepatitis B and C are critical and relatively unrecognized public health issues in the United States that have reached epidemic proportions,” said lead author Scott D. Holmberg, MD, MPH, chief of the Epidemiology and Surveillance Branch, Division of Viral Hepatitis,

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Centers for Disease Control and Prevention, in a presentation at the meeting. Dr. Holmberg and colleagues studied death certificate data in the United States from 1999 to 2007 using information from the National Center for Health Statistics. The database includes cause-of-death data for individuals in all 50 states and the District of Columbia. Investigators looked only at deaths from HIV, HCV and HBV. Other major causes of mortality, like heart disease and cancer, were not studied. Over the eight-year study period, approximately 22 million deaths were recorded. HIV accounted for the most deaths of three diseases and was the underlying or a contributing factor to 24,063 deaths. HCV mortality was marginally lower, at 21,711 deaths. HBV was associated with far fewer deaths, at 2,239.

‘Hepatitis B and C are critical and relatively unrecognized public health issues in the United States that have reached epidemic proportions.’ —Scott D. Holmberg, MD, MPH

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However, the data showed that an increasing number of adults were dying from HCV each year, with a statistically significant average annual age-adjusted mortality rate increase of 0.18 deaths per 100,000 individuals per year. Put another way, the annual mortality rate for hepatitis C rose from about three per 100,000 in 1999 to 4.57 in 2007, with the most marked surges over the past few years. At the same time, deaths from HIV fell from six per 100,000 in 1999 to 4.16 deaths per 100,000 individuals per year, representing a significant average annual age-adjusted mortality decrease of 0.02 deaths per 100,000 individuals per year. Deaths from hepatitis B remained relatively stable over the study period, with a slight decrease of 0.02 deaths per 100,000 persons per year. The age-adjusted mortality rate for hepatitis B was 0.56 deaths per 100,000. Most hepatitis-related deaths occurred for people in their 40s, 50s and 60s. In 2007, 59.4% of HBV-related deaths and 73.4% of HCV-related deaths were in people between ages 45 and 64 years. The study found that people of nonHispanic Asian or Pacific Islander

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descent were overrepresented among hepatitis-related deaths. The mortality from hepatitis B was 11 times higher in this population than other ethnic groups. A similar but less dramatic relationship was observed for hepatitis C–related deaths among non-Hispanic blacks, Hispanics and non-Hispanic American Indian or Alaskan Native populations. Diana Sylvestre, MD, executive director of OASIS, an inner city nonprofit clinic in Oakland that is dedicated to treating HCV in drug users, said that the study findings reflect trends that started decades ago. “A great many people were infected through the blood supply before testing became available in 1992, and now, 20 years later, we are seeing the natural history of HCV rear its ugly head,” she said. “HCV is usually fairly silent for a couple of decades, and only then do we begin to see the emergence of consequences in terms of cirrhosis, end-stage liver disease, liver cancer and deaths.” At the same time, HIV treatment moved ahead of HCV in terms of developing highly effective antivirals, which resulted in a vast reduction of HIVrelated mortality. Dr. Sylvestre said that more systematic screening of at-risk individuals, improved treatment access and dedicated efforts to focus HCV transmission education at drug treatment programs, sexually transmitted disease clinics and syringe-exchange programs are important.

‘Now, 20 years later, we are seeing the natural history of HCV rear its ugly head.’ —Diana Sylvestre, MD

“We need to focus HCV testing at these kinds of sites because they are ground zero for new cases and the treatment of HCV is extremely effective when the infection is acute.” The study authors cautioned that it is difficult to tease out a single cause of death in many cases. Many who died with a hepatitis B or C infection frequently had co-infection with HIV, other hepatitis viruses, chronic liver disease or alcohol-related conditions. The data is based on death certificates, which often are completed by someone other than the primary physician and may include inaccurate information. However, it’s likely that the analysis underestimates the true effect of viral hepatitis because many undiagnosed individuals die of the disease. Up to 50% of all people infected with hepatitis B

‘HCV is usually fairly silent for a couple of decades, and only then do we begin to see the emergence of consequences in terms of cirrhosis, end-stage liver disease, liver cancer and deaths.’ —Diana Sylvestre, MD

or C are unaware that they are infected, whereas around 80% of people with HIV are diagnosed during their lifetime. “Even if one cannot easily assign a cause

of death among persons with HBV, HCV or HIV infection, approximately 16,000 deaths among HCV- and HBV-infected persons were registered in 2007, and this

figure must represent only a fraction of a larger burden of morbidity and mortality from viral hepatitis,” Dr. Holmberg said. The authors suggest that health care providers, policymakers and the public should borrow from the example of HIV. The decreasing mortality rate associated with HIV follows years of awareness campaigns, resources for prevention and development of effective therapies. “We think that a similar commitment to decrease morbidity and mortality from chronic hepatitis B and C is warranted,” n the authors said.

For overt HE* patients

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

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*HE=hepatic encephalopathy. † Over a 6-month period; P<0.0001 vs placebo.2 ‡ Over a 6-month period; P=0.0129 vs placebo.2 § HE-related hospitalization deﬁned as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.2

IMPORTANT SAFETY INFORMATION XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age. In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. XIFAXAN has not been studied in patients with MELD scores >25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C). XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. Clostridium difﬁcile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal ﬂora of the colon which may lead to overgrowth of Web site: www.salix.com 1700 Perimeter Park Drive, Morrisville, NC 27560 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIF 12/16

C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. The most common adverse reactions occurring in >8% of patients in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), ascites (11%), muscle spasms (9%), pruritus (9%), and abdominal pain (9%). Xifaxan550 is not available for sale outside the U.S. Xifaxan550 is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see adjacent brief summary of Prescribing Information. References: 1. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017. 2. Xifaxan [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2010.

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New CDC Initiative Aims To Improve Hepatitis B Screening Among Foreign-born U.S. Residents By chriStina Frangou San FranciSco—The Centers for Disease Control and Prevention (CDC) has launched a demonstration project to find, screen and treat immigrants and refugees living in the United States who come from countries where hepatitis B is endemic.

The project goal is to slow the spread of hepatitis B among foreign-born residents of the United States, who now account for the majority of chronic hepatitis B cases in this country. “In order to eliminate hepatitis B from the United States, imported cases of hepatitis B must be addressed,” said Kathy K. Byrd, MD, MPH, of the CDC’s Division

of Viral Hepatitis, in a presentation at The Liver Meeting 2011. Hepatitis B has decreased markedly among Americans born in the United States over the past decades due, largely, to the implementation of vaccination programs for newborns, infants and adolescents. But among foreign-born individuals living in the United States, the

prevalence is rising. Today, it is estimated that somewhere between 40% and 70% of all hepatitis B chronic infections in the United States are in people born outside of the country. One study suggests that between 1.04 and 1.61 million foreignborn U.S. residents have chronic hepatitis B infection (Kowdley K. Hepatology 2011 Nov 22. [Epub ahead of print]). That brings the total prevalence of chronic hepatitis B in the United States to as high as 2.2 million or “significantly greater than previously reported,” according to the study. And in many cases, people are unaware that they are infected. Since 2008, CDC guidelines have recommended routine serologic hepatitis B serum antigen (HBsAg) screening for all foreign-born persons from countries with hepatitis B prevalence rates of 2% or higher, regardless of their vaccination history, and for unvaccinated U.S.-born children of foreign-born parents from countries with high endemicity; there is, however, no formal mechanism for evaluating newly arrived immigrants and refugees.

Screening Project, Part I In order to target the populations at highest risk, the CDC launched a project that will begin community-based screening, vaccination and referral for foreignborn individuals.

‘In order to eliminate hepatitis B from the United States, imported cases of hepatitis B must be addressed.’ —Kathy K. Byrd, MD, MPH

In the first part of the two-part project, the CDC plans to identify and map foreign-born populations living in the United States. The goal is to pinpoint counties and neighborhoods populated by immigrants and refugees from countries with high or intermediate rates of hepatitis B. People from countries that have high and intermediate risk for hepatitis B account for a majority of the approximately 1.5 million who move to the United States annually. High-endemic countries are defined as those with a prevalence of 8% or higher, whereas

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intermediate-endemic countries are those with an infection rate between 2% and 7%. In low-endemic countries like the United States and Canada, less than 2% of the population is infected with hepatitis B. In China, between 8% and 20% of the population carries the HBsAg. China is the most common country of origin for imported cases of hepatitis B, followed by the Philippines, Vietnam, India and Korea. All five countries have high endemicity for hepatitis B. Immigrants from countries with intermediate endemicity, such as those in Latin and Central America, account for about 37% of immigrants and refugees.

to begin screening target populations for hepatitis B. They will vaccinate anyone susceptible to the disease and refer chronically infected people for care and treatment. Dr. Byrd said the CDC will choose a project area this year and begin screening. They expect the screening portion of the project to last about one year. Kris Kowdley, MD, director of research and director of the Liver Center of Excellence at Virginia Mason’s Digestive Disease Institute, Seattle, said that the CDC plan is greatly needed. Dr. Kowdley, who

is first author of the recent study showing much higher-than-expected rates of hepatitis B among foreign-born people living in the United States, noted that without substantial changes in screening and awareness, the disease burden related to chronic hepatitis B in the United States is likely to increase. “If you look at recent patterns of immigration to the United States, there has been an increase in immigration from high-endemic countries,” Dr. Kowdley said. “What that tells me is that we’re going to have a higher

percentage of foreign-born individuals with hepatitis B who will be at risk for complications from liver disease; in addition, there may be an increased risk of transmission to others without broader vaccination efforts.” Dr. Kowdley would like to see universal screening for foreign-born populations, a goal that he says is achievable. “It may be more feasible now than previously, given the growing emphasis on improving health care insurance coverage to underserved populations. If see HBV Initiative, page 16

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hepatitis B who will be at risk for complications from liver disease.’ —Kris Kowdley, MD

Of added concern to investigators is that hepatitis B is transmitted and develops differently in high-endemic countries. In countries where hepatitis B is endemic, the majority of infections occur among infants and young children as a result of perinatal or horizontal transmission, which differs from the United States where the hepatitis B often is contracted as an adult. Additionally, the risk for chronic infection is much higher when an individual is infected in early childhood. More than 90% of children infected under 1 year of age will develop chronic infection compared with approximately 5% of people infected after the age of 5 years. Mortality also is inversely related to the age of infection, said Dr. Byrd. About 25% of adults who become chronically infected during childhood later die from liver cancer or cirrhosis.

Screening Project, Part 2 Once the CDC has mapped out the areas that have many immigrants and refugees from these countries, they will move on to the second stage of the project—identifying the community-based organizations and clinical venues that provide hepatitis B services, particularly those that work with foreign-born individuals. Organizers hope to use these venues

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HCC Surveillance

DAAs

continued from page 6

with increased consistent HCC surveillance was being in the care of a hepatologist (OR, 7.39; 95% CI, 1.48-37.0). Surveillance rates were 51.7% among patients followed in subspecialty gastroenterology clinics compared with 16.9% for those followed in primary care clinics (P<0.001). Based on the study results, the researchers called for interventions that increase HCC surveillance rates, adding that interventions will likely need to address multiple failure points to be effective. Hepatologists can improve surveillance by educating patients and other physicians, particularly primary care physicians, about the need for better surveillance of patients with known cirrhosis, said the

continued from page 11

investigators. “The majority of patients with cirrhosis in the United States are cared for by primary care doctors, not subspecialists,” Dr. Singal said. “Within many health care systems, there’s no way that all these patients can be cared for by hepatologists. Really, I think our job as hepatologists is to educate the primary care providers how to care for cirrhotics with things like HCC surveillance.” Dr. Singal and colleagues are currently undertaking a prospective study monitoring surveillance rates in a population of patients with cirrhosis. n There were no financial conflicts of interest related to this study.

ber for Boehringer Ingelheim, Bristol-Myers Squibb, Cilag, Gilead, Janssen Pharmaceuticals, Roche, Schering-Plough, Tibotec and Wyeth; he has received speaking and teaching fees from GlaxoSmithKline. Dr. Berg has served on the advisory committee or review panel for Abbott Laboratories, Bristol-Myers Squibb, Gilead, Janssen Pharmaceuticals, Merck & Co., Novartis, Roche, Tibotec and Vertex Pharmaceuticals; he has consulted for Bristol-Myers Squibb, Gilead, Janssen Pharmaceuticals, Roche, Tibotec and Vertex Pharmaceuticals; he has received grant/research support from Boehringer Ingelheim, BristolMyers Squibb, Gilead, Janssen Pharmaceuticals, Novartis, Roche, ScheringPlough, Tibotec and Vertex Pharmaceuticals; and he has received support for speaking and teaching from Bayer, Bristol-Myers Squibb, Gilead, Janssen Pharmaceuticals, Merck & Co., Novartis, Roche, Schering-Plough, Tibotec and Vertex Pharmaceuticals. Dr. Bacon has served on the advisory committee or review panel for Gilead, ISIS, Merck & Co., Three Rivers Pharmaceuticals and Vertex Pharmaceuticals; he has consulted for Merck & Co.; he has received grant/research support from Bristol-Myers Squibb, Gilead, Merck & Co., Roche, Three Rivers Pharmaceuticals, Valeant Pharmaceuticals and Vertex Pharmaceuticals; and he has received support for speaking and teaching from Gilead, Merck & Co., and Three Rivers Pharmaceuticals.

Transplantation

HBV Initiative

continued from page 9

continued from page 15

Dr. Skaro acknowledged that risk aversion would be justified if outcomes improved. But that’s not the case. The data suggest that certain centers provide consistently excellent outcomes even for high-risk patients. These centers may be good examples for others, he said. “It may be that the answer to preserve access is to adopt the center of excellence–type of paradigm so we can learn from these centers that have had excellent outcomes and apply that more broadly to the nation.” Dr. Wang said that modifying the risk adjustment used in the CMS policy

is “necessary to preserve access to liver transplantation among high-risk recipients and sustain the optimal use of marginal donors. “We believe that there is a need for mitigating factors that could justify inferior outcomes by transplant centers under specific circumstances. Failure to reach consensus on such a mechanism would result in continued risk-averse behavior by transplant centers, undermining innovation and hampering advancement of the field of transplantation and ultimately compromising patient care.” n

we have more primary care and more preventive health care services, we should be able to implement these kinds of strategies.” Gastroenterologists can play a significant role in curbing the spread of hepatitis B. Dr. Kowdley urged gastroenterologistss to speak with patients about screening for hepatitis B, particularly those from countries with high and intermediate endemicity. “If [a gastroenterologist] happens to be practicing in an area with a large population of immigrants from Asia, sub-Saharan Africa or Brazil, there is an excellent opportunity for the gastroenterologist to educate their patients about the importance of hepatitis B screening and vaccination during points of care, such as when patients come for a screening colonoscopy or for evaluation of other GI symptoms,” Dr. Kowdley said. “Ask patients ‘have you ever been exposed?’ Add it to your standard intake forms that we ask patients to fill out. This might permit testing and/or vaccination opportunities for those with a family history of liver cancer, family n history of hepatitis or immigrants from high-endemic countries.”

Potential First-in-Class Hepatitis C Vaccine Enters Phase I/II Trials A preventive vaccine against hepatitis C virus (HCV) that would potentially be the first in that class is entering a Phase I/II clinical trial, according to the Basel, Switzerland-based biopharmaceutical company Okairos�

This is the first multicenter, double-blinded, randomized, placebo-controlled trial of a vaccine to prevent HCV infection, the company stated� The trial, born of collaboration between Okairos and the National Institute of Allergy and Infectious Diseases, will be conducted by co-principal investigators from Johns Hopkins university and the university of California, San Francisco� The Phase I/II trial follows promising Phase I results published in January in Science Translational Medicine (Barnes E et al� 2012;4:115ra1)� In that study in healthy volunteers, the T-cell–based preventive vaccine was safe and well tolerated, and, the authors reported, it was shown possible “to generate very strong, broad, long-lasting, and functional T-cell responses against HCV in healthy donors using an adenovirusbased approach�” The Phase I/II trial will test the vaccine’s potential effectiveness in protecting against chronic HCV infection� Enrolling 350 subjects, the trial will begin with an interim Phase I analysis of safety and immunogenicity data in a subset of the participants� The study’s primary end points will measure the incidence of chronic HCV infection, and the vaccine’s safety and tolerability� Okairos’ HCV vaccine is based on a technology platform that uses proprietary, chimpanzee-derived adenovirus vectors to stimulate a robust T-cell response against selected antigens� —Based on an Okairos press release and the article in Science Translational Medicine

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Expert’s Picks:

Silymarin for NAFLD Compiled and written by David Wild Gastroenterology & Endoscopy News medical advisory board member, Alan Cutler, MD, provides a review of the literature

on silymarin in the treatment of liver disease.

Alan Cutler, MD Clinical Associate Professor of Medicine Wayne State University Detroit, Michigan

Silymarin, commonly known as milk thistle, was used in classical Greece to treat hepatic and gallbladder diseases and to protect the liver from toxins. Somewhat more recently, there has been renewed interest in its potential efficacy in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), particularly given the role that oxidative stress is thought to play in the pathogenesis of NAFLD and the anti-oxidant properties of the herb. This month, Gastroenterology & Endoscopy News Medical Advisory Board member Alan Cutler, MD, provides a snapshot of, and commentary on, some of the most noteworthy research on silymarin.

Placebo-Controlled Trial of Silymarin in Patients With Nonalcoholic Fatty Liver Disease (Hashemi SJ et al� Hepatitis Monthly 2009;9:265-270) Researchers at the Qazvin University of Medical Sciences in Qazvin, Iran, prospectively enrolled 100 NAFLD patients they had treated between 2007 and 2008. The participants had laboratory-confirmed disease, with elevated levels of alanine aminotransferase (ALT) and asparate aminotransferase (AST). None of the patients had viral or autoimmune hepatitis, or had a history of excessive alcohol consumption or relevant drug use. The investigators randomized 50 subjects to receive 280 mg silymarin daily for 24 weeks and the same number of patients to a placebo arm. The two groups were similar in age and gender distribution and had similar mean levels of ALT and AST at study outset. According to the findings, mean serum ALT levels in the treatment group dropped from 113.03 IU/L at baseline to 73.14 IU/L after 24 weeks of treatment (P=0.001). In contrast, mean ALT levels decreased in the placebo group from 104.54 IU/L at baseline to 89.92 IU/L after six months (P=0.237). Similarly, mean AST levels among silymarin recipients fell from 71.02 IU/L at baseline to 49.66 IU/L after six months of treatment (P=0.006), while mean AST levels in the placebo group were 73.02 at baseline and 66.16 at six months (P=0.343). A data analysis showed ALT levels normalized to below 40 IU/L in 52% of silymarin subjects and 18% of placebo patients at six months (P=0.001). AST levels similarly normalized to below 40 IU/L in 62% and 20% of treatment and placebo patients, respectively (P=0.0001).

There were no serious adverse events in either group, the researchers reported. As glucose metabolism, hyperlipidemia and body mass index (BMI) remained statistically unchanged before and after the study in both groups, the improvements in liver function were due to treatment with silymarin, the investigators concluded.

he Efficacy of Silymarin in Decreasing Transaminase Activities in Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial (Hajaghamohammadi A et al. Hepatitis Monthly 2008;8:191-195)� An Iranian team randomly assigned 50 patients with high AST and ALT levels and ultrasound-proven liver steatosis to receive either 140 mg silymarin daily for two months or a placebo for the same duration. Subjects included 32 men and 18 women. Participants were a mean 40 years old in either group and had mean BMIs of approximately 30 kg/m2. None of the patients had a history of diabetes, alcohol abuse or autoimmune or viral hepatitis. According to the results, mean serum ALT levels in the treatment group dropped from 103.1 IU/L at baseline to 41.4 IU/L following treatment (P<0.001). In contrast, mean serum ALT in the placebo group dropped from 96.6 IU/L at baseline to 88.8 IU/L at two months (P=not significant). Similarly, mean serum AST levels dropped significantly in the silymarin group, from 53.07 IU/L to 29.1 IU/L at two months, but decreased from 56.3 IU/L at baseline to 54.1 IU/L after two months in the control group (P<0.001 for baseline vs. 2 months in silymarin group; P=not significant in placebo group). The authors did not report any adverse events associated with use of silymarin. In a discussion of their findings, they wrote that, “the duration and the recommended dosage [of silymarin] should be studied in future research.” Furthermore, they said, “in our study, the effect of silymarin on a patient’s prognosis was not [evaluated].” Effects on long-term disease progression should be studied in future research, they suggested.

Dr. Cutler’s comment:

The studies by Hashemi et al and Hajaghamohammadi et al were the first to utilize milk thistle as a solo agent in randomized controlled trials of patients with fatty liver disease. Both studies demonstrated statistically significant improvements in liver function tests in NAFLD patients treated with milk thistle. Previous studies of fatty liver disease and vitamin E in children were complicated by weight loss in the control group and subsequent liver function test improvements in the placebo arm. Importantly, in the studies by Hashemi and Hajaghamohammadi, there was no change in mean weight or BMI in either treatment or control groups, allowing for a more accurate evaluation of the milk thistle treatment.

he Effect of Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study (Loguercio C et al� Dig Dis Sci 2007;52:2387-2395) This prospective, open-label Italian study examined the efficacy of silybin—the active ingredient in silymarin— in combination with vitamin E and phosphatidylcholine (Realsil, Instituto Biochimico Italiano, Lorenzini S.p.a., Italy). The trial included 85 consecutive patients with

ultrasonography-proven NAFLD, including 26 patients with hepatitis C virus (HCV) genotype 1 infection. The researchers randomized 39 patients with NAFLD and no HCV to receive the combination treatment for six months and assigned 20 similar patients to a control untreated arm. They also randomized 14 of the HCVpositive participants to receive the active treatment for six months and 12 subjects to receive no treatment. Those in the non-HCV infection group had failed to respond to prior treatment with interferon and ribavirin and had discontinued those medications approximately one year prior to study outset. Non-HCV NAFLD patients were a median 44 years of age while HCV-positive patients were a median 51 years of age. None of the subjects had other possible underlying causes of chronic liver damage such as high daily alcohol consumption, drug use or associated autoimmune or genetic diseases. Participants were followed for one year from study outset. Mean baseline ALT levels were higher in the treatment group than in the control group (79 IU/L in treated non-HCV vs. 54 IU/L in control non-HCV; 69 IU/L in treated HCV-positive vs. 47.8 IU/L in control HCV-positive). However, all other parameters were similar between the treatment and control groups.

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GastroenteroloGy & endoscopy news • May 2012

‘The four studies reviewed support the use of milk thistle in patients with NAFlD, either alone or in combination with vitamin E.’ —Alan Cutler, MD

The results showed a significant decrease in ALT levels in the treated non-HCV and HCV-positive patients after six months, with levels in the former group nearly halving, from 79 IU/L at baseline to 40 IU/L (P<0.01). ALT levels in the HCV-positive group fell from a mean 69 IU/L at baseline to 45 IU/L at six months (P<0.01). While ALT levels in the treated non-HCV group rebounded six months following treatment discontinuation, they remained significantly lower than baseline levels, the researchers found. Serum g-glutamyltranspeptidase (g-GT) levels also dropped significantly in the treated non-HCV and HCV-positive groups (for non-HCV: 75 IU/L at baseline vs. 59 IU/L and 60 IU/L at 6 and 12 months, respectively; P<0.01; for HCV-positive: 118 IU/L at baseline vs. 56 IU/L and 83 IU/L at 6 and 12 months; P<0.01 for 6 months vs. baseline). There were no significant changes in ALT or g-GT levels in the untreated group, the investigators reported. According to the findings, treated patients in both the non-HCV and HCV-positive groups experienced significant improvements in insulinemia and homeostatic model assessment (HOMA) scores at six and 12 months, while there were no similar improvements in the control groups.

ilybin Combined with Phosphatidylcholine and Vitamin E in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (Loguercio C et al� Free Radic Biol Med 2012;52:1658-1665) In a follow-up to the above trial, Italian and Romanian researchers examined the efficacy of the same silybin/ vitamin E acetate/phosphatidylcholine formulation in patients with non-HCV NAFLD and HCV-related NAFLD. They analyzed prospectively-collected data from 108 patients with histologically-confirmed NAFLD and 30 HCV genotype-1 patients with NAFLD. Half the patients were randomized to receive the combination treatment twice daily for one year and half received a placebo. None of the subjects were undergoing other NAFLD or HCV treatments or had other underlying causes of liver steatosis. According to the investigators, many of the non-HCV patients had near-normal AST, ALT and g-GT levels at baseline. However, at one year, an additional 41% to 45% of treatment recipients achieved normalized AST, ALT and g-GT levels, compared with an additional 5% to 19% of placebo patients who experienced the same normalization of liver function tests. There were no significant differences in absolute AST or ALT levels among treatment and placebo recipients at one year. A subgroup analysis of HCV-positive patients showed 54% and 20% of treatment and placebo subjects, respectively, experienced normalization of g-GT levels at one year (P=0.02 for treatment vs. placebo). Additionally, mean blood glucose values were 48% lower at one year than at baseline among the HCV-positive treatment group patients, while there were no appreciable improvements in blood glucose in the placebo group. The silybin combination also significantly improved HOMA values in those with baseline scores greater than 2.7, the researchers found. Liver fibrosis, lobular inflammation, ballooning and NAFLD activity scores (NAS) all significantly improved in the treatment group at one year but did not do so in the placebo group, the investigators reported. Although there were marked improvements in patients with moderate to severe steatosis who received the active treatment, overall liver steatosis grades were not statistically different between the two groups after one year.

Mediterranean Diet Boosts Liver Health in Patients With NAFLD By chriStina Frangou San FranciSco—A new study has provided one more reason to adopt the Mediterranean diet: It improves liver health in patients with non-alcoholic fatty liver disease (NAFLD) even if weight loss is not achieved, according to the results presented at The Liver Meeting 2011� “This small, highly controlled study demonstrated that a six-week Mediterranean dietary intervention could lead to a reduction of liver fat by 39% compared with a current recommended healthy diet,” said lead author Marno Ryan, MBBS, MD, a gastroenterologist and hepatologist at St� Vincent’s Hospital, in Melbourne, Australia� The Mediterranean diet emphasizes eating primarily plant-based foods, along with fish and healthy fats like olive oil, whereas the National Heart Foundation (NHF) recommends a low-calorie, low-fat diet� The new finding could change the way patients are counseled about dietary management of NAFLD, said Dr� Ryan� “Previously, dietary studies in NAFLD have been lacking� We can now offer patients evidence-based dietary advice that will reduce their risk for diabetes and liver disease even without weight loss�”

Dr. Cutler’s comment:

The two studies by Loguercio et al used a unique combination of milk thistle, vitamin E and phospholipids in patients with NAFLD. The initial study demonstrated that the treatment improved liver enzymes, sonic evidence of steatosis and indices of liver fibrosis in patients with NAFLD. The follow-up study was a randomized, controlled trial that included liver histology. It showed that active treatment with the combination agent caused significant improvements in liver enzymes, insulin resistance and liver histology in patients with NAFLD. The only issue in these two studies is that both evaluated only the combination product and did not include arms utilizing each treatment agent individually. It is therefore not possible to determine the importance of each element of the combination product and whether these elements work synergistically in fatty liver disease. Certainly, the four studies reviewed support the use of milk thistle in patients with NAFLD, either alone or in combination with vitamin E. n Dr. Cutler has a financial interest in Cass Labs, which markets and distributes EThistileTM, a combination of milk thistle and vitamin E to support liver wellness.

‘Previously, dietary studies in NAFlD have been lacking. We can now offer patients evidence-based dietary advice that will reduce their risk for diabetes and liver disease, even without weight loss.’ —Marno Ryan, MBBS, MD Researchers studied 12 patients without diabetes who had NAFLD� The patients were randomized to receive either the Mediterranean diet or the NHF diet for six weeks, following a six-week washout� All patients underwent a three-hour hyperinsulinemic euglycemic clamp stamp to determine insulin

see Mediterranean Diet, page 22

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sensitivity, as well as magnetic resonance imaging (MRI) and 1H spectroscopy of the liver at baseline and at the end of the study� Analysis showed a 38�4% reduction in hepatic fat associated with the Mediterranean diet, as measured by spectroscopy, whereas hepatic fat decreased only 7% in patients on the NHF diet� Hepatic fat fraction measured by MRI also declined significantly on the

Mediterranean diet compared with the other diet� Similarly, hepatic steatosis decreased significantly after the Mediterranean diet� Patients who consumed the Mediterranean diet also showed a significant improvement in insulin sensitivity (2�7±1�0 to 3�7±0�4 mg/kg/min-1; P=0�05); the patients on the NHF diet, however, showed no significant change (2�7±1�0 to 2�9±0�4 mg/kg/min-1; P=0�33)�

Currently, there is no consensus on what the most appropriate diet or dietary composition should be for patients with NAFLD, said Paul Angulo, MD, professor of medicine and section chief of hepatology, university of Kentucky Medical Center, in Lexington� Because most patients with NAFLD are overweight or obese, many physicians recommend a low-calorie diet centered on low fat and low carbohydrates�

The Mediterranean diet ‘demonstrates a clear improvement in both insulin sensitivity and the amount of steatosis, and this was seen regardless of significant weight loss.’ —Paul Angulo, MD

When patients following the diet recommendations increase physical activity, they typically lose weight, but that’s a difficult task for most overweight and obese patients� The reported results with the Mediterranean diet “are pretty compelling,” said Dr� Angulo� “This study on the Mediterranean diet—which is high in omega-3 fatty acids—is key in the field; it demonstrates a clear improvement in both insulin sensitivity and the amount of steatosis, and this was seen regardless of significant weight loss�” He added that the improvement of both insulin resistance and steatosis with the Mediterranean diet is consistent with animal data and builds on earlier observations from small human studies that omega-3 fatty acids are of potential benefit for patients with insulin resistance and NAFLD� The data reported by Dr� Ryan and colleagues must be reproduced in larger, well-controlled clinical trials, including liver histology as an end point, he said� “The results of these trials will allow us to make meaningful conclusions on the beneficial effect of diets rich in omega-3 fatty acids�”

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Milk Thistle Does Not Alter Disease Activity in Hepatitis C Patients By chriStina Frangou San FranciSco—One of the first rigorous trials to test the popular herbal extract milk thistle (silymarin) has shown that this treatment does not relieve symptoms or slow disease progression in patients with hepatitis C who are nonresponsive to interferon (IFN). “We must conclude that oral silymarin, given in higher than customary doses, did not significantly alter biochemical or virologic disease activity in hepatitis C patients previously treated with interferon-based regimens,” said lead author Michael W. Fried, MD, professor of medicine and director of hepatology, University of North Carolina, Chapel Hill. Dr. Fried presented the study at The Liver Meeting 2011. Milk thistle has been used for 2,000 years as an herbal remedy for many ailments, particularly liver, kidney and gallbladder conditions. However, its value

as a liver therapy has never been proven. Several animal studies have shown that milk thistle can help protect the liver, but results from human studies are mixed. Previous studies have been confounded by a lack of well-defined efficacy end points, inclusion of heterogeneous populations of patients and use of nonstandardized silymarin preparations. In a multicenter trial, 154 patients with hepatitis C who had not responded to IFN therapies were randomized to

treatment with placebo or with a standardized silymarin preparation (Legalon® 140, Rottapharm Madaus) at 420 mg daily or 700 mg three times daily. The patients had serum alanine aminotransferase (ALT) enzyme levels greater than 65 IU/L, with a median of 106 IU/L; a normal level is 45 IU/L. Patients who received silymarin took doses that were 4.5 to 7.5 higher than typically given. The doses were set based on the results of a Phase I pharmacokinetic

study (Hoc C et al. Clin Cancer Res 2006;12:2944-2950). Researchers felt that the high doses increased the chance of finding a therapeutic benefit. After 24 weeks of treatment, serum ALT tests revealed no significant improvements in patients in any of the three arms of the study. Only two participants from each group met the primary end point of serum ALT less than 45 IU/L or a serum ALT decline of at least 50% from baseline.

Inadequate Bowel Preps: A Problem With Potentially Serious Consequences

‘We must conclude that oral silymarin, given in higher than customary doses, did not significantly alter biochemical or virologic disease activity in hepatitis C patients previously treated

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

with interferon-based regimens.’ —Michael W. Fried, MD

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

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

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The secondary end points, too, were similar across the three groups. The change in serum ALT was negligible during the course of treatment and there were no changes in hepatitis C virus (HCV) RNA levels or quality of life. Silymarin, however, was well tolerated; the most common adverse events were mild and mostly related to gastrointestinal symptoms. Additionally, patients adhered to the medication rules at an unusually high rate. Based on dose cups returned, more than 90% of participants met or exceeded an 80% adherence to the

study medications, despite the requirement to take 15 capsules a day. The study had one notable weakness. The highest dose group included more blacks and more cirrhotics than the other two arms, although analysis did not identify any change in outcomes based on race or cirrhosis.

Is There a Future for Milk Thistle In HCV? With the latest study results, it is unlikely that oral silymarin will have a future role in the care of patients with

hepatitis C infection, although it still will be considered for other liver conditions for which no therapeutic options exist, said Joseph K. Lim, MD, associate professor of medicine and director of the Yale Viral Hepatitis Program at the Yale University School of Medicine, New Haven, Conn. “Although the study cannot entirely exclude the possibility of a benefit from much higher doses of oral silymarin or intravenous silymarin, in this era of rapid advances in high-potency directacting antiviral agents, which may soon

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

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

Low*

49.1

Intermediate*

% of Patients

40 30 20

High*

34.2

33.1

20.0 15.4

10 0

Easy†

12.4

Difficult† Difficulty of Colonoscopy

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

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

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March, 2012

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eliminate interferon, clinical interest in adjunctive therapies with significant pill burden or intravenous formulations with unproven benefit will be very limited.” Dr. Lim added, “Once simplified nontoxic, oral–oral regimens with high sustained viral response rates materialize in the next several years, supplements such as silymarin may lose relevance.” Attendees at the meeting said that they hope patients pay attention to the results of the study. “Thank you for saving our patients from financial stress and false hope, possibly leading to delays in definitive therapy,” one attendee tweeted during the session. However, to others, the results were disappointing. In poorer areas of the world where the newer hepatitis drugs are simply too expensive, the silymarin compound could be extremely useful, said one hepatologist. It may be that there is a future role for silymarin or silibinin in hepatitis treatment when the extract is given in higher doses or different formulations than used in the current randomized study. In one study published in January in the Journal of Hepatology, investigators studied changes in HCV RNA levels in 25 patients receiving 10, 15 or 20 mg/kg per day of Legalon SIL, a chemically hydrophilized version of silibinin (Guedj J et al. 2012;56:1019-1024). Patients showed a significant drop in viral load, particularly between days 2 and 7. The investigators concluded that Legalon SIL may affect hepatitis virus by blocking both viral infection and production/release. In another study, investigators found that IV-administered silibinin had a “substantial antiviral effect” against HCV in 20 IFN nonresponders (Ferenci P et al. Gastroenterology 2008;135:1561-1567). And, still another study showed that oral Silybum marianum significantly affected serum HCV RNA levels, ALT levels, quality of life and psychological wellbeing (Gordon A et al. J Gastroenterol n Hepatol 2006;21:275-280). Dr. Fried serves on advisory committees on review panels for GlaxoSmithKline; he serves as a consultant for Abbott Laboratories, Merck & Co., Pharmasset, Roche and Tibotec; he receives research support from, Abbott, Anadys Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Roche, Tibotec and Vertex Pharmaceuticals; and he is a shareholder in Pharmasset. Dr. Lim reports research contracts with Abbott Laboratories, Boehringer Ingelheim, Bristol-Meyers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Roche, Tibotec and Vertex Pharmaceuticals; he has received consulting fees/honoraria from Bristol-Meyers Squibb, Gilead Sciences, Merck & Co., and Vertex Pharmaceuticals.

GastroenteroloGy & endoscopy news • May 2012

From the Literature

Anesthesia continued from page 1

increased dramatically in gastroenterology (GI)—is only noteworthy because it has been published in the prominent Journal of the American Medical Association (Liu H� 2012;307:1178-1184)� “The findings of this study are neither surprising nor novel,” commented Lawrence B� Cohen, MD, associate professor, Mount Sinai School of Medicine, New york City� “If it had been published in Gastrointestinal Endoscopy, you wouldn’t know anything about it,” added Douglas K� Rex, MD, professor in the Department of Medicine at Indiana university School of Medicine and director of endoscopy at Indiana university Hospital, Indianapolis� “And the truth is, if you look at this reference list here, it has been published in Gastrointestinal Endoscopy [Inadomi JM et al� 2010;72:580-586]�”

Increased Use, Increased Cost With the financial support of Ethicon Endo-Surgery (EES), researchers from the RAND Corporation compiled a retrospective analysis of claims data for 1�1 million Medicare patients and 5�5 million privately insured adults to assess trends in the use of anesthesiologists and nurse anesthetists for upper endoscopy and colonoscopy, and to examine regional variation in the use of anesthesiology services and payment for these services� The investigators found that in both the Medicare and privately insured populations, the proportion of those using anesthesia services increased from about 14% in 2003 to more than 30% in 2009, and that two-thirds of those services were delivered to patients considered low risk based on their American Society of Anesthesiologists (ASA) status� Regional variation was substantial, with anesthesia services used least frequently in the West (around 13%) and most frequently in the Northeast (59%)� Not surprisingly, as use of anesthesia services grew, so did the expense of the procedure� The addition of anesthesia services increased the cost of a procedure by $150 if the patient received Medicare, and by $500 if the patient was privately insured� The researchers estimated that the use of anesthesia services for these procedures amounted to $1�1 billion in 2009� The researchers noted the link between the uptick in use of anesthesia services and the increasing popularity of propofol, which must be administered only by persons trained to administer

general anesthesia according to both the Centers for Medicare & Medicaid Services (CMS) and the FDA� The researchers stated that to the best of their knowledge, their study is the first to quantify spending on anesthesia services for outpatient GI procedures in both government-insured and privately insured patients, and that they were the first to stratify anesthesia use by ASA status� They concluded that the number of GI procedures and use of anesthesia services climbed considerably between 2003 and 2009; that the regional variation and use of anesthesia services in low-risk patients suggests much of the spending could be considered discretionary; and that colonoscopy screening programs will increasingly come under the scrutiny of payers and policymakers as costs continue to climb�

Can We Afford ‘Discretionary’ Anesthesia? In a related editorial, “Assessing the value of ‘discretionary’ clinical care: the case of anesthesia services for endoscopy,” Lee A� Fleisher, MD, from the Department of Anesthesiology and Critical Care at the Perelman School of Medicine, and Leonard Davis Institute of Health Economics at the university of Pennsylvania, Philadelphia, noted possible explanations for the escalated use of anesthesiology services (JAMA 2012;307:1200-1201)� One is that use of anesthesia services and deep sedation might allow endoscopists to perform exams in less time, and to conduct potentially more thorough exams, noting that the latter is of some debate� Another reason might be patient acceptance or preference, although this too, is hard to quantify� “At the Hospital of the university of Pennsylvania [HuP], only about 30% of our low-risk outpatients get anesthesia; the rest receive moderate sedation,” Dr� Fleisher told Gastroenterology & Endoscopy News� “But in one of our satellites, it’s 100%� Is this really patient-driven? Our endoscopists don’t feel that everyone needs anesthesia, and they make rational decisions about who requires it at HuP�” The widespread geographic variability the study reported also gave Dr� Fleisher pause� “This says there’s something else going on� Do people in the Northeast believe you need anesthesia more than

people in the Southwest? Or is this really about different payment schemes, and if so, who’s driving this?”

‘Endoscopy currently has a certain amount of [relative value units] related to moderate sedation, which does not go away when [endoscopists] use anesthesia services. So there is payment for sedation for the endoscopist, and the anesthesia payment.’ —Lee A. Fleisher, MD

Dr� Fleisher believes the increased use of anesthesiology services is being driven by endoscopists and facilitated by anesthesiologists� “There is no financial disincentive to use anesthesia services,” Dr� Fleisher said� But this trend, he said, is financially untenable� “Endoscopy currently has a certain amount of [relative value units] related to moderate sedation, which does not go away when [endoscopists] use anesthesia services� So there is payment for sedation for the endoscopist, and the anesthesia payment,” Dr� Fleisher said� “I don’t think we can afford this� We don’t want to change things so much that people will stop getting colonoscopy screening, but we need to come up with more rational payment schemes�” In his editorial, Dr� Fleisher suggested bundling of services as a payment option� This would require the anesthesiologist and gastroenterologist to establish a value for their services� “In such a system, there are appropriate incentives for the gastroenterologist and facility to decide if everyone receives anesthesia and its attendant costs, or if only a subset of patients require anesthesia,” he said� Dr� Cohen and colleagues noted the regional differences in use of anesthesia services years ago, and attributed it to patterns of influence� “In the early 2000s, we conducted a large survey of practitioners across the country� There were pockets in the country where this was done, and pockets where it was not� If one or two doctors introduced propofol, the whole area would quickly adopt that practice� That’s how it went from a negligible amount of anesthesia utilization 20 years ago, to nearly 50% today�”

Define ‘Discretionary’ Dr� Cohen found the presentation of data in the article and its conclusion somewhat misleading, and objected to use of use of the word “discretionary�” “It implies that the anesthesia provision of propofol is optional or even unnecessary,” he said� “The pharmaceutical properties of propofol are such that it is the ideal agent for sedation of patients undergoing short, rather abbreviated ambulatory procedures� use of a benzodiazepine and an opioid in the 21st century is really sort of antiquated�

GastroenteroloGy & endoscopy news • May 2012

“I think the real question is not that health care is paying for discretionary services, but how can our health care system provide high-quality sedation service for patients undergoing endoscopy in a cost-effective manner,” Dr� Cohen said� A further question is not whether propofol is appropriate, but who should be administering it, he added�

it and who should be paying for it is indeed a complex and knotty issue� “A lot of the behaviors that are occurring now are being driven by financial incentives; none of the behavior is being driven by evidence,” said Dr� Rex, who laid out the politics of the issue in a recent opinion piece (Ann Intern Med 2011;154:622-626)� use of anesthesia services for such common procedures as upper endoscopy and colonoscopy would certainly seem to benefit anesthesiologists, providing a steady stream of relatively easy and lucrative work� But endoscopists, too, can and do benefit from this arrangement� “They hire anesthesiologists, pay them fees, bill for their services and pocket the difference between what they bill and what they pay,” Dr� Rex said� “That can be a really substantial source of income� There are a lot of people in the GI community who like this, and it’s perfectly legal�” Dr� Rex has long been involved in the politics and science of propofol, and originally delivered it to patients through nurse-administered propofol sedation� He and his colleagues had to discontinue this practice in early 2010 due to CMS regulations� “Now we use anesthesiologists, too� We’ve produced a lot of evidence and done a lot of studies, but this is not about evidence, it’s about other issues that are out of our control,” he said�

‘I think the real question is not that health care is paying for discretionary services, but how can our health care system provide high-quality “We just need to figure out the appropriate financial models� The dollars are there in health care: They’re paying for colonoscopy, they’re paying for biopsy, they’re paying for facility fees,” Dr� Cohen said� “It’s just a matter of how you can configure the dispersal of those dollars to cover the additional cost of sedation�”

Complex Issue The increasing use of anesthesia services and the questions of which sedating agent should be used, who should be receiving it, who should be administering

sedation service for patients undergoing endoscopy in a cost-effective manner.’ —Lawrence B. Cohen, MD

Dr� Rex agrees with Dr� Fleisher that the escalation of anesthesia services in GI due to financial considerations is unlikely to change unless reimbursement systems do�

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opinion?

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“Episode-based care would probably change it immediately, with the caveat that the anesthesia profession is probably the best organized of all the specialties in regard to lobbying and to their behavior with insurance companies,” he said� “They also have a very large [political action committee], and the [ASA] very effectively lobbies for and protects the interests of the anesthesia community with regard to the financial issues� That’s what a lot of professional societies in medicine do, but I think they’re one of the more effective ones�”

SEDASYS According to David J� Shaffer, director of worldwide communications for EES, the medical device company financed the current study to gain marketing knowledge for a computer-assisted personalized sedation system they have been developing� “We funded this study to better understand the health care environment in which this product, if approved, would be used,” he said in an email� The SEDASyS System keeps check on a patient undergoing propofol sedation by measuring a number of physiologic parameters, such as blood pressure, heart rate, electrocardiography, oxygen saturation level and capnography� It also communicates with the patient throughout the procedure and asks the patient to repeatedly press a handheld button� “The idea is that if they don’t answer by pushing the button, the machine will stop infusing the drug,” Dr� Rex said� In a randomized controlled trial comparing SEDASyS with fentanyl and midazolam, patients sedated by the former were less likely to be deeply sedated,

and both patients and doctors preferred the computerized system (Pambianco DJ et al� Gastrointest Endosc 2011;73:765772)� The authors concluded that the system provided a safe and effective onlabel way for endoscopist–nurse teams to deliver propofol� In spring 2010, the FDA rejected EES’s application for approval of the SEDASyS System, despite its having been recommended for approval by an advisory panel in an 8 to 2 vote� In February of this year, EES received an approvable letter from the FDA’s Center for Devices and Radiological Health (CDRH) that outlines conditions that must be met in order to receive FDA approval� “[This] largely reflects an agreement EES reached in November 2011 with the CDRH on a path forward to permit continued review of the Premarket Approval Application,” Mr� Shaffer wrote� “We are pleased to have reached this milestone in our efforts to bring this important innovation to market, because we believe the SEDASyS System, if approved, has the potential to benefit patients, physicians and nurses�” EES is not proposing that the system would replace anesthesia professionals� “Our intended use is to enable physician–nurse teams to provide minimal to moderate sedation with propofol during colonoscopy and esophagogastroduodenoscopy procedures,” Mr� Shaffer wrote� The system is meant to be used during routine screening and diagnostic colonoscopy and esophagogastroduodenoscopy for patients classified as ASA classes I and II� “There will always be a need for anesthesiologists in higher-risk endoscopy procedures�”

GastroenteroloGy & endoscopy news • May 2012

Obese Children Require less Propofol By Michael VleSSideS chicago—Contrary to what many physicians might think, a recent study suggests that the effective dose of propofol is significantly lower for obese children than for their non-obese counterparts. These findings become even more important, the researchers said, given that propofol decreases systemic vascular resistance, and that unnecessarily large doses may

result in moderate to severe hypotension. “There’s an increasing number of obese children presenting for surgery,” said study leader Olutoyin A. Olutoye, MD, staff anesthesiologist at Texas Children’s Hospital in Houston. “We’re faced with the challenge of how to exactly dose intravenous anesthetics in this subset of patients.” As much as 75% of excess weight in obese children is fat, which alters the distribution of lipophilic drugs such as propofol.

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Dr. Olutoye and her colleagues enrolled 40 obese and 40 non-obese children (aged 3-17 years), all of whom were undergoing ambulatory surgical procedures. Each patient was assigned to receive a dose of propofol between 1 and 4.25 mg/kg, based on the previous patient’s response. “If a patient did not fall asleep with their assigned dose, the next patient received the next higher dose in the sequence,” Dr. Olutoye explained. “If a patient fell

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asleep, the next patient was randomized using a prestudy randomization process with a 95% probability to receive the same dose or 5% probability to receive the next lower dose. We started at the lowest dose of propofol where we did not expect a response,” said Dr. Olutoye, who presented her group’s findings at the 2011 annual meeting of the American Society of Anesthesiologists (abstract 048). “That way we would be able to increase the dose until we got the desired effect.” The effective dose for 95% of patients (ED95) was significantly lower in obese patients (1.99 mg/kg; 95% confidence interval (CI), 1.745-2.183 mg/kg) than in non-obese patients (3.183 mg/kg; 95% CI, 2.681-3.225 mg/kg). The lack of overlap for the confidence intervals in the two groups indicates the results are statistically significant, Dr. Olutoye said. The researchers also measured blood pressure throughout the procedures, given propofol’s well-documented hemodynamic effects. Obese patients had a higher baseline blood pressure than non-obese patients. Both systolic and diastolic blood pressures were significantly lower two minutes after propofol therapy in both groups of patients. “We should bear this in mind, because propofol decreases blood pressure, and if these patients get an unnecessarily large dose to induce loss of consciousness— particularly in patients who have been fasting prior to surgery—they could have an exaggerated decrease in blood pressure,” Dr. Olutoye said. Cheryl K. Gooden, MD, associate professor of anesthesiology and pediatrics at Mount Sinai School of Medicine, in New York City, said the results were impressive. “It is not part of my routine practice to administer less propofol to my obese pediatric patients on a milligram-per-kilogram basis as compared with non-obese patients,” Dr. Gooden said. “However, after reviewing the results of this study, I would definitely consider giving less propofol on a milligram-per-kilogram basis to n my obese patients.”

Q&A

GastroenteroloGy & endoscopy news • May 2012

A D V E R T I S E M E N T

What is the CRH O’Regan System™? The CRH O’Regan System™ is a single-use, disposable device that treats all grades of hemorrhoids easily and painlessly by band ligation. This simple procedure can be performed in the office or ambulatory surgical center (ASC) and is effective in treating 99.1%1 of your patients with symptomatic hemorrhoid disease. No preparation or sedation is needed, and patients typically return to work the same day.

I currently do not treat hemorrhoids—why should I add this to my practice?

Q. A.

I would like to add this procedure to my practice—what do I do next?

1023 or at info@crhmedcorp.com and CRH will provide you with additional information, including the Medicare rates for your practice. Please also visit our Web site, GENews.CRHsystem.com, where you can find informational videos, supportive literature and how the CRH O’Regan SystemTM can help your patients and your practice.

1. Cleator IGM, Cleator MM. Banding Hemorrhoids Using the O’Regan Disposable Bander. Business Briefing: US Gastroenterology Review 2005:69-73. 2. Johanson JF, Sonnenberg A. The prevalence of hemorrhoids and chronic constipation. An epidemiologic study. Gastroenterology 1990;98:380-386.

With 50% of the population having symptomatic hemorrhoids by the age of 50 and a prevalence rate of 4.4%,2 there is a tremendous demand for these services. Often these patients have been told to “live with them” for years—which is why they will be so appreciative of your care. These will typically become your favorite patient interactions! With the CRH O’Regan System™, you’ll provide a continuum of care to your existing patients, as well as attract new patients to your practice (many of whom will require additional procedures).

What kind of training is available?

CRH will train you at your practice. A board-certified surgeon will provide a didactic presentation reviewing general anorectal care, along with a “hands-on” session where you will begin treating your own patients. This session, along with any follow-up “refresher” sessions are offered at no cost!

When it comes to hemorrhoid removal, there’s good news for you and your patient.

What about complications?

The complication rate is 1%,1 including pain (treated with topicals) and bleeding (treated by cautery). CRH offers “24/7” consultative support provided by its board-certified surgeons should any questions arise.

What is so different about this procedure?

A. The CRH O’Regan System™ affords a quick, effective, safe and economical alternative to help care for your patients. No special equipment is required, the technology is portable and convenient, and there are no capital expenses. The procedure also is covered by most insurance plans.

What else does CRH offer?

A. CRH provides a comprehensive support program for you and your staff. In addition to the initial training, we offer refreshers, front office training, and billing/ coding support. CRH will provide patient education and other marketing materials, and also drives thousands of new patients to our Partner physicians from a powerful web marketing program. All of this is offered at no cost!

The CRH O’Regan System™ is a non-surgical hemorrhoid removal procedure that is fast, painless and 99% effective. The result is improved patient care and increased practice revenue. Join the 1000+ gastroenterologists and surgeons who’ve adopted the CRH O’Regan System™ by calling 866.473.3024 x 1023 to schedule a free training session at your ofﬁce or ASC. Happiness awaits. Visit GEnews.CRHsystem.com for more information.

Opinion

GastroenteroloGy & endoscopy news • May 2012

Maintenance of Certification: The “Grandfather” Clause Tania Haddad, MD, DMD Staff Anesthesiologist Valley Anesthesiology Consultants Phoenix, Arizona

In the 1970s and 1980s, recertification of internal medicine physicians by the American Board of Internal Medicine (ABIM) was voluntary. In 1990, the ABIM developed the Maintenance of Certification (MOC) program and began issuing certificates with a 10-year duration, requiring renewal to maintain certified diplomate status. The goals of recertification are to improve the care of patients, set standards for the practice of medicine and encourage life-long learning, thus reassuring patients and the public that doctors remain competent and are in constant pursuit of improvement.1 For example, as a member of the American Board of Medical Specialties (ABMS), the American Board of Anesthesiology (ABA) recognized the importance of recertification and implemented the Maintenance of Certification in Anesthesiology (MOCA) exam in 1999. In recent years, the increased concern of the public about the quality movement within health care has ignited a search for a way to qualify physician quality ratings. In 2003, the ABIM commissioned the Gallup Organization to poll the public about their views on recertification of physicians.2 The survey revealed that consumers of health care highly value recertification. Some respondents suggested they would change doctors if their own physician’s certification had expired.3 Based on these results, many specialty boards have been in a constant search for new methods to increase and gain the public’s confidence. A survey from the Journal of Pediatrics, which focused on physician board certification, found that most respondents felt hospitals and health plans should require board certification, in addition to informing the public about the board certification status of their physicians.4 The goal of continuously improving the quality of physicians has laid the foundation for changing MOCA requirements over time. Since its inception 10 years ago with a closed-book cognitive skills examination, the MOCA has incorporated 140 additional continuing medical education credits, a simulator session and assessment of practice performance. The expectation of these requirements is to decrease morbidity, mortality and health care costs by ensuring that physicians’ knowledge and skills are current.5

the time of primary certification, and new knowledge, consisting of rapidly evolving medical and technological advances. Older physicians perform as well as younger physicians—as long as questions are directed at knowledge that has not changed since they were trained.11-14 In addition to the changing of the knowledge base, older physicians were less likely to adhere to agreed-upon standards of practice. Czaja surveyed physicians to assess adherence to guidelines for cancer screening endorsed by the American Cancer Society and the National Cancer Institute, and found that physicians who were more than 20 years out from primary certification were less likely to follow recommended practices.15 The fear of failure, therefore, is completely rational.

Respect Your Elders, But Don’t Coddle Them

In 2003, the American Board of Internal Medicine commissioned the Gallup Organization to poll the public about their views on recertification of physicians. The survey revealed that consumers of health care highly value recertification. Some respondents suggested they would change doctors if their own physician’s certification had expired. Not All Physicians on Board Among physicians, however, the recertification process is controversial. Criticisms have emerged on several fronts, including the time and cost required to prepare for the exam, fear of failure and consequent loss of certification, and the lack of evidence supporting the individual components of the MOCA process.6-8 Not to mention the discontent that the ABA does not treat all physicians equally, allowing certain individuals to be “grandfathered out” of participating in the MOCA process. The time required away from practice while preparing for a one-size-fits-all exam—including the review of material that may no longer be relevant to one’s practice—is a key driver of opposition to recertification.8 Wendy Levinson, MD, a practicing internist in Toronto, Canada, and a proponent of the process, recently participated in the ABIM’s maintenance of certification process and found it “far more challenging and demanding” than the requirements currently existing in

Canada.9 Dr. Levinson reported studying for four months and worrying that she would fail. The fear of failure related to recertification is not without justification. Recertification clearly is a high-stakes exam with potential loss of a physician’s practice and livelihood as a consequence.8 Ramsey and colleagues demonstrated that the likelihood of passing the examination declined in relation to the number of years since initial certification. More than two-thirds (68%) of physicians who had received initial certification 15 years before would have failed the recertification exam, according to the researchers.7 Studies of performance on voluntary recertification exams have found a decline with age or time since completion of training.10,11 Day reported that recertification exams that focus on the ability of the physician to update knowledge place those physicians further out from training at a disadvantage. This study and others suggest that there are distinct types of knowledge: stable knowledge, amassed at

The practice of anesthesiology often is compared to aviation. As an instrumentrated commercial pilot, I understand the stringent requirements that a general and commercial pilot must adhere to for continued currency and proficiency. These requirements are irrespective of experience (hours of flight time), ratings or age. In 2007, the Federal Aviation Administration raised the retirement age of commercial pilots to 65 years. In the private sector, workers look toward age 65 for retirement. As physicians, we are honored to be allowed to practice medicine without a required retirement age. However, the goals proposed by the ABMS and the desires of the public in terms of recertification of physicians are being ignored. Some form of recertification is necessary if aging physicians are to keep current with changing practice. Davis showed that the ability of physicians to accurately assess and evaluate themselves is limited.16 Numerous studies have demonstrated a decline in up-to-date knowledge in older physicians and lower adherence to standards of practice compared with their younger counterparts.11,12,15 Norcini and colleagues documented a 0.5% increase in patient mortality from acute myocardial infarction for every year since the treating physician had graduated from medical school.17 Another study found an association between physician age and lower performance.14 Therefore, with the abundant information in the literature, why does the “grandfather” status remain? n

GastroenteroloGy & endoscopy news • May 2012

ACGME continued from page 3

Between formal site visits, the ACGME will carry out periodic site visits of sponsoring institutions approximately every 18 months to “assess the learning environment” and help lowperforming programs identify where they can improve. “The visits to sponsoring institutions will ensure that residents are exposed to an appropriate learning environment and the milestones will ensure that they demonstrate readiness for independent practice and possess the attributes that the public deems to be important in physicians,” wrote Dr. Nasca and colleagues. The NAS will give some freedom to high-performing programs. Programs that demonstrate high-quality outcomes will have more relaxed process standards that specify elements of residents’ formal learning experiences. For example, these high-performers may be able to modify the hours of lecture or bedside teaching if they continue to show high education standards. Professional associations and the residency review committee for each specialty are developing the educational milestones, which have not been finalized for gastroenterology (GI). Program directors have received few specifics about what the new program will entail for procedure-based programs like gastroenterology, in part because the ACGME wanted to leave specialties some flexibility. Program directors and gastroenterology associations have until July 2014 to develop appropriate milestones and strengthen content to fit the new program requirements. Many program directors have questions about the milestones for GI and how they will be integrated with the internal medicine milestones.

References 1. Norcini JJ. Recertification in the United States. BMJ. 1999;319:1183-1185. 2. The Gallup Organization for the American Board of Internal Medicine. Awareness of and Attitudes Toward Board-Certification of Physicians. Princeton, NJ: The Gallup Organization; 2003. 3. Brennan TA, Horwitz RI, Duffy FD, Cassel CK, Goode LD, Lipner RS. The role of physician specialty board certification status in the quality movement. JAMA. 2004;292:1038-1043. 4. Freed GL, Dunham KM, Clark SJ, Davis MM. Perspectives and preferences among the general public regarding physician selection and board certification. J Pediatr. 2010;156:841-845.

“It is not yet clear if specific aspects of medical knowledge related to liver disease versus luminal disease, etc, would be included in the competencies for GI, but this could not include a specific timeline as GI fellows tend to rotate through different areas at different times,” said Dr. Imaeda.

gastroenterology or not, since we don’t know the details. Overall, though, I think the move is in the right direction,” said Darrell S. Pardi, MD, associate professor of medicine, Mayo Clinic, Rochester, Minn. Amy Oxentenko, MD, GI Fellowship Program director at the Mayo Clinic in

The milestones will be based on the six competencies: patient care, medical knowledge, professionalism, interpersonal and communications skills, practice-based learning and improvement and systems-based practice.

Between formal site visits, the ACGME will carry out periodic site visits of sponsoring institutions approximately every 18 months to ‘assess the learning environment’ and help low-performing programs identify where they can improve. Gastroenterologists and program directors expressed mixed feelings about the program: They are apprehensive about the difficulties involved with implementing changes and are anxious to see the final educational milestones, but they are optimistic about the long-term benefits. “It is difficult to say for sure whether the NAS will be a good thing for

Rochester, said she believes GI trainees ultimately will benefit from the new program. “Although that opinion may seem premature given that we do not know exactly what the NAS will involve for GI programs, I am optimistic that the NAS goals of allowing training programs to have comparable metrics across programs, ensuring programs are providing

5. Brown DL. Guide to maintenance of certification in anesthesiology. The American Board of Anesthesiology, Inc.

10. Norcini JJ, Lipner RS, Benson JA, Webster GD. An analysis of the knowledge base of practicing internists as measured by the 1980 recertification examination. Ann Intern Med. 1985;102:385-389.

6. Wasserman SI. Maintenance of certification and maintenance of professionalism (editorial). J Allergy Clin Immunol. 2011;128:465-466. 7. Ramsey PG, Carline JD, Inui TS, et al. Changes over time in the knowledge base of practicing internists. JAMA. 1991;266:1103-1107.

11. Day SC, Norcini JJ, Webster GD, Viner ED, Chirico AM. The effect of changes in medical knowledge on examination performance at the time of recertification. Proc Annu Conf Res Med Educ. 1988;27:139-144.

8. Levinson W, King TE Jr. American Board of Internal Medicine maintenance of certification program. N Engl J Med. 2011;362:948-952.

12. Eva KW. The aging physician: changes in cognitive processing and their impact on medical practice. Acad Med. 2002;77:S1-S6.

9. Levinson W. Revalidation of physicians in Canada: are we passing the test? (editorial). CMAJ. 2008;179:979-980.

13. Holmboe ES, Lipner R, Greiner A. Assessing quality of care: knowledge matters. JAMA. 2008;299:338-340.

a culture of patient safety and quality improvement, and providing educators more opportunity for innovation, will be met,” said Dr. Oxentenko, one of the panelists who spoke at an American Gastroenterological Association webinar on the new ACGME requirements. The increased data reporting is expected to create some logistical problems in the short term as programs set up their reporting programs. “My hope is that once we know what is required, and after each program has gone through the reporting process once or twice, it will eventually free up more time overall for educational innovation,” said Dr. Oxentenko. Rowen K. Zetterman, MD, a gastroenterologist and dean of Omaha’s Creighton University School of Medicine, said the NAS will increase the reporting burden on the institution while granting programs more autonomy in training their residents and fellows. “The NAS looks more at how well fellows are trained instead of prescribing what they have to do along the way in order to meet the needs of the ACGME,” said Dr. Zetterman, who recently joined the ACGME board. “We all need to go into this with an open mind. This has the opportunity to be better for all of us that are involved with training gastroenterology fellows and work to develop our program along the line of the next accreditation system.” ACGME acknowledges that the program is still in its infancy, adding “much more work remains to be done.” The program was not piloted in its entirety, but “pivotal elements” were tested in internal medicine and a multiyear pilot in emergency medicine. The ACGME’s new system will cover more than 9,000 medical residency programs across the n country.

14. Choudhry N, Fletcher R, Soumerai S. Systematic review between clinical experience and quality of health care. Ann Intern Med. 2005;142:260-273. 15. Czaja R, McFall SL, Warnecke RB, Ford L, Kaluzny AD. Preferences of community physicians for cancer screening guidelines. Ann Intern Med. 1994;120:602-608. 16. Davis DA, Taylor-Vaisey A. Translating guidelines into practice: a systematic review of theoretic concepts, practical experience, and research evidence in the adoption of clinical practice guidelines. CMAJ. 1997;157:408-416. 17. Norcini JJ, Kimball HR, Lipner RS. Certification and specialization: do they matter in the outcome of acute myocardial infarction? Acad Med. 2000;75:1193-1198.

GastroenteroloGy & endoscopy news • May 2012

Retraction continued from page 1

“Those of us in the U.S. had applauded the ESA for being more fairminded and scientifically rigorous than the American Society of Anesthesiologists in their assessment of the published data, and for their willingness to remain objective and avoid conflicts of interest that would jeopardize that objectivity,” said Lawrence B. Cohen, MD, associate clinical professor of medicine, Mount Sinai School of Medicine, in New York City. “Their actions now, which demonstrate that financial self-interest and political influence can trump scientifically valid, evidence-based practice guidelines, reflect poorly on the specialty of anesthesiology and weaken the credibility of the ESA as leaders in the field of sedation and patient safety.” John Vargo, MD, vice chairman of the Digestive Disease Institute and chairman of the Department of Gastroenterology and Hepatology, Cleveland Clinic, in Ohio, noted that the retraction does seem in keeping with the landscape of propofol-mediated sedation in the United States, but nonetheless he was surprised by the ESA’s reversal of support. “Perhaps what was the most surprising thing to me was the article by [Azriel] Perel, which questioned whether it was appropriate to adopt strict evidencebased criteria to make these decisions and instead continue to rely on expert opinion [Perel A. Eur J Anaesthesiol 2011;28:580-584]. “We now have nearly 600,000 patients in the literature showing that gastroenterologist-directed propofol, when administered by properly trained personnel in appropriately selected patients, is extremely safe,” Dr. Vargo said. “I really feel this is more of an issue regarding the ‘pharmacoeconomics’ of private practice of sedation in these countries, rather than overall safety issues.” Ludwig T. Heuss, MD, assistant professor of medicine and director of the medical clinic at Zollikerberg Hospital, in Zurich, Switzerland, deemed the retraction not only ridiculous but scandalous. “In my view, the ESA gave up their status of a serious scientific society and ended in a selfish, income-guided lobby,” he wrote in an email. “The retraction of the endorsement was enforced against scientific evidence, through a political vote. According to this kind of negation of scientific evidence, I would invite them to decide that the Earth is flat and that the sun is circling around the Earth.” The guidelines were originally endorsed by the three societies that

‘I really feel this is more of an issue regarding the “pharmacoeconomics” of private practice of sedation in these countries, rather than overall safety issues.’ —John Vargo, MD

‘In my view, the ESA gave up their status of a serious scientific society and ended in a selfish, income-guided lobby. According to this kind of

General Assembly, and they were only about 3% of all ESA members or less,” I would invite them to decide that said Eberhard Kochs, MD, chairman, Department of Anesthesia, Klinikum the Earth is flat and that the sun rechts der Isar der Technischen Universität München, in Munich, and presiis circling around the Earth.’ dent of the ESA. “The board is a little —Ludwig T. Heuss, MD bit uneasy about this, but as a democratic society we have to follow the wish of the General Assembly.” created them: the ESA, the European Dr. Kochs firmly believes the safest Society of Gastrointestinal Endoscopy practice for the administration of proand the European Society of Gastroen- pofol is to restrict its use solely to anesterology Nurses and Associates. The lat- thesiologists, and he strongly disagrees ter two continue to support the original with the suggestion that financial interguidelines. ests were at the heart of the retraction. It is not clear whether the ESA’s Motivation for the retraction, however, retraction reflects the opinion of the does appear to be mainly political, he bulk of anesthesiologists in Europe, explained. “In some countries of Europe, where sedation practices and poli- colleagues fear that sedation will be cies vary from country to country. The given by nonspecialists. The problem retraction was made after a little more is that at the moment in several Eurothan half of the members present at the pean countries, anesthesiologists do not ESA’s General Assembly Meeting last have enough manpower to do all the year voted to do so. sedations in ambulatory and hospital “It was not the opinion of the board, practice. In addition, many health care but of the present members in the systems do not reimburse the costs of

negation of scientific evidence,

providing sedation by anesthesiologists outside operating rooms.” Dr. Kochs does not believe the retraction will have much of an impact on anesthesia practices. “At least right now it will not change anything, because you cannot change a whole system based on some thoughts; you have to fulfill all the criteria, you have to have the manpower,” he said. “This cannot be answered by our side for all of Europe; it is a task for the national societies to organize within their respective countries.” Dr. Heuss does not anticipate the retraction will have any effect in Switzerland where, according to his 2010 survey, nearly three-fourths of gastroenterologists administer propofol themselves or supervise nurses without anesthesiologist support (Heuss LT. Endoscopy 2012 Mar 2 [Epub ahead of print]). “I am convinced the ESA’s retraction will have no impact on our practice in Switzerland, or in Germany, where non–anesthesiologist-administered propofol is also very common,” he wrote. But “the retraction will certainly have implications in other European countries, where the threshold to use screening endoscopy is held artificially high through the additional costs of unnecessary anesthesiologist fees.” Italy appears to be one of those countries. When the guidelines were originally endorsed by the ESA, Alessandro Repici, MD, the Istituto Clinico Humanitas, in Milan, with support of their anesthesia department, developed a program to train all endoscopists in the administration of propofol and help them obtain advanced cardiac life support certification. “After a few months, we started gastroenterologist administration of propofol, and in the preliminary analysis of our results in terms of safety and patient satisfaction [it] was extremely positive, with more than 4,000 patients treated,” wrote Dr. Repici, director of that institution’s Digestive Endoscopy Department, in an email. “After the ESA retraction, the board of directors of our hospital has stopped this practice according to advice received by our lawyers and experts in legal medicine.” At the moment, the ESA, together with the European Board of Anaesthesiologists, is forming a new task force to produce new guidelines for both anesthesiologist-administered- and non– anesthesiologist-administered propofol. “It should be a guideline on sedation itself, and everyone has to make up his mind whether or not he is competent in n doing this,” Dr. Kochs said.

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40 30

p <0.05

33.0 ±16.1

26.2

30.1 ±16.4

30.6 ±17.4

±14.7

20 10 0

B. lactis Group

Double-blind, parallel, placebocontrolled study in 72 adults consuming 3 containers (125g each) per day of ACTIVIA® or a control product.

Control Group

The improvement in total colonic transit time was statistically significant in both men (p<0.03) and in women (p<0.05), although the effect was more pronounced in women, particularly those with a slower baseline transit time (>40 hours).1

Before ingestion of B. lactis or control product After ingestion of B. lactis product After ingestion of control product

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GastroenteroloGy & endoscopy news • May 2012

Update on the Diagnosis and Treatment of

Hepatitis C ARUN B. JESUDIAN, MD Gastroenterology Fellow NewYork-Presbyterian Hospital/ Weill Cornell Medical College New York, New York

IRA M. JACOBSON, MD Vincent Astor Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director, Center for the Study of Hepatitis C NewYork-Presbyterian Hospital/Weill Cornell Medical College New York, New York EDITOR’S NOTE: This article went to press in advance of the International Liver Congress 2012/47th annual meeting of the European Association for the Study of Liver Disease, held April 18-22, 2012. New research from this meeting and from the 2012 Digestive Disease Week meeting will be included in an updated version of this review, scheduled for publication in October 2012.

epatitis C virus (HCV) infection is a national and global public health concern, affecting up to 4 million individuals in the United States and 200 million individuals worldwide.1,2 Despite

a declining incidence of new HCV infections in the United States, the prevalence of advanced liver disease secondary to chronic HCV infection, including cirrhosis and hepatocellular carcinoma (HCC), is expected to rise in the coming years.3 Image courtesy of CDC/E.H.Cook, Jr.

Diagnostic Considerations Ideally, testing for HCV is performed in asymptomatic patients who are determined to be at increased risk for HCV infection.4 Various societies have implemented guidelines pertaining to medical history and behaviors that constitute an increased risk for HCV. The American Association for the Study of Liver Diseases published guidelines on the diagnosis, management, and treatment of HCV in 2009.5 Criteria for individuals who should be screened for HCV include: • Children born to HCV-infected mothers • Hemodialysis • Hemophilia (recipients of clotting factor concentrates prior to 1987) • HCV-infected sexual partner(s) • HIV infection • Needlestick injury or mucosal exposure to HCV-positive blood • Recipients of blood product transfusions or organ transplants prior to July 1992 • Use of illicit IV drugs in the remote past

• Unexplained elevated serum aminotransferase levels Initial testing for HCV infection involves a screening assay to detect anti-HCV antibodies. The most widely used test is the enzyme immunoassay (EIA), marketed under several trade names. The newest “third-generation” EIAs are highly specific (>99%).6 Recently, an over-the-counter antibody test with comparable accuracy, called Hepatitis C Check (Home Access Health Corporation), was approved by the FDA. For this test, a blood sample is collected via a finger stick and mailed to the manufacturer. Results are reported within 10 business days, and post-test counseling and provider referral are offered. Additionally, a newly FDA-approved rapid test for HCV called OraQuick (OraSure Technologies, Inc.) has comparable accuracy to EIAs. This test uses a finger stick or venipuncture blood sample, and yields a result within 20 minutes. For confirmatory testing for HCV infection, direct detection of HCV RNA has largely replaced

recombinant immunoblot assay, which previously had been used to identify false-positive anti-HCV results. Testing for HCV RNA also is indicated for patients in whom anti-HCV antibody might be falsely negative, including immunocompromised patients such as those infected with HIV, organ transplant recipients, and patients on hemodialysis, as well as patients in whom there is suspicion of acute HCV infection. Molecular testing for HCV RNA traditionally has fallen into 2 categories: qualitative assays and quantitative assays. Qualitative assays, which yield a positive or negative result for detection of HCV RNA, have been supplanted by real-time polymerase chain reaction (PCR) assays. These PCR assays have a high sensitivity (25-43 international units (IU)/mL HCV RNA) and have the ability to quantify viral load simultaneously.7 Quantitative PCR for HCV RNA is indicated at initiation of HCV therapy and at defined intervals during therapy to evaluate treatment response. It should be noted that viral load does not correlate with disease severity.5

VICTRELIS plus peginterferon alfa/ribavirin (PR) vs PR

AN ADDED EDGE AGAINST CHRONIC HEPATITIS C VIRUS (HCV) GENOTyPE 1 (G1)

INDICATIONS AND USAGE VICTRELIS is indicated for the treatment of chronic HCV G1 infection, in combination with PR, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy. The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection: • VICTRELIS must not be used as monotherapy and should only be used in combination with PR • VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors • VICTRELIS in combination with PR has not been studied in patients documented to be historical null responders (<2-log10 HCV-RNA decline by Treatment Week 12) during prior therapy with PR. The clinical studies included subjects who were poorly interferon responsive. Subjects with <0.5-log10 HCV-RNA decline in viral load at Treatment Week 4 with PR alone are predicted to have a null response (<2-log10 viral load decline at Treatment Week 12) to PR therapy

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• Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistanceassociated substitutions upon treatment failure, compared to patients with a greater response to PR http://createqrcode.appspot.com/

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Visit http://www.victrelis.com or scan this QR code to go there directly Google Chart API URL http://chart.apis.google.com/chart?cht=qr&chs=500x500&chl=http%3A//m.victrelis.com/%3FWT.mc_id%3DVI018&chld=H|0

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VICTRELIS + PR vs PR: In adult patients with chronic HCV G1 infection who previously failed PR therapy

An added edge thata nearly tripled virologic cure (SVR) rates OVERALL SVR RATES

~3X increase P<0.0011 P<0.001

59%

66%

23% (96/162)2

(107/161)2

(18/80)2

VICTRELIS RESPONSE-GUIDED THERAPY (RGT)

VICTRELIS PR48

PR48

• VICTRELIS, in combination with PR, has not been studied in patients documented to be historical null responders (<2-log10 HCV-RNA decline by Treatment Week 12) during prior therapy with PR RESPOND-2 study design. A randomized, parallel-group, double-blind, Phase 3 study in previously treated patients with chronic HCV G1 infection (N=403). Subjects had demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load ≥2-log10 by Treatment Week 12, but never achieved SVR [partial responders] or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma [relapsers]). All subjects received a 4-week lead-in of PR (peginterferon alfa-2b 1.5 μg/kg/week subcutaneously plus weight-based ribavirin 600 to 1400 mg/day orally BID), followed by either: a response-guided regimen that consisted of 32 weeks of triple therapy with PR + VICTRELIS 800 mg orally TID, followed by 12 additional weeks of PR if virus not cleared by Treatment Week 8 (VICTRELIS RGT); 44 weeks of triple therapy (VICTRELIS PR48); or 44 weeks of PR + placebo (PR48). Primary study end point = SVR.1 All subjects with detectable HCV-RNA in plasma at Treatment Week 12 were discontinued from treatment. SVR was defined as plasma HCV-RNA undetectable at follow-up Week 24. Plasma HCV-RNA results at follow-up Week 12 were used if plasma HCV-RNA results at follow-up Week 24 were missing.

SELECTED SAFETy INFORMATION • All contraindications to PR also apply since VICTRELIS must be administered with PR • Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use 2 or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin • VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS is also contraindicated in coadministration with potent CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy BID = twice a day; RESPOND-2 = Retreatment with HCV Serine Protease Inhibitor Boceprevir and PR-2; RNA = ribonucleic acid; TID = 3 times a day. Sustained virologic response (SVR) was defined as undetectable HCV-RNA from serum by a sensitive polymerase chain reaction (PCR) assay 24 weeks following the discontinuation of therapy. This is generally considered a “virologic cure,” as the rate of late relapse (beyond 24 weeks) is <1%.3,4

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SELECTED SAFETy INFORMATION • Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam • Anemia and/or Neutropenia–The addition of VICTRELIS to PR is associated with an additional decrease in hemoglobin concentrations compared with PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of PR • Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate • The most commonly reported adverse reactions (>35%) in clinical trials in adult patients receiving the combination of VICTRELIS with PR were: fatigue, anemia, nausea, headache, and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates ≥5% above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously untreated subjects that were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (58% vs 59%), anemia (50% vs 30%), nausea (46% vs 42%), and dysgeusia (35% vs 16%), respectively. The incidence of these adverse reactions in previous treatment failure patients that were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55% vs 50%), anemia (45% vs 20%), nausea (43% vs 38%), and dysgeusia (44% vs 11%), respectively • VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drugdrug interactions must be considered prior to and during therapy Please see Brief Summary of Prescribing Information on the pages that follow. References: 1. Bacon BR, Gordon SC, Lawitz E, et al; for HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207–1217. 2. Birnkrant D. Direct-acting antivirals: a new era for the treatment of chronic hepatitis C. Slide deck presented at: Antiviral Drugs Advisory Committee Meeting; April 27, 2011; Silver Spring, MD. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/AntiviralDrugsAdvisoryCommittee/UCM254076.pdf. Accessed October 5, 2011. 3. Ghany MG, Strader DB, Thomas DL, et al. AASLD practice guidelines. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335−1374. 4. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis. 2011;52(7):889–900. Create QR Code

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Other brands mentioned are the trademarks of their respective owners and are not trademarks of Schering Corp., a subsidiary of Merck & Co., Inc. 1/5/12 3:22 PM

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VICTRELIS™ (boceprevir) CONTRAINDICATIONS Contraindications to peginterferon alfa and ribavirin also apply to VICTRELIS combination treatment. VICTRELIS combination treatment is contraindicated in: • Pregnant women and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin. • Coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events, including those in Table 2. • Coadministration with potent CYP3A4/5 inducers, where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy, including those in Table 2. Table 2: Drugs that are contraindicated with VICTRELIS Drug Class Alpha 1-Adrenoreceptor antagonist

Drugs Within Class that are Contraindicated With VICTRELIS Alfuzosin

Clinical Comments Increased alfuzosin concentrations can result in hypotension.

Anticonvulsants

Carbamazepine, phenobarbital, phenytoin

May lead to loss of virologic response to VICTRELIS

Antimycobacterial

Rifampin

May lead to loss of virologic response to VICTRELIS.

Ergot Derivatives

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Potential for cardiac arrhythmias.

GI Motility Agent

Cisapride

Herbal Products

St. John’s Wort (hypericum perforatum) May lead to loss of virologic response to VICTRELIS.

HMG-CoA Reductase Inhibitors

Lovastatin, simvastatin

Potential for myopathy, including rhabdomyolysis. Potential for hyperkalemia.

Oral Contraceptives

Drosperinone

PDE5 enzyme Inhibitor

REVATIO® (sildenafil) or ADCIRCA® Potential for PDE5 inhibitor-associated (tadalafil) when used for the treatment adverse events, including visual abnormalities, hypotension, prolonged of pulmonary arterial hypertension* erection, and syncope.

Neuroleptic

Pimozide

Potential for cardiac arrhythmias.

Sedative/Hypnotics

Triazolam; orally administered midazolam†

Prolonged or increased sedation or respiratory depression.

* See Drug Interactions, Table 5 for coadministration of sildenafil and tadalafil when dosed for erectile dysfunction. † See Drug Interactions, Table 5 for parenterally administered midazolam. WARNINGS AND PRECAUTIONS Pregnancy (Use with Ribavirin and Peginterferon Alfa) Ribavirin may cause birth defects and/or death of the exposed fetus. 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. Women of childbearing potential and men must use at least 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. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS. Two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with VICTRELIS and concomitant ribavirin. Anemia (Use with Ribavirin and Peginterferon Alfa) Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. Complete blood counts should be obtained pretreatment, and at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g/dL, a decrease in dosage or interruption of ribavirin is recommended; and if hemoglobin is less than 8.5 g/dL, discontinuation of ribavirin is recommended. Refer to the Package Insert for ribavirin for additional information regarding dosage reduction and/or interruption. In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less than 10 g/dL and less than 8.5 g/dL was higher in subjects treated with the combination of VICTRELIS with PegIntron®/REBETOL® than in those treated with PegIntron/REBETOL alone (see Table 4). With the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g/dL. Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of VICTRELIS with PegIntron/REBETOL than in those treated with PegIntron/REBETOL alone. In clinical trials with VICTRELIS, dose modifications (generally of PegIntron/REBETOL) due to anemia occurred twice as often in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL (26%) compared to PegIntron/REBETOL (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL and 1% in subjects who received PegIntron/REBETOL. The use of erythropoiesis stimulating agents was permitted for management of anemia, at the investigator’s discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an erythropoiesis stimulating agent was 43% in the VICTRELIS-containing arms compared to 24% in the PegIntron/REBETOL arms. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects in the VICTRELIS-containing arms compared to less than 1% in subjects who received PegIntron/REBETOL alone. Thromboembolic events have been associated with erythropoiesis stimulating agent use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with VICTRELIS among subjects receiving the combination of VICTRELIS with PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone, regardless of erythropoiesis stimulating agent use. No definite causality assessment or benefit risk assessment can be made for these events due to the presence of confounding factors and lack of randomization of erythropoiesis stimulating agent use. Neutropenia (Use with Ribavirin and Peginterferon Alfa) In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had neutrophil counts of less than 0.5 x 109/L compared to 4% of subjects receiving PegIntron/REBETOL alone (see Table 4). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of VICTRELIS with PegIntron/REBETOL. Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. Refer to Package Inserts for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation for peginterferon alfa and ribavirin. Drug Interactions See Table 2 for a listing of drugs that are contraindicated for use with VICTRELIS due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity. Please refer to Table 5 for established and other potentially significant drug interactions. Laboratory Tests HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or less than 25 IU/mL, and a limit of HCV-RNA detection of approximately 10-15 IU/mL. For the purposes of assessing Response-Guided Therapy milestones, a confirmed “detectable but below limit of quantification” HCV-RNA result should not be considered equivalent to an “undetectable” HCV-RNA result. Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Refer to the Package Inserts for peginterferon alfa and ribavirin, including pregnancy testing requirements.

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ADVERSE REACTIONS See peginterferon alfa and ribavirin Package Inserts for description of adverse reactions associated with their use. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of VICTRELIS cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling: Anemia and neutropenia. The most commonly reported adverse reactions (>35% of subjects regardless of investigator’s causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when VICTRELIS was used in combination with PegIntron and REBETOL. The safety of the combination of VICTRELIS 800 mg three times daily with PegIntron/REBETOL was assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3, randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously untreated) evaluated the use of VICTRELIS in combination with PegIntron/ REBETOL with or without a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone. SPRINT-2 (subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy) evaluated the use of VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL with a four-week lead-in period with PegIntron/ REBETOL compared to PegIntron/REBETOL alone. The population studied had a mean age of 49 years (3% of subjects were >65 years of age), 39% were female, 82% were white and 15% were black. During the four week lead-in period with PegIntron/REBETOL in the VICTRELIS-containing arms, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and 12% for subjects receiving PegIntron/REBETOL alone. Events resulting in discontinuation were similar to those seen in previous studies with PegIntron/REBETOL. Only anemia and fatigue were reported as events that led to discontinuation in >1% of subjects in any arm. Adverse reactions that led to dose modifications of any drug (primarily PegIntron and REBETOL) occurred in 39% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL compared to 24% of subjects receiving PegIntron/REBETOL alone. The most common reason for dose reduction was anemia, which occurred more frequently in subjects receiving the combination of VICTRELIS with PegIntron/REBETOL than in subjects receiving PegIntron/REBETOL alone. Serious adverse events were reported in 11% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and in 8% of subjects receiving PegIntron/REBETOL. Adverse events (regardless of investigator’s causality assessment) reported in greater than or equal to 10% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and reported at a rate of greater than or equal to 5% than PegIntron/REBETOL alone in SPRINT-1, SPRINT-2, and RESPOND-2 are presented in Table 3. Table 3: Adverse Events Reported in ≥10% of Subjects Receiving the Combination of VICTRELIS with PegIntron/REBETOL and Reported at a Rate of ≥5% than PegIntron/REBETOL alone Adverse Events

Body System Organ Class

Previously Untreated (SPRINT-1 & SPRINT-2)

Previous Treatment Failures (RESPOND-2)

Percentage of Subjects Reporting Adverse Events

VICTRELIS + PegIntron + REBETOL (n=1225)

PegIntron + REBETOL (n=467)

VICTRELIS + PegIntron + REBETOL (n=323)

PegIntron + REBETOL (n=80)

197

216

253

104

Median Exposure (days)

Blood and Lymphatic System Disorders Anemia

Neutropenia

Gastrointestinal Disorders Nausea

Dysgeusia

Diarrhea

Vomiting

Dry Mouth

General Disorders and Administration Site Conditions Fatigue

Chills

Asthenia

Metabolism and Nutrition Disorders Decreased Appetite

Musculoskeletal and Connective Tissue Disorders Arthralgia Nervous System Disorders Dizziness Psychiatric Disorders Insomnia

Irritability

Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Exertional

Skin and Subcutaneous Tissue Disorders Alopecia

Dry Skin

Rash

Other Important Adverse Reactions Reported in Clinical Trials Among subjects (previously untreated subjects or those who failed previous therapy) who received VICTRELIS in combination with peginterferon alfa and ribavirin, the following adverse drug reactions were reported. These events are notable because of their seriousness, severity, or increased frequency in subjects who received VICTRELIS in combination with peginterferon alfa and ribavirin compared with subjects who received only peginterferon alfa and ribavirin. Gastrointestinal Disorders Dysgeusia (alteration of taste) was an adverse event reported at an increased frequency in subjects receiving VICTRELIS in combination with peginterferon alfa and ribavirin compared with subjects receiving peginterferon alfa and ribavirin alone (Table 3). Adverse events such as dry mouth, nausea, vomiting and diarrhea were also reported at an increased frequency in subjects receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Laboratory Values Changes in selected hematological parameters during treatment of adult subjects with the combination of VICTRELIS with PegIntron and REBETOL are described in Table 4. Hemoglobin Decreases in hemoglobin may require a decrease in dosage/interruption or discontinuation of ribavirin. Neutrophils and Platelets The proportion of subjects with decreased neutrophil and platelet counts was higher in the VICTRELIS-containing arms compared to subjects receiving PegIntron/REBETOL alone. Three percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had platelet counts of less than 50 x 109/L compared to 1% of subjects receiving PegIntron/ REBETOL alone. Decreases in neutrophils or platelets may require a decrease in dosage or interruption of peginterferon alfa, or discontinuation of therapy.

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Gastro & endoscopy news • May 2012

General Treatment Considerations Table 4: Selected Hematological Parameters Previously Untreated (SPRINT-1 & SPRINT-2)

Previous Treatment Failures (RESPOND-2)

Percentage of Subjects Reporting Selected Hematological Parameters

VICTRELIS + PegIntron + REBETOL (n=1225)

Hematological Parameters

Table 5: Established and Other Potentially Signiﬁcant Drug Interactions (continued)

VICTRELIS + PegIntron + REBETOL (n=323)

PegIntron + REBETOL (n=467)

PegIntron + REBETOL (n=80)

Concomitant Drug Class: Drug Name ritonavir

Effect on Concentration of Boceprevir or Concomitant Drug

Recommendations

Π Ξ or Π HIV protease Ξ atorvastatin

Hemoglobin (g/dL) Ξ Neutrophils (x 109/L) salmeterol Platelets (x 109/L)

Opioid Dependence:

DRUG INTERACTIONS See also Contraindications and Warnings and Precautions. Potential for VICTRELIS to Affect Other Drugs

contraceptives:

Ξ salmeterol Ξ or Π Ξ or Π

Ξ Π

estradiol in vitro.

in vitro

Ξ Ξ Ξ

Potential for Other Drugs to Affect VICTRELIS

Established and Other Potential Signiﬁcant Drug Interactions

Table 5: Established and Other Potentially Signiﬁcant Drug Interactions

Concomitant Drug Class: Drug Name

Effect on Concentration of Boceprevir or Concomitant Drug

Ξ Ξ

Recommendations

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category X: Use with Ribavirin and Peginterferon Alfa Ξ

Ξ or Π

desipramine

VICTRELIS. Monitor INR closely.

Ξ Ξ desipramine

VICTRELIS 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. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214. Pregnancy Category B: VICTRELIS

Ξ Ξ Ξ Ξ Ξ

Ξ Nursing Mothers

Pediatric Use Geriatric Use

Renal Impairment Hepatic Impairment

Π boceprevir Ξ recommended.

Human Immunodeﬁciency Virus (HIV) Co-Infection

clinical monitoring is recommended.

Hepatitis B Virus (HBV) Co-Infection

Ξ nicardipine systemic:

Π boceprevir

Ξ Ξ Ξ bosentan Reverse Transcriptase

Organ Transplantation

Chronic HCV infection places patients at risk for developing progression of hepatic fibrosis to cirrhosis and HCC. The overall goal of HCV therapy is to prevent these complications through viral eradication. Viral eradication in response to treatment is predicted by sustained virologic response (SVR), which is defined as undetectable serum HCV RNA at 24 weeks after discontinuation of treatment. This response portends a 99% likelihood of remaining HCV RNA-negative in long-term follow-up.8 Both viral and host characteristics influence the likelihood of response to treatment. Host factors include race, obesity, insulin resistance, and severity of hepatic fibrosis.9-11 Viral characteristics include viral genotype and viral load at initiation of therapy.12 There are six major genotypes of HCV.13 In the United States, HCV genotype 1 is the most common, comprising 60% to 70% of HCV isolates, followed by HCV genotypes 2 and 3.14 The remaining HCV genotypes are uncommon in the Western world. Response to treatment is highly dependent on viral genotype; therapy with pegylated interferon-alpha (PEGIFNα) and ribavirin (RBV) yields SVR rates of 70% to 80% in patients with HCV genotypes 2 and 3, and significantly lower rates in patients with HCV genotype 1.15

Advances in Treatment of HCV Genotype 1 Until very recently, standard therapy for chronic HCV genotype 1 infection consisted of a combination of PEG-IFNα and RBV. Despite advances in the understanding of the relationship between viral kinetics and treatment response and the importance of weight-based dosing of RBV in patients with HCV genotype 1, viral eradication rates remain suboptimal with PEG-IFNα/ RBV therapy. SVR rates for HCV genotype 1 are approximately 40% following 48 weeks of PEG-IFNα/ RBV therapy and even lower in black patients and in patients with high viral load or advanced fibrosis.16-18 The treatment of patients with chronic HCV genotype 1 infection was bolstered by the recent discovery of a group of single nucleotide polymorphisms (SNPs) in the region of the interleukin 28B (IL28B) gene (encoding interferon-λ-3) through genome-wide association

GastroenteroloGy & endoscopy news • May 2012

Table 1. Regimens for HCV Treatment-Naive Patients

Trial

Treatment Regimena

SVR Rate, %

ADVANCE (telaprevir)

PR48

T12

PR48

BOC/PR48

RGT

PR48

BOC/PR48

RGT

SPRINT-2 (boceprevir), non-black patients

SPRINT-2 (boceprevir), black patients

ADVANCE, A New Direction in HCV Care: A Study of Treatment-Naïve Hepatitis C Patients with Telaprevir; BOC, boceprevir; PR48, pegylated interferon-α/ribavirin for 48 weeks; RGT, response-guided therapy; SPRINT-2, Safety and Efficacy of Boceprevir in Previously Untreated Subjects With Chronic Hepatitis C Genotype 1; SVR, sustained virologic response; T8, telaprevir, 8 weeks; T12, telaprevir, 12 weeks a

See text for complete dosing regimen details.

studies.19 These SNPs are to date the most powerful predictor of SVR in HCV genotype 1 patients treated with PEG-IFNα/RBV. The IL28B test confers the ability to predict SVR by a range of more than 2-fold (roughly 70% in patients with the favorable CC genotype of the IL28B rs12979860 polymorphism compared with 25% to 30% in patients with the CT or TT genotype). For this reason, testing for IL28B genotype has become a part of the informed discussion between the physician and the patient about treatment for HCV. A major milestone in the evolution of therapy for HCV genotype 1 occurred in May 2011 with the approval of telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck), the first commercially available members of a new class of direct-acting antiviral agents (DAAs). Unlike PEG-IFN and RBV, whose antiviral effects are nonspecific, DAAs are the product of intensive study of HCV structure and replication and are targeted to inhibit enzymes involved in the viral life cycle. The addition of these new HCV protease inhibitors to standard therapy has been demonstrated to improve SVR rates dramatically, in both treatment-naive patients and those who have had prior treatment failure (relapsers and nonresponders).

Telaprevir Telaprevir is a selective peptidomimetic NS3 protease inhibitor that forms a covalent, reversible enzyme–inhibitor complex. An early study demonstrated potent in vitro antiviral activity in HCV replicon systems.20 The efficacy of telaprevir in combination with PEG-IFN/RBV, in both treatmentnaive and treatment-experienced patients with HCV genotype 1, was demonstrated in the Phase 2b PROVE 1, 2, and 3 (Protease Inhibition for Viral Evaluation 1, 2, and 3) trials.21-25 These landmark trials established the superior efficacy of telaprevir in combination with PEG-IFN/RBV over PEG-IFN/RBV alone, showed that RBV is an essential component of the regimen, and laid the foundation for the concept of response-guided therapy (RGT), in which treatment duration is determined by viral response early in the course of therapy. The pivotal Phase 3 ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naïve Hepatitis C Patients with Telaprevir) trial, compared telaprevir-based RGT with standard of care in 1,088 patients with chronic HCV genotype 1 infection.26 Patients were randomized to 1 of 3 treatment arms: telaprevir plus PEGIFN/RBV for 8 weeks followed by additional weeks of PEG-IFN/RBV (T8PR), telaprevir plus PEG-IFN/RBV

for 12 weeks followed by additional weeks of PEG-IFN/RBV (T12PR), or standard of care with PEG-IFN/ RBV for 48 weeks (PR48). Patients in the telaprevir treatment arms who achieved undetectable HCV RNA at weeks 4 and 12 (extended rapid viral response [eRVR]) were treated for a total of 24 weeks, whereas those who did not achieve eRVR were treated for 48 weeks. Treatment with telaprevir led to significantly higher SVR rates, at 75% and 69% in the T12 and T8 groups, respectively, compared with 44% in the PR48 (control) group (P<0.0001 for both comparisons). (It should be noted that a reanalysis using revised criteria led to different SVR rates— 79%, 72%, and 46%, respectively— which are published in the telaprevir package insert.) Relapse rates were 9% in both telaprevir groups compared with 28% in the control group. In the T12PR treatment arm, which received the subsequently approved treatment regimen, 58% of patients achieved eRVR, of whom 89% achieved SVR. Discontinuation of therapy for adverse events (AEs) during treatment was more common in the telaprevir groups: 10% of patients in both telaprevir groups discontinued therapy versus 7% of patients in the control group. Grade 3 rash occurred in 6% of patients in the T12PR group versus 4% in the T8PR group. As suggested in earlier studies, telaprevir was associated with an incremental decline in hemoglobin concentration of 1.0 to 1.5 g/dL compared with patients in the control group during the period of telaprevir dosing. Notably, anorectal complaints were more prevalent in telaprevir-treated patients. The overall discontinuation rate secondary to AEs was lower in the ADVANCE trial than in the PROVE trials. This was partly attributable to a strategy of sequential instead of “all-at-once” discontinuation of the study drugs when severe rash occurred in patients in the ADVANCE trial, with telaprevir being stopped first, unlike the case in earlier studies of telaprevir. The Phase 3 open-label ILLUMINATE study further established the role of RGT in telaprevir-based regimens and helped to determine treatment duration in treatment-naive patients.27 All patients were treated with 12 weeks of telaprevir plus PEGIFN/RBV; patients who achieved eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized

to receive either 12 or 36 weeks of additional PEG-IFN/RBV therapy. Of 540 patients enrolled in the trial, 352 (65%) achieved eRVR with 12 weeks of telaprevir-based therapy. The investigators found the 24-week treatment regimen to be non-inferior to the 48-week regimen, with SVR rates of 92% and 88%, respectively, in patients who achieved eRVR. The overall SVR rate in the study was 72%. Discontinuation of all medications secondary to AEs occurred in 17% of patients: Discontinuation was secondary to anemia and rash in 0.6% and 1.1% of patients, respectively, during the telaprevir treatment phase. The Phase 3 REALIZE trial (Re-treatment of Patients with telaprevir-based Regimens to Optimize Outcomes) evaluated treatment-experienced patients.28 In this prospective trial, 662 HCV genotype 1 relapsers, partial responders, and null responders (<2 log10 decline in HCV RNA at week 12 on prior therapy) were randomized to 3 groups: telaprevir plus PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV for 36 weeks (simultaneous-start arm); a lead-in phase of PEG-IFN/RBV for 4 weeks followed by telaprevir plus PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV for an additional 32 weeks (delayed-start arm); or 12 weeks of placebo plus PEG-IFN/ RBV followed by 36 weeks of PEGIFN/RBV alone. The delayed-start arm was the only arm with a leadin phase of PEG-IFN/RBV in the entire development program for telaprevir. Among relapsers, the SVR rate was 83% in the simultaneousstart arm, 88% in the delayed-start arm, and 24% in the control group. For prior partial responders, SVR rates were 59% and 54% in the simultaneous- and delayed-start arms, respectively, versus 15% in the control group. Finally, 29% and 33% of null responders achieved SVR in the simultaneous and delayed-start arms, respectively, versus 5% in the control group. The authors concluded that although both telaprevirbased regimens were superior to the control treatment regimen, the lead-in (delayed-start) regimen did not significantly improve SVR rates compared with a simultaneous start. An analysis of the impact of hepatic fibrosis on SVR rates in the REALIZE trial demonstrated that among relapsers, SVR was minimally affected, even if cirrhosis was present, but that cirrhosis did result

GastroenteroloGy & endoscopy news • May 2012

in decreased SVR rates in partial and null responders. The effect was most dramatic in the latter group, of whom about 40% achieved SVR if mild or bridging fibrosis was present compared with 14% of patients with cirrhosis. HCV genotype also had an impact on SVR: Rates were 10% to 15% in prior nonresponders with HCV genotype 1a versus 1b. Yet another analysis of the lead-in arm from the REALIZE trial examined the association between the degree of HCV RNA decline after 4 weeks of PEG-IFN/RBV and the subsequent chance of achieving SVR: If HCV RNA declined by less than 1 log10 at week 4, relapsers had an SVR rate of 62% compared with 94% for those with a 1 log10 or greater decline in HCV RNA at week 4. For partial responders, SVR rates were 56% and 59% for those groups, respectively. The greatest effect of HCV RNA at week 4 occurred in null responders, with SVR rates of 15% and 54% for those with a less than 1 log10 and a 1 log10 or greater decline, respectively.29 Further subgroup analyses of SVR rates by IL28B genotype were performed for the ADVANCE and REALIZE trials.30,31 In the ADVANCE trial, 42% of patients, all of whom were white, underwent IL28B testing. Of these, 33% had the CC polymorphism, 49% had the CT polymorphism, and 18% had the TT polymorphism. Telaprevir improved SVR rates for all IL28B subtypes, with the largest increase in efficacy occurring in patients with the CT and TT polymorphisms but the highest overall SVR rate observed in the CC group. An eRVR, and concomitant eligibility for a shortened course of therapy, were more common in the CC group. In the REALIZE study, 80% of patients underwent genetic testing. Of these, 18% had the CC polymorphism; 61%, the CT polymorphism; and 21%, the TT polymorphism. The authors concluded that the IL28B genotype was not predictive of response to treatment in this patient population, and that it appears to be of limited use in assessing patients who underwent prior treatment and will be re-treated with a telaprevir-based regimen. Based on results from these studies, telaprevir is approved for the treatment of chronic HCV genotype 1 infection. The medication is available in oral tablet form and is indicated at a dose of 750 mg to be taken 3 times daily in combination with PEG-IFN/ RBV.32 Package instructions state

that patients must receive the 3-drug regimen for 12 weeks, followed by RGT of either 12 or 36 additional weeks of PEG-IFN/RBV, depending on viral response and prior response. For treatment-naive patients and prior relapsers, those with undetectable HCV RNA at weeks 4 and 12 should undergo therapy with 12 additional weeks of PEG-IFN/ RBV. The exception to this guideline is for treatment-naive patients with cirrhosis and undetectable HCV RNA at weeks 4 and 12: 36 additional weeks of PEG-IFN/RBV is suggested for these patients. For prior partial and null responders, all patients should receive 12 weeks of the 3-drug regimen, followed by 36 weeks of PEG-IFN/RBV. Discontinuation is recommended for patients with HCV RNA greater than 1,000 IU/mL at week 4 or 12, or detectable HCV RNA at week 24. Because telaprevir is a potent inhibitor of the cytochrome enzyme CYP3A, it is contraindicated for concurrent use with medications that are highly dependent on CYP3A for clearance. Noteworthy medications include lovastatin, simvastatin, and atorvastatin. Similarly, concurrent use of medications that strongly induce CYP3A, and can thereby lead to reduced efficacy, should be avoided. Because exposure to ethinyl estradiol may be reduced when telaprevir is coadministered, hormonal contraceptives should not used as 1 of the 2 required methods of contraception for PEG-IFN/RBV therapy while telaprevir is being given and for 2 weeks after telaprevir is discontinued. Clinicians should consult the list of contraindicated drugs and the more extensive list of drugs with potential interactions available in the telaprevir package insert. Dose reduction and telaprevir monotherapy are strictly prohibited in order to minimize the emergence of viral resistance. Boceprevir Boceprevir is another selective peptidomimetic NS3 protease inhibitor that forms a covalent but reversible enzyme–inhibitor complex. Early studies established potent in vivo antiviral activity in the HCV replicon system and benefit in HCV genotype 1 patients treated with IFN. As with telaprevir, RBV is an essential component of boceprevircontaining treatment regimens.33,34 The multicenter Phase 2 SPRINT-1 (Serine Protease Inhibitor Therapy-1) trial demonstrated improved viral

eradication rates with the addition of boceprevir to standard therapy, and also suggested the potential role of a 4-week lead-in period of PEG-IFN/RBV before the initiation of boceprevir therapy to achieve optimal SVR rates and minimize the rates of virologic resistance with the 3-drug regimen.35 The Phase 3 SPRINT-2 trial (Safety and Efficacy of Boceprevir in Previously Untreated Subjects With Chronic Hepatitis C Genotype 1) studied boceprevir in combination with PEG-IFNα2b/RBV in 1,097 treatment-naive HCV genotype 1 patients (938 non-black, 159 black).36 All patients received a 4-week lead-in PEG-IFN/weight-based RBV (600-1,400 mg daily), and were randomized to the following treatment arms: placebo plus PEGIFN/RBV for an additional 44 weeks; boceprevir plus PEG-IFN/RBV for an additional 44 weeks; or an RGT arm with boceprevir plus PEG-IFN/RBV for an additional 24 weeks, followed by 20 more weeks of PEG-IFN/RBV if serum HCV RNA was detectable at any time during weeks 8 through 24. In all 3 groups, treatment was discontinued for patients with detectable HCV RNA at week 24, according to a standard futility rule. The non-black and black patient cohorts were analyzed separately. In the non-black cohort, the SVR rate in the standard-of-care group (placebo plus PEG-IFN/RBV) was 40%. Rates were significantly higher in both boceprevir groups: 68% in the 48-week treatment group (P<0.0001 vs control) and 67% in the RGT group (P<0.0001 vs control). As expected, SVR rates in black patients were lower (23%) than in non-black patients in the standard-of-care arm. The addition of boceprevir significantly improved SVR rates in black patients, to 53% in the 48-week treatment group (P=0.004 vs control) and 42% in the RGT group (P=0.04 vs control). A modified intention-to-treat analysis, which included only patients who received at least a single dose of boceprevir, demonstrated SVR rates of 53% and 47%, respectively, in the same cohort. SVR rates were also assessed based on viral response during the 4-week lead-in phase. In the nonblack cohort, high responsiveness to PEG-IFN/RBV, as shown by a 1 log10 or greater decline in HCV RNA, was strongly predictive of SVR for all groups compared with a less than 1 log10 decline (82% vs 39%

in the 48-week treatment group, respectively; 82% vs 29% in the RGT group, respectively; and 52% vs 5% in the control group, respectively). Relapse rates were lower in non-black patients who received boceprevir (8% in the 48-week treatment group, 9% in the RGT group, and 23% in the control group); however, this was not the case in black patients (17%, 12%, and 14%, respectively). The authors noted that the number of events in the smaller black cohort was too low to allow comparison between treatment groups. Discontinuation of therapy secondary to AEs in the SPRINT-2 trial was similar for all 3 groups: 16%, 16%, and 12% for the control, 48-week, and RGT groups, respectively. As first observed in the SPRINT-1 trial, anemia was more common in patients treated with boceprevir, at 49%, than in control patients, at 29%. Although dose reduction secondary to anemia was required more often in patients on boceprevir than in those in the control group (21% vs 13%, respectively), treatment discontinuation was rare (2% vs 1%). Unlike the telaprevir regimen, erythropoietin use was permitted in the boceprevir study and was more frequent in both boceprevir arms. A modest incidence of neutropenia of unclear clinical significance was noted with boceprevir use, as was an increased incidence of dysgeusia. The Phase 3 HCV-RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor boceprevir and Pegintron/Rebetol 2) trial evaluated boceprevir-based regimens in treatment-experienced patients. 37 The prior nonresponders were “partial” responders—they had experienced a 2 log10 or greater reduction in HCV RNA by week 12 of prior therapy—but they had persistent viremia at week 24 or they were patients who relapsed, having attained undetectable HCV RNA at the end of treatment but not having achieved SVR. Patients were randomized to receive a 4-week leadin with PEG-IFN/RBV followed by PEG-IFN/RBV for 48 weeks (control group); a 4-week lead-in with PEGIFN/RBV followed by boceprevir plus PEG-IFN/RBV for 44 weeks; or a 4-week lead-in with PEG-IFN/RBV followed by RGT. Patients in the RGT arm received boceprevir plus PEGIFN/RBV for 32 weeks if serum HCV RNA was undetectable at week 8, or an additional 12 weeks of PEG-IFN/ RBV for patients with detectable

GastroenteroloGy & endoscopy news • May 2012

Table 2. Regimens for HCV Treatment-Experienced Patients Trial

Treatment Regimena

SVR Rate, %

REALIZE (telaprevir), all patients

PR48

T12, simultaneous start

T12, delayed start

PR48

T12, simultaneous start

T12, delayed start

PR48

T12, simultaneous start

T12, delayed start

PR48

T12, simultaneous start

T12, delayed start

PR48

BOC/PR48

RGT

PR48

BOC/PR48

RGT

PR48

BOC/PR48

RGT

REALIZE (telaprevir), relapsers

REALIZE (telaprevir), partial responders

REALIZE (telaprevir), null responders

RESPOND-2 (boceprevir), all patients

RESPOND-2 (boceprevir), relapsers

RESPOND-2 (boceprevir), partial responders

BOC, boceprevir; PR48, pegylated interferon-α/ribavirin for 48 weeks; REALIZE, Re-treatment of Patients with telaprevir-based Regimens to Optimize Outcomes; RESPOND-2, Retreatment with HCV Serine Protease Inhibitor boceprevir and Pegintron/Rebetol 2; RGT, response-guided therapy; SVR, sustained virologic response; T8, telaprevir, 8 weeks; T12, telaprevir, 12 weeks a

See text for complete dosing regimen details.

HCV RNA at week 8. Patients with detectable HCV RNA at week 12 discontinued all treatment and were advanced to follow-up. SVR rates in the control group were poor (21%) compared with the 48-week treatment group (66%; P<0.001) and the RGT group (59%; P<0.001). As expected, prior relapsers had higher SVR rates than prior non-responders in all 3 groups. The authors noted that patients with a 1 log10 or greater decline in HCV RNA at the end of the 4-week leadin period (good response to IFN) had the highest SVR rates (79% and 73% in the 48-week and RGT groups, respectively). Patients in the

boceprevir treatment groups with a less than 1 log10 decline in HCV RNA during the lead-in period (poor response to IFN) had significantly higher SVR rates than corresponding patients in the control group (34% and 33% vs 0%, respectively). Discontinuation secondary to AEs was reported at 2%, 12%, and 8% in the 3 study arms, respectively. Anemia was more common in the boceprevir groups (43% and 46%) than in the control group (20%), although overall treatment discontinuation secondary to anemia was rare in all groups (0%, 3%, and 0% in the control, 48-week, and RGT groups, respectively).

An analysis of SVR rates based on IL28B subtype was performed for approximately two-thirds of patients in the SPRINT-2 and RESPOND-2 trials for whom the results of genetic testing were available.38 Overall, 29% of patients had the CC polymorphism; 54%, the CT polymorphism; and 18%, the TT polymorphism in the 2 boceprevir studies. In the control group in the SPRINT-2 trial, SVR rates were approximately 50% higher in patients with the favorable CC genotype than in those with the CT or TT genotype. The patients with the CC genotype in the boceprevir treatment groups had SVR rates that were 9% to 27% higher than patients with the CT or TT genotype, but the proportional increase in SVR was much greater in the CT and TT genotype patients. In prior treatment failure patients in the RESPOND-2 trial, SVR rates in the control group were not clearly affected by IL28B genotype. Boceprevir significantly increased SVR rates across all IL28B genotypes. Viral response at the end of the 4-week lead-in period superseded the predictive value of IL28B for SVR in both treatmentnaive and treatment-experienced patients. Boceprevir is approved for the treatment of chronic HCV genotype 1 infection administered in oral tablets at a dosage of 800 mg 3 times daily in combination with PEG-IFN/ RBV.39 Per the package instructions, patients should receive a 4-week lead-in with PEG-IFN/RBV, followed by the addition of boceprevir 3 times per day in combination with PEG-IFN/RBV. Duration of treatment is determined by response, which is based on HCV RNA level at treatment weeks 8, 12, and 24. For treatment-naive patients with undetectable HCV RNA at weeks 8 and 24, 3-drug therapy is terminated at week 28. For treatment-naive patients with detectable HCV RNA at week 8 and undetectable HCV RNA at week 24, the 3-drug regimen is completed through week 36, followed by PEG-IFN/RBV alone through week 48. In previously partial responders or relapsers with undetectable HCV RNA at week 8 and week 24, the 3-drug regimen is continued through week 36. Patients with detectable HCV RNA at week 8 and undetectable HCV RNA at week 24 are treated with the extended course of the 3-drug regimen through week 36, followed by PEGIFN/RBV alone through week 48. Treatment is deemed futile if HCV

RNA is 100 IU/mL or greater at week 12 or if HCV RNA is detectable at week 24, at which points the 3-drug regimen should be discontinued. Package instructions state that RGT was not studied in patients who had a less than 2 log10 reduction in HCV RNA during prior PEG-IFN/RBV therapy. Physicians are encouraged to treat these patients for the longer duration of therapy. This longer 48-week duration of therapy also is suggested for patients with a poor response to IFN at week 4 or those with compensated cirrhosis. Like telaprevir, boceprevir is a potent inhibitor of CYP3A, although its major metabolic pathway is aldo-keto reductase. It is contraindicated for concurrent use with medications that are highly dependent on CYP3A clearance. It is also contraindicated for concurrent use with medications that strongly induce CYP3A. Familiarity with the drugs listed as contraindicated or capable of potential interactions with boceprevir, which overlap considerably with those for telaprevir, is essential. Dose reduction and monotherapy are strictly prohibited.

Future Directions In addition to telaprevir and boceprevir, numerous other DAAs from several classes are being studied. These include novel HCV protease inhibitors, as well as medications that target the NS5A replication complex protein and the NS5B RNA-dependent RNA polymerase. Additionally, drugs that inhibit host factors that can augment viral replication, such as cyclophilin antagonists, are being evaluated. A novel NS3/4a protease inhibitor given once daily, TMC435, in combination with PEG-IFN/RBV has shown promising results in early trials.40 The PILLAR study is a dose- and duration-ranging study incorporating RGT. In a preliminary report, 79% to 86% of patients in the TMC435 treatment arms were able to cease therapy at week 24, and SVR rates in these patients ranged from 88% to 97%. Viral response was enhanced with the addition of TMC435 compared with standard of care in all IL28B genotypes. There was no significant difference in AEs between TMC435-treated patients and patients in the placebo arm, with discontinuation of therapy secondary to AEs occurring in 7.1% and 7.8% of study participants, respectively. In a contemporaneous study in treatment-experienced patients,

GastroenteroloGy & endoscopy news • May 2012

called ASPIRE, TMC435 combined with PEG-IFN/RBV yielded higher rates of on-treatment response than PEG-IFN/RBV alone, including response rates at week 24 of higher than 70% in prior null responders.41 Other protease inhibitors that have demonstrated incremental increases in SVR or on-treatment response rates in treatment-naive patients and/or prior nonresponders include BI201335, danoprevir (which is being studied with ritonavir boosting), and BMS650032, among others.42-45 Inhibitors of the HCV NS5A protein, which is active within the viral replication complex, appear extremely promising. The first data on SVR rates in patients treated with a drug from this class, BMS790052, were presented in early 2011. Patients were given BMS790052 at 3, 10, or 60 mg once daily in combination with PEG-IFN/RBV for 48 weeks or PEG-IFN/RBV alone. SVR rates in patients who received the 2 higher doses of BMS790052 were 92% and 83% compared with 25% in the control group; the drug also was well tolerated.46 Favorable rates of HCV suppression have been shown with use of RG7128, a potent nucleoside analog polymerase inhibitor of HCV. In the PROPEL study, patients in 4 treatment arms received different doses and/or duration of treatment with RG7128 in combination with PEG-IFN/RBV, and were compared with a fifth group of patients who received PEG-IFN/RBV alone.47 The combination of RG7128 with PEGIFN/RBV was safe and well tolerated, yielding rapid virologic response (RVR) rates of 39% to 63% and complete early virologic response (cEVR, defined as undetectable HCV RNA at week 12) rates of 68% to 87% in patients with HCV genotypes 1 and 4, 20% of whom had cirrhosis. Preliminary results from a second study of RG7128, the JUMP-C trial, were presented recently.48 Of patients treated with RG7128 at the now established dose of 1,000 mg twice daily plus PEGIFN/RBV who achieved eRVR, 76% went on to achieve SVR at 12 weeks after cessation of therapy. However, a relapse rate of 24% in this group raised questions about whether 24 weeks represents an optimal treatment duration with this drug. Another nucleoside polymerase inhibitor, PSI-7977, has shown promising SVR rates in treatmentnaive HCV genotype 1 patients in a Phase 2 study.49 In the PROTON

study, 121 patients were randomized to receive PSI-7977 200 or 400 mg or placebo once daily plus PEG-IFN/ RBV. Overall, 98% of patients in the PSI-7977 treatment groups achieved RVR, with 100% of patients reaching week 12 with undetectable HCV RNA. There were no observed viral breakthroughs. In a smaller cohort of patients with HCV genotypes 2 and 3, 100% of patients treated with PSI-7977 plus PEG-IFN/RBV for 12 weeks achieved SVR, except for 1 patient who was lost to follow-up. These data reinforce the prevailing evidence that nucleoside analogs are distinct for their much higher barrier to viral resistance than HCV protease inhibitors or HCV NS5A inhibitors, and as outlined below, they may be an attractive option for DAA combination regimens. As with several DAA agents, a cyclophilin inhibitor, alisporivir, has demonstrated favorable SVR rates in combination with PEG-IFN/ RBV.50 In a recent trial, treatmentnaive HCV genotype 1 patients were randomized to receive alisporivir plus PEG-IFN/RBV for 48 weeks, alisporivir plus PEG-IFN/RBV for 24 weeks, alisporivir plus PEG-IFN/ RBV in an RGT fashion (24 weeks for those achieving RVR and 48 weeks for those not doing so), or placebo plus PEG-IFN/RBV for 48 weeks. SVR rates were 76%, 53%, and 69% in each of the alisporivir treatment groups, respectively, compared with 55% in the control group. Another recent development is the potential use of PEG-IFNλ to achieve viral suppression with more favorable safety and tolerability than with PEG-IFNα.51 In a study of 526 treatment-naive patients with chronic HCV infection who were randomized to receive ribavirin plus PEG-IFNλ 240, 180, or 120 mcg or ribavirin plus PEG-IFNα, cEVR rates were significantly higher for all PEGIFNλ doses than for standard of care (56.3%, 55.9%, and 55.0% vs 37.9%, respectively) in patients with HCV genotypes 1 and 4. Treatment with PEG-IFNλ also was associated with fewer hematologic toxicities and flulike and musculoskeletal symptoms than PEG-IFNα. Recently, attention has focused on alternative approaches to HCV drug development. Given the tolerability profile of IFN-based regimens, it has been speculated that HCV could be eradicated with IFN-free regimens that combine different DAAs. The INFORM-1 (Interferon-free Regimen for the Management of HCV-1) study

evaluated the combination of an HCV protease inhibitor, RG7227 (now called danoprevir), and RG7128, an HCV nucleoside polymerase inhibitor.52 This trial demonstrated marked viral suppression over a 2-week treatment period, with no virologic breakthrough related to resistance in more than 70 HCV genotype 1 patients. Additionally, other recently presented studies that evaluated combinations of antiviral drugs have reinforced the promise of the INFORM-1 study, with intriguing early results that illustrate emerging principles governing the design of IFN-free regimens. Combinations of DAA agents can indeed confer marked viral suppression. However, for optimal prevention of emergent viral resistance, dual combinations appear to require that at least one component be a drug with a high barrier to HCV resistance, such as a nucleoside analog. Barring this component, RBV appears to be a potentially viable adjunctive third drug. This was illustrated in a trial of an HCV protease inhibitor and a non-nucleoside polymerase inhibitor in the presence or absence of RBV: virologic breakthroughs in the absence of RBV and a protective effect was observed in the presence of RBV. 53 Breakthroughs also occurred in a combination therapy trial involving telaprevir and a non-nucleoside drug, VX-222. 54 In contrast, in another study of a protease inhibitor and a nonnucleoside polymerase inhibitor, RBV appeared to prevent virologic breakthroughs.55 The past year was historic not only for the approval of the first 2 protease inhibitors, but for the demonstration of the eagerly awaited proof of concept that HCV infection can be cured without interferon. At least 4 such studies have appeared in various forms, ranging from press releases to published papers. A small but highly influential study examined the combination of asunaprevir (previously known as BMS650032), a protease inhibitor, and daclatasvir (previously known as BMS790052), a potent NS5A inhibitor that is believed to act via inhibition of the HCV replication complex in infected cells, in 11 HCV genotype 1 null responders. Seven of 11 patients (63.6%) achieved RVR when treated with the 2-drug combination for 24 weeks.56 Additionally, 5 patients had undetectable HCV RNA at 24 weeks, and 4 patients achieved SVR at week 12—2 of 2 patients with HCV genotype

1b and 2 of 9 patients with HCV genotype 1a. Most of the remaining patients had virologic breakthrough, with detection of resistant variants to both drugs. Intriguingly, all of 10 null responders who received a quadruple regimen containing PEGIFN/RBV and the 2 DAAs achieved an SVR, fueling intense interest in further investigation of quadruple therapy. Studies on both IFN-free therapy and quadruple therapy with PEG-IFN/RBV and 2 DAAs have been initiated or are being planned. The high response rate of HCV genotype 1b to a dual DAA regimen was demonstrated in another IFNfree trial combining asunaprevir and daclatasvir in HCV genotype 1b null responders.57 Out of 10 enrolled patients, 9 patients completed 24 weeks of treatment, all of whom achieved SVR at weeks 12 and 24. The ELECTRON trial examined the previously mentioned nucleoside polymerase inhibitor, PSI-7977 (now known as GS-7977). In this trial, an SVR rate of 100% was observed in 40 treatment-naive patients with HCV genotypes 2 and 3 in all study arms, including 12-week regimens of PSI7977 plus PEG-IFN/RBV (the latter given for 4, 8, or 12 weeks) and an IFN-free arm of PSI-7977 plus RBV for 12 weeks.58,59 In a 10-patient cohort of PSI-7977 monotherapy, all patients had undetectable HCV RNA at end of treatment, but four patients had relapsed at the time the initial data were presented. However, in HCV genotype 1 null-responders treated with a 12-week regimen of PSI7977 and RBV, promising early viral suppression with 100% undetectable HCV RNA at the end of treatment did not prevent virologic relapse, with nearly all patients relapsing within 4 weeks of the end of treatment.60 This and other observations have raised the question of whether intrinsic IFN responsiveness might still influence the response to IFN-free antiviral regimens, perhaps depending on the subtype of HCV genotype 1 and on components of the antiviral regimen (eg, HCV genotype 1a becomes resistant more readily, at least to protease inhibitors, than HCV genotype 1b). Data from an HCV genotype 1 treatment naïve cohort are eagerly awaited.

Conclusion The exciting developments described here mandate education of all physicians who treat patients with HCV in the proper use of the new agents, including management

of side effects. Individualization of treatment decisions, both in treatment-naive and treatmentexperienced patients, remains of paramount importance. We can expect studies in patients for whom the role of the already approved agents has not been clearly defined, such as HIV-coinfected patients (studies are in progress with protease inhibitors), transplant recipients, and patients with decompensated liver disease. Trials involving DAAs of several classes, as well as drugs with other mechanisms of action, either with or without PEG-IFN/RBV, are proceeding at a remarkable pace. Ultimately, it would appear that the field of HCV therapy is moving inexorably toward the development of interferon-free therapy for many if not most or even all patients.

References 1. Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20(1):1-16. 2. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-714. 3. Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138(2):513-521. 4. Alter MJ, Seefe LB, Bacon BR, et al. Testing for hepatitis C virus infection should be routine for persons at increased risk for infection. Ann Intern Med. 2004;141(9):715-717. 5. Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374. 6. Colin C, Lanoir D, Touzet S, et al. Sensitivity and speciﬁcity of thirdgeneration hepatitis C antibody detection assays: an analysis of the literature. J Viral Hepat. 2001;8(2):87-95. 7. Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastroenterology. 2002;122(6):1554-1568. 8. Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010;139(5):1593-1601. 9. Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131(2):470-477. 10. Reddy KR, Shiffman ML, RodriguezTorres M, et al. Induction pegylated interferon alfa-2a and high dose

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ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads. Gastroenterology. 2010;139(6):1972-1983. 11. Romero-Gómez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128(3):636-641. 12. Martinot-Peignoux M, Marcellin P, Pouteau M, et al. Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology. 1995;22 (4 pt 1):1050-1056. 13. Simmonds P, Alberti A, Alter HJ, et al. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology. 1994;19(5):1321-1324. 14. Dusheiko G, Schmilovitz-Weiss H, Brown D, et al. Hepatitis C virus genotypes: an investigation of type-specific differences in geographic origin and disease. Hepatology. 1994;19(1):13-18. 15. Davis GL, Lau JY. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology. 1997;26 (3 suppl 1):122S-127S. 16. McHutchinson JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339(21):1485-1492. 17. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-982. 18. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weightbased or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46(4):971-981. 19. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399-401. 20. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899-909. 21. Jacobson IM, Everson GT, Gordon SC, et al. Interim analysis results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naïve subjects with hepatitis C. Hepatology. 2007;46 (4 suppl 1):315A-316A. Abstract 177. 22. McHutchinson JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827-1838. 23. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir in combination with peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839-1850. 24. Zeuzam S, Hézode C, Ferenci P, et al. Telaprevir in combination with

peginterferon alfa-2a with or without ribavirin in the treatment of chronic hepatitis C: Final results of the PROVE 2 study. Hepatology. 2008;48 (4 suppl):418A-419A. Abstract 243. 25. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292-1303. 26. Jacobson IM, McHutchinson JG, Dusheiko GM, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-2416. 27. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: ﬁnal results of phase 3 ILLUMINATE study. Hepatology. 2010;52(4 suppl):401A402A. Abstract LB-2. 28. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417-2428. 29. Foster GR, Zeuzem S, Andreone P, et al. Subanalyses of the telaprevir leadin arm in the REALIZE study: response at week 4 is not a substitute for prior null response categorization. J Hepatol. 2011;54(suppl 1):S3-S4. Abstract 6. 30. Jacobson IM, Catlett I, Marcellin P, et al. Telaprevir substantially improved SVR rates across all IL28B genotypes in the ADVANCE trial. J Hepatol. 2011;54 (suppl 1):S542-S543. Abstract 1369. 31. Pol S, Aerssens J, Zeuzem S, et al. Similar SVR rates in IL28B CC, CT or TT prior relapser, partial- or null-responder patients treated with telaprevir/peg-IFN/ ribavirin: retrospective analysis of the REALIZE study. J Hepatol. 2011;54(suppl 1):S6-S7. Abstract 13. 32. INCIVEK (telaprevir). Prescribing information. www.incivek.com. Accessed August 24, 2011. 33. Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother. 2006;50(3):1013-1020. 34. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology. 2007;132(4):1270-1278. 35. Kwo PY, Lawitz EJ, McCone J, et al. Efﬁcacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis C infection (SPRINT-1): an open label, randomized, multicentre phase 2 trial. Lancet. 2010;376(9742):705-716. 36. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-1206. 37. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated

chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207-1217. 38. Poordad F, Bronowicki JP, Gordon SC, et al. IL28B polymorphism predicts virological response in patients with hepatitis C genotype 1 treated with boceprevir combination therapy. J Hepatol. 2011;54(suppl 1):S6. Abstract 12. 39. VICTRELIS (boceprevir). Prescribing information. www.victrelis.com. Accessed August 24, 2011. 40.Fried MW, Buti M, Dore GJ. Efﬁcacy and safety of TMC435 in combination with peginterferon a-2a and ribavirin in treatment-naïve genotype-1 HCV patients: 24-week interim results from the PILLAR study. Hepatology. 2010;52 (4 suppl):403A-404A. Abstract LB-5. 41. Zeuzem S, Foster GR, Fried MW, et al. The ASPIRE trial: TMC435 in treatmentexperienced patients with genotype-1 HCV infection who have failed previous PEGIFN/RBV treatment. J Hepatol. 2011; 54(suppl 1):S546. Abstract 1376. 42. Sulkowski MS, Ceasu E, Asselah T, et al. SILEN-C1: sustained virologic response (SVR) and safety of BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype 1 HCV infection. J Hepatol. 2011;54(suppl 1):S27. Abstract 60. 43. Sulkowski MS, Bourliere M, Bronowicki JP, et al. SILEN-C2: sustained virologic response (SVR) and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype-1 patients with non-response to P/R. J Hepatol. 2011;54(suppl 1):S30. Abstract 66. 44.Larrey D, Carenco C, Guyader D, et al. High sustained virologic response (SVR) rate after danoprevir for only 14 days associated with peg-interferon alfa-2a and ribavirin in treatment-naïve chronic HCV genotype 1 patients. J Hepatol. 2011;54(suppl 1):S481. Abstract 1218. 45. Bronowicki JP, Pol S, Thuluvath PJ, et al. BMS-650032, an NS3 inhibitor, in combination with peginterferon alpha2a and ribavirin in treatment-naïve subjects with genotype 1 chronic hepatitis C infection. J Hepatol. 2011;54 (suppl 1):S472. Abstract 1195. 46. Pol S, Ghalib RH, Rustgi VK, et al. First report of SVR12 for a NS5A replication complex inhibitor, BMS-790052 in combination with PEG-IFNa-2A and RBV: phase 2a trial in treatment-naïve HCV-genotype 1 subjects. J Hepatol. 2011;54(suppl 1):S544-S545. Abstract 1373. 47. Jensen DM, Wedemeyer H, Herring RW, et al. High rates of early viral response, promising safety proﬁle and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study. Hepatology. 2010;52 (4 suppl 1):360A-361A. Abstract 81. 48. Pockros P, Jensen D, Tsai N, et al. First SVR data with the nucleoside analogue polymerase inhibitor mericitabine (RG7128) combined with peginterferon/ ribavirin in treatment-naive HCV G1/4 patients: interim analysis from the JUMP-C trial. J Hepatol. 2011;54(suppl 1):S538. Abstract 1359.

GastroenteroloGy & endoscopy news • May 2012

49. Nelson DR, Lalezari J, Lawitz E, et al. Once daily PSI-7977 plus PEG-IFN/ RBV in HCV GT1: 98% rapd virologic response, complete early virologic response: the PROTON study. J Hepatol. 2011;54(suppl 1):S544. Abstract 1372. 50. Flisiak R, Pawlotsky JM, Crabbe R, et al. Once daily Alisporivir (DEB025) plus PEG-IFN-alfa2a/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naïve patients. J Hepatol. 2011;54(suppl 1):S2. Abstract 4. 51. Zeuzem S, Arora S, Bacon B, et al. Pegylated interferon-lambda (PEGIFNγ) shows superior viral response with improved safety and tolerability versus PEGIFNα-2A in HCV patients (G1/2/3/4): EMERGE phase IIB through week 12. J Hepatol. 2011;54(suppl 1):S538-S539. Abstract 1360.

60.Gane E, Stedman C, Anderson J, et al. 100% Rapid virologic response for PSI-7977 + ribavirin in genotype 1 null responders (ELECTRON): early viral decline similar to that observed in genotype 1 and genotype 2/3 treatment-naive patients. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 6, 2012; Seattle, WA: Paper 54LB. AUTHOR DISCLOSURES—Dr. Jesudian reported no conﬂicts of interest. Dr. Jacobson has received grants and research support, and has served as a consultant, advisor, and member of the speakers’

bureau for Bristol-Myers Squibb, Gilead Sciences, Merck & Co., Roche/Genentech, and Vertex Pharmaceuticals. He has received grants and research support, and has served as a consultant and advisor for Boehringer Ingelheim, GlobeImmune, Human Genome Sciences, Novartis, Pﬁzer, Pharmasset, Tibotec, Vertex Pharmaceuticals, and ZymoGenetics. He has served as a consultant and advisor for Achillion Pharmaceuticals, Biolex, and GlaxoSmithKline. DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the author(s).

Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright © 2012, McMahon Publishing, 545 West 45th Street, 8th Flo or, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.

52. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomized, double-blind, placebo-controlled, dose escalation trial. Lancet. 2010;376(9751):1467-1475. 53. Zeuzem S, Buggisch P, Agarwal K, et al. Dual, triple, and quadruple combination treatment with a protease inhibitor (GS9256) and a polymerase inhibitor (GS9190) alone and in combination with ribavirin (RBV) or PEG IFN/RBV for up to 28 days in treatment naïve, genotype 1 HCV subjects. Hepatology. 2010;52 (4 suppl 1):400A-401A. Abstract LB-1. 54. Di Bisceglie AM, Nelson DR, Gane E, et al. VX-222 with TVR alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: ZENITH study interim results. J Hepatol. 2011;54 (suppl 1):S540. Abstract 1363. 55. Zeuzem S, Asselah T, Angus PW, et al. Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI201335, the HCV polymerase inhibitor BI207127 and ribavirin in patients with chronic hepatitis C. Hepatology. 2010;52(4 suppl 1):876A-877A. Abstract LB-7. 56. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366(3):216-224. 57. Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55(3):742-748. 58. Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: Pegylated interferon-alfa not required for complete rapid viral response in treatment-naïve patients with HCV GT2 or GT3. Hepatology. 2011;54 (suppl 1):377A. Abstract 34. 59. Lalezari J, Lawitz E, Rodriguez-Torres M, et al. Once daily PSI-7977 plus PEGIFN/RBV in a phase 2B trial: rapid virologic suppression in treatment-naïve patients with HCV GT2/GT3. J Hepatol. 2011;54(suppl 1):S28. Abstract 61.

INCIVEK HAS ARRIVED INDICATION INCIVEK, in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment naïve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers. The following points should be considered when initiating treatment with INCIVEK: INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance–associated substitutions emerge on treatment with INCIVEK combination treatment INCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or other HCV NS3/4A protease inhibitors IMPORTANT SAFETY INFORMATION Contraindications Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. INCIVEK combination treatment is contraindicated in women who are or may become pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. If ribavirin is used during pregnancy or in the event of a pregnancy while on treatment, inform the patient of the potential hazard to a fetus. INCIVEK combination treatment is also contraindicated in men whose female partners are pregnant. INCIVEK is contraindicated when combined with drugs that 1) are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events and 2) strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVEK. Contraindicated medications are alfuzosin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort, atorvastatin, lovastatin, simvastatin, pimozide, sildenafil (Revatio®) or tadalafil (Adcirca®) for pulmonary arterial hypertension, oral midazolam, and/or triazolam. Warnings and precautions Pregnancy: Ribavirin may cause birth defects and/or death of the exposed fetus. 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 just before initiation of therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during combination treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping all treatment. Female patients may continue hormonal contraceptives but they may not be reliable during INCIVEK dosing and for up to two weeks after stopping INCIVEK. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception.

Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome (SJS) were reported in less than 1% of subjects receiving INCIVEK combination treatment. These reactions required hospitalization and all patients recovered. Presenting signs of these reactions may include rash, facial edema, target lesions, mucosal ulcerations, and evidence of internal organ involvement. If serious skin reactions occur, all components of INCIVEK combination treatment must be discontinued immediately and the patient referred for urgent medical care. Rash developed in 56% of patients who received INCIVEK combination treatment. Severe rash was reported in 4% of patients treated with INCIVEK combination treatment. Severe rash may have a prominent eczematous component. Patients with rash should be followed for progression of rash or development of systemic symptoms. If rash becomes severe or systemic symptoms develop, discontinue INCIVEK. Peginterferon alfa and ribavirin may be continued. Anemia has been reported with peginterferon alfa and ribavirin treatment. Adding INCIVEK is associated with additional decrease in hemoglobin compared to peginterferon alfa and ribavirin alone. Hemoglobin values of ≤10 g/dL were observed in 36% of subjects, and <8.5 g/dL in 14% of subjects who received INCIVEK combination treatment. Hemoglobin should be monitored at baseline and at weeks 2, 4, 8, and 12, or as clinically appropriate. Use the labeled ribavirin dose modification guidelines to manage anemia; if ribavirin dose reductions are inadequate, consider discontinuing INCIVEK. If ribavirin is permanently discontinued, INCIVEK must also be permanently discontinued. The dose of INCIVEK must not be reduced and must not be restarted if discontinued. Adverse reactions The most common adverse reactions seen with an incidence ≥5% with INCIVEK over controls were rash (56%), fatigue (56%), pruritus (47%), nausea (39%), anemia (36%), diarrhea (26%), vomiting (13%), hemorrhoids (12%), anorectal discomfort (11%), dysgeusia (10%), and anal pruritus (6%). Please see the Brief Summary on the adjacent pages. INCIVEK combination treatment = INCIVEK + pegIFN-RBV for 12 weeks, and an additional 12 or 36 weeks of pegIFN-RBV. Visit www.INCIVEK.com for: • Latest information • Free resources • Guidance & Patient Support (GPS) information Or call toll-free at 1-877-824-4281.

INCIVEK and the Blue Arrow logo are trademarks of Vertex Pharmaceuticals Incorporated. The brands listed are trademarks of their respective owners. ©2012 Vertex Pharmaceuticals Incorporated. All rights reserved. | VX12-2529 | 1/12

FDA Update & Product News

GastroenteroloGy & endoscopy news • May 2012

New York State Approves Blood Test To Assess Colorectal Cancer Risk Questions Raised by Independent Expert Gastroenterology and Nutrition Service at Memorial Sloan-Kettering Cancer Center in New york City, raised questions about the data supporting ColonSentry: “I do not feel that it is ready for clinical use�” The company defended its test� ColonSentry uses RNA contained in blood to measure the level of expression

INCIVEKTM (telaprevir) Tablets Brief Summary of Prescribing Information. See package insert for full prescribing information. INDICATIONS AND USAGE INCIVEKTM (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers. The following points should be considered when initiating treatment with INCIVEK: must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. had telaprevir resistance–associated substitutions emerge on treatment with INCIVEK combination treatment. CONTRAINDICATIONS Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. INCIVEK combination treatment is contraindicated in: during pregnancy, or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus. concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). INCIVEK is contraindicated when are listed below. Drugs that are Contraindicated with INCIVEK

56%

34%

Fatigue

56%

50%

Pruritus

47%

28%

Nausea

39%

28%

36%

17%

Diarrhea

26%

17%

Vomiting

13%

Hemorrhoids

12%

11%

Clinical Comments

Potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia

Cisapride

Potential for cardiac arrhythmias

St. John's wort (Hypericum perforatum)

Plasma concentrations of telaprevir can be reduced by concomitant use of the herbal preparation St. John’s wort. Potential for myopathy including rhabdomyolysis

Neuroleptic

Pimozide

Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics

PDE5 inhibitor

® ) or tadalafil ® ) [for treatment of pulmonary arterial hypertension]a

Potential for PDE5 inhibitor-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope

Sedatives/hypnotics

Orally administered midazolamb, triazolam

Prolonged or increased sedation or respiratory depression

See table under Drug Interactions for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction. b See table under Drug Interactions for parenterally administered midazolam. WARNINGS AND PRECAUTIONS Pregnancy: Use with Ribavirin and Peginterferon Alfa. a

a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Because INCIVEK must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients as significant teratogenic and/or embryocidal effects Female Patients-Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to two weeks following cessation of INCIVEK. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Examples may include barrier methods or intrauterine devices (IUDs). Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. Serious Skin Reactions. Johnson Syndrome (SJS) were reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all patients recovered. The Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips). If a serious skin reaction occurs, all components of INCIVEK combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care. Rash. vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component. Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended. Anemia. is associated with an additional decrease in hemoglobin concentrations. Hemoglobin values less than or equal to 10 g/dL were observed in 36% of subjects who received INCIVEK combination treatment compared to 17% of subjects who received peginterferon alfa and ribavirin. Hemoglobin values less than 8.5 g/dL were observed in 14% of subjects who received INCIVEK combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin. In subjects receiving INCIVEK combination treatment, 4% discontinued INCIVEK, 1% discontinued INCIVEK combination treatment, and 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia. In subjects treated with peginterferon alfa and ribavirin alone, there were two discontinuations and 12% underwent ribavirin dose modification due to anemia. Hemoglobin should be monitored prior to and at least every 4 weeks during INCIVEK combination treatment. For the management of anemia, ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of INCIVEK should be considered. If ribavirin is permanently discontinued for the management of dose of INCIVEK must not be reduced and INCIVEK must not be restarted if discontinued. Drug Interactions. See the table above for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening Drug Interactions for established and other

Description of Selected Adverse Drug Reactions Rash. In controlled clinical trials, rash events (all grades) were reported in 56% of subjects who received INCIVEK combination treatment and any time during INCIVEK combination treatment. Improvement of rash occurs after INCIVEK dosing completion or discontinuation; however, rashes may take weeks for complete resolution. of subjects. Anemia. In controlled clinical trials, the overall incidence and severity of anemia increased with INCIVEK combination treatment compared to peginterferon alfa and ribavirin alone. The incidence of anemia adverse events was 36% with INCIVEK combination treatment compared lowest values reached at the end of INCIVEK dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after INCIVEK dosing was completed. Anorectal Signs and Symptoms. In the controlled clinical trials, 29% of subjects treated with INCIVEK combination treatment experienced anorectal adverse events, compared to 7% of those treated with peginterferon alfa and ribavirin alone. The majority of these events (e.g., hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate in severity; less than 1% led to treatment discontinuation and all resolved during or after completion of INCIVEK dosing. Laboratory abnormalities White Blood Cells: Treatment with peginterferon alfa is associated with decreases in mean values for total white blood cell, absolute neutrophil, and absolute lymphocyte count. More INCIVEK-treated subjects had decreases in lymphocyte counts to 499/mm3 or less (15% compared to 5%). Decreases in total white cell counts to 1,499/mm3 or less were comparable (8% compared to 5%). The incidence of decreases in absolute neutrophil counts to 749/mm3 or less was 15% in subjects treated with peginterferon alfa and ribavirin alone compared to 12% among those treated with INCIVEK combination treatment. Platelets: Treatment with peginterferon alfa is associated with decreases in mean platelet counts. More patients treated with INCIVEK combination treatment had decreases in mean platelet values of all grades: 47% compared to 36% treated with peginterferon alfa and ribavirin alone. Three percent of INCIVEK combination treatment subjects had decreases to 49,999/mm3 or less compared to 1% of those treated with peginterferon alfa and ribavirin-treated alone. Bilirubin: Forty one percent of INCIVEK-treated subjects compared to 28% of peginterferon alfa and ribavirin-treated subjects had all grade elevations in bilirubin levels; 4% and 2% of subjects, respectively, had greater than or equal to 2.6 x ULN elevations. Bilirubin levels increased most steeply during the first 1 to 2 weeks of INCIVEK dosing, stabilized and between Weeks 12 and 16 were at baseline levels. Uric Acid: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg/dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation. DRUG INTERACTIONS Potential for INCIVEK to Affect Other Drugs plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. INCIVEK is also an inhibitor of P-gp. Co-administration of INCIVEK with drugs that are substrates for P-gp transport may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. If dose adjustments of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK is completed. Potential for Other Drugs to Affect INCIVEK plasma concentrations. Established and Other Potentially Significant Drug Interactions The table below provides effect of concentration of INCIVEK or concomitant drug with INCIVEK. These recommendations are based on either adverse events or loss of efficacy. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name

Effect on concentration of INCIVEK or Concomitant Drug

Clinical Comment

ANTIARRHYTHMICS lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine

antiarrhythmics

Co-administration with telaprevir has the potential to produce serious and/ or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir.

digoxin

Concentrations of digoxin were increased when co-administered with telaprevir. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.

telaprevir antibacterials

Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin.

Concentrations of warfarin may be altered when co-administered with

ANTIBACTERIALS clarithromycin erythromycin telithromycin

ANTICOAGULANT warfarin

➞

potentially significant drug-drug interactions. Laboratory Tests.

10%

➞

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

N=493

➞

concentrations.

Herbal products

Peginterferon alfa and ribavirin

Dysgeusia

Potential for hypotension or cardiac arrhythmia

Ergot derivatives

INCIVEK, peginterferon alfa, and ribavirin Combination Treatment N=1797

➞ ➞

Drugs within Class that are Contraindicated with INCIVEK

INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in INCIVEK-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone. Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK

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Drug Class

of seven genes that serve as biomarkers, potentially allowing physicians to identify patients who have an increased current risk for colorectal cancer, according to an Enzo Biochem press release� Patients at higher risk may receive a strong recommendation for colonoscopy� David Goldberg, MS, MBA, vice president of

warfarin

when warfarin is co-administered with telaprevir. ANTICONVULSANTS

which must be co-administered with INCIVEK. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:

adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received INCIVEK combination treatment and 493 who received peginterferon alfa and ribavirin. Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK combination treatment compared to none of the subjects treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with INCIVEK combination treatment were skin disorders (rash and/or pruritus) and anemia. Fourteen percent of subjects discontinued INCIVEK due to adverse drug of INCIVEK.

telaprevir carbamazepine or phenytoin or phenobarbital

Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Telaprevir may be less effective in patients taking these agents concomitantly. Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response.

➞

repeated courses of INCIVEK. Hepatic Impairment. INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score

carbamazepine phenobarbital phenytoin

telaprevir escitalopram desipramine trazodone

Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir. Concomitant use of trazodone or desipramine and telaprevir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with telaprevir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.

➞ ➞

including pregnancy testing requirements. General. INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with INCIVEK.

➞

Hematology evaluations (including white cell differential count) are recommended at weeks 2, 4, 8 and 12 or as clinically appropriate thereafter. Chemistry evaluations (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as

➞ ➞ ➞

The New york State Department of Health has approved Enzo Clinical Labs’ ColonSentry, a blood-based test for assessing a patient’s risk for colorectal cancer� The Toronto-based GeneNews, the test’s

original developer, granted New york– based Enzo Biochem, Inc�, exclusive rights to use of the product in the New york metropolitan area� Enzo Biochem is offering the test through its subsidiary, Enzo Clinical Labs� Independent expert, Sidney J� Winawer, MD, Paul Sherlock Chair in Medicine,

➞ ➞

By george ochoa

ANTIDEPRESSANTS

desipramine trazodone

FDA Update & Product News

GastroenteroloGy & endoscopy news • May 2012

corporate development at Enzo Biochem and interim president of Enzo Clinical Labs, said, “We hope to drive people to colonoscopy because it’s the best tool we have out there�” He added: “If you’re not identified as higher than normal risk, you should have regular screening� One hundred percent of people should be compliant�” Dr� Winawer commented on ColonSentry after reviewing two published studies

Effect on concentration of INCIVEK or Concomitant Drug

Clinical Comment

Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir. Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, high doses of itraconazole or ketoconazole (greater than 200 mg/day) are not recommended. Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole. QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole. Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use.

sirolimus

cyclosporine sirolimus tacrolimus

Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied.

salmeterol

Concentrations of salmeterol may be increased when co-administered with telaprevir. Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

INHALED BETA AGONIST salmeterol

colchicine

Patients with renal or hepatic impairment should not be given colchicine

NARCOTIC ANALGESIC Concentrations of methadone were reduced when co-administered with telaprevir. No adjustment of methadone dose is required when initiating co-administration of telaprevir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.

➞

colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function. Treatment of gout flares: co-administration of colchicine in patients on telaprevir: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. If used for prophylaxis of gout flares: co-administration of colchicine in patients on telaprevir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): co-administration of colchicine in patients on telaprevir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

PDE 5 INHIBITORS sildenafil tadalafil vardenafil

➞

ANTI GOUT colchicine

PDE 5 inhibitors

➞

telaprevir rifabutin

➞

zolpidem (non-benzodiazepine

alprazolam

Concomitant use of alprazolam and telaprevir increases exposure to alprazolam. Clinical monitoring is warranted.

midazolam

Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with telaprevir is contraindicated.

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parenterally administered

➞

BENZODIAZEPINES

zolpidem

Exposure to zolpidem was decreased when co-administered with telaprevir. Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response.

➞

diltiazem felodipine nicardipine nifedipine nisoldipine verapamil

amlodipine

➞

CALCIUM CHANNEL BLOCKERS

calcium channel blockers

Exposure to amlodipine was increased when co-administered with telaprevir. Caution should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended. Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered. Caution is warranted and clinical monitoring of patients is recommended.

➞ ➞

telaprevir

➞ ➞

Inhaled/Nasal fluticasone budesonide

prednisone methylprednisolone

➞

Systemic dexamethasone

fluticasone budesonide

Systemic corticosteroids such as prednisone and methylprednisolone are concentrations of these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended. telaprevir plasma concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered. Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

➞

ENDOTHELIN RECEPTOR ANTAGONIST bosentan

= increase, = decrease,

= no change) indicates the direction

In addition to the drugs included in the table above, the interaction between INCIVEK and the following drug was evaluated in clinical studies and no dose adjustment is needed for either drug: esomeprozole. USE IN SPECIFIC POPULATIONS Pregnancy Because INCIVEK must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment Pregnancy Category X: abortifacient. See the prescribing information for ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all 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 (see also ribavirin prescribing information). Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information). 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 effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. Systemic hormonal contraceptives may not be as effective in women while taking INCIVEK. Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with INCIVEK and concomitant ribavirin. 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. Health care providers and patients are encouraged to report such cases by calling 1-800-593-2214. INCIVEK (telaprevir) Tablets Pregnancy Category B: Telaprevir treatment alone in mice and rats did not result in harm to the fetus. The highest doses tested produced exposures equal to 1.84- and 0.60-fold the exposures in humans at the recommended clinical dose, respectively. Telaprevir treatment alone 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile sperm count) were observed in a rat fertility study at exposures 0.30-fold the human exposures at the recommended clinical

CORTICOSTEROIDS Systemic prednisone methylprednisolone

of the change in PK.

➞

Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.

Concentrations of PDE5 inhibitors may be increased when coadministered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE5 inhibitor-associated adverse events. QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended. Co-administration of sildenafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated. Co-administration of tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is not recommended. ➞

ANTIMYCOBACTERIAL rifabutin

Clinical Comment

➞ ➞ ➞

itraconazole posaconazole or voriconazole ➞

➞ ➞

itraconazole posaconazole voriconazole

Effect on concentration of INCIVEK or Concomitant Drug

IMMUNOSUPPRESSANTS ketoconazole telaprevir

➞ ➞ ➞

ANTIFUNGALS

Concomitant Drug Class: Drug Name

to be shown to detect early curable cancers to be effective� Detecting late-stage cancers is of no benefit� The test needs extensive clinical trials to demonstrate its sensitivity and specificity and PPV [positive predictive value] for early-stage cancers�” Dr� Winawer added: “I would like to emphasize that a sensitive and specific blood-based marker to identify people who have advanced adenomas and early

➞

Concomitant Drug Class: Drug Name

of the test (Marshall KW et al� Int J Can 2010;126:1177-1186; yip KT et al� J Exp Clin Cancer Res 2010;29:128)� “The problem with the test is that there is considerable overlap between patients with colorectal cancer and controls,” Dr� Winawer said� “In addition, there is no data on the stage of the cancers� We have [been] down this road before with bloodbased markers� A screening test needs

bosentan

Concentrations of bosentan may be increased when co-administered with telaprevir. Caution is warranted and clinical monitoring is recommended.

telaprevir atazanavir

Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.

➞ ➞

telaprevir darunavir

Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir.

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telaprevir fosamprenavir

Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir.

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telaprevir lopinavir

Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir.

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HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs)

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telaprevir efavirenz

Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.

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HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

telaprevir tenofovir

Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities.

tenofovir disoproxil

percent of nonviable conceptuses per litter. These effects are likely associated with testicular toxicity in male but contributions of the female cannot be ruled out. There are, however, no adequate and well-controlled studies in pregnant women. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients—both during treatment and for 6 months after the completion of all treatment. INCIVEK combination treatment should not be started unless a female patient has a negative pregnancy test immediately prior to initiation of treatment. Pregnancy testing should occur monthly during INCIVEK combination treatment and for 6 months after all treatment has ended. Pregnancy testing in non-pregnant female partners is recommended before INCIVEK combination therapy, every month during INCIVEK combination therapy, and for 6 months after ribavirin therapy has ended. Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to two weeks following cessation of INCIVEK. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods prescribing information for ribavirin. Nursing Mothers It is not known whether telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in rat pup body weight gain was similar in offspring from telaprevir-treated and control dams. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment. See also the prescribing information for ribavirin. Pediatric Use The safety, efficacy and pharmacokinetic profile of INCIVEK in pediatric patients have not been established. Geriatric Use Clinical studies of INCIVEK did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of INCIVEK in geriatric patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy. Hepatic Impairment INCIVEK is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) because no pharmacokinetic or safety data are available regarding the use of INCIVEK in HCV-infected patients with moderate or severe hepatic impairment, and appropriate doses have not been established. No dose adjustment of INCIVEK is necessary for patients with mild co-administered with INCIVEK. Renal Impairment No dose adjustment is necessary for INCIVEK in HCV-infected patients with mild, moderate or severe renal impairment. INCIVEK has not been studied in HCV-infected patients with CrCl less than or equal to 50 mL/min. The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750 mg to HCV-negative subjects with severe renal Co-infection The safety and efficacy of INCIVEK have not been established in patients co-infected with HCV/HIV or HCV/HBV. Solid Organ Transplantation The safety and efficacy of INCIVEK have not been established in solid organ transplant patients. OVERDOSAGE The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with INCIVEK alone. In that study, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting. No specific antidote is available for overdose with INCIVEK. Treatment of overdose with INCIVEK consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required. It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

HORMONAL CONTRACEPTIVES/ESTROGEN ➞

ethinyl estradiol norethindrone

Exposure to ethinyl estradiol was decreased when co-administered with telaprevir. Two effective non-hormonal methods of contraception should be used during treatment with telaprevir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.

Manufactured for Vertex Pharmaceuticals Incorporated U.S. Patent No. 7,820,671 ©2011 Vertex Pharmaceuticals Incorporated Pharmaceuticals Incorporated. The brands listed are the registered trademarks of their respective owners and are not trademarks of Vertex Pharmaceuticals Incorporated.

stage cancer would be very desirable� We could then target a small subset of the general population for diagnostic and therapeutic colonoscopy� This could be a very effective strategy to reduce the incidence and mortality of colorectal cancer without the need for screening colonoscopy in the larger general population�” Mr� Goldberg responded to Dr� Winawer comments in an email: “ColonSentry is not a screening test—it has been cleared by the New york State Department of Health to assess the risk for a patient having colon cancer at a particular point in time� It is not a test designed to ‘stage’ cancers� What ColonSentry is designed for is to give primary care physicians a tool [with] which to help assure compliance with regular colonoscopy screening� … By helping to identify those [who] might be [at] greater risk for having the disease, it is hoped that such compliance can be increased, especially in those individuals�” Requiring a small blood sample, ColonSentry can be incorporated readily into annual physical examinations, according to a company press release� “It fits in with the routine work of the clinician,” said Mr� Goldberg� The report that is delivered to the ordering physician is easy to interpret, he noted� “Green is good, red is bad� The higher the risk score, the more potential for having colorectal cancer at that point in time�” The idea of a blood-based test to aid in colorectal cancer detection is not new� For example, Quest Diagnostics already offers ColoVantage (methylated Septin 9), a test based on one gene� Mr� Goldberg distinguished the two tests: According to the Quest Diagnostics Web site, a physician has to submit 10 mL frozen EDTA plasma (5 mL minimum), whereas Enzo’s test, said Mr� Goldberg, requires only a “regular tube of blood� We wanted to make it as seamless as possible for doctors�” He also stated that no competitor’s test “is as comprehensive as seven genes�” Wendy H� Bost, spokesperson for Quest Diagnostics, Madison, N�J�, responded in an email: “We … do not believe the specimen amount is a barrier to adoption of the test�” Referring to the basis of ColoVantage—DNA methylation of the Septin 9 gene—she noted: “This marker has been more rigorously studied than any other gene marker for aiding the detection of colon cancer via blood testing� Several companies are working on or have introduced tests based on it�” Dr. Winawer reported no relevant financial disclosures. Mr. Goldberg and Ms. Bost reported only their stated company affiliations.

Opinion

GastroenteroloGy & endoscopy news • May 2012

Money for Drugs

Part 1 of a 3-Part Series

Should Physicians Be Paid for Pharmaceutical Development and Clinical Investigations? [Editor’s Note: The following article was originally published in Missouri Medicine, September/October 2011;108:321]

yes, Physicians Must Interact YES With Pharma Charles Van Way III, MD Professor of Surgery Sosland/Missouri Endowed Chair of Trauma Services university of Missouri Kansas City, Missouri

The Cause of the Day for many pundits and academics is the terrible wrongness of physicians taking any sort of payment from pharmaceutical companies. Drug companies, otherwise known as Big Pharma, have been demonized by the media, academia and politicians. They make too much money; charge too much; market too aggressively. We’ve all heard the litany of complaints. But, are they really evil? Are we really wrong to interact with them?

If physicians cannot ethically be paid to develop and test new drugs, then who is to carry out this vital work? Nonphysicians? Employees of drug companies? Congress and the media? We are having a national discussion over the propriety of physician relationships with industry. The tone of that discussion is hostile to both physicians and industry. The discussion is being largely conducted within medical journals, which themselves are partly supported by drug company advertising, and reported by news media that also profit from commercial advertising. Two of the most popular books on the subject were written by former editors of a journal that accepts drug advertising, and charges a lot for it.1,2 Should we have different ethical standards for medical journals than we do for individuals? Perhaps so. But that argument is not being made. There is a whiff of hypocrisy about the whole discussion.

It would be well to define some common assumptions. First, physicians can, and should, be paid for their time. The ethical position that physicians should work for nothing may be valid, but it pretty much closes off this discussion. Second, it is unethical for physicians to sell their opinions to the highest bidder. We should not go out and urge other physicians to use a given product simply because we are paid to do so. This is, contrary to what many believe, a complex issue. To begin, is it ethical to work on drug development and clinical investigation? Most of us would say yes. How can it be otherwise? If physicians cannot ethically be paid to develop and test new drugs, then who is to carry out this vital work? Nonphysicians? Employees of the drug companies? Congress and the media? Suppose a physician serves on an advisory panel for, let us say, the development of a new cardiac drug. That involves time and travel, perhaps other expenses. If physicians cannot participate, I ask again: Who is going to do it? It is in society’s interest that the best clinicians advise the companies. Can it seriously be claimed that the companies should develop drugs without input from physician clinicians? Most drug studies are funded by contracts with institutions, although see Money for Drugs, page 49

No, Physicians Must Remain Independent of Pharma NO George Bohigian, MD Professor of Clinical Ophthalmology Department of Ophthalmology and Visual Sciences Washington university St� Louis, Missouri

The new PhRMA Code of the pharmaceutical companies requires speakers to limit their discussion only to what is contained in the drug insert information. Open discussion usually follows. Local physician speakers often are given an honorarium ranging from $500 to $1,000. The American Medical Association Code of Ethics 8.061—“Gifts from Industry to Physicians”—states that honorariums should be reasonable. I believe that “local” speakers, certainly those who are not recognized as experts in their field, should not receive any honorariums or compensation. It is their duty under the oath of Hippocrates “to teach to give knowledge without fee or covenant.” Out-of-town speakers should have their travel expenses covered, but should only receive a small honorarium for educational purposes and not be motivated by profit. Frequently, a grant by a pharmaceutical company is given to a university department, and then the university chooses the appropriate speaker. Despite peer-group discussion and interaction among colleagues, the

presentations certainly can be biased.2 In order to obtain a more unbiased view, it would be preferable to read the literature and attend university and hospital conferences. There has been much written about conflict of interest of physicians, pharmaceutical companies, royalties and medical device companies in the lay literature such as The Wall Street Journal, St. Louis Post-Dispatch and The Kansas City Star.3-5 Movies such as “The Fugitive” and “The Constant Gardener” have highlighted this conflict. It is estimated that $8,000 to $13,000 is spent yearly by the pharmaceutical industry on each physician to promote their products.6

Physicians should not receive even fully disclosed money from drug companies and medical device makers for research, consultation, royalties, lectures or CME efforts. The federal government is establishing rules and regulations to minimize these conflicts requiring listing on the Internet of all monies given to physicians from pharmaceutical companies as a matter of public record. The Department of Health and Human Services published a draft proposal of new rules that relate to financial conflict of interest, which includes disclosure by either the company or the institution. This is part of the Sunshine laws, section 6002, in the new Patient Protection and Affordable Care Act passed by Congress.7 Currently, the public has access to how much a physician in Missouri and other states receives from the top eight pharmaceutical companies in honorariums and compensation by searching the site Pro Publica, an independent nonprofit organization that was awarded the 2010 Pulitzer Prize for investigative reporting.8 Research money by the medical see Money for Drugs, page 50

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Opinion

GastroenteroloGy & endoscopy news • May 2012

Money for Drugs continued from page 44

some are with individual physicians or groups. Does it make an ethical difference whether the money goes directly to a physician or indirectly through the salary from a university? Surely not. Otherwise, anything could be justified by simply laundering the money through some convenient institution. One may argue that certain institutions, like universities and hospitals, have such high ethical standards that it is inconceivable that they are influenced by mere money. One may argue that, but one is unlikely to be believed. Consider a quotation from Dr. Gordon Gee, president of The Ohio State University. Time magazine named Dr. Gee the best college president in the country in 2009, so he must be pretty well up in the profession. Recently, Ohio State football coach Jim Tressel was caught in a particularly flagrant alleged violation of the NCAA rules. When asked whether he would fire the coach, he responded, “No. Are you kidding? I’m just hoping the coach doesn’t dismiss me.”3 Perhaps he was making a

YES

joke. A medical school dean once told me, many years ago, “Charlie, there is no such thing as dirty money.” In short, as much as universities would like to believe otherwise, there is little justification for handing the ethical decision making to them. Perhaps the most troubling facet of this issue is represented by speakers’ bureaus. We all benefit from experts traveling about the country and teaching the rest of us. Most frequently, that teaching is at medical meetings, but it also occurs at universities or in hospitals. Funding comes from a variety of sources. Leading universities fund such activities out of their endowments, but other universities and most hospitals find the money where they can. Frequently, the money comes from the pharmaceutical industry, directly or indirectly. Medical societies receive dues from members, but also grants from drug companies. For some, it may feel good to say that no such money should ever be accepted. But we would be the poorer if these activities were to be curtailed. Indeed, we regard it as virtuous that

physicians seek out continuing medical education, and our licensing agencies even require it. We should realize that some physicians are abusing the system. We have a few colleagues going around the country making hundreds of thousands a year advocating this or that particular treatment. Many others don’t make as much money, but are nevertheless shills for one company or another. Sure, they probably believe in the treatment they are promoting. They may use it themselves. But if you were in their audiences, knowing how much they were paid would influence how much credibility they might be accorded. We need more transparency. Put the information out there, and let everyone see. A number of states, such as Minnesota and Maine, have enacted reporting laws.

Several c o m p a nies, including Pfizer, Merck, Eli Lilly, and GlaxoSmithKline, report their financial transactions with physicians.4 There is also a public database that reports such monies.5 The health care reform law, the Patient Protection and Affordable Care Act, mandates a national database. Specifically, drug and device companies must report all payments to doctors and teaching hospitals. Companies must post the information. The Department of Health and Human Services will also post data, beginning in 2013, and there are serious fines for failure to report.5 see Money for Drugs, page 50

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Opinion

Money for Drugs continued from page 49

Our profession exists YES in symbiosis with the pharmaceutical industry. It is in society’s interest for us to work with drug companies to ensure that they develop the drugs we and our patients need. But we are not their apologists. It is strongly in our interest to see that we and they behave in an ethical manner. If that causes us distress and soul-searching over the next few years, so much the better. Make no mistake. There have been problems, and they are our collective responsibility. We should not tolerate the “bad apples” in our midst. We should assist in efforts to make the process as transparent as possible. Moreover, we should educate policymakers and the public on the complexities of our interaction with those who produce the drugs and devices on which we all

Money for Drugs continued from page 44

industry may be given the researcher but it NO to has been demonstrated that industry-supported research is considerably more biased than grants from the National Institutes of Health.9 It is unethical for a physician to have a financial interest in the company from which he or she is seeking the funding, for example, if he or she has a paid consulting relationship with the company, is a co-founder of the company or otherwise holds equity in the company, and so on. An example of this type of policy can be seen in the Washington

GastroenteroloGy & endoscopy news • May 2012

depend. Let us not be seduced by the arguments of people who are not our friends. We cannot practice medicine without pharmaceuticals. But we can practice medicine just fine without politicians or the media. They are not our friends; nor are they unbiased. They have unquestionably hurt the medical profession over the past two decades. Neither the U.S. Senate nor The New York Times can make drugs or develop new ones. Yet they are generating a demand for an unrealistic ethical purity law, prohibiting all paid constructive contact with drug companies. Their arguments are that physicians are greedy, foolish and easily manipulated by drug companies. But there is neither merit nor reality in that specious assertion. Most physicians are actually fairly hard to manipulate. Ask anyone who has to deal with us. Most physicians are ethical. Greed is a characteristic of politicians far

more than of physicians. The public trusts physicians much more than they trust journalists. To counter these arguments, we can advance the principles of autonomy, individual responsibility and professionalism. These are often brushed aside. Yet it is our professionalism, judgment and responsibility as physicians that make us of value to our patients. Without these, we become simple health care workers, cogs in the machine. There are certainly problems in our relationships with Big Pharma, and we must repair them. But barring all contact would be a poor answer. Ultimately, we serve our patients, and through them, society at large. We owe them our best judgment, and we owe them our professionalism. We will not accomplish either by adhering to a mindless prohibition, as appealing as that may appear to the moralist in all of us. n

University in St. Louis Conflict of Interest Guidelines.10 The physician-researcher should remain independent of the pharmaceutical company sponsoring the project and be able to publish the results both positive and negative in any journal he or she wishes. All information should be transparent and honest with the pharmaceutical companies. Keeping the best interest of the patient in mind should be our guiding principle. We need to keep the trust of our patients and the public sacred. n

2. Roseman M. et al. Reporting of conflicts of interest in meta-analysis of trials of pharmacological treatments JAMA. 2011;305(10):1008-1017.

References 1. Glover T. PM 360, The full spectrum of product management, Jan 2009. www.inventivhealth. com/about_us/downloads/pm360_2009-01.pdf.

3. Gregorian C. Doctors talk about drug firm payments. St. Louis Post-Dispatch, November 28, 2010. www.stltoday.com/lifestyles/health-medfit/fitness/article_ff1fe84a-671b-5ed7-9ae81944bb62e8ef.html. 4. Gregorian C. Database has payment to 17,000 Doctors. St. Louis Post-Dispatch, November 29, 2010. www.stltoday.com/lifestyles/health-medfit/fitness/article_0cd2662c-970e-5311-ad0f61418464cb33.html. 5. Carreyrou J. Top spine surgeons reap royalties, medicare bounty. Wall Street Journal. December 20, 2010. http://online.wsj.com/article/SB100014 24052748703395204576024023361023138.html. 6. Wazana A. Physicians and the pharmaceutical industry: is a gift ever just a gift? JAMA.

References 1. Angell M. The Truth About the Drug Companies: How They Deceive Us and What to Do About It. New York, NY: Random House; 2005. 2. Kassirer J. On the Take: How Medicine’s Complicity with Big Business Can Endanger Your Health. Oxford: Oxford University Press; 2005. 3. Waiting For Next Year (WBNY ). www. waitingfornextyear.com/2011/03/the-geecomment-no-im-not-talkin-alonzo. Accessed March 29, 2011. 4. ProPublica. Dollars for Docs. http://projects. propublica.org/docdollars. Accessed April 3, 2011. 5. Weintraub A. New health law will require industry to disclose payments to physicians. Kaiser Health News. April 26, 2010. www. kaiserhealthnews.org/Stories/2010/April/26/ physician-payment-disclosures.aspx. Accessed April 5, 2011.

Dr. Van Way reported no relevant conflicts of interest.

2000;283(3):373-380. 7. Congressional Record Office of the Legislative Counsel. Patient Protection and Affordable Care Act Section 6002 June 9, 2010 p 624 http://docs. house.gov/energycommerce/ppacacon.pdf. 8. Ornstein, C. What drug companies are paying your doctor. Dec 10, 2010. Pro Publica http:// projects.propublica.org/docdollars. 9. Benkelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003; 289(4):454-465. 10. Washington University Guidelines on Conflict of Interests. http://research.wustl.edu/ComplianceAreas/COI/Pages/COI.aspx.

Dr. Bohigian reported no relevant conflicts of interest.

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When chronic anal fissure strikes, RECTIV treats the pain1,2 The first and only FDA-approved nitroglycerin formulation for the treatment of moderate to severe pain associated with chronic anal fissure RECTIV (nitroglycerin) Ointment 0.4%: s Delivers a significant reduction in moderate to severe pain from chronic anal fissure vs placebo (P=0.038)1,2,* s Produces dose-related headaches, which may be severe. They are typically short in duration, can be treated with an analgesic, and are reversible upon discontinuation of treatment1 s Dosage and Administration: Apply 1 inch of ointment intra-anally every 12 hours for up to 3 weeks

For more information on RECTIV, please visit www.rectiv.com. 7HEN USED ")$ BASED ON ABSOLUTE CHANGE IN HOUR AVERAGE PAIN INTENSITY FROM BASELINE TO BETWEEN DAYS AND AS MEASURED BY A MM VISUAL ANALOG SCALE 6!3 -EAN 6!3 SCORE AT BASELINE WAS MM FOR 2%#4)6 AND MM FOR PLACEBO MEAN 6!3 SCORE BETWEEN DAYS AND WAS MM FOR 2%#4)6 AND MM FOR PLACEBO $IFFERENCE IN MEAN CHANGE IN PAIN SCORE BETWEEN THE GROUPS WAS MM P #) MM MM "ASED ON A HYBRID ANALYSIS OF BASELINE OBSERVATION CARRIED FORWARD LAST OBSERVATION CARRIED FORWARD 2

Indication and Usage s 2%#4)6 NITROGLYCERIN /INTMENT IS INDICATED FOR THE TREATMENT OF MODERATE TO SEVERE PAIN ASSOCIATED WITH CHRONIC ANAL lSSURE Important Safety Information s 2%#4)6 IS CONTRAINDICATED IN PATIENTS TAKING PHOSPHODIESTERASE TYPE 0$% INHIBITORS EG SILDENAlL VARDENAlL AND TADALAlL WHICH CAN POTENTIATE THE HYPOTENSIVE EFFECT OF ORGANIC NITRATES AND IN PATIENTS WITH SEVERE ANEMIA INCREASED INTRACRANIAL PRESSURE OR KNOWN HYPERSENSITIVITY TO NITROGLYCERIN OTHER NITRATES AND NITRITES OR ANY COMPONENTS OF THE OINTMENT s 0ATIENTS WITH CARDIOVASCULAR DISORDERS SHOULD BE CLOSELY MONITORED WHILE USING 2%#4)6 6ENOUS AND ARTERIAL DILATION AS A CONSEQUENCE OF NITROGLYCERIN TREATMENT CAN RESULT IN HYPOTENSION s %XERCISE CAUTION IN PATIENTS WITH ANY OF THE FOLLOWING CONDITIONS BLOOD VOLUME DEPLETION EXISTING HYPOTENSION CARDIOMYOPATHIES CONGESTIVE HEART FAILURE ACUTE MYOCARDIAL INFARCTION OR POOR CARDIAC FUNCTION FOR OTHER REASONS s 4HE ADVERSE REACTIONS OF 2%#4)6 ARE LIKELY TO BE MORE PRONOUNCED IN THE ELDERLY s .ITROGLYCERIN PRODUCES DOSE RELATED HEADACHES WHICH MAY BE SEVERE s 4HE FOLLOWING DRUG INTERACTIONS MAY OCCUR IN PATIENTS TAKING 2%#4)6 0$% INHIBITORS POTENTIATION OF HYPOTENSIVE EFFECTS OF ORGANIC NITRATES CONCOMITANT USE IS CONTRAINDICATED !NTIHYPERTENSIVES POSSIBLE ADDITIVE HYPOTENSIVE EFFECTS !SPIRIN INCREASED NITROGLYCERIN LEVELS 4ISSUE TYPE PLASMINOGEN ACTIVATOR T 0! DECREASED THROMBOLYTIC EFFECT (EPARIN ANTICOAGULANT EFFECT OF HEPARIN MAY BE REDUCED -ONITOR ACTIVATED PARTIAL THROMBOPLASTIN TIME !044 %RGOTAMINE INCREASED BIOAVAILABILITY OF ERGOTAMINE !LCOHOL ADDITIVE VASODILATORY EFFECTS TO NITROGLYCERIN #ONSUMPTION OF ALCOHOL SHOULD BE AVOIDED _ ARE HEADACHE AND DIZZINESS s 4HE MOST COMMON ADVERSE REACTIONS > s 2%#4)6 OINTMENT IS FOR INTRA ANAL USE AND NOT FOR ORAL OPHTHALMIC OR INTRAVAGINAL USE Please see brief summary of US Prescribing Information for RECTIV on the following page. References: 1. 2%#4)6 53 0RESCRIBING )NFORMATION *UNE 2. $ATA ON lLE !PTALIS 0HARMA 53 )NC

Aptalis Pharma US, Inc. 22 Inverness Center Parkway Birmingham, Alabama 35242 USA Tel (800) 472-2634 Fax (205) 991-8426 www.aptalispharma.com

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GastroenteroloGy & endoscopy news • May 2012

Unreported Clinical Trial Data Rampant, lead to Research Bias By george ochoa Clinical drug trials often are hailed as the standard for relevant and reliable information on potential new products. But, according to an editorial published in the January issue of British Medical Journal, the truth is that researchers often fail to report relevant clinical trial data (Lehman R, Loder E. BMJ 2012;344:d8158).

“We are not dealing here with trial design, hidden bias or problems of data analysis—we are talking simply about the absence of the data,” the authors wrote. This behavior, in turn, biases research, wastes health care resources and may harm patients, the editorialists said. “Moreover, researchers or others who deliberately conceal trial results have breached their ethical duty to trial participants,” they wrote. Asked to account for the current burst

RECTIV (nitroglycerin) Ointment 0.4%, for intra-anal use Rx Only Initial U.S. Approval: 1955 Brief summary of Prescribing Information. Please consult package insert for full Prescribing Information. INDICATIONS AND USAGE: RECTIV™ (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure. CONTRAINDICATIONS: PDE5 inhibitor use - Administration of RECTIV is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see DRUG INTERACTIONS]. Severe anemia - RECTIV is contraindicated in patients with severe anemia. Increased intracranial pressure - RECTIV is contraindicated in patients with increased intracranial pressure. Hypersensitivity - RECTIV is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites. Skin reactions consistent with hypersensitivity have been observed with organic nitrates. WARNINGS AND PRECAUTIONS: Cardiovascular disorders - Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly. Headache - RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs. ADVERSE REACTIONS: 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 most common adverse reaction of RECTIV (nitroglycerin) Ointment 0.4% applied to the anal canal is headache. Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment. In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1): Table 1: Incidence of Adverse Reactions (≥ 2%) in Study REC-C-001 RECTIV Placebo N = 123 N = 124 System Organ Class Patients Events Patients Events Preferred term n (%) n n (%) n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0

Hypotension: Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Allergic Reactions: Flushing, allergic reactions and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely. Methemoglobinemia: In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia (see OVERDOSAGE). DRUG INTERACTIONS: PDE5 inhibitors - Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of RECTIV within a few days of PDE5 inhibitors is contraindicated. Antihypertensives - Patients receiving antihypertensive drugs, betaadrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly. Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with RECTIV in patients with angina pectoris, additional hypotensive effects may occur. Aspirin - Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of RECTIV may be enhanced by concomitant administration of aspirin. Tissue-type Plasminogen Activator (t-PA) - Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving RECTIV during t-PA therapy. Heparin - Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and RECTIV concurrently, the anticoagulation status of the patient must be checked. Ergotamine - Oral administration of nitroglycerin

of interest in unreported data, editorial co-author and clinical epidemiology editor of BMJ, Elizabeth Loder, MD, MPH, said, “A critical mass of interested people may have accumulated by now.” In fact, a slew of studies accompanying the editorial in the journal “confirm the fact that a large proportion of evidence from human trials is unreported, and much of what is reported is done so inadequately,” Dr. Loder wrote in the editorial. The studies explore the

markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore the possibility of ergotism in patients receiving RECTIV should be considered. Alcohol - The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol. USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category C - Animal reproduction and teratogenicity studies have not been conducted with RECTIV. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. RECTIV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin. Nursing Mothers - It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RECTIV is administered to a nursing woman. Pediatric Use - The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established. Geriatric Use - Clinical studies of RECTIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting. Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. OVERDOSAGE: Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of RECTIV overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemia: Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required. PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information and Instructions for Use) in the full prescribing information. Interaction with PDE5 inhibitors - Advise patient not to use RECTIV with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of RECTIV and other nitrate drugs. Hypotension - Advise patients that treatment with RECTIV may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly. Headaches - Advise patients that headaches sometimes accompany treatment with RECTIV. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops. Advise patients that if they experience headache they should not alter the schedule of their RECTIV treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches. Dizziness - Advise patients that dizziness has been reported as a side-effect of treatment with RECTIV. Advise patients not to drive or operate machinery immediately after applying RECTIV. Aptalis Pharma US, Inc, 22 Inverness Center Parkway, Birmingham, Alabama 35242 USA, Tel (800) 472-2634, Fax (205) 991-8426, www.aptalispharma.com Revised: June 2011

extent and consequences of leaving out data from clinical trials. In one study, investigators showed that the addition of unpublished data to published meta-analyses of drug trials often changed the results (Hart B et al. BMJ 2012;344:d7202). The study researchers integrated previously unpublished data into existing meta-analyses of nine FDA-approved drugs and showed that the recalibrated trial data produced identical estimates of drug efficacy in three of 41 cases (7%), but 46% greater and 46% lower drug efficacy in the remaining 38 cases (19 for each). The editorialists acknowledged that “it is sometimes assumed that incorporation of missing data will reduce estimates of drug benefits, but this study shows that ‘publication bias’ can cut both ways. Each increment of data can change the overall picture, but in most cases with no certainty that the picture is complete.” Not only is evidence frequently missing from trials, but the requirements for mandatory trial registration and appropriately timed sharing of results also often are not followed properly. Another study found that fewer than half of trials funded by the National Institutes of Health (NIH) are published in a peer-reviewed journal within 30 months of trial completion, and even at 51 months, one-third of results remained unpublished (Ross JS et al. BMJ 2012;344:d7292). Furthermore, in the United States, in 2009, only 22% of drug trials subject to mandatory reporting requirements disclosed their results within the required one year after the trial ended (Prayle et al. BMJ 2012;344:d7373). “So it seems that most trials haven’t reported results, which we think is serious,” said lead author Andrew P. Prayle, BMedSci, BMBS, MRCPCH, clinical research fellow, Child Health, University of Nottingham, in Nottingham, United Kingdom. A recent Cochrane review provided

GastroenteroloGy & endoscopy news • May 2012

“FDA has identified a number of factors that skew the data and impact the percentage of results Prayle [et al] reported,” wrote Ms. El-Hinnawy. As for enforcement, Ms. El-Hinnawy said that FDA has focused on providing information and assistance “to encourage compliance and to ensure an understanding of the responsibilities.” “I can’t speak for FDA as to its enforcement decisions,” said Frederick Stearns, JD, partner, Keller and Heckman LLP, in Washington, D.C., in an interview, “but I suspect that policing the clinical trial

an example of allegedly unreported data ( Jefferson T et al. Cochrane Database Syst Rev 2012;1:CD008965). Attempting to study the anti-influenza antiviral drugs zanamivir (Relenza, GlaxoSmithKline) and oseltamivir (Tamiflu, Genentech USA, Inc., member of the Roche Group), the researchers received cooperation from GlaxoSmithKline, but reported that they were “unable to obtain the full set of clinical study reports or obtain verification of data” from Roche despite five requests between June 2010 and February 2011. By email, lead author Tom Jefferson, MD, an independent epidemiologist in Rome, wrote: “We have come up with tentative conclusions which are at odds with the manufacturers’ statements,” but “[f ]ull testing of all these findings, which may have a profound public health impact, cannot be done in the absence of the complete data set.” Reached for comment, Roche maintained that it does make “detailed clinical trial reports” available and that it “stands behind the robustness and integrity of our data supporting the efficacy and safety of Tamiflu.” The lack of reporting appears to violate the FDA Amendments Act of 2007, and this violation prompted Rep. Henry A. Waxman (D-Calif.) and congressional colleagues to write to the heads of the NIH and the FDA, asking what had happened and why the penalty of $10,000 per day for violating the law had apparently not been enforced. When asked about the letter, the NIH reported that it would respond to the representatives, and FDA spokeswoman Pat El-Hinnawy, said by email that numerous factors must be analyzed to determine whether data are due. For example, she said, there may be a delay if a clinical trial sponsor is seeking approval of a new use of the drug or device.

reporting requirements is a lower-priority issue, given all of the other matters the agency is responsible for.” In addition, he said that the $10,000 per day monetary penalty may seem “unduly harsh for a data submission requirement.” Dr. Loder pointed out, however, that most clinical interventions in use today are based on trials carried out before the era of mandatory registration. “And here the task of data retrieval by systematic reviewers and national advisory bodies becomes impossible,” the editorialists wrote. “Our patients will

have to live with the consequences of these failures for many years to come.” Potential solutions to the problem of underreporting of data have been proposed. Dr. Prayle suggested that “a greater awareness of the reporting requirement will go a long way,” and Dr. Jefferson commented, “Reform and transparency are needed across the board.” Dr. Loder proposed a harsher solution: “Penalties for not reporting trial data need to be enforced,” adding that academic institutions and professional see unreported Data, page 54

GastroenteroloGy & endoscopy news • May 2012

Industry-Sponsored Studies More likely To Generate Positive Results By ted BoSworth San diego—Randomized controlled trials sponsored by a pharmaceutical company for cancer treatments were more likely to generate positive results than trials generated by a public agency, according to a recent analysis.

Trials performed by the two different funding sources tended to have different emphases, which could explain the differences between the two. Two concepts are useful when considering the differences between the results in randomized controlled trials (RCTs). The first is the “equipoise principle” in which investigators cannot predict the

effects of treatments in advance. As a result, based on the fact that the new treatment will sometimes be superior to the standard, sometimes inferior and sometimes comparable, the overall success of discovery of new treatments should be around 50%. The second concept is known as “design bias,” which postulates that trials are undertaken only

if there is high likelihood of detecting therapeutic success in favor of sponsor’s treatment. Speaking at the 2011 annual meeting of the American Society of Hematology, Benjamin Djulbegovic, MD, PhD, reported that the equipoise hypothesis appears to drive the results observed in publicly sponsored trials, whereas the design-bias hypothesis can explain the outcomes obtained in the industrysponsored trials. This conclusion was based on a retrospective analysis of the results of all Phase III studies sponsored by GlaxoSmithKline (GSK) or the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) from 1980 through June 2010. Using three metrics to assess treatment success in clinical trials, Dr. Djulbegovic, of the Center for Evidence-Based Medicine and Health Outcomes Research, University of South Florida and H. Lee Moffitt Cancer Center & Research Institute in Tampa, and colleagues found that new treatments are favored over standard treatments in industry-sponsored trials in comparison with trials funded by the public funder for each metric used.

unreported Data continued from page 53

organizations need to be involved, and researchers doing meta-analyses need to look beyond published trials. Sir Iain Chalmers, MBBS, MSc, DSc, editor, James Lind Library, James Lind Initiative, in Oxford, United Kingdom, also took a tough stance. Sir Chalmers wrote by email: “Inform the public about the scandal of biased underreporting of research. Require all studies to which human volunteers have contributed be reported, if necessary by requiring this

GastroenteroloGy & endoscopy news • May 2012

‘The differences in the results clearly point to differences in research agendas between publicly versus industry-

placebo as a comparator, as well as differences in mix between the proportion of explanatory and pragmatic trials in industry versus publicly sponsored trials. Pragmatic trials are rarely done by industry and the effect sizes are expected to be larger in explanatory trials, which can explain the differences in the results. Overall, Dr. Djulbegovic concluded, “the differences in the results clearly point to differences in research agendas

between publicly versus industry-sponsored trials.” Asked to comment on these results, Smita Bhatia, MD, director of outcomes research at City of Hope in Duarte, Calif., called this a “a well-conducted study” that generated “intriguing findings,” but she considers the conclusions to be preliminary and awaits a study with a larger scope. “While the findings provide food for thought, they need to be confirmed in

future studies that include representation by more than one pharmaceutical company, unlike the current study that relied on data from only one,” Dr. Bhatia said. The findings may be useful when considering differences between industry- and public-funded studies. n Dr. Djulbegovic has received research funding from Millennium. Dr. Bhatia reported no relevant conflicts of interest.

sponsored trials.’ —Benjamin Djulbegovic, MD, PhD

Of the 40 trials funded by industry (19,889 patients) and the 77 trials funded by NCIC CTG (33,260 patients), 42% of the industry-sponsored studies and 25% (P=0.04) of the public sector–sponsored studies showed a statistically significant superiority of experimental treatment over the control arm for the primary end point. Investigators themselves concluded that new treatments were superior to standard treatments in 80% of GSK versus 44% of NCIC CTG trials (relative risk, 1.81; P<0.001). Pooled quantitative analysis for the primary outcome indicated higher success rate in GSK trials (odds ratio [OR], 0.61; 99% confidence interval [CI], 0.47-0.78] vs. OR, 0.86; CI, 0.74-1.00; P=0.003). However, testing for the effect of treatment over time indicated that treatment success has become similar in the last decade. In addition to equipoise versus design bias as the main explanation of the results, a number of other explanations are possible. They include a possibility that the results can be explained by the larger proportion of industrysponsored trials relying on the use of

in law.” This, he said, was important “because patients suffer avoidably as a result of incomplete, biased evidence.” Looking to the future, the editorialists wrote, “Retrospective disclosure of full individual participant data would be an important first step toward better understanding of the benefits and harms of many kinds of treatment.” “The optimal systematic review would have complete information about every trial—the full protocol, final study report, raw data set, and any journal publications and regulatory submissions,” n they concluded.

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Opinion

GastroenteroloGy & endoscopy news • May 2012

National Honor Society Mark Fleisher, MD Gastroenterologist The Borland-Groover Clinic Jacksonville, Florida

Good things can happen. In fact, more good things happen than bad things. Now it is true that bad things tend to get all the attention in the press, but rest assured, good will always triumph over evil. It may just take a while. You have to be patient. And you have to try to make good things happen. Why, just in our little world of medicine, good things have happened. In the old days, ghost writers under the cloak of darkness would write most of the journal articles. Gurus would affix their names to the article and like a Chia Pet on steroids, curricula vitae and resumes would blossom. Those days are numbered. Authors are writers and writers must come out, come out wherever they are. See—good triumphed. The other day I was flown down to Miami for a speaker training meeting by a drug company. Let’s deconstruct this scenario. What exactly is a speaker training meeting? It is when a company gets some of the finest physicians in our nation together in one room. Sometimes an invitation gets mislabeled and I’m invited. So you have a bunch of physicians, mostly from academic settings, meeting to be taught how to speak. Now my mother would always lament things she wished she had said but didn’t. Her scenes usually took place at a wedding and involved someone named Connie or Dottie or Yetta. I, on the other hand, have repetitively hamstrung my career and relationships secondary to things I should not have said. Speaker training is just what I need! Or so I thought… So, all these gurus are in a room and we’re shown a promotional slide deck on inflammatory bowel disease (IBD) and the company’s biologic drug. Yikes! Not an educational deck, mind you—a promotional deck. Then the drug company asked for our input. Not that it matters. I have never seen a promotional slide deck altered because of our input. These slide decks are made by a marketing team and a legal team, and maybe a physician or two. However, the speaker is just that—a speaker. We are told not to deviate from the promotional deck. We are told that we will be compensated so much for in-town talks and so much more for out-of-town talks. As if our integrity can be remunerated and prorated. In essence, we spent our entire careers trying to answer to a higher calling only to sell out for a few dollars. We are instructed not to say

what we think. If we do, we might get shot by a pharma-hired sniper lurking in the kitchen. More likely, the drug rep will have a heart attack and drop dead in his ahi tuna appetizer. Sounds like good is not triumphing, does it. How about this setting? No more promotional slide decks. If you want me to teach my colleagues, I’d love to. Set up the meeting, fly me out, put me up in a hotel and pay me a stipend.

Then leave us alone: just me and my colleagues and my own slide deck. If you think I’m such a guru, let me impart my wisdom. I am a healer and a teacher, not a speaker and a marionette. I have spent my career trying to help people. Let me help my colleagues help my fellow Americans. I am not here to help you sell your drug. I am here to be Socrates going over the new drug line and not Willie Loman selling the

new dress line. Now I know that many will cry out and proclaim their honor despite the honorarium. However, the day a promotional deck contains information about all the medications available for our patients with, let’s say IBD—the day a slide deck talks about Remicade and Cimzia and Humira and Tysabri—that is the day I have kept my word to our sons, Max and Samuel. It is all about character.

Opinion

GastroenteroloGy & endoscopy news • May 2012

How about this setting? No more promotional slide decks. If you want me to teach my colleagues, I’d love to. Set up the meeting, fly me out, put me up in a hotel and pay me a stipend. Then leave us alone—just me and my colleagues and my own slide deck. The other night I had the pleasure to go to Max’s National Honor Society ceremony near my home in Jacksonville. Many years ago I was inducted at South Shore High School in Brooklyn, N.Y. Gosh, have I forgotten? I am just starting

to remember the tenets: service, scholarship, leadership and character. Our son volunteered to speak about his favorite: character. He gave many clear examples of a nebulous concept. He spoke about doing the right thing when no one is

watching. That one hit home. Samuel, sitting next to me, nodded imperceptibly and smiled at me. Just the other day a teacher told us how Samuel tutors others. And without an honorarium! Just doing the right thing when no one was watching would suffice. Once again, my two local thought leaders led me from darkness into enlightenment. It is when you are flown in from out of town and say what you think—not what you are paid to say—that shows character. This is a quality a speaker either has or does not. It does not come with

speaker training in a hotel ballroom in Miami. Maybe if speakers prepare their own talks, our audiences will believe and respect us. So you think I’m naive? The drug companies will never go for it? Perhaps. But maybe, just maybe, if enough of us say “enough is enough,” then that will be enough. Maybe if the physicians refuse to attend canned promotional talks, the public will remember that we represent our nation’s Honor Society. Maybe physicians can take back control of their profession by acting professionally. Good can triumph. Let’s do it! n

GastroenteroloGy & endoscopy news • May 2012

CMS continued from page 1

But, in a move that will prove more significant in the long term, CMS has adopted new quality measures for ASCs. The quality reporting system will be integrated over the next two years and will affect payments beginning in 2014. ASCs that fail to successfully report the quality measures will face a 2% reduction in facility fee reimbursement in 2014. Representatives of the Ambulatory Surgical Center Association (ASCA), a national organization that represents these centers and advocates on their behalf, said its members welcome the changes even though the new policy will increase the data collection and paperwork for centers. “Overall, we’re very pleased that CMS put a national quality reporting program in place, and it’s gratifying to see that CMS, in its proposed and final rule, adopted most of the quality measures proposed by [a coalition of affected societies, including the ASCA and other specialty societies],” said David Shapiro, MD, a Florida-based anesthesiologist and president of ASCA. However, the CMS proposals are somewhat “complex,” requiring ASCs to report data through three different sites. The national association representing the centers has asked CMS to simplify the reporting process in the future. “We would like to minimize the burden on ASCs because most are small businesses,” said Dr. Shapiro. The quality reporting program will eventually require centers to provide data on eight measures that CMS has deemed important for patient outcomes. Right now, CMS has not established how the method for payment penalties to centers that do not report will be calculated. A proposal is expected in the next year. Data collection for five quality measures will start on Oct. 1, 2012, and will affect

2014 payment determinations. These measures include patient burns; patient falls; wrong site, side, patient, procedure and impact; hospital transfer/admission and prophylactic IV antibiotic timing. This first set of measures will be reported through claims-based mechanisms. Over the next two years, CMS will add three additional measures, including use of a safe surgery checklist, ASC facility volume data for selected procedures and a National Healthcare Safety Network infection control measure that calls for influenza vaccination coverage among health care personnel. ASCs will need to report their use of a safe surgery checklist during 2012 via a CMS Web-based tool that will be available between July 1, 2013, and Aug. 15, 2013. Additionally, ASCs will need to report their 2012 all-patient volume data for some procedure codes using the same tool during the same period. CMS has not specified a specific surgery checklist. The American Gastroenterological Association (AGA) created a basic template that can be used by ASCs providing gastroenterology services. The American Society for Gastrointestinal Endoscopy (ASGE), the Association of Perioperative Registered Nurses, the World Health Organization and SafeSurgery.org also have suitable checklists. A measure for vaccination coverage is still being finalized and will affect payments for 2016, with data collection beginning in October 2014. In other changes, federal regulations that restricted ASCs from hosting operations on the same day that physicians and patients scheduled the procedures were lifted in December. This allows providers performing services in ASCs to provide same-day services that patients could alternatively receive in the hospital outpatient department. The CMS also is finalizing its proposed policy to make data that an ASC

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has submitted for the quality reporting program available on a CMS Web site after providing an ASC an opportunity to preview the data to be made public. The changes will have an important effect on physicians working at these centers, particularly gastroenterologists, general surgeons and anesthesiologists and who perform surgical and endoscopic procedures. The AGA, along with the ASGE and the American College of Gastroenterology, will be sponsoring free webinars on the upcoming Medicare quality reporting over the course of the year as CMS releases additional program details. The AGA suggests that ASCs designate a quality point person or physician champion, review the measure specifications and develop a process for recording occurrences and track them at quality meetings. Only six new procedures were added to the ASC list of covered surgical procedures for 2012, although 232 procedure codes were reviewed. The new procedures are primarily vascular and include transcatheter therapy, transcatheter placement of intravascular stents and vessel mapping for hemodialysis access. Dr. Shapiro said physicians who work at ASCs would like to see more procedures added to the list and want CMS to increase the transparency of the selection process for procedures. “The current system is a bit of a black box,” he said. “They [CMS] are not mandated to tell us what exclusionary criteria they use. We’re often put in a position that we can no longer do things in an ASC when a patient turns 65 even though they’re

Many commonly performed procedures will have an estimated modest increase in aggregate Medicare payments under the revised ASC payment system, including 5% for colorectal screening and 4% for diagnostic colonoscopy and lesion removal colonoscopy. commonly done at ASCs for younger patients.” The changes to 2012 reimbursement rates for endoscopic and surgical procedures performed at ASCs is mixed. Overall, surgical specialists who treat the digestive system are expected to receive a 4% increase in payments under the revised payment system, according to a summary statement prepared by the AGA and Hart Health Strategies, a bipartisan consulting and lobbying firm specializing in legislative and regulatory health care issues. Many commonly performed procedures will have an estimated modest increase in aggregate Medicare payments under the revised ASC payment system, including 5% for colorectal screening and 4% for diagnostic colonoscopy and lesion removal colonoscopy. There is also an estimated 1% decrease in aggregated payment for upper gastrointestinal endoscopy performed for diagnosis or biopsy. Approximately 5,000 ASCs in the United States participate in Medicare. n

Opinion

GastroenteroloGy & endoscopy news • May 2012

The Medical Arms Race Jon C. White, MD Chief of Surgical Services, VAMC Professor of Surgery George Washington university Washington, DC

The term “mad” has always had numerous uses, but during the 1960s Cold War, it became popular as an acronym—MAD—shorthand for “mutually assured destruction.” It referred

to the bizarre logic of the nuclear arms race, whereby the United States and the Soviet Union kept building up their nuclear arsenals to equal and then exceed the opposition, presumably as a deterrent to aggression. Eventually, the size of the arms buildups reached a point at which either country could destroy the other many times over. This policy was truly deserving of its ominous yet descriptive acronym.

Today, there is a similar situation in medicine that has appropriately been named “the medical arms race,” whereby competing hospitals or medical systems try to purchase the most up-to-date equipment and technology, which then can be used as a marketing ploy to compete for patients. Insurers do not question the provision of these services but pass along the added expense to their customers. Many of these technologies

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need only be available in a single center in a local catchment area, but the rules of competition dictate that everyone who wants to be competitive must offer all of them. The result is to duplicate unnecessary equipment, which is purchased and now requires use. As the expression goes, “when you have a hammer, everything starts to look like a nail.” Potential health care consumers are constantly barraged with advertising hype about the best hospitals in the area, which usually highlight their advanced technologies that start with catchy words such as “robotic,” “laser” or “cyber.” When is the last time you heard an advertisement on television or the radio claiming that a medical center provides the least expensive or most appropriate care in the area? This sales approach is in sharp contrast to other industries that always advertise the lowest price for automobiles, computers, airfares, or any product or service they are selling. Consequently, the cost of medical care is higher in communities where there is a lot of competition between providers than in communities that have little to no competition. This surprising finding runs contrary to long-held theories of capitalism, which postulate that competition should drive down the prices of services. This aberration in health care economics can be explained by the medical arms race, which is more intensely practiced in medically competitive communities. Hospitals or medical centers that are not

Opinion

GastroenteroloGy & endoscopy news • May 2012

Today, there is a situation in medicine that has appropriately been named ‘the medical arms race,’ whereby competing hospitals or medical systems try to purchase the most up-to-date equipment and technology, which then can be used as a marketing ploy to compete for patients.

competing for their share of the market have a lower need to provide boutique services or unneeded cutting-edge technology to attract patients. They can apply themselves to providing the most costeffective and appropriate care. The medical arms race, which is as wrong-headed and financially destructive as its nuclear forerunner, is one reason that we find ourselves in the difficult financial situation we face today. There are other reasons, however, including a dysfunctional tort system, a failure to audit and control Medicare and Medicaid expenditures and an inability to control expenditures for futile care, especially in the terminal stages of life. All of these are difficult problems, but they can be fixed. Another popular concept from the Cold War era, the “Nash Equilibrium,” is useful to consider in this context. This game theory concept, first suggested by John Forbes Nash, holds that in most standoffs neither side gains by changing its behavior unilaterally, and therefore nobody changes. During the Cold War, neither the United States nor the Soviet Union would disarm unilaterally because each country feared that the loss of equilibrium would be at its own expense. You might compare this standoff to situations occurring in medicine today. A huge increase in diagnostic studies is one problem that contributes to our rapidly increasing medical expenses. Doctors

cannot be cost-conscious in their use of diagnostics because of the medical-legal consequences of not ordering the most sophisticated, and usually most expensive, diagnostic procedures. This situation should be addressed by appropriate tort reform. Lawyers, however, will not allow changes in the medical-legal system, which has been very profitable for them. Neither side will act unilaterally. Another example is the sustainable growth rate (SGR) formula, which was developed to curb unsustainable inflation. Physicians, noting that their income

will decrease with the application of the SGR formula, have been successful in temporarily blocking it for years and are trying to get it repealed. Lawmakers who see the tremendous inflation in medical expenses do not want to abandon the SGR formula, which they see as the best way to rein in expenses. Every two to six months, the issue is painfully revisited to the detriment of both parties involved. The eventual thawing of the Cold War was achieved by a progressive deescalation of the irrational arms buildups through a series of acts such as the

Nuclear Test Ban Treaty (1963), the Nuclear Non-Proliferation Treaty (1970), the Helsinki Accords (1975), the Strategic Arms Limitation Treaties I and II (1972 and 1979) and the Strategic Arms Reduction Treaties I and II (1991 and 1993). This negotiated drawdown led to restructuring (perestroika) and openness (glasnost) in the Soviet Union, which culminated in opening that country’s borders to the West. On the other side of the world, things changed as well. The North see Medical Arms Race, page 62

Opinion

GastroenteroloGy & endoscopy news • May 2012

Medical Arms Race continued from page 61

American Aerospace Defense Command (NORAD), the American–Canadian entity, which was built to detect and respond to intercontinental ballistic missiles, has been retooled in a swordsto-plowshares strategy. According to its Web site, the organization is now tracking mainly domestic flights. Recently, one of the highest-level alerts was for a small Cessna that had flown too close to the U.S. Capitol building.

The field of medicine needs the same kind of negotiated disarmament. First, physicians and lawyers have to discuss tort reform. Doctors should accept that malpractice does exist and sometimes the victims should be compensated. On the other hand, judgments should be reviewed and adjudicated by experts. In the case that payment is appropriate, it should go to the victim. The lawyers should not be the main beneficiaries of the system but should work on an hourly basis and not for a percentage of the award. They should not work on

contingency, and frivolous suits should be discouraged by appropriate penalties. Additionally, there should be regulations to limit unnecessary diagnostics. For example, the U.S. Preventive Services Task Force (part of the Department of Health and Human Services) has studied and advises against screening colonoscopies after 75 years of age, for prostate cancer after 75, and for cervical cancer after 65. In all these cases the risks outweigh the benefits, yet Medicare and Medicaid pay for all procedures even when the recipients are outside of these recommended age limits.

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Medicare and Medicaid also pay for implantable cardiac defibrillators, cardiac stents and certain vertebral procedures (such as vertebroplasty and kyphoplasty) for patients to whom these procedures provide no benefit and are sometimes harmful. In fact, it has been estimated that Medicare spends from 15% to 30% of its budget on contraindicated procedures, which translates roughly into $75 billion to $150 billion annually (nytimes.com/2011/05/26/ opinion). Patients and their doctors insist on these procedures and the purchasers of health insurance and the taxpayers are saddled with the bill. Endof-life decisions also are a political hot potato that nobody wants to handle. A significant portion of our health care resources is poured into the last days or weeks of life, often when it is known that the efforts are futile. All these issues call for a negotiated de-escalation and should be on the table. In each situation described, there are some people who want to continue business as usual and to receive every kind of medical device, advanced technology, diagnostic procedure or end-of-life measure that is available, despite evidence that it will not be helpful. I think this is fine: People should be allowed to make choices about what treatment they wish to receive, but if the efficacy of the treatment they demand is not supported by clinical evidence, they should purchase it at their own expense. The medical insurance industry (and their customers) or the taxpayers should not be obligated to pay for ineffective, futile or harmful care. Taking on these very emotional issues will require the political will and courage of our profession, the legal industry and lawmakers. In the 1960s, when our country was brought to the brink by the Cuban Missile crisis, the need for negotiation became clear. I think we are on the brink again, this time with health care financing; and it is time again for us to roll up our sleeves and start on the road to détente. When I was in school in the 1950s and 1960s, we practiced what to do in case of a nuclear war. We were taught to crouch under our desks, put our heads between our legs and so forth. Some enterprising families in our neighborhood were digging bomb shelters and stocking them with nonperishable food. In contrast, today’s students are being told what clothes to pack when they travel to Moscow and Beijing on school trips. Basements, these days, are for game rooms stocked with flatscreen TVs, XBox consoles and snacks. It seems the negotiated de-escalation of the nuclear arms race has been successful. I hope that in medicine, we can follow this example. Maybe if we learn to n negotiate, we won’t be so mad.

GastroenteroloGy & endoscopy news • May 2012

Health Officials Seeking More Secure Mobile Devices By george ochoa Mobile devices, from smartphones to tablet computers, are increasingly used in hospitals and other health care settings� But regulators fear that manufacturers have not taken adequate steps to safeguard privacy and security with the technology� To help seal those gaps, the Department of Health and Human Services (HHS) has launched the Privacy & Security Mobile Device project� The initiative will be managed by the Office of the National Coordinator for Health Information Technology’s (ONC) Office of the Chief Privacy Officer and the HHS Office for Civil Rights� The project also will work to develop case studies to help communicate to health care providers how to secure and protect health information when using mobile devices� An example of a provider use case scenario is the health care provider who is at home and on call, using a laptop to read a patient’s electronic medical record� “The rationale behind this specific project is that the use of mobile devices in health care has skyrocketed in the last year,” said Joy Pritts, JD, chief privacy officer for ONC, in an interview� “The concern is that health information is some of the most sensitive information that there is�” Information at risk includes

financial as well as medical records� Medical identity theft can lead to fraudulently obtaining health care services in other people’s names, Ms� Pritts said� “People lose trust with health care providers when they learn their information is less than secure,” Ms� Pritts said� The goal of the project, she said, is to “educate people about practical ways to protect data�” HHS hosted a public roundtable on

March 16, live and by webcast, to gather information from different stakeholders, Ms� Pritts said� The project is not the government’s first foray into health care–related mobile devices� Last July, the FDA issued draft guidance defining a small subset of mobile medical applications that may affect the performance or function of currently regulated medical devices, and therefore require agency oversight�

Get recognized for promoting Quality and Safety in your endoscopy unit

“In order to foster innovation and protect patients, the FDA must provide clarity to manufacturers and application developers of how we plan to oversee this product area in a very narrow and focused way,” Bakul Patel, MSEE, MBA, an FDA policy adviser, said in an email interview� The agency is still reviewing public comments on the draft guidance, but Mr� Patel said officials hoped to finalize the rule this year�

ASGE Endoscopy Unit Recognition Program ASGE’s Endoscopy Unit Recognition Program honors endoscopy units committed to the highest standards of quality and safety. It is the only national program recognizing quality and safety in the practice of endoscopy. > Gain recognition among healthcare professionals, public and private regulatory bodies, and patients as a unit dedicated to quality care > Prepare to meet the changing expectation of public and private regulatory bodies > Promote improvement and create uniformity in your practice > Other marketing tools for promoting your recognition Certain eligibility criteria apply, including completion of the ASGE Quality Course, “Improving Quality and Safety in your Endoscopy Unit,” by a representative of your unit within one year of program application. In 2012, ASGE will offer the course as follows: • March 9 – Scottsdale, AZ • July 14 – Dallas/Ft. Worth, TX • September 13 – Washington, DC Receive the ASGE Certiﬁcate of Recognition to proudly display in your endoscopy unit’s ofﬁce

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

Questions, comments, suggestions? Contact the Editor 212�957�5300 x277 cgordon@mcmahonmed�com IF ENDOSCOPY IS YOUR PRACTICE, ASGE IS YOUR PARTNER

FDA Update & Product News

GastroenteroloGy & endoscopy news • May 2012

FDA Approves New Surgical Device To Treat GERD LINX Provides Option for Patients With Suboptimal Response to Acid Suppression Therapy

On March 22, the FDA approved the LINX Reflux Management System for individuals with chronic gastroesophageal reflux disease (GERD) who continue to experience symptoms despite medical therapy� LINX is a small, flexible band of interlinked titanium beads with magnetic cores that is placed laparoscopically around the esophageal sphincter� Magnetic attraction between the beads is intended to help the sphincter resist opening to gastric pressure, thereby preventing reflux� Higher pressures from swallowing can overcome the magnetic forces, permitting food and liquid to pass into the stomach� Once the food passes though the lower esophageal sphincter, LINX returns to its resting state� The device is manufactured by Torax Medical, Inc� “The LINX Reflux Management System is a sterile, single-use, surgically placed device used to treat the symptoms associated with GERD,” said Christy Foreman, director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health� “LINX offers an option to patients and their health care providers and is an alternative to current surgical procedures�” In January, the FDA’s Gastroenterology and urology Devices Advisory Panel voted unanimously in favor of approval of LINX� The advisory panel affirmed LINX’s efficacy, safety and risk–benefit ratio in treating pathologic GERD, as defined by abnormal pH testing in patients with chronic GERD symptoms despite long-term anti-reflux therapy� In the pivotal clinical trial presented at the advisory panel meeting, 100 patients with GERD symptoms, despite medical therapy, were implanted with the LINX Reflux Management System� The primary effectiveness end point was reduction in total distal esophageal acid exposure time, as assessed by esophageal pH testing at baseline and 12 months� Treatment was deemed successful if, at 12 months, either pH was normalized or the total time that pH was less than 4�0 was reduced by 50% from baseline� Among the 100 patients in the pivotal clinical trial, there was a 64% success rate� “The evidence for safety and effectiveness present in the clinical trial were quite good over the period of study,” said panel member Steven D� Schwaitzberg, MD,

associate professor of surgery, Harvard Medical School, and chief of surgery, Cambridge Health Alliance, Cambridge, Mass� In the advisory panel meeting, the FDA noted that the study was limited by the lack of a control arm and the lack of blinding� Additionally, 76 patients experienced adverse events, dysphagia being the most common and pain the second most common� Five patients had the device explanted� Amy Derosier, vice president of clinical affairs of Torax Medical, said the company considered including comparative GERD therapies (medical therapy, Nissen fundoplication) in the pivotal trial, but these were rejected as unsuitable� Additionally, she said, objective evidence, through pH testing, reduced the need for blinding in this study� “No single measure defines treatment success for reflux disease,” Ms� Derosier added� “The totality of the clinical results … was sufficient for the FDA advisory panel to provide a unanimous vote regarding the questions of efficacy, safety and net benefit–risk ratio�” In clinical trials, the most common adverse events experienced with LINX included difficulty swallowing, pain when swallowing food, chest pain, vomiting and nausea� Importantly, patients implanted with the LINX device cannot undergo magnetic resonance imaging procedures; the magnetic The lINX Reflux Management System is a small, flexible beads interfere with the machine and can band of interlinked titanium beads with magnetic cores that cause the device to be damaged and the is placed laparoscopically around the esophageal sphincter to control symptoms of gastroesophageal reflux disease. patient to be injured� As a condition of approval, Torax Medical will institute a required training program to educate fundoplication in terms of simplicity, yet at the same time new users on patient selection, device implantation and should be placed by surgeons who have a distinct longpostprocedural care of patients treated with LINX� Dr� standing and committed interest in the management of Schwaitzberg emphasized the role that surgeons will play GERD,” he said� Dr. Schwaitzberg reported no relevant in the implementation of the device� financial disclosures. “[LINX] will have some advantages over Nissen

Illustration presented at the Gastroenterology and urology Medical Devices Panel Meeting, Jan� 11, Gaithersburg, Md�; available at www�fda�gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/ MedicalDevicesAdvisoryCommittee/Gastroenterology-urologyDevicesPanel/uCM287512�pdf�

By george ochoa

Hecoria, a Generic Tacrolimus for Transplant Recipients, Now Available by Brand Name Now available in u�S� pharmacies, Hecoria is the first generic tacrolimus that can be prescribed by its brand name, according to its distributor, Novartis Pharmaceuticals� An AB-rated generic therapeutic bioequivalent to Prograf (tacrolimus capsules), Hecoria is an immunosuppressant approved for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants� As a branded generic, Hecoria offers a cost savings while presenting an option for physicians who want their patients to receive the same brand of tacrolimus

at every refill, said Novartis� Available in 0�5-, 1- and 5-mg capsules, Hecoria has its brand name printed on the capsule� “Hecoria complements our extensive portfolio of transplant immunosuppressant medications, and underscores our ongoing commitment to delivering a broad range of treatment options to our customers and their patients,” said usman Azam, MD, head of u�S� Medical & Drug Regulatory Affairs, Novartis Pharmaceuticals, East Hanover, N�J�, in a statement� The FDA approval of Hecoria was

based on comparative, randomized, single-dose, two-way crossover, bioavailability studies of tacrolimus and Prograf 5-mg capsules in healthy volunteers following a standard meal and under fasting conditions� Results demonstrated that tacrolimus and Prograf capsules are bioequivalent under fed and fasting conditions� According to Novartis, health plans will generally reimburse patients for Hecoria as an AB-rated generic and generally will make the medication available to patients at a generic price� Through

its Patient Assistance Program, Novartis is offering the same level of financial support for Hecoria as for other branded Novartis products� More information about the Novartis Patient Assistance Program is available at www�patientassistancenow�com� For more information about Hecoria, including potential adverse events and drug–drug interactions, see the full prescribing information, available at www� hecoria�com� —Based on a press release from Novartis

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FDA Update & Product News

GastroenteroloGy & endoscopy news • May 2012

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Boston Scientific Introduces WallFlex Biliary Transhepatic Stent System Biliary RX Fully Covered Stent and the WallFlex Biliary Transhepatic Fully Covered Stent System are CE-marked for the treatment of benign biliary strictures� However, the safety and effectiveness of the WallFlex Biliary RX Stent System and the WallFlex Biliary Transhepatic Stent System for use in the vascular system have not been established� For more information on the WallFlex System, visit the Boston Scientific Endoscopy Channel at www�youtube�com/bostonscientificendo�

Applying Recent Evidence in Hereditary Angioedema: Optimizing Individual Care MN1111 expires October 1, 2012

—Based on a press release from Boston Scientific

SPECIAL FEATURES

Photo courtesy of Boston Scientific

Boston Scientific Corporation recently launched the WallFlex Biliary Transhepatic Stent System in the united States and internationally for use in the palliative treatment of biliary strictures from malignant tumors� The WallFlex System is available in fully, partially and uncovered versions in multiple sizes to accommodate different anatomic and clinical requirements� The covered stents come with a silicone polymer Permalume coating to reduce the potential for tumor or tissue ingrowth, as well as an integrated retrieval loop for endoscopic removal or repositioning during the initial procedure in patients that may have an endoscopic retrograde cholangiopancreatography performed� The WallFlex Biliary RX Stents and the WallFlex Biliary Transhepatic Stents are CE-marked and have received FDA clearance for the palliative treatment of malignant biliary strictures� Additionally, the WallFlex

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GastroenteroloGy & endoscopy news • May 2012

FDA Clears Genii gi 4000 Generator for Sale Genii, Inc., has received 510(k) clearance from the FDA to market its new gi 4000 electrosurgery generator. This generator introduces Genii’s patented compact argon technology and is the first truly standardizable generator ever offered to the flexible endoscopy market. Joshua Colton, MD, medical director for Genii and a practicing gastroenterologist in Minnesota, said, “This generator represents a revolution in

ease of use while at the same time provides the power to perform even the most complex procedures. It brings the graphical interface into this century—it will do for GI electrosurgery what Apple did for cell phones and personal computers.” Genii, a privately held Minnesota corporation, launched its first unique product, the TouchSoft Coagulator® in May 2011. Sales have been increasing rapidly since, and the

introduction of the flagship gi 4000 will position the company to become a leader in the industry. “Our tagline, ‘generating ingenuity,’ really says what our mission is about,” said Genii CEO Marcia Morris. “As the first company ever to be equally expert in both electrosurgery AND endoscopy, we understand the increasing pressure on our customers to be able to do more with less. We are harnessing ingenuity to rethink problems and

deliver real solutions.” Gi 4000 generators are in production and ready for sale. Contact customerservice@genii-gi.com for more information, or to place an order. More information about gi 4000 generators is available at www.geniigi.com.

Senators Press for Unique Identifiers for Medical Devices Four u�S� senators have introduced legislation to require unique numerical identifiers for medical devices, so that the devices can be tracked through the distribution chain and once they are used with patients� The legislation, the Ensuring Safe Medical Devices for Patients Act (S� 2193), would require the FDA to issue a final unique Device Identifier (uDI) rule by the end of 2012� The FDA Amendments Act of 2007 authorized the uDI system, but it has yet to be implemented� The new bill would require implementation of the uDI system no later than one year after issuance of final regulations� The bill, introduced on March 15, also would add medical devices to the Sentinel postmarketing surveillance initiative, launched in 2008 to create a national, integrated, electronic system to monitor the safety of FDA-approved drugs� Medical devices would have to be monitored in a comparable manner, with priority given to class II and III devices that are implantable, life-supporting or life-sustaining, or pose significant risk to users� The bipartisan legislation was introduced by Sen� Jeff Merkley (D-OR), Chuck Grassley (R-IA), Michael Bennet (D-CO) and Herb Kohl (D-WI)� “Strong postmarketing surveillance of medical devices will ensure that those that are defective or cause harm can be quickly identified, patients and their physicians can be notified, and dangerous products can be removed from the market,” Sen� Merkley said in a statement�

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

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

Bottles of 120 capsules Bottles of 4 capsules

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

—Based on a press release from Sen. Merkley and the text of the bill

GM 08/22-1

Salix Pharmaceuticals, Inc. Raleigh, NC 27615 MANUFACTURED FOR:

L A S R A E H N: O E I S R S Y MI R R E E H N: V R N O I E E S S I E H SE YOUR MTAIN ISSIO IN REM A M UC

Maintain ulcerative colitis (UC) remission with once-daily APRISO so your adult patients can experience what they love, for longer* Proven to maintain remission in 2 clinical trials for up to 6 months1 INTELLICOR» delayed- and extended-release delivery initiates at pH ≥6, providing coverage throughout the colon1,2 1.5-g once-daily dose (4 capsules) can be taken with or without meals1 The most common adverse reactions (incidence ≥3% and >placebo) are headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, influenza and influenza-like illness, and sinusitis1

APRISO is the fastest-growing once-daily 5-ASA in the United States2 APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. *The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials. References: 1. APRISO [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 2. Data on ﬁle. Salix Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information, including Important Safety Information. Please see full Prescribing Information available at AprisoRx.com. APRISO™ and INTELLICOR™ are trademarks of Salix Pharmaceuticals, Inc. ©2012 Salix Pharmaceuticals, Inc. All rights reserved. GM 11/45-2