Journal of Managed Care Medicine Volume 17, Number 1

Page 1

Vol. 17, No. 1, 2014

Educating Medical Directors of Employers, Health Plans and Provider Systems

FEATURED ARTICLES INCLUDE: How Behavioral Health Drives Health Care Costs: Managing ER Utilization GBEMTI Perspectives:Impact of Accountable Care Organization Models on Biopharmaceuticals and Specialty Products Epidemiology and Economic Burden of Conjunctivitis: A Managed Care Perspective


A significant achievement for patients with fecal incontinence (FI)...

A good day.

It’s no accident. Solesta: a unique treatment for FI • An injectable, biocompatible gel • Nonsurgical, in-office procedure • No anesthesia required • May preclude need for more invasive surgical procedures

Find out more at solestainfo.com. Indication Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg. diet, fiber therapy, anti-motility medications).

Number of episodes/14 days

Durable efficacy with Solesta 25

P=0.001

n=136

20 15

53%

15.0

10

8.6

5

6.2

7.0

7.0

12

24

36

0

Baseline

3

Months

Important Safety Information about SOLESTA SOLESTA® (hyaluronic acid/dextranomer) is contraindicated in patients with active inflammatory bowel disease, immunodeficiency disorders or ongoing immunosuppressive therapy, previous radiation treatment to the pelvic area, significant mucosal or full thickness rectal prolapse, active anorectal conditions (including abscess, fissures, sepsis, bleeding, proctitis, or other infections), anorectal atresia, tumors, or malformation, rectocele, rectal varices, presence of existing implant (other than SOLESTA) in anorectal region, or allergy to hyaluronic acid-based products. SOLESTA must not be injected intravascularly as injection of SOLESTA into blood vessels may cause vascular occlusion. Injection in the midline of the anterior wall of the rectum should be avoided in men with an enlarged prostate. SOLESTA should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program on the SOLESTA injection procedure. The most common adverse reactions with SOLESTA (incidence >4%) in the clinical study were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. Please see brief summary of full Prescribing Information on following page. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is a registered trademark of Galderma S.A. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. SOL 13/121


T:6.875”

Safety Data

Brief Summary

Please consult Package Insert for full prescribing information.

Indication for Use

Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (e.g., diet, fiber therapy, anti-motility medications).

Contraindications

Solesta is contraindicated in patients with the following conditions: • Active inflammatory bowel disease • Immunodeficiency disorders or ongoing immunosuppressive therapy • Previous radiation treatment to the pelvic area • Significant mucosal or full thickness rectal prolapse • Active anorectal conditions including: abscess, fissures, sepsis, bleeding, proctitis, or other infections • Anorectal atresia, tumors, stenosis or malformation • Rectocele • Rectal varices • Presence of existing implant (other than Solesta) in anorectal region • Allergy to hyaluronic acid based products

Warnings

• Do not inject Solesta intravascularly. Injection of Solesta into blood vessels may cause vascular occlusion. • Injection in the midline of the anterior wall of the rectum should be avoided in men with enlarged prostate.

Precautions

SLTA13CDNY0608_Solesta_BS_6.875x9.875_r3.indd 1

The primary safety data set includes data from 206 patients treated with either Solesta or Sham in the Pivotal study. The data show that a total of 232 treatment-related adverse events for either Solesta or Sham were reported up to 18 months after treatment. Three (3) adverse events assessed as related to Solesta, or 1.3% of the treatment-related adverse events, were deemed serious by the investigators. These three (3) serious adverse events occurred in three (3) patients, including one case of an E. coli bacteremia, and two (2) cases of rectal abscesses (one event per patient). All of these serious adverse events resolved following treatment without any sequelae within approximately 30 days of treatment. Overall, 96% of the 203 Solesta treatment-related adverse events in the Pivotal study were of mild to moderate intensity and 97% of the events required no intervention or required medical or simple non-invasive interventions, including application of local pressure, silicone ointment, water irrigation and warm baths. Seven (7) events required more invasive procedures including: perianal drainage of abscesses (4 events), one (1) case of rubber band ligation of an anal prolapse, one (1) case of lancing of a hemorrhoid, and one (1) case of a Kenalog injection in a pre-existing anal scar. The most frequent adverse events following Solesta treatment pertained to post-treatment proctalgia, minor anal or rectal bleeding, post-treatment fever, abdominal complaints (such as diarrhea and constipation), and events potentially related to peri-operative infection.

Patient Counseling Information

The patient should be advised that Solesta treatment is not effective for all patients with fecal incontinence and that repeat treatment might be required for treatment effect. It should also be made clear to the patient that the available clinical study data are not sufficient to predict in whom Solesta treatment will be effective. The patient should be informed about post-treatment care and potential adverse events. The patient should also be made aware that the implants might be detected during future anorectal examinations and radiographic imaging of the pelvis. Patients should be instructed to inform all future treating physicians about the presence of Solesta gel. If there should be a need for future surgery (e.g., hemorrhoidectomy) the Solesta implant can be resected.

Directions for Use

Solesta should be administered by qualified physicians with experience in the treatment of anorectal conditions and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. Solesta should only be used after a thorough physical evaluation of the patient to exclude treatable underlying disorders. Please consult Package Insert for full directions for use and method of administration.

Post-treatment care

1. The patient should be instructed to avoid taking hot baths during the first 24 hours post-treatment. 2. The patient should be informed of the risk of infections and bleeding. 3. The patient should be instructed to contact the clinic or physician’s office immediately if symptoms of rectal bleeding, bloody diarrhea, fever, tenesmus or problems with urinating occur. 4. Anti-diarrheal drugs should not be used for one week after treatment. 5. Stool softeners may be used until the first defecation occurs. 6. Analgesics other than Non-steroidal Anti-inflammatory Drugs (NSAIDs) may be prescribed, if needed. 7. The patient should be instructed to: – Avoid physical activity for 24 hours – Avoid sexual intercourse and strenuous physical activity for one week (e.g., horse back riding, bicycling and jogging, etc.) – Avoid anal manipulation for one month (e.g., insertion of suppositories or enemas and rectal temperature recording)

Re-treatment procedure

1. If the patient does not have an adequate response to Solesta after the first injection, a re-injection with a maximum of 4 mL Solesta can be performed, no sooner than 4 weeks after the first injection. 2. The re-treatment procedure and all pretreatment preparations are performed the same way as the initial treatment procedure. All pretreatment preparations and injection procedures should be performed as described in “Methods of Administration” above. However, the point of injection should be made in between the initial injections, shifted one-eighth of a turn (e.g., left posterolateral, left anterolateral, right anterolateral, and right posterolateral).

How Supplied

Solesta is supplied in a glass syringe with a standard Luer-lock fitting containing 1 mL gel. Each syringe is terminally moist heat sterilized in a pouch. Four pouches, each containing one syringe are packed in a carton together with five Sterican needles (21G x 4¾ inches, 0.80 mm x 120 mm), patient record labels and a package insert. The needles are sterilized by ethylene oxide.

Storage

Store at a temperature up to 25°C (77°F) and protect from sunlight and freezing. To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is registered trademark of Galderma S.A.

©2013 Salix Pharmaceuticals, Inc. All rights reserved. Printed in the USA. SOL-RALAB18-102013

11/19/13 12:14 PM

T:9.875”

General precautions • Solesta should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. • The safety and effectiveness of Solesta have not been investigated in patients with complete external sphincter disruption or significant chronic anorectal pain. • The safety and effectiveness of Solesta have not been investigated in patients with previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with rubber band within 3 months, anorectal implants and previous injection therapy, Stapled Transanal Rectal Resection (STARR) or stapled hemorrhoidectomy. • The safety and effectiveness of Solesta have not been studied in patients under the age of 18 years. • The safety and effectiveness of Solesta have not been studied in pregnant or breastfeeding women. • The durability of Solesta has not been studied past 12 months. • The safety and effectiveness of Solesta have been studied in patients who received one or two treatments. In the Pivotal study, the majority of patients received two treatments, four weeks apart. Patient related precautions • Patients with bleeding diathesis or patients using anticoagulant or antiplatelet agents, as with any injections, may experience increased bleeding at injection sites. • Patients should be counseled that a repeated Solesta injection procedure may be required to achieve a satisfactory level of improvement in incontinence. Procedure related precautions • Adequate bowel preparation of the rectum using enema is required prior to injection. The enema should be given immediately prior to the procedure to ensure evacuation of the anorectum. It is recommended that additional cleansing of the injection area with an antiseptic be performed prior to injection. Use of prophylactic antibiotics is recommended. • Solesta should be injected slowly to avoid undue stress on the Luer-lock connection which could cause leakage of the gel. • After injection of Solesta, hold the needle at the injection site for an additional 15-30 seconds to minimize leakage of Solesta. • Injections too close to the dentate line or too deep in the tissue might cause excessive pain. • Injection should be stopped if excessive bleeding or pain occurs. • One sterile needle should be used per syringe and injection. Device related precautions • The use of needles other than those supplied may impede injection of Solesta due to the properties of the gel and may cause device malfunction. • Solesta is supplied ready to use in a prefilled syringe with a Luer-lock fitting. Carefully examine the unit to verify that neither the contents nor the package has been damaged in shipment. Do not use if damaged. • Solesta is supplied sterile and is intended for single use only. Do not re-sterilize, as this may damage or alter the product. • In the event of accidental contamination of a needle, discard the needle. • Never mix Solesta with other products. • Solesta is to be stored at up to 25°C (77°F), and used prior to the expiration date printed on the label. Do not expose Solesta to either sunlight or freezing, as this may damage or alter the product. • Care should be taken when handling the glass syringes and disposing of broken glass to avoid laceration or other injury. • After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements. Adverse Events Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal fissure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back pain, constipation, C-reactive protein increased, chills, cold sweat, defecation urgency, dermatitis, diarrhea, device dislocation, dizziness, dyspareunia, escherichia bacteremia, fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal pain, genital discharge, genital prolapse, hematochezia, hematospermia, hemorrhoids, infection, injection site abscess, injection site discomfort, injection site hemorrhage, injection site hematoma, injection site inflammation, injection site irritation, injection site nodule, injection site pain, injection site pustule, injection site swelling, injection site ulcer, intestinal mass, malaise, mucosal inflammation, musculoskeletal pain, perineal abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, proctitis, pyrexia, rectal abscess, rectal discharge, rectal hemorrhage, rectal lesion, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum abscess, urinary retention, vaginal discharge, vulvovaginal pain. The adverse event profile of Solesta beyond 18 months is not known, but is under investigation in post-market studies.

The safety evaluation of Solesta in the treatment of fecal incontinence (FI) is based on the results from the Pivotal clinical study, and is supported by the Open-Label multicenter clinical study and one single site Proof-of-Concept study. The analysis of safety was based on the safety cohort of all 206 patients treated in the Pivotal study with either Solesta or Sham. Safety data for Solesta are available from 359 treatments in 197 total patients followed for up to 18 months post treatment (i.e., 136 subjects from the blinded phase and 61 subjects from the open phase).


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Journal of Managed Care Medicine The Official Journal of the

National Association of Managed Care Physicians

American Association of Integrated HealthCare Delivery Systems American College of Managed Care Medicine

American Association of Managed Care Nurses A Peer-Reviewed Publication

Vol. 17, No. 1, 2014

TABLE OF CONTENTS How Behavioral Health Drives Health Care Costs: Managing ER Utilization Mark Rosenberg, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 A Case-Based Approach for Overactive Bladder to Evaluate and Implement Successful Treatment Strategies Pamela Ellsworth, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Changing Paradigms in MS Therapies John R. Corboy, MD, FAAN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Best Practices in the Diagnosis and Treatment of Inflammatory Bowel Disease Mark Lazarev, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Customizing Therapeutic Strategies to Optimize Outcomes in the Management of Advanced NSCLC Jonathan Goldman, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Recent Advances in Melanoma Therapy Adil Daud, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Implementing Guideline-Based Strategies to Improve Adherence in Asthma Patients Robert Sussman, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Improving Patient Outcomes with Effective Treatment Strategies in the Management of Type 2 Diabetes Mellitus Timothy S. Reid, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Improving the Management of Severe Hemophilia Mark T. Reding, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 New Treatment Paradigms in the Management of Metastatic Breast Cancer Sara A. Hurvitz, MD, FACP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Optimizing the Treatment and Management Strategies of Pulmonary Arterial Hypertension Yon K. Sung, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Improving Treatment Strategies in the Management of Castrate-Resistant Prostate Cancer Maha Hussain, MD, FACP, FASCO. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 GBEMTI Perspectives – Impact of Accountable Care Organization Models on Biopharmaceuticals and Specialty Products Eric Faulkner, Joshua Ransom, Jeffery Taylor, RPh, MS, Geneva Briggs PharmD, BCPS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Epidemiology and Economic Burden of Conjunctivitis: A Managed Care Perspective John E. Schneider, PhD, Cara M. Scheibling, Darron Segall, MHS,Robert Sambursky, MD, Robert L. Ohsfeldt, PhD, Laura Lovejoy, MA . . . . . . . . . . . . . . . . 78

www.namcp.org | Vol. 17, No. 1 | Journal of Managed Care Medicine 4


Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross

Sarath Gunatilake, MD, DrPH Professor, Health Science Department California State University, Long Beach

Philip Painter, MD Chief Medical Officer Humana

Devena Alston-Johnson, MD Medical Director CIGNA

John W. Heryer, MD, FACS Medical Director Blue Cross Blue Shield of Kansas City

E. Paul Amundson, MD Chief Medical Officer Dakotacare

Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University

Mary H. Pak, MD Medical Director Unity Health Plans Insurance Corporation

Linda Ash-Jackson, MD Medical Director Hometown Health Paul Bluestein, MD Chief Medical Officer Connecticare

Larry L. Hsu, MD Medical Director Blue Cross Blue Shield of Hawaii (HMSA)

Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions, Inc. Carlos Ramirez, MD Chief Medical Officer Valley Baptist Health Plans

Richard Bock, MD, MBA Chief Medical Officer Molina Health Care of California

Stephen Keir, DrPH Co-Director, Center for Quality of Life Support Care Research Robert Preston Tisch Brain Tumor Center

Paul Rein, DO Medical Director Port Warwick Ambulatory Surgery Center

Anthony Bonagura, MD Chief Medical Officer Aetna, Inc.

John Knispel, MD, CPE, FACOG Regional Medical Officer Humana

Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc.

Philip M. Bonaparte, MD Chief Medical Officer Horizon NJ Health

Karen Knowles, MD Internal Medicine Physician HCA/Emcare

Mark R. Rosenberg, MD, PhD President/CEO Behavioral Health Management

Salil V. Deshpande, MD Market Medical Officer United Healthcare

Catherine Marino, MD Chief Medical Officer MagnaCare

Joseph Schappert, MD Chief Medical Officer PAML

Jeff Martin, PharmD Clinical Account Director Innoviant, Inc.

Christine M. Seals, MD Medical Director Umpqua Health Alliance

Monte Masten, MD, MBA, MPH Senior Consultant, Health & Group Benefits Towers Watson

Jacque J. Sokolov, MD Chairman SSB Solutions

Michael Fine, MD Medical Director Health Net John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint

Wesley Mizutani, MD Talbert Medical Group

Ronald Y. Fujimoto, DO, FAAFP Chief Medical Officer United Healthcare

Ray Mummery, MD, CMCE Chief Medical Officer Dimension Health

Howard Garber, MD, MPH Medical Director Johns Hopkins Health Care Uwe G. Goehlert, MD, MSC, MPH, MBA Principle Goehlert & Associates Steven E. Goldberg, MD, MBA Vice President of Medical Affairs Coventry Health Care of Kentucky Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer MMM Healthcare, Inc./PMC Medicare Choice Puerto Rico

Thomas Morrow, MD Genentech

Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare Tim Newman, MD Medical Director FirstEnergy Denis O’Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans

Scott Spradlin, DO, FACPF, ACOI Vice President Medical Affairs/Chief Medical Officer Group Health Plan William D. Strampel, DO, FACOI Dean, College of Osteopathic Medicine Michigan State University Prentiss Taylor, MD Corporate Medical Director Advocate At Work at Advocate Health Care Pamella Thomas, MD,MPH, FACOEM Consulting Medical Director Wellness Health & Productivity Strategies Robert A. Ziff, MD, MBA, FACS, CPE East Central Region Medical Director, Senior Products Humana

Gary Owens, MD Principle Gary Owens Associates

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 5


Managing ER Utilization: How Behavioral Health Drives Health Care Costs Mark Rosenberg, MD, PhD

Introduction

Emergency room utilization management has risen to the forefront of health care concerns in terms of severity and importance. Emergency room visits are among the most costly method of care and contribute greatly to the rising costs of health care. Some of the issues contributing to these costs include long wait times, overcrowded emergency rooms, and the use of the emergency rooms in lieu of primary care. Long wait times negatively impact patient and employee satisfaction and increase the likelihood of patients leaving without being seen. Overcrowding increases health care costs through longer lengths of stay and increased negligence claims. However, the use of an emergency room visit as a primary care visit alternative is one of the greatest factors driving up the cost of health care today. One of the primary drivers of emergency room costs is treating patients with a behavioral health and physical health comorbidity. Treating behavioral health within the traditional emergency room setting requires more resources, more time, more expertise, and longer bed usage. Also, additional processes are required, such as a psychiatric evaluation and the additional time needed to reach out to the behavioral health provider and/or family. Perhaps, even more importantly, there is increased potential for patient safety issues (both to the patient and those in close proximity). All of these issues contribute to the rising costs of health care. Managing behavioral health patients in the emergency center setting can reduce health care costs, reduce emergency wait times, and solve the problem of overcrowding. Statistics

• The National Association of State Mental Health Program Directors (NASMHPD) estimated that states have cut $3.4 billion in mental health funding since FY 2009, while the demand for services has increased during this time period by 56 percent and the demand for emergency room, state hospital, and emergency psychiatric care has climbed 18 percent.1 • According to a 2010 survey by the Schumacher Group, more than 70 percent of emergency department administrators said that they have kept patients

waiting in the ER for 24 hours and 10 percent said that they “boarded” some patients for a week or more. Boarding patients – keeping them in the ER after they have been admitted to the hospital because no inpatient beds are available – places a large economic burden on communities. For example, in Texas, the average cost per day of community-based services is $12 for adults and $13 for children, as compared to $401 for a state hospital bed and $986 for an emergency room visit.2 • According to the North Carolina Hospital Association (NCHA), from 2008 to 2010, emergency room visits by mental health and substance abuse patients increased by 38 percent, compared with an overall 6 percent increase in ER trips. According to the same study, the average stay for behavioral health patients has increased 65 percent since 2010, to almost 16 hours per patient per stay.3 • In 2007, according to United States Agency for Healthcare Research and Quality, there were 12 million visits to the emergency department for behavioral health conditions.4 Broad Areas for Potential Solutions

There are three main areas in which solutions may be implemented to reduce costs for behavioral health treatment in the emergency room: Input, Throughput, and Output (Exhibit 1). We will now examine these areas and potential solutions to mitigating the overutilization of emergency services. Potential Solutions

There are many issues surrounding the treatment of mental health patients in an emergency setting and there are just as many, if not more, potential solutions. Following is a list of some of the more prevalent solutions that may assist in overcoming the obstacles and barriers currently in existence. Action Plan

Create an action plan between the patient and the behavioral health provider. Emergencies are likely to occur with behavioral health patients. Creating an action plan before the fact may help to reduce emergency room visits. The action plan is a document which provides instructions to the patient in the event his condition escalates. It spells out who

6 Journal of Managed Care Medicine | Vol. 17, No. 1 | www.namcp.org


Exhibit 1: Three Main Areas Where Cost-Reducing Solutions Could Prove Beneficial

Input (the community)

Throughput (emergency room)

Output (rest of hospital)

• The flow of patients to the emergency room is one of the most difficult aspects to control.

• Throughput refers to emergency department processes that impact patient flow.

• Output refers to the ability of the emergency department to dischange patients either for inpatient admission or for follow-up care in the community.

to contact, how to contact, and when to contact. It establishes a contact list of family members, friends, behavioral health providers/counselors, local crisis centers, and, as a last alternative, the emergency department. After an emergency has passed, the action plan is reviewed and tweaked to make the process even smoother next time. Community- Based Clinics

Many community-based clinics are specially licensed, certified and staffed for the substance use disorder population. Community organizations are equipped to manage the medical and psychological aspects for this patient base and also have the specific licensure to run programs both as a dedicated outpatient facility, or in a hospital- based facility. Community clinics deliver the medical home equivalent that keeps chronic disease and substance use disorder patients out of the emergency room and into the most appropriate medical service environment – reducing unnecessary hospitalization, adjusting length of stay to appropriate and effective parameters, and improving quality indicators and data outcomes. Crisis Stabilization Unit

A Crisis Stabilization Unit (CSU) is an emergency mental health resource. It allows patients to receive prompt action, gentle response and effective support in a respectful environment. These facilities are open 24 hours a day, seven days a week and are staffed with a multi-disciplinary team of RNs, LPNs, social workers, psychologists, mental health professionals and a psychiatrist to provide assessment and evaluation to best determine an appropriate level of care for individuals with mental illness, mental retardation, and/or substance abuse issues. Team members evaluate and stabilize the crisis, and make referrals to the most appropriate level of care. Psychiatric consulta-

tion and medication are available when necessary. Education

Education for all involved parties is essential in decreasing unnecessary emergency room utilization and should include efforts on the part of the payers, providers, patients, and community. From the payer side, there can be specific guidelines as to the appropriate and inappropriate use of the emergency room. Appropriate use might be such things as a suicide attempt, the inability to function because of confusion, a new or recent onset of hallucinations, and extreme anxiety. Examples of inappropriate use might include the refill of medications, the patient doesn’t have a place to stay, the patient can’t sleep, or other non-life-threatening reasons. These stipulations should be spelled out plainly in the insurance information and reviewed with the insured, as well as with any contracted organizations which provide Utilization Management or authorization services so that all parties know what is and is not appropriate in terms of emergency room admissions. From the patient perspective, education should be a joint effort on the part of the primary care provider, behavioral health specialist, and any other health plan or party involved. Patients who may be high risk for emergency room utilization, such as those with a behavioral/physical comorbidity or a chronic condition, should be specifically focused on for educational initiatives. Care Management, Case Management, and Integrated Care can be extremely helpful as part of this initiative. Education should allow the patient to be appropriately informed of what constitutes a crisis and what does not, where they can receive after hours or emergency assistance outside of the emergency room, and why it benefits them from a care perspective to receive treatment in a more appropriate setting. Those with chronic con-

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ditions, or comorbidities, can also benefit from coordinated care follow-ups which can mitigate the occurrence of their condition becoming unmanageable, and thereby requiring emergency treatment. These follow-ups can include monitoring of medication adherence, verification of attendance at regularly scheduled appointment (with either a primary care physician, or behavioral health specialist) and assistance with other issues that may be impacting care (such as transportation and housing). For primary care and behavioral health providers, an effort should be made to route patients to the most appropriate treatment facility and options should be provided to people outside of the emergency room for after-hours care and urgent situations. For the most part, primary care and behavioral health practitioners emphasize the emergency room as a treatment option by relaying messages to patients (online and via phone recording) that tell patients to either call 911 or go directly to the emergency room. Additionally, many primary care physicians send their patients to the emergency room if they don’t have the capacity to treat them, either because of scheduling or availability. Often times this patient could be more effectively treated in another way, such as via an urgent care center or through another primary care provider. Educating primary care as to the many community resources and/or having a live clinical person to speak with could make a difference between routing large numbers of patients to the emergency room, or referring them to a more cost efficient and more treatment appropriate alternative. Communication

Communication should occur between the hospital and both primary and behavioral care providers as part of overall case management, and as a means of working toward total care integration. Both behavioral health providers and primary care providers should be made aware that their patient has presented to the emergency room and should be notified once treatment has begun, the patient has been admitted, the patient has been discharged, or the patient has been transferred to a more appropriate facility. Hospitals that are starting to institute these processes are experiencing positive results. More widespread adaptation of these communicative measures can continue to decrease unnecessary emergency room utilization. Relationships should be formed amongst health care providers. Referral networks should be established to help reduce the number of behavioral health patients who are treated in the emergency room, and education should be emphasized. Many patients would receive better care through mobile

crisis units, psychiatric emergency facilities, and behavioral health clinics. These patients require a different skill set than most emergency rooms are able to offer, but there is currently a gap in referrals. This trend is changing, but the change is slow and there are great strides to be made in this area which can be accomplished by education and communication. ER Throughput Process

The throughput process is the efficiency by which a patient flows through the emergency department. A throughput review should be conducted including triage, appropriate staffing levels, and the availability of community- and hospital-based behavioral health resources. Having psychiatric staff in the emergency department who are licensed to perform consults will greatly assist in the patient flow. Many times the mental health patients are kept in the emergency room for extended periods of time, which slows the process down considerably and occupies valuable bed space. Other processes should be reviewed for efficiency such as when a patient is escorted to the emergency room by the police – either with or without a mental health warrant. The flow of these patients tends to be particularly slow and causes bottlenecks to occur. The sooner a consult can be completed, the sooner the patient can be moved to an inpatient or psychiatric unit, as appropriate. Additionally, the emergency room can use mobile crisis units to assess and begin treatment in an expedient fashion. Emergency departments should thoroughly analyze this process from beginning to end to discover inefficiencies in care, and establish process efficiencies. Benchmarks for treatment times should be established, and protocols should be put in place to route or re-route patients to avoid costly delays. Fast Track Triage

Hospitals, such as Spartanburg Regional Medical Center, have instituted fast track triage to specialty areas beyond the traditional trauma center. Some of these specialty areas include: major care, chest pain, women’s, pediatric, urgent care, disaster preparedness, and behavioral health. These fast track mechanisms allow for quick triage and the appropriate care to begin in an expedient manner, based upon level of acuity and whether the patient is behavioral and/or medical. For example, placing behavioral health patients in a designated area is vital to patient, staff, and other visitor safety. The behavioral area provides almost a safe haven. Access to behavioral health professionals, an appropriate level of compassion, and a heavily monitored area are some of the advantages to behavioral health fast tracking. Triage that emphasizes appropriate patient flow allows staff to be trained effectively

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to deal with specialty cases, and those patients or services that is prone to over utilization can be dealt with more effectively and in a more cost-efficient manner. Conclusion

The cost of health care is rising astronomically. There are many measures that have been put in place to help reduce these costs such as Healthcare Reform. A high portion of the costs are attributed either directly or indirectly to the utilization management of the emergency room and specifically the treatment of behavioral health patients. Many emergency rooms are either not staffed with mental health professionals or the processes that are in place are targeted to treating medical conditions primarily. This causes overcrowding, long wait times, and more importantly, the inability to properly diagnose and treat mental health patients in particular. Currently, the emergency rooms are doing a disservice to this population. Many hospitals are beginning to look at their processes and patient flow to find better, more economical ways to treat patients. This epidemic requires additional communication and education to all who are or could be involved in the patient’s care. Some of the players include: the patient and the patient’s support system, the hospitals, the emergency room, primary care, behavioral health providers, and com-

munity resources, just to name a few. Health care costs are the responsibility of everyone, not just the emergency room; however, by effectively examining the issue as a whole, change can be made. Mark Rosenberg, MD, PhD is President of BHM Healthcare Solutions and serves as Director of the NAMCP Behavioral Health Institute.

Acknowledgements:

Thank you to the members of the Behavioral Health Institute for their discussion and input on this article.

References

1. (National Association of State Mental Health Program Directors) National Association of State Mental Health Program Directors. n.d. 13 June 2013. www.nasmhpd.org/index.aspx. 2. (The Schumacher Group) The Schumacher Group. Emergency Department Challenges and Trends: 2010 Survey of Hosptial Emergeny Department Administrators. Lafayette, Jan 2010. electronic pdf survey. 13 June 2013. www. acep.org/uploadedFiles/ACEP/newsroom/NewsMediaResources/StatisticsData/schu2010surveyPDF.pdf 3. (North Carolina Hospital Association) North Carolina Hospital Association. "North Carolina Hospital Association Behavioral Health Emergency Department Utilization Quarterly Report." Quarterly Report. North Carolina Hospital Association, 2012. 2013. www.ncha.org/doc/455. 4. Owens, Pamela L., Ryan Mutter and Carol Stocks. "Healthcare Cost and Utilization Project: Statistical Brief #92." Brief. Agency for Healthcare Reserach and Quality, 2010. Electronic Document. 2013. www.hcup-us.ahrq.gov/ reports/statbriefs/sb92.pdf

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A Case-Based Approach for Overactive Bladder to Evaluate and Implement Successful Treatment Strategies Pamela Ellsworth, MD

Summary Overactive bladder (OAB) is a symptom complex that has a significant impact on the quality of life for those affected. Clinicians need to assess for bladder issues and educate patients on the available treatment options. Effective treatments are available that range from behavioral interventions to surgical implantation of neurostimulators. Key Points • OAB affects more than 33 million individuals in the U.S. • Urgency, frequency, and urgency urinary incontinence are the hallmark symptoms. • First-line therapy is behavioral intervention. • Second- line therapy is pharmacotherapy. • Third-line therapies include neurostimulation and bladder injections. • Effective treatment will likely require a combination of approaches.

OAB is not a disease. It is a symptom complex of urgency, frequency, and urgency urinary incontinence (UUI). Urgency is the sudden compelling desire to void that is difficult to defer. Frequency is defined as eight or more micturitions in 24 hours. Patients may also complain of nocturia. The typical patient with OAB has a long journey before being appropriately diagnosed and treated. Symptoms of an overactive bladder are highly prevalent in the general population; more than 33 million individuals have symptoms of OAB, with more than half of these women with UUI (Exhibit 1).1-3 Many people wait long periods after symptom onset to seek treatment; more than half wait over one year (mean = 3.1 years). While UUI is the primary reason for seeking help, many still do not consult about their OAB symptoms with a health care provider. In surveys, less than half of patients with probable

overactive bladder discussed the symptoms with a health care provider. When a conversation is initiated, patients are usually the ones initiating. Health care providers do not typically screen for bladder issues. Physicians often do not ask because they are too busy, they have so many more things to screen for, they don’t understand the impact, it is not lifethreatening, and they assume the patient will bring it up if bothered.4,5 In one study, at the time of analysis, a small proportion of patients with symptoms of OAB were prescribed medication and an even smaller proportion was currently on treatment (Exhibit 1). OAB is much more than just the symptoms. It causes skin infections, depression, urinary tract infections, and falls. Additionally, it has significant impact on quality of life (Exhibit 2).6,7 There are now guidelines for identifying and

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Exhibit 1: OAB is Prevalent, Underdiagnosed, and Undertreated1-3

OAB Prevalence 33.3 MM

Presenting Patients 15.2 MM

Diagnosed Patients 6.5 MM

Treated Patients 3 MM

managing OAB developed by The American Urological Association/Society of Urodynamics and Female Urology (AUA/SUFU).8 Other disorders that could be the cause of the patient’s symptoms should be excluded. The initial evaluation should include a focused history, a focused physical examination (including abdominal, pelvic, and neurologic), a urinalysis, and an assessment of the degree of bother to the patient. The urinalysis is to rule out hematuria, infection, and glucose in the urine. If patients are having symptoms but are not especially bothered or inconvenienced by these symptoms, treatment may not be necessary. Bladder diaries and a post-void residual (PVR) are additional aids in making the diagnosis. The bladder diary is helpful in tracking symptoms and voiding patterns. Normal voiding habits are considered six to seven trips to the bathroom daily. Eight or more trips may indicate an overactive bladder. A PVR is not necessary if the person is being treated with

first-line behavioral interventions or is uncomplicated. A PVR would be necessary if there is a history of obstructive symptoms, history of incontinence or prostatic surgery, neurologic disease and in men with obstructive symptoms prior to starting antimuscarinic therapy.8 Urodynamics or cystoscopy are not indicated in the initial evaluation of an uncomplicated patient. Red flags for further evaluation include frequent UTIs, sensation of incomplete emptying, straining to void, significant pelvic organ prolapse, prior pelvic surgery or radiation therapy, hematuria and neurologic conditions that may affect bladder function. Additional studies are not indicated in the patient case. Management of OAB is multifaceted (Exhibit 3). Patients have to be educated regarding normal bladder function. They may have a goal of only voiding three times per day, but this is not realistic. Getting to a more normal voiding pattern (less than eight

Case Study: Sally is a 53-year-old seeing her physician for an annual visit. She is excited but worried about her son’s upcoming wedding. She states, “What happens if I have the urge to go during the ceremony? I don’t want to have to wear a diaper, and I just can’t control my bladder.” She asks, “Can you fix me before my son’s wedding in two months?” Past Medical History: hypertension, hypercholesterolemia Medications: diuretic, beta-blocker, cholesterol lowering agent Review of Systems: urinary frequency 12 to 14 times per day, urgency urinary incontinence 2 to 3 times per day, bowels regular, no frequent UTIs Physical Exam: normal Lab Evaluation: urinalysis – normal.

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Exhibit 2: Impact of Overactive Bladder on Quality of Life6,7

Physical • Limitations or cessation of physical activities Sexual • Avoidance of sexual contact and intimacy

Psychological • Guilt/depression • Loss of self-esteem • Fear of -Being a burden -Lack of bladder control -Urine odor

Quality of Life Social • Reduction in social interaction • Limit and plan travel around toilet accessibility

Occupational • Absence from work • Decreased productivity

Domestic • Require specialized underwear, bedding • Special precautions with clothing

times daily) is the ultimate goal of treatment. Patients need to understand that OAB is not cured, it is managed. Patient goals are often task oriented instead of number oriented (i.e., watch a movie without interruption). Various forms of behavioral modification can be helpful in the management of OAB and are first-line treatments. Useful strategies for behavioral modification include patient education, timed or delayed voiding, and positive reinforcement of any changes made. Pelvic floor exercises have been found useful for women, primarily those with concomitant stress urinary incontinence. Additionally, learning to tighten the correct muscles can suppress an involuntary bladder contraction which can be used to reduce the incidence of UUI. Dietary changes such as avoiding spicy foods, citrus fruits and juices, tomato-based foods, alcohol and drinks with caffeine can also help in the management of OAB. There are not strong data to support dietary changes, but sequential elimination of these problem foods may help some patients. A not often thought of behavioral intervention for OAB is weight loss. There is an association between excess weight and various types of incontinence. Several studies have shown a decrease in incontinence episodes with surgical and nonsurgical weight loss.9 Generally, behavioral therapy is equivalent to medications in reducing incontinence episodes, improving voiding parameters, and enhancing quality

of life. The patient in the case study would benefit from behavioral therapy, but she would likely not get optimal benefit by the time of her son’s wedding. She will likely need some medication to manage her condition more quickly. Pharmacologic therapy is the second line of attack in managing OAB. For many years only antimuscarinic agents were available for treatment. In recent years, another class of medication, beta agonist, has been approved. In the detrusor, the postjunctional muscarinic (M3) receptor is the predominant subtype mediating contraction. Antimuscarinic agents block the M3 receptor which stabilizes the bladder (detrusor) muscle, increases bladder capacity, diminishes frequency of involuntary bladder contractions, and delays the initial urge to void. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride are all antimuscarinic agents. All are effective for treating OAB symptoms, but there are differences in adverse effect profiles and thus tolerability. Today, there are also multiple different dosage forms including extendedrelease oral, liquids, topical patch, topical gel, and bladder instillation. It can require trying several different agents to find an effective and tolerable agent. The guidelines suggest that clinicians should manage constipation and dry mouth before abandoning effective antimuscarinic therapy. The patient should be asked before therapy is started about constipation. Many patients will fluid restrict and don’t realize the

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Exhibit 3: Treatment of OAB

Education

Management Strategies

OAB Treatment Behavioral Modification

Medications Neurostimulation Procudures

Exhibit 4: Additive Effect of Combining Behavioral and Drug Therapies10 Behavioral Therapy

Combined Therapy

Drug Therapy

Combined Therapy

Mean Reduction in UI, %

0 -20 -40 -60

-57.5% -72.7%

-80 -100

-88.5%

-84.3%

P = .001

P < .05

impact on their bowel habits and the bladder irritant effect of concentrated urine. In the case study, Sally should be asked about constipation, dry mouth, and fluid intake before a therapy is selected. There are several ways patients can deal with dry mouth related to antimuscarinics. Some tips include sipping cool water throughout the day, drinking milk to lubricate the oral mucosa, restricting caffeine and alcohol intake since both can cause dry mouth, using sugar-free gum to stimulate saliva flow, and saliva replacement products. Mirabegron [Myrbetriq®] is a selective beta-3 adrenoceptor agonist. It activates beta-3 adrenoceptors on the detrusor muscle of bladder to facilitate filling of the bladder and improved storage. Essentially, this is a bladder relaxant that does not affect detrusor contractility. This agent is only available as a oncea-day, extended-release tablet that cannot be crushed

which is a consideration if patients have difficulty swallowing. Mirabegron is a CYP2D6 inhibitor so it may cause some drug interactions. Additionally it can increase blood pressure so this should be monitored. Unlike with the antimuscarinics, neither dry mouth nor constipation is a major concern with this agent so it would be a good choice for the person who already has these issues. With medications, patients should see a response within one to two weeks of starting therapy. A significant reduction should be seen by the end of a month. Thus, patients should give the medication at least one month to assess efficacy. Response can continue to increase up to 12 weeks. Timing of dose titration varies based on prescribing information recommendations, medication naïve versus nonnaïve, and patient tolerance and preference.

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For effective control of their symptoms, most patients will need both behavioral and pharmacologic therapy. As shown in Exhibit 4, the combination is more effective than either alone.10 If combination therapy fails, then patients will need to move to third-line therapies. Third-line therapies include neuromodulation and onabotulinum toxin A injections. Neuromodulation can be with either sacral nerve stimulation or percutaneous tibial nerve stimulation. Sacral nerve stimulation (SNS) is a minimally invasive surgical procedure. It requires a two-step process with an initial test stimulation and, if good response occurs with the test, permanent stimulator implantation. Small doses of electric current are sent from the stimulator to the sacral nerve. A systematic review of four randomized controlled trials found that 80 percent of patients achieved continence or greater than 50 percent improvement in main incontinence symptoms after SNS versus 3 percent of control subjects.11 The benefits persisted for three to five years after implantation. There are a few issues with SNS. The reoperation rate in implanted cases is 33 percent.12 Patients may require reoperation for relocation of the generator due to pain or infection. Percutaneous tibial nerve stimulation (PTNS) is an external device treatment that is given in the office for 30 minutes once a week for 12 weeks. Patients who respond may require occasional medication to sustain response. In a trial of PTNS compared with antimuscarinic therapy, 79.5 percent of those in the PTNS arm reported significant improvement compared to 54.8 percent of subjects on tolterodine (p = 0.01).13 It is an alternative to sacral nerve stimulation if the patient has failed other options and doesn’t want the implanted device. Onabotulinum toxin A [Botox ®] works at the parasympathetic nerve terminal to prevent the release of acetylcholine. In OAB, this agent reduces contractions of the detrusor muscle. The key about this toxin is it does not diffuse very far through the bladder. Thus, 20 to 30 injection sites, one centimeter apart, are required to treat the entire bladder. In a Phase III, randomized, placebo controlled trial, onabotulinum toxin A injections significantly decreased the frequency of UUI episodes per day versus placebo (-2.65 vs -0.87, p<0.001).14 Nine percent of the patients treated with the toxin became dry versus 6.5 percent of those given a placebo injection. It takes about two week’s onset of efficacy. Patients are seen at two weeks to check for efficacy and urinary retention with a post-void residual. Although the most common adverse effect is urinary tract infection, 5.4 percent of patients will develop urinary retention. Due to the risk of urinary reten-

tion, only people who are willing and able to initiate catheterization post-treatment, if required, should be considered for treatment. The need for self-catheterization can last for the duration of the drug efficacy, which is 12 weeks or more. The people who are at most risk for this adverse effect are the frail elderly. There is a maximum total body dose of the toxin that can be given. This is primarily an issue if someone is getting an injection somewhere else in the body for another indication. Onabotulinum toxin A injections do not cause a permanent change; repeat injections will be required. The median time between injections appears to stay about the same over time within an individual, but will vary from person to person. Conclusion

OAB is a prevalent but underdiagnosed and undertreated condition. Patients need to be educated about all the available treatment options. Antimuscarinic therapy may fail if patient expectations and adverse effects are not appropriately managed. Most patients will require a combination of behavioral and pharmacologic therapy. Newer agents available for OAB include beta agonists and onabotulinum toxin A. The future will define whether a combination of antimuscarinic and beta agonists are efficacious. Pamela Ellsworth, MD is a Professor of Urology/Surgery at the Alpert School of Medicine at Brown University.

References 1. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-36. 2. Rovner E, Wein A. Incidence and prevalence of overactive bladder. Curr Urol Rep. 2002;3:434-8. 3. Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87:760-6. 4. Ricci JA, Baggish JS, Hunt TL, et al. Coping strategies and health careseeking behavior in a US national sample of adults with symptoms suggestive of overactive bladder. Clin Ther. 2001;23:1245-59. 5. Irwin DE, Milsom I, Kopp Z, et al. Symptom bother and health care-seeking behavior among individuals with overactive bladder. Eur Urol. 2008;53(5):1029-37. 6. Kobelt G, Kirchberger I, Malone-Lee J. Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU Int. 1999;83:583-90. 7. Tubaro A. Defining overactive bladder: epidemiology and burden of disease. Urology. 2004;64(suppl 6A):2-6. 8. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. 2012. Available at www.auanet.org. 9. Whitcomb EL, Subak LL. Effect of weight loss on urinary incontinence in women. Open Access J Urol. 2011;3:123-32. 10. Burgio KL, Locher JL, Goode P, et al Combined behavioral and drug therapy for urge incontinence in older women. J Am Geriatr Soc. 2000;48:370-4.

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11. Janknegt RA, Hassouna MM, Siegel SW, et al. Long-term effectiveness of

13. Peters KM, Macdiarmid SA, Wooldridge LS, et al. Randomized trial of per-

sacral nerve stimulation for refractory urge incontinence. Eur Urol.

cutaneous tibial nerve stimulation versus extended-release tolterodine: results

2001;39(1):101-6

from the overactive bladder innovative therapy trial. J Urol. 2009;182(3):1055-61.

12. Brazzelli M, Murray A, Fraser C, et al. Efficacy and safety of sacral nerve

14. Nitti VW, Dmochowski R, Herschorn S, et al. Onabotulinum toxin A for the

stimulation for urinary urge incontinence: a systematic review. J Urol.

treatment of patients with overactive bladder and urinary incontinence: results of

2006;175(3 pt 1):835-41.

a phase 3, randomized, placebo controlled trial. J Urol. 2013;189(6):2186-93.

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Changing Paradigms in MS Therapies John R. Corboy, MD, FAAN

Summary The majority of damage and disability from multiple sclerosis (MS) occurs in the first five years of the disease. The current treatment paradigm uses lower efficacy but lower risk medications. A focus on efficacy as the primary determinant of medication choice should be the new paradigm of MS treatment. Key Points • Majority of damage in MS occurs in the first five years. • Damage on MRI scans early in the disease process can be used to predict the course of the disease. • Patients with MRI markers for relapsing course should be treated aggressively with the most efficacious medications available. • The more efficacious medications are relatively more risky and thus require closer monitoring. • Early intervention with higher efficacy medications is the best choice in MS to minimize long-term disability and overall costs.

Multiple sclerosis (MS) is a presumptively autoimmune disorder affecting the CNS exclusively. It is a complex disorder with genetic and environmental causes that can affect anyone, but the greatest risk is in young women. MS is the most common cause of disability in young women and second most common cause in young men, after trauma. Clinically, MS can be divided into four different types. Relapsing-remitting (RRMS) accounts for about 85 percent of cases. The median age of onset for RRMS is 25. Primary- Progressive (PPMS) occurs in about 15 percent of cases. The majority of people with RRMS (60 to 80%) will eventually convert to Secondary-Progressive (SPMS). Progressive-Relapsing (PRMS) is the least common type, accounting for only 1 percent of cases. Clinically Isolated Syndrome (CIS) is, in retrospect, the first attack of the disease. Between 10 and 20 percent of MS cases will be “benign MS”. These patients have rare attacks with little disability. Possibly, because of the widespread use of MRI, more people are being discovered with benign

MS. About 5 percent of MS cases will be “malignant MS” which is rapidly progressive. These patients will be wheelchair-bound in five years and bed-bound in 10 years. Unfortunately, it cannot be predicted which patients will have these disease courses. Most people with MS fall somewhere between these extremes. Factors predicting a favorable outcome with MS include young age at onset, Caucasian, female, low relapse rate, longer time to second relapse, mostly sensory symptoms, no early disability, normal brain MRI scan at presentation, and nonsmoking. Unfavorable prognostic factors include older age at onset, African American, male, high relapse rate, short interval to second relapse, early cerebellar or motor involvement, early disability, cognitive impairment, high lesion load on first brain MRI, atrophy and holes on MRI, PPMS, and smoking. Pathologically, MS is a demyelinating disease. Myelin, the tissue surrounding and protecting the axons, is destroyed by the body’s own immune system. This process leads to axonal transection and loss and ultimately to permanent neurologic disability. MS therapies targeting remyelination are not yet approved

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Exhibit 1: Key Parameters in MS Management: Disability1

Expanded Disability Status Scale

Death Normal neurologic exam

0

0.5

1.0

Increased limitation in walking ability

Minimal disability

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

Need for walking assistance

5.5

6.0

6.5

7.0

Restriction to wheelchair

7.5

8.0

8.5

Helpless bed patient

9.0

9.5 10.0

Patient Disability Classification

Exhibit 2: Modern Era of MS Therapy • 1993 Interferon ß -1b (Betaseron®) • 1996 Interferon ß -1a (Avonex®) • 1996 Glatiramer Acetate (Copaxone®) • 1999

Mitoxantrone (Novantrone®)

• 2002 Interferon ß -1a (Rebif ®) • 2004

Natalizumab (Tysabri®)

• 2010 Fingolimod (Gilenya®) • 2012

Teriflunomide (Aubagio® approved 9/12/12)

• 2013 Dimethyl Fumarate (Tecfidera®, approved 3/27/13) • 2014+ Alemtuzumab (FDA advisory committee voted in favor of 11/12/13). Ocrelizumab, Laquinimod, Daclizumab, and others pending further research results

by the FDA. An important aspect of MS that can currently be treated is inflammation. Immunomodulatory agents target this early process of MS pathology. Although they are not curative, immunomodulatory agents represent disease-modifying therapies. MRI scans have revolutionized the diagnosis and understanding of prognosis. MRI scans can show acute lesions resulting from breakdown of the blood brain barrier. These heal within six to eight weeks. MRI scans can also identify the permanent damage that occurs with MS including atrophy, enlarging ventricles, and black holes. This permanent damage predicts disability over time. The Expanded Disability Status Scale (EDSS) is one of the most widely used assessment instruments in MS clinical studies to measure changes in disability over time (Exhibit).1 Important numbers to keep

in mind on the EDSS are 3 (moderate disability) and 6 (needing assistive device for walking). However, it focuses on lower-body function and physical mobility and fails to account for other aspects of disability that may develop with MS, such as impairment in upper-body function or cognition. Also, because the EDSS is an ordinal and not linear rating scale and 1 point does not represent the same degree of change across all parts of the scale, changes or differences in EDSS scores can be difficult to interpret. MS is a significant disease that results in major disability and higher mortality compared with people without MS.2 Most untreated patients develop disability.3 The first five years of disease are what really matter in the ultimate development of disability. From the population perspective, the impact of any therapeutic agent targeting the in-

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Exhibit 3: Determinants of Therapy Choice • Patient issues - Ease of use, mode of administration, side effects - Risk issues, with highly variable interpretations - Efficacy - Cost issues

- May see major differences between meds, but all expensive

• Doctor issues - Familiarity with medications, “tried and trusted” - Risk issues, with highly variable interpretations - Efficacy • Insurance issues - Typically requires failure of “first-line therapies” prior to payment for “second-line therapies”, ie 1+ “step edits”

Exhibit 4: More Effective MS Agents Agent Alemtuzumab*

Dosage Form/Interval

MOA

IV 5 days in a row and repeat Monoclonal antibody against for 3 days at one year CD52+ cells

ARR 55% less than IFN

Dimethyl Fumarate

Oral bid

Unknown

50% less than Pb

Fingolimod

Oral daily

S1P superagonist - traps lymphocytes in lymph nodes

50% less than Pb

Natalizumab

IV q 28 days

Humanized monoclonal antibody against α4-integrin

62% less than Pb

Teriflunomide

Oral daily

Dihydro-orotate dehydrogenase inhibitor that reduces proliferation of autoreactive T- and B- cells

33% less than Pb

*Approved by EMA 9/17/2013, pending FDA approval as of 12/2013 MOA, mechanism of action; ARR, annualized relapse rate; Pb, placebo; S1P, sphingosine 1-phosphate receptor

flammatory processes in MS, and hence ability to modify recurrence of relapses, has the greatest potential during periods of high relapse activity.4 Patients with more relapses in the first few years of disease reach EDSS of 6 more rapidly.5,6 Direct and indirect costs of MS increase dramatically as disability progresses.7 MS is a very expensive disease to treat if patients are allowed to become disabled. Treatment of MS falls into four broad categories - behavioral changes, acute attack treatment, symptomatic therapies, and disease-modifying therapies (DMTs).

The focus of the remainder of this article is the use of DMTs to alter the natural history of the disease. All the DMTs are only approved for and useful for RRMS. In the early forms of the disease (relapsing), the disease is highly inflammatory and autoimmune. As people age, especially after 45 or 50, MS acts more like a neurogenerative disorder. This is especially true for those who enter a progressive phase. With aging, there are very few enhancing lesions seen on MRI and few acute attacks. Pathologically, macrophages and other immune cells are not seen in the lesions.

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Exhibit 5: New Paradigm for RRMS

Severity

More

Neg

Less

“Low-Risk” Medications

JCV Status Pos

Natalizumab Rituximab* Ocrelizumab*

IL-21 Autoimmune Risk

High

Low

If Fail JCV/IL-21 Risk

Alemtuzumab Do Well

Fingolimod/DMF Teriflunomide/Laquinimod* Daclizumab* Do well

High Do Poorly Need Alternative

Continue Indefinitely

Continue

Low

Natalizumab Alemtuzumab* Rituximab*/Ocrelizumab*

GA responder Pregnancy GA

IFN responder

Interferon

*Not currently FDA approved for RRMS

Thus, the disease changes over time. The DMTs really only have an impact early in the illness and only when there is evidence of ongoing inflammation. Exhibit 2 shows the currently approved DMTs for RRMS and some which are likely to be approved. The current “first-line” therapies or platform therapies are the various interferons and glatiramer. These are the older, relatively lower risk agents with well-known adverse effect profiles but with modest reward. These agents all reduce annualized relapse rates (ARR) to a similar degree in placebo controlled and active comparator trials. The decrease ranges from 29 to 32 percent.8-11 Even when interferon and glatiramer are combined, only 33 percent of patients have disease free activity. There tends to be poor tolerance and compliance with these first-line agents because they are injectable. Compared with the second-line agents, the older agents have slightly lower acquisition costs. The second-line therapies have primarily been used as therapy escalation or rescue approach. This includes natalizumab, fingolimod, DMF, teriflunomide, and off-label use of rituximab, cyclophosphamide, and mycophenolate. These second-line therapies have a higher perceived risk. Because the three newest agents (fingolimod, DMF, teriflunomide) are oral, there is better tolerance and compliance but at a higher acquisition cost. Some long-term studies have been published with

the first-line therapies that further illustrate that therapy with these agents is not ideal. In a glatiramer 15-year follow-up study, even in those who stayed on drug for the entire 15 years, 35 percent developed SPMS. In recently presented 20-year data from this study, 47 percent developed SPMS.12 Essentially in this trial, whether patients remained on therapy (43% of patients for median 13.6 years) or not (57% for mean duration of 4.8 years), there was very little difference in outcomes. The measured outcomes were mean change EDSS at last observation (0.96 on therapy vs.1.0), mean EDSS change per year (0.2 vs. 0.5) and percentage reaching EDSS of 6.0 (23% vs. 27%). In the 15-year follow-up study of Interferon β-1a use, almost one-third of those still on the drug reached EDSS 6.0, and almost twice as many no longer on the medication reached EDSS 6.0.13 These very long-term, follow-up studies show that even patients doing relatively well have significant risk of major disability with first-line agents. The two newest approved medications are teriflunomide [Aubagio®] and dimethyl fumarate [Tecfidera®]. Teriflunomide is an oral agent given as a single daily dose and is generally well-tolerated. Teriflunomide is the active metabolite of leflunomide, previously approved for treating rheumatoid arthritis. Although available as 7 mg and 14 mg doses, the 14 mg dose has better efficacy data. Because of the possibility of liver toxicity, liver function tests

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have to be monitored monthly for the first four to six months of therapy. Because of teratogenicity, this agent is pregnancy category X and is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Because it is also found in sperm, men taking teriflunomide should use reliable contraception to minimize possible risk. Transient hair loss occurs in about 15 of patients. This agent has modest effects on ARR (33%) and disability and is really only better than the present first-line agents. Compared to either dimethyl fumarate or fingolimod, teriflunomide has had a modest impact on the field overall. Dimethyl fumarate (DMF, formerly called BG12) is another new oral agent given twice a day. The most common adverse effects are gastrointestinal upset and flushing. These occur in about 40 percent of patients. GI upset is especially common in the first few weeks. Approximately 15 to 20 percent of patients may discontinue therapy because of adverse effects. Taking DMF with food may help; it should also be given as a lower dose for first two weeks to improve tolerance. The flushing is similar to what is seen with niacin. A small percentage of patients may develop significant lymphocytopenia. This product [Tecfidera®] is similar to Fumaderm®, also containing DMF, is used to treat psoriasis in Europe. Four cases of progressive multifocal leukoencephalopathy (PML) have been reported with Fumaderm or a compounded version. No cases of PML have been seen so far with this product. DMF efficacy appears to be better than current first-line therapies. Use of this agent leads to about a 50 percent ARR reduction and 70 to 80 percent fewer galadium enhancing central nervous system lesions. There have been less impressive effects on slowing disability or slowing brain atrophy. Exhibit 3 outlines the determinants of therapy choice. Primarily because of insurance coverage issues, one or more first-line agents are used before moving on to second-line agents. As mentioned previously, there are issues with compliance with the first-line agents because of injection issues. Patients are very interested in therapies that are easy to use such as oral agents and are many times willing to accept the possible adverse effect risks. In general, patients accept more risk than their physicians.14 Risk tolerance is highly variable with men willing to tolerate more risk than women. Those with greater disability or a recent relapse tolerate more risk. Thus, risk tolerance should be a patient determination. It is the physician’s job to inform the patient about the risks; it is the patient’s job to conclude how they respond to the risk. MRIs are helpful early in the course of MS to

help define which patients to treat aggressively with the newer agents. Brain and spinal cord lesions seen on MRI early in the disease course predict a relapsing disease course. Early MRI findings also predict long-term disability. The number of lesions seen on MRI in the CNS at the first episode of symptoms can predict the course of disability over time.15 Brain atrophy over two years predicts EDSS at eight years.16 Thus, MRI can be used to define those patients who need to be treated aggressively from the outset. It is not appropriate to allow patients to accumulate the level of disability still seen with the current first-line therapies. These first-line therapies reduce the ARR in the 30 percent range compared with 50 percent reductions or more with the more effective agents (Exhibit 4). Thus, starting with the current first-line therapies is really not the best course of action. In comparison trials between the newer and older agents, the new agents, in general, are superior in efficacy.17,18 Teriflunomide was equal in efficacy to interferon but has other benefits in that it resulted in fewer discontinuations and greater patient satisfaction. In the trial comparing alemtuzumab (not yet FDA approved) to interferon, the mean change in EDSS score (P<.0001) with alemtuzumab was -0.17 and 0.24 with interferon.18 The negative change in EDSS score means the patients actually got better on the scale.18 Six-month sustained reduction in disability (P=.0002) was 29 percent in the alemtuzumab group and 13 percent in the interferon group. In the FDA evaluation of alemtuzumab, some issues have been raised so its approval is not guaranteed. The studies conducted so far have not showed reduction in accumulation of new T2 lesion burden. Another study did not show greater effect on slowing sustained accumulation of disability, a primary endpoint. On Nov. 8, 2013, the FDA raised concerns about trial design (was not double dummy), blinding in one study (resulting in high interferon dropout and potential effect on sustained accumulation of disability), and safety.19 The potential safety issues include an array of autoimmune diseases including immune thrombocytopenia, autoimmune hemolytic anemia, immune pancytopenia, anti-glomerular basement membrane disease, membranous glomerulonephritis, thyroid disorders, endocrine ophthalmopathy, acquired hemophilia A, type 1 diabetes mellitus, acute epitheliopathy of the retina, autoimmune skin disease, and undifferentiated connective tissue disorders, along with the incidence of malignancies, notably including thyroid cancer and melanoma. The advisory committee voted in favor of approval as second-line therapy because of the safety issues. Because of some very positive trials with rituximab in MS, a more humanized version of that

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drug, ocrelizumab, is in Phase 3 trials and will likely reach the U.S. market in 2015. The early data that has been reported is very exciting. Patients had no new disease activity at 72 weeks after treatment.20 There are no comparison trials with natalizumab, which most experts consider the most effective MS agent currently available. In the Tysabri Observational Program conducted by the manufacturer, patients who get natalizumab as their first medication do better than those patients previously treated with something else in terms of probability of relapse by year three (31% vs. 43%, p=.002) and lower EDSS scores over time.21 The two treatment groups had similar ARR. There is definitely a higher reward with higher risk with the newer agents. Management of risk requires more testing and time for patient and physician. Biomarkers can be used to minimize risk of some of the newer therapies. John Cunningham virus ( JCV) status is one example. PML is the only substantial risk with natalizumab. Risk for PML is related to JCV status, amount of JCV antibodies, duration of use, and prior chemotherapy or immunosuppression. The risk is about one in 310 overall. JCV status can be measured over time. Another biomarker under investigation is the use of interleukin 21 levels to predict risk of autoimmunity with alemtuzumab. Exhibit 5 presents a new paradigm for MS treatment which starts with higher efficacy/higher risk medications in patients with more severe disease based on MRI markers. The new paradigm presented here is one possible alternative approach, with qualitative conclusions; there are undoubtedly many others. This assumes approval of several investigational medications, confirmation of biomarker test utility in screening for adverse event risk, availability of screening tests, and insurance company agreement. The algorithm will change as more information is gained, especially with comparison trials.

References 1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-52. 2. Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. Neurology. 2013;81(2):184-92. 3. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112 (Pt 1):133-46. 4. Tremlett H, Zhao Y, Joseph J, et al. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79(12):1368-74. 5. Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis, a geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt 7):1914-29. 6. Boggild M, Palace J, Barton P, et al. Multiple sclerosis risk sharing scheme: two year results of clinical cohort study with historical comparator. BMJ. 2009;339:b4677. 7. Grima DT, Torrance GW, Francis G, et al. Cost and health related quality of life consequences of multiple sclerosis. Mult Scler. 2000;6(2):91-8. 8. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285-94. 9. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268-76. 10. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-504. 11. Khan O, Rieckmann P, Boyko A, et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73(6):705-13. 12. Ford C, et al. ECTRIMS, 2013. Poster 577. 13. Bermel RA, et al Intramuscular interferon β-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler. 2010;16:588-96. 14. R. Fox et al, 65th Annual Meeting of the American Academy of Neurology, 2013. Abstract P07.097. 15. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain. 2008;131(pt 3):808-17.

Conclusion

16. Fisher E, Rudick RA, Simon JH, et al. Eight-year follow-up study of brain

It is time to flip the treatment paradigm in RRMS. A focus on efficacy as the primary determinant of medication choice has to be the new paradigm of MS treatment. Glatiramer and interferon should be second-line agents and the newer medications which have proven higher efficacy should be firstline therapy. Therapy can be transitioned, as necessary, to “safer” therapies when the risk of disease itself is similarly lower ( i.e., later). It is time to stop having 40-year-old disabled women.

atrophy in patients with MS. Neurology. 2002;59(9):1412-20. 17. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-97. 18. Cohen JA, Coles AJ, Arnold DL, et al Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819-28. 19. Center for Drug Evaluation and Research (CDER). FDA. Peripheral and Central Nervous System Drugs Advisory Committee Meeting Alemtuzumab (BLA 103948\5139) Background Package. November 13, 2013. 20. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial.

John R. Corboy, MD, FAAN is a Professor of Neurology at the Univer-

Lancet. 2011;378(9805):1779–87.

sity of Colorado School of Medicine and is Co-Director of the Rocky

21. Butzkueven, et al. American Academy of Neurology 64th Annual Meeting,

Mountain MS Center at the Anschutz Medical Campus.

2012. Abstract P06.172.

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Best Practices in the Diagnosis and Treatment of Inflammatory Bowel Disease Mark Lazarev, MD

Summary Inflammatory bowel disease (IBD) is a complex disease that is costly both in terms of medical costs and quality of life. The major goal of treating IBD is to induce and maintain remission. An evolving goal is to completely heal the intestinal mucosa. There are a variety of effective agents for IBD. Better use of these agents is occurring with the use of top-down therapy and the targeting of those patients most likely to have complications for aggressive therapy. Key Points • IBD is a significant, costly disease that impacts quality of life. • Ulcerative colitis primarily affects the colon, whereas Crohn’s disease can affect the entire GI tract. • Treatments include 5-amiosalicylic acid derivatives, thiopurines, TNF inhibitors, and natalizumab. • Therapy is moving to a top-down approach with more aggressive therapy being used earlier. • Mucosal healing is becoming a goal of treatment.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, which affects up to 1.4 million persons in the United States. It is typically divided into ulcerative colitis (UC) and Crohn’s disease (CD). IBD generally presents in people in their teens or 20s. A few predisposing factors for developing IBD include genetics, gastrointestinal infections, nonsteroidal anti-inflammatory medication uses, and antibiotics. The prevalence of IBD is 120 to 200 per 100,000 for UC and 50 to 200 per 100,000 for CD in the Western world.1 The U.S., Canada, and some parts of Europe and Scandinavia have very high rates. It is unclear why the rate is so high in these countries and continues to increase but it may be related to increased recognition, increased use and abuse of antibiotics, heavily processed food diets, and increased hygiene. In non-westernized countries, many people are colonized with helminthes and bacteria that may protect against autoimmune diseases. The direct medical costs for IBD are significant. IBD patients are more likely to have emergency room visits, hospitalizations and surgeries than pa-

tients without IBD. Hospital costs make up a significant portion of costs of an IBD patient. This disease also significantly impacts quality of life. UC is a diffuse mucosal inflammation limited to the colon; it almost always affects the rectum, and it may extend proximally in a symmetrical, uninterrupted pattern to involve all or part of the large intestine.2,3 CD, by contrast, is a patchy, transmural inflammation that may involve any part of the gastrointestinal tract from mouth to anus. Based on population-based and health care claims databases, UC affects approximately 250,000 to 500,000 people in the U.S. Between 7000 and 46,000 persons are newly diagnosed with UC annually. Common symptoms include rectal bleeding, urgency, frequency, and systemic signs of toxicity in more severe disease (fever, weight loss, anemia, elevated inflammatory markers). Most people have moderate symptoms and are controlled by conventional therapies (Exhibit 1).3,4 UC is associated with frequent outpatient medical visits, hospitalizations, and high drug and hospitalization costs due to relapses in disease activity. Thirty to 40 percent of UC

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Exhibit 1: Ulcerative Colitis3,4 100%

Fulminant Disease (9%)

Patients with UC

80%

60%

Moderate to Higher Activity (71%)

40%

20% Low Activity (20%) 0% Disease Activity

patients ultimately require colectomy during their disease course, whether for medically refractory symptoms, fulminant colitis or dysplasia/cancer. Crohn’s disease is a chronic inflammatory disorder of the entire gastrointestinal tract. The primary symptoms are chronic, occasionally bloody diarrhea and crampy abdominal pain. There are 10,000 to 47,000 new diagnoses annually. Up to 30 percent of patients can develop perianal CD with abscesses, fistulas, and fissures. Traditionally, up to 75 percent of patients will require at least one surgery. IBD is diagnosed based on symptoms, laboratory tests, bowel studies, and bowel biopsies. Exhibit 2 compares the advantages and disadvantages of the various methods for assessing structural features of IBD. In most cases, CD is readily distinguished from UC by clinical, radiologic, endoscopic, and pathologic features. Biomarkers are increasingly being used to distinguish between UC and CD. Autoantibodies and antibody levels against various bacteria can be used to measure the amount of inflammation within the body. Increasing amounts of immune reactivity has been shown to indicate increasing disease complications and more aggressive disease phenotypes in adults and children with CD.5 Fecal calprotectin, another biomarker which is frequently used, is elevated with increased mucosal inflammation in IBD. Fecal calprotectin represents 40 to 60 percent of cytosolic proteins in neutrophils. The amount of calprotectin in feces is therefore pro-

portional to the neutrophil migration to the gastrointestinal mucosa. It accurately distinguishes IBD from non-IBDs such as irritable bowel syndrome and furthermore predicts clinical relapse in IBD patients. It has been found to be more sensitive and specific than other inflammatory markers such as erythrocyte sedimentation rate (ESR). Currently, there is no cure for CD. The only cure for ulcerative colitis is taking out the colon. Thus, all but the patients with the mildest of disease will need to be on chronic, lifelong therapy. Because these are chronic conditions, medication adherence can be an issue. Once patients are feeling well, they are less likely to continue their medications, which can lead to a disease flare-up. The goals of therapy are to induce and maintain a clinical remission, avoid complications of the disease, achieve a good quality of life, and minimize short- and long-term toxicity. The medications for IBD include 5-aminosalicylic acid (ASA) agents, corticosteroids, thiopurines, anti-TNF agents, and natalizumab. Each class has benefits and risks in treating IBD. The 5-ASA agents are considered the safest agents for IBD. They have been used for decades. They are anti-inflammatory but are not immunosuppressives. They are effective for induction and maintenance of remission of mild to moderate ulcerative colitis. These come in multiple different forms including oral tablets and rectal topicals. Oral agents include sulfasalazine [Azulfidine®] and mesalamine [Pen-

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Exhibit 2: Methods for Assessing Structural Features in IBD Advantages

Disadvantages

Validated, widely available Sensitive to changes Prognostic value

Limited to luminal structures Incomplete examinations 20%

Widely available Detection penetrating/stricturing complications

Patient tolerance Radiation exposure Bowel transit time No information about extraenteric disease, misses mild disease

CT

Widely available, reproducible Less interobserver variation Fast study Extraenteric structures

Radiation exposure and overuse Misses mild disease

MRI

High sensitivity & specificity Reproducible over time Extraenteric structures No radiation Better for perianal disease

Limited availability Heterogeneity in image acquisition and interpretation Have to lie still for appropriate breath-holding sequences Misses mild disease

Detects more small bowel lesions than cross-sectional imaging Widely available

Heterogeneity in interpretation Lower specificity for Crohn’s disease Capsule retention

Ileocolonoscopy

Small Bowel follow through

Wireless Capsule Endoscopy

tasa®, Asacol®, Lialda®, Apriso®]. Rectal topicals include mesalamine enema [Rowasa® ] or suppository [Canasa®]. Often, combination therapy with oral and rectal 5-ASA works better than oral alone. For proctitis, topical ASA can be used alone. The 5-ASA agents are generally very safe and well tolerated. With some formulations, there is a need to take up to 12 pills a day. A minority of patients will actually get worse on this class of medications. Interstitial nephritis can rarely be caused by 5-ASA agents and thus kidney function needs to be monitored at least once a year. Corticosteroids are effective in the induction, but not maintenance of remission in both CD and UC. The most commonly used steroids are prednisone and budesonide [Entocort ®]. In UC, steroids are usually used with active flare-ups when 5-ASAs are not working. This usually involves starting prednisone at 40mg a day, and tapering over eight to 10 weeks. In CD involving the small intestines and right colon (the most common locations), budesonide is preferred over prednisone. Budesonide has fewer systemic side effects because of the way it is metabolized. The long-term risks of steroids are well known and significant. They include diabetes, hyperten-

sion, increased risk of infection, osteopenia and osteoporosis, avascular necrosis of the hip, weight gain, cataracts, skin thinning and bruising, hormonal imbalance, and anger, anxiety or other psychiatric effects. Overall, 55 percent of patients on corticosteroids will have an adverse event and will have to discontinue therapy. Historically, patients with CD on corticosteroids have a high likelihood of becoming steroid dependent or requiring surgery. Because of the risks, long-term treatment of IBD with steroids is inappropriate and should be avoided. Thiopurines (azothioprine [Imuran®], 6-mercaptopurine) are steroid-sparing oral agents. They are purine-antagonist anti-metabolites that interfere with nucleic acid synthesis in white blood cells, especially in T-lymphocytes, which are important in the production of inflammatory mediators. Thiopurines are effective in maintaining remission in CD and UC in about 50 percent of patients. They are usually started when 5-ASAs are not enough to control moderate to severe symptoms or for steroid dependence. They have no role for inducing a remission because it takes two to four months for maximum effectiveness. The thiopurines are usually combined with a steroid taper to initiate therapy. Thiopurines can cause some significant adverse

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Exhibit 3: ACG Guidelines for CD (2009) •

Mild to moderate disease - Sulfasalazine at 3-6g/d for colonic disease - Budesonide for ileal/right colon disease

Moderate to severe disease - Prednisone for induction - Azathioprine for maintenance of remission - Anti-TNFs for patients with inadequate response with steroids, immunomodulators • Infliximab and infliximab/azathioprine more effective than azathioprine alone - Natalizumab for patients with inadequate response to anti-TNF Exhibit 3: ACG Guidelines for UC (2010)7,8

Mild to moderate disease - Sulfasalazine at (4-6g/d) 5-ASAs - Thiopurines for patients who don’t respond to steroids - Infliximab for patients steroid refractory or dependent who have failed thiopurine

Moderate to severe disease - 5-ASAs effective in reducing relapses - Thiopurines for maintenance of remission - Infliximab effective for induction and maintenance

events, including leukopenia, increased risk for infection, elevated liver function tests, pancreatitis, allergic reaction, and fatigue. One adverse effect of major concern is the increased risk for lymphoma. The risk of non-Hodgkin’s lymphoma with longterm use of thiopurines is about four to five times that of the general population.6 The chances of getting lymphoma in the general population is two out of 10,000. The risk with thiopurines is nine out of 10,000, but the absolute risk is still low. This risk has to be compared with the risk of not taking the medication and achieving remission. Patients will have to be closely monitored especially when a thiopurine is first started. Overall, about 10 percent of patients will need to stop the medication because of an adverse event. Tumor necrosis factor (TNF) levels are elevated in the serum, stool, and intestinal tissues of patients with inflammatory bowel diseases, and it may play a pivotal role in the pathogenesis of CD. The anti-TNF biologic agents are approved for induction and maintenance of remission for CD (infliximab [Remicade®], adalimumab [Humaria®], certolizumab [Cimzia®]) and UC (infliximab, adalimumab, golimumab [Simponi®]). They are usually started when 5-ASAs or thiopurines are not enough to control moderate to severe symptoms, or for steroid dependence. Anti-TNF agents are the most effective

therapy available for perianal fistulizing disease. The anti-TNF agents have some well-known, adverse events including immediate or delayed infusion or injection site reaction and increased risk for infection. The risk of lymphoma related to these agents is unknown. Overall, about 10 percent of patients will have an adverse event, but only one in 250 events will be serious. Because of the risk of significant immunosuppression, caution must be taken in combining these medications with steroids for an extended period. Additionally, up to 50 percent of patients will lose response to anti-TNF agents over time. In this case, a switch to another anti-TNF agent can be made, but the second agent is usually less effective. Natalizumab [Tysabri®] is a humanized monoclonal antibody against the cell adhesion molecule α4integrin. The drug is believed to work in IBD by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines. It is effective in inducing and maintaining remission in CD. This agent is administered as a once- monthly infusion. It is usually started in patients who have failed an anti-TNF agent and for whom surgery is not a good option. Patients must be off all immunosuppressants other than steroids before starting this agent. The potential adverse effect of most concern with

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Exhibit 4: AGA IBD QI Measures 2012 PQRS 1. Document disease activity and severity 2. Recommend steroid-sparing therapy after 60 days 3. Assess bone health if steroid-exposed 4. Recommend influenza vaccine 5. Recommend pneumococcal vaccine 6. Document recommendation for cessation of smoking 7. Assess for HBV status pre-anti-TNF 8. Assess for latent TB pre-anti-TNF Exhibit 4: CCFA Process Measures9,10 • Test for TB before anti-TNF therapy • Test for C. difficile in flares • Flex sig. for CMV in steroid-refractory hospitalized UC • Check TPMT before starting thiopurines • Recommend steroid-sparing agents if >4m steroids • Recommend colectomy or close surveillance for low-grade dysplasia in colitis • Recommend smoking cessation if smoker with CD • Educate patients regarding vaccinations HBV = Hepatitis B virus; TB = Tuberculosis; CMV = Cytomegalovirus; TPMT = Thiopurine S-methyltransferase (ability to metabolize thiopurines)

Exhibit 4: CCFA Outcome Measures • Steroid-free clinical remision • Days lost from work/school • Days hospitalized • ED visits • Malnutrition • Anemia • Normal health related QOL • Narcotic use • Nighttime BMs or leakage • Incontinence

natalizumab is progressive multifocal leukoencephalopathy (PML). There is a one in 1000 risk of developing PML while on natalizumab. It is a concerning event because it is very often fatal or debilitating if acquired. The major risk factors for developing PML are John Cunningham (JC) virus exposure, prior immunosuppressives, and natalizumab use greater than 24 months. Patients on natalizumab need close monitoring with neurologic exams. If it does not work in the first three months, it should be discontinued. Exhibit 3 outlines the A level recommendations for CD and UC from the American College of Gastroenterology guidelines.7,8 Additionally, the American Gastroenterological Association (AGA) and Crohn’s and Colitis Foundation of America (CCFA) have published quality and process measures in IBD which can be used to assess care for these patients (Exhibit 4).9,10 Traditionally, when a patient was diagnosed, the least toxic agents were started and then therapy would be moved forward once failure occurred. Top-down therapy refers to starting with the most aggressive therapy rather than the least. This method is most applicable to CD and refers to starting an

anti-TNF agent, often with a thiopurine agent, as initial therapy. New data are emerging that combination therapy may be most effective early in the course of disease. The hope is that early aggressive treatment will decrease complication, hospitalization and surgery rates. There is a need to weigh the benefits and risks of combination therapy. It is important to try to predict at diagnosis those patients who will have an aggressive course with complications. Currently, this prediction is made based on severity of disease based on initial presentation, level of immune markers, and bowel study findings. Increasingly, the management of IBD is moving toward mucosal healing as a goal of therapy. Studies are now using mucosal healing as a marker of medication efficacy. There is evidence that patients in clinical remission who also achieve mucosal healing are less likely to flare over time. Clinical remission of symptoms does not always mean that mucosal healing has occurred. Currently our medications do an overall poor job at achieving mucosal healing. There is no clear consensus as to how we should strive to achieve mucosal healing as a goal of therapy.

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An area of frequent concern for patients is whether anti-TNF or thiopurine therapy can be stopped. In most cases, therapy cannot be safely stopped without a significant risk of relapse. In patients on an anti-TNF agent in combination with a thiopurine agent, a subset of patients may be able to stop the thiopurine. In order to stop a medication, patients should have clinical and endoscopic remission, as well as have no elevated markers of inflammation and mucosal healing. We are only now learning which factors predict the ability to come off medication. Sometimes medical therapy is inappropriate. Examples include patients with recurrent obstructive episodes from scarred down stricture that is best approached with surgery, extensive fistulizing disease or abscess within the abdomen which needs surgery (followed by medical therapy). It is important to address these situations with surgery. There is a growing push to use more biologic agents in IBD. Biologics have been shown to decrease the rate of hospitalization and surgery. A recent systematic review in Crohn’s disease, found that infliximab and adalimumab were cost effective when given as induction therapy followed by episodic therapy for five years.11 It is unclear if biologics are still cost effective when given as maintenance therapy. Episodic therapy is only using the agent when the patient is having a flare-up, but this strategy is not as effective as maintenance therapy nor is it recommended by any guidelines. A few new agents are under development for IBD. Vedolizumab, similar to natalizumab but without the risk of PML, is being studied for both UC and CD. Tofacitinib is an oral agent beginning Phase III study for UC. Ustekinumab is in Phase III trials for CD. Conclusion

morbidity and associated costs to society. Effective medications are available, but can be very expensive and thus need to be used wisely. Mark Lazarev, MD is an Assistant Professor of Medicine at the Johns Hopkins University School of Medicine.

References 1. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1785-94. 2. Loftus CG, Loftus EV Jr, Harmsen WS, et al. Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000. Inflamm Bowel Dis. 2007;13(3):254-61. 3. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17. 4. Langholz E, Munkholm P, Nielsen OH, et al. Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987. Scand J Gastroenterol. 1991;26(12):1247-56. 5. Dubinsky MC, Lin YC, Dutridge D, et al. Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am J Gastroenterol. 2006;101(2):360-7. 6. Siegel CA. Review article: explaining risks of inflammatory bowel disease therapy to patients. Aliment Pharmacol Ther. 2011;33(1):23-32. 7. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104(2):465-83. 8. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-23. 9. AGA. Adult Inflammatory Bowel Disease Physician Performance Measures Set. 2011. Available at http://www.gastro.org/practice/quality-initiatives/ IBD_Measures.pdf 10. Melmed GY, Siegel CA, Spiegel BM, et al. Quality indicators for inflammatory bowel disease: development of process and outcome measures. Inflamm Bowel Dis. 2013;19(3):662-8 11. Tang DH, Harrington AR, Lee JK, et al. A systematic review of economic studies on biological agents used to treat Crohn’s disease. Inflamm Bowel Dis. 2013;19(12):2673-94.

IBD is a complex, heterogeneous condition that affects patients for many decades. It causes significant

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Customizing Therapeutic Strategies to Optimize Outcomes in the Management of Advanced NSCLC Jonathan Goldman, MD

Summary There are many exciting advances happening in the treatment of advanced nonsmall cell lung cancer (NSCLC). Many of these advances are coming from evolving understanding of the genetic mutations that drive the growth of cancer cells. As the mutations are identified, targeted therapies are being developed. The ones that have reached the market are transforming the treatment of this disease. Key Points • Determination of histology at diagnosis is mandatory. • Many different driver genetic mutations are being identified in NSCLC. • Erlotinib is first-line therapy for EGFR-positive disease. • Crizotinib is first-line therapy for EML4-ALK rearrangements. • Platinum-based chemotherapy is still the standard of care (except for subpopulations of patients with “driving mutations” in EGFR and ALK). • For patients with squamous histology, platinum-based chemotherapy doublet is standard therapy. • For nonsquamous histology without mutations, platinum-based doublet therapy alone or with bevacizumab is the main treatment options.

Lung cancer is the most common cause of cancer death in the United States and worldwide. Approximately 200,000 Americans die every year of lung cancer, with it being the leading cause of death in both men and women. Smoking is still the primary reason most people develop lung cancer, and one in seven smokers will die of the disease. Overall for all lung cancers, the five-year survival rate is 15 percent. Lung cancer is divided into two major types – small cell and non-small cell (NSCLC, Exhibit 1).1 NSCLC is the most common type. Small cell lung cancer is found in about 15 percent of overall lung cancer cases. This has declined over the years, possibly as a result of changing cigarette composition. Small cell lung cancer is usually metastatic at the

time of diagnosis. The primary treatment is chemotherapy with cisplatin and etoposide as standards. Rare patients are surgical candidates. For limited stage disease, chemotherapy will be combined with radiation. In limited stage patients with complete response, chemotherapy and radiation will be followed with prophylactic whole brain radiotherapy. Relapses are frequent. Unfortunately, most patients die within one year. Because the majority of advances in lung cancer have been in the NSCLC arena, the remainder of this article will focus on NSCLC. Stage I and II disease is typically treated with surgical resection. Radiation is becoming an option when patients cannot tolerate surgery. Adjuvant chemotherapy with four cycles of a cisplatin-based regimen provides a real,

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Exhibit 1: Lung Cancer Subtypes1

Small Cell Lung Cancer (SCLC) ~ 15%

Squamous Cell Carcinoma 25% - 30% Adenocarcinoma 35%-40%

Non-Small Cell Lung Cancer (NSCLC) ~ 85%

Large Cell Carcinoma 10%-15%

but marginal, mortality benefit - 4.1 percent absolute benefit at five years for overall survival (40.4% no adjuvant chemotherapy vs. 44.5% with adjuvant therapy). Stage III NSCLC is when there is mediastinal, supraclavicular or scalene lymph node involvement or the primary tumor invades local structures, such as the heart, spine, or great vessels. Chemotherapy and radiation are the primary therapies at this stage, but surgery may be considered. Stage IV NSCLC can be subdivided into M1A or M1B disease. M1A disease has pleural or pericardial effusion, pleural nodules, or a nodule in the contralateral lung. M1B disease has spread outside the chest. Brain, bone, liver, and adrenal are the most common sites of metastases in NSCLC. There have been significant advances in the understanding of lung cancer histology and growth driving genetic mutations, which has led to better, more effective treatments. Both histology and underlying tumor mutations are important for selecting therapy. Therefore, determination of histology at diagnosis is mandatory. Testing for genetic mutations is less well defined. The NCCN guidelines recommend testing patients with nonsquamous cell histology and squamous cell in never-smokers for the two best defined mutations - epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations.2 One of the most important chemotherapy trials in lung cancer that showed that histology makes a difference in treatment selection was the trial comparing cisplatin/gemcitabine with cisplatin/pemetrexed. Because thymidylate synthetase is lower in nonsquamous cell lung cancer, it was thought it

could be sufficiently suppressed with pemetrexed and therefore there might be incremental benefit of pemetrexed over gemcitabine. When divided by histology, those subjects with nonsquamous disease had better outcomes with pemetrexed than those with squamous cell cancer (SCC). Conversely, those with squamous histology did best with gemcitabine treatment. Thus, histology has become the primary decision point when looking at chemotherapy as the treatment choice. Exhibit 2 outlines the first-, second-, and third-line chemotherapy agents that are used based on histology.2 For patients identified with a genetic mutation in their tumor, targeted therapy will be used. In lung cancer, approved therapies target three areas - vascular endothelial growth factor (VEGF), EGFR, and ALK. There are FDA approved monoclonal antibodies against VEGF and EGFR. There are also tyrosine kinase inhibitors that target EGFR. Crizotinib targets ALK mutations. Targeting angiogenesis in lung cancer was a hot topic about 10 years ago, but interest has somewhat flared out. Bevacizumab [Avastin®], a VEGF inhibitor, blocks continued growth of blood vessels that provide tumors with nutrients. Combining bevacizumab with carboplatin and paclitaxel increases median survival by 2.3 months and two-year survival from 15 percent to 23 percent compared with carboplatin/paclitaxel.3 In lung cancer, there has been concern about the rare adverse effects of antiangiogenesis agents. Bevacizumab can cause hemoptysis, which is often fatal. It also can cause stroke, heart attack, and peripheral blood clots. Fifty to 70 percent of nonsquamous patients should be eligible for bevacizumab, but only about 30 percent are actually

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Exhibit 2: NSCLC Chemo Approaches by Histology2 Nonsquamous Squamous First-line First-line Platinum + pemetrexed Platinum + gemcitabine or taxane Carboplatin/paclitaxel/bevacizumab Cisplatin/vinorelbine/cetuximab Carboplatin/pemetrexed/bevacizumab (?) Second-line Second-line Taxane or gemcitabine Taxane or Pemetrexed Erlotinib Erlotinib Others Others Vinorelbine Gemcitabine or vinorelbine

Exhibit 3: Incidence of Single Driver Mutations AKT1 NRAS MEK1

No Mutation detected

MET AMP HER2

PIK3CA

KRAS 22%

BRAF 2% Double Mutants 3%

EGFR 17%

EML4-ALK 7% KRAS: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog AKT1: V-akt murine thymoma viral oncogene homolog1 NRAS: Neuroblastoma RAS viral oncogene homolog MEK1: mitogen-activated protein kinase kinase1 MET AMP: MET amplification HER2: human epidermal growth factor receptor2 PIK3CA: phosphatidylinositol 3-kinase BRAF: v-Raf murine sarcoma viral oncogene homolog B1

receiving it. It is not used in patients with SCC because a Phase II trial demonstrated a higher rate of fatal or near fatal hemoptysis in that patient group. Another target in therapy is EGFR. Many cancers, including some lung cancers, overexpress EGFR on the tumor cell surface. Anti-EGFR antibodies provide a small incremental improvement in outcome. The anti-EGFR antibody that has been studied but has not had much uptake, even though it is included in the NCCN guidelines, is cetuximab [Erbitux ®]. Addition of cetuximab to cisplatin/vinorelbine led to a one-month survival advantage.4 Part of the lack of excitement about cetuximab is that cisplatin/vinorelbine is an infrequently used chemotherapy combination. Small molecule inhibitors are where the excite-

ment is currently with lung cancer. These are protein peptides that can be taken orally. The protein docks into a receptor or enzyme to block activity. As stated previously, EFGR may be over expressed in many lung cancers but a true mutation of EGFR is rare in the U.S., occurring in only about 10 percent of cases. Higher rates of EGFR mutations are seen in those who have never smoked, women, and those of Asian descent. Gefitinib and erlotinib [Tarceva®] are EGFR tyrosine kinase inhibitors (TKI) and have been studied in advanced NSCLC in numerous trials. Only erlotinib has been approved in the U.S. Tumors with EGFR mutations are dependent on the tyrosine kinase pathway for growth. In selected populations (those with EGFR mutation only), the response rates are 70 to 80 percent. Gefitinib and

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Exhibit 4: NSCLC Driving Mutations

Genetic Alteration (i.e., driver event)

Available Targeted Agents with Activity against driver event in Lung Cancer

EGFR Mutations

Erlotinib, afatinib

ALK Rearrangements

Crizotinib

HER2 mutations

Trastuzumab*, afatinib

BRAF mutations

Vemurafenib**, dabrafenib**

MET amplification

Crizotinib

ROS1 gene fusions

Crizotinib

RET gene fusions

Carbozantinib***

* FDA approved for HER2 positive breast cancer **FDA approved for BRAF mutation positive melanoma ***FDA approved for medullary thyroid cancer

erlotinib are reversible inhibitors of tyrosine kinase. Second-generation EGFR inhibitors have been developed that are irreversible. The first second-generation TKI approved was afatinib [Gilotrif ®]. Two others under study are dacomitinib and neratinib. These EGFR inhibitors affect both mutated and wild type EGFR. This leads to adverse effects of rash and diarrhea, which occur at higher rates with second-generation inhibitors. At this time, there has not been a clearly demonstrated advantage of irreversible TKIs over the reversible inhibitors. The progression-free survival is about 10 months with erlotinib and 14 months with afatinib but with a higher rate of adverse effects. The next area of excitement is with ALK inhibitors. About 4 percent of NSCLC tumors have echinoderm microtubule-associated protein-like 4 (EML4) ALK translocation fusion which is an oncogene.5 Although rare, this is primarily found in adenocarcinoma cases. Crizotinib [Xalkori®] is an ALK inhibitor that has shown dramatic results in patients with this gene fusion. Nearly all patients have initial benefit with this agent. Unfortunately, resistance does develop to this agent. Targeted therapy has been compared with chemotherapy for first-line therapy and shows improvement in progression-free survival in patients with the specific genetic mutations targeted.6 Targeted therapy provides about a year of survival benefit compared with a few months for chemotherapy. If patients have one of the genetic mutations for which a therapy is available, targeted therapy is recommended as first-line therapy.2

Many other driving mutations have been identified in lung cancer. In testing by the Lung Cancer Mutation Consortium, driving mutations were found in 54 percent (280/516) of tumors completely tested (CI 50-59%).7 Exhibit 3 outlines the mutations found.7 Exhibit 4 outlines which therapies target which mutations. As noted previously, resistance can develop to targeted therapies. The cancer will begin to regrow, usually after about a year. In EGFR mutations, about 60 percent of the resistance is due to a secondary mutation that prevents the drug from binding correctly. There are medications under development to bypass this secondary mutation. Immunotherapy is another exciting area. Not long ago, it was thought that immunotherapy did not have a role in lung cancer. Unlike what can occur with melanoma and kidney cancer, no spontaneous remissions caused by an activated immune system had been seen in lung cancer. Typically we don’t want our immune system to attack the body so it has “brakes”. The two brakes that are targeted with immunotherapy are cytotoxic T-lymphocyte antigen four (CTLA-4) and programmed death one (PD-1). Both these agents turn off T cells. Agents targeting both are under study, but so far PD-1 inhibitors are showing more promising results in lung cancer. Blocking PD-1 allows T cells to live longer and attack cancer cells. One interesting thing that can happen with immunotherapy is initial tumor growth followed by significant regression and even total disappearance. This is allowing two to three years of disease control.

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Conclusion

It is an exciting time for treating advanced NSCLC. Mutation testing for EGFR and EML4-ALK is now part of routine clinical practice. Erlotinib is firstline therapy for EGFR- positive disease and crizotinib for EML4-ALK rearrangements. Therapies are in development for the other common mutations found in NSCLC. For patients with squamous histology or no squamous histology and no identified mutations, platinum-based chemotherapy doublet is standard therapy. For no squamous histology, bevacizumab may be added to the regimen. Harnessing the immune system to attack lung cancer is the next therapy on the horizon.

References 1. National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ ®). Available at http://www.cancer.gov/cancertopics/pdq/treatment/non-smallcell-lung/healthprofessional 2. National Comprehensive Care Network Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 2.2014. Available at www.nccn.org. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-50. 4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373(9674):1525-31. 5. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-6. 6. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-57.

Jonathan Goldman, MD is an Assistant Professor of Medicine and Di-

7. Lung Cancer Mutation Consortium. Incidence of single driver mutations.

rector of Clinical Trials in Thoracic Oncology at UCLA.

Available at www.golcmc.com

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Recent Advances in Melanoma Therapy Adil Daud, MBBA

Summary Tremendous advances are occurring in the treatment of melanoma. Two things that are driving these advances are the discovery of specific genetic mutations that facilitate tumor growth and various ways of activating the immune system to attack the cancer. Several agents targeting genetic mutations and activating the immune system have reached the market with more on the way. Key Points • More than 50 percent of melanomas have BRAF mutations. • These mutations can be targeted with BRAF inhibitors or a combination of BRAF and MEK inhibitors. • Two BRAF inhibitors and one MEK inhibitor have been FDA approved for treating metastatic BRAF mutated melanoma. • More of these agents are under development. • Immunotherapy with ipilimumab and several soon to be approved agents is another avenue for targeting melanoma.

Skin cancers are the most common human cancer. More than 3.5 million skin cancers in over two million people are diagnosed annually.1 As shown in Exhibit 1, although melanoma is one of the least common skin cancers, it is the cause of the majority of annual deaths from skin cancer.1-3 Many of these deaths are occurring in relatively young people. There is increasing recognition among the public that melanoma causes a great deal of morbidity and mortality. In recent years, there have been exciting advances in the treatment of melanoma. One of the crucial insights in this field was the observation by Helen Davies and colleagues in 2002 that many melanoma tumors had a mutation in BRAF gene.4 It has since been discovered that certain genetic mutations are more common depending on the area of the body where the melanoma arises.5-7 For example, the majority (57%) of tumors arising on the trunk and legs have BRAF mutations, whereas none of those occurring in the eyes have this mutation. Melanomas

most commonly occur on the trunk in men and legs in women. Many of the mutations discovered in melanoma so far are located in two cell growth and proliferation pathways --mitogen-activated protein (MAP) kinase and phosphatidylinositide 3 (PI3) kinase. Over 65 percent are in the MAP kinase pathway; the most common mutations found in this pathway are BRAF V600E or V600K. Thus, targeting various aspects of these pathways has been the focus of recent drug development. Three agents that have been FDA approved (vemurafenib [Zelboraf ®], dabrafenib [Tafinlar ®], trametinib [Mekinist ®]) target BRAF mutations found in the MAP kinase pathway. Agents targeting the PI3 pathway are under development. Essentially prior to 2010, there were no truly effective medications for treating melanoma. Various combinations of chemotherapy were studied but only resulted in dismal response rates and no changes in overall survival.

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Exhibit 1: Annual Incidence and Deaths from Skin Cancer in the United States1-3

600

Deaths 8,000

2,500

60,000

Basal Cell

700,000

Squamous Melanoma

Incidence

Merkel Cell

2,800,000

Exhibit 2: Effects of Blocking Inhibitory and Negative Regulation Signals

T T Cell

APC

MHC

T Cell

TCR

TCR

Activation Signals B7 CD28

Tumor Cell

T Cell

MHC

Negative Regulation PD-1 PD-L1

Inhibitory Signals B7

Ipilimumab

CTLA-4

Anti-PD-1 antibodies (Nivolumab, lambrolizumab)

The development of BRAF inhibitors in 2010 changed the treatment landscape. Overall response rates in the 80 percent range were seen with vemurafenib compared to 10 to 15 percent response rates with chemotherapy. The change in overall survival with BRAF inhibition is not huge but is an increase of about six months, which is an improvement over chemotherapy. Similar to HIV, it appears that monotherapy with a BRAF inhibitor leads to the development of resistance. Based on the rationale that acquired resistance to vemurafenib results in MAP kinase pathway reac-

Anti-PD-L1 Antibodies

tivation through mitogen activated kinase (MEK), the combination of MEK and BRAF inhibition may be able to overcome or delay acquired resistance. One combination being studied is dabrafenib with trametinib [Mekinist ®], a MEK inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. In the one study published of the combination, the BRAF inhibitor alone produced a median 5.8 months progression-free survival (PFS) and the combination resulted in a median PFS of 9.4 months.8 Another possible benefit of the com-

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Exhibit 3: Responses with Lambrolizumab Compared with Ipilimumab + Nivolumab12,13

n

Any PR

VGPR*

Any CR

Confirmed CR

10 mg/kg Q2W

52

56%

40%

17%

10%

Any Q2W dose

65

35%

23%

6%

2%

Total (all doses)

117

44%

31%

11%

5%

Best dose level

17

53%

41%

17%

???

All dose level

52

40%

31%

10%

???

Dose Level Lambrolizumab

Ipilimumab + Nivolumab

Q2W, every two weeks; PR, partial response; VGPR, very good partial response; CR, complete response *Very good partial response, defined as best target lesion response >80% from baseline

bination is a reduction in BRAF inhibition induced squamous cell skin cancers. In this trial the rate of cutaneous squamous-cell carcinoma was 7 percent in patients receiving combination versus 19 percent in those receiving dabrafenib alone.8 Cobimetinib is an investigational MEK inhibitor currently in Phase 3 trials. Preliminary data released by the manufacturer from a trial of this agent in combination with vemurafenib revealed that an objective response was seen in 85 percent of subjects with metastatic disease who had not previously been treated with a BRAF inhibitor.9 The response rate was much lower in those who had already been exposed to BRAF inhibition. The other area of therapy for melanoma is immunotherapy. This type of treatment has a long history in the treatment of melanoma. It has been known since the 1930s that when patients got an infection or illness a remission of their melanoma could occur, although rare. This made people begin to investigate activating the immune system to directly attack the cancer. Interleukin and interferon have both been used for several years for immunotherapy in melanoma. The downside has been the difficulty in predicting who will benefit from these costly and difficult to tolerate treatments. For example, interleukin 2 treatment requires an intensive care unit stay and may only be possible for very young relatively healthy patients. Within the immune system, antigen presenting cells (APCs) recruit T cells to go and kill tumor cells (Exhibit 2). Therapies that target turning on and off T cells through cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death (PD-1), and programmed death ligand (PD-1L) are being devel-

oped to activate the immune system. Ipilimumab [Yervoy®] was the first of these approved. It is a fully human monoclonal IgG1 antibody against CTLA-4, an immune-inhibitory molecule expressed in activated T cells and in suppressor T regulatory cells.10 Interaction of ipilimumab with CTLA-4 blocks inhibitory signals generated through this receptor and enhances T cell activation, leading to increased antitumor responses. Essentially, it blocks the “turn-off ” receptor on T cells so they stay activated for a long duration. Ipilimumab does not have a significant impact on PFS in melanoma and patients can actually have initial tumor growth, but there does appear to be a very long-term survival benefit in a small percentage of patients (~10%).11 The next evolution in immunotherapy is anti PD1. The PD-1 receptor is a negative regulator of T cell effector mechanisms that limits immune responses against cancer. One agent under investigation is lambrolizumab, an anti-PD-1 antibody previously known as MK-3475. In the one published trial of this agent, 81 percent of the patients who had a response (42 of 52) were still receiving treatment at the time of data analysis in March 2013.12 Another anti PD-1 antibody under evaluation is nivolumab. It has been studied in combination with ipilimumab.13 In this study, about 53 percent of subjects responded. If patients respond to this combination, it appears to work fairly quickly unlike ipilimumab alone which takes several weeks before response is seen. One concern with the combination is toxicity. The toxicity of each agent appears additive. Colitis and pneumonitis are two serious adverse effects that occur with immunotherapy. Ex-

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Exhibit 4: In-vivo Electroporation14

Injection of plasmid

Electrode Insertion

hibit 3 provides a comparison of the early response rates with nivolumab and ipilimumab compared with lambrolizumab. Both of these anti PD-1 agents will likely receive FDA approval in 2014. In the studies with immunotherapy agents, if a patient has a response to treatment, it appears that they continue to have a response, at least up to one year. Dramatic tumor shrinkage and even disappearance can be seen. The issues yet to be resolved include how long treatment should be continued, the optimal dosing interval of the individual agents, and how to identify those who will most likely respond. One of the other areas of research in activating the immune system to attack melanoma is through intratumoral gene electroporation (Exhibit 4).14 This process uses electric charges to facilitate entry of plasmid DNA encoding for interleukin-12 (IL12) into tumor cells. Our bodies normally produce interleukin 12 (IL-12) in response to foreign agents such as viruses and cancers. It is a crucial signaling molecule that mediates communication between macrophages and effector T cells and natural killer (NK) cells. With this process, the introduced plasmid DNA begins producing IL-12 to attack the tumor. This may be a way to trigger systemic antitumor immune responses without the systemic toxicity associated with intravenous cytokine delivery and potentially offers complete long-term tumor regression. Conclusion

In recent years, unprecedented advances in melanoma therapy have occurred. BRAF inhibitors may be the primary choice for patients with BRAF mutations, but resistance to therapy will typically occur. Combinations of agents that target different tumor growth pathways are a possible way to overcome or prevent acquired resistance. Immunological therapies hold great promise for harnessing the immune system to attack melanoma tumors. One agent is approved

Electroporation

and several more will likely make it to market soon. Adil Daub, MBBA is a Clinical Professor of Medicine and Co-Director of the Melanoma Program at the University of California in San Francisco.

References 1. Rogers, HW, Weinstock, MA, Harris, AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287. 2. American Cancer Society. Cancer Facts & Figures 2013. Available at http:// www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/ document/acspc-036845.pdf. 3. Skin Cancer Foundation. Skin Cancer Facts. Available at http://www.skincancer.org/skin-cancer-information/skin-cancer-facts. 4. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-54. 5. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191-96. 6. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-6. 7. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164(4):776-84. 8. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med. 2012;367:1694-170. 9. Press Release. Exelixis Announces Presentation of Updated Phase 1b Data for Cobimetinib (GDC-0973/XL518) in Combination with Vemurafenib at ECC 2013. Data from BRIM7, ongoing phase 1b trial in patients with locally advanced/unresectable or metastatic melanoma with the BRAFV600 mutation. September 28, 2013. 10. Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res. 2012;65(1):9-22. 11. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21(8):1712-7. 12. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134-44. 13. Wolchok JD, Kluger H, Callahan MK , et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33. 14. Cha E, Daud A. Plasmid IL-12 electroporation in melanoma. Hum Vaccin Immunother. 2012;8(11):1734-8.

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Implementing Guideline-Based Strategies to Improve Adherence in Asthma Patients Robert Sussman, MD

Summary Despite effective treatments, many people with asthma continue to have functional impairments, require emergency room care or hospitalization and even die unnecessarily from their disease. Being adherent with asthma medication, particularly inhaled corticosteroids, improves outcomes. Providers can help those with asthma be more adherent by providing education and ongoing support. Key Points • Many patients with asthma do not achieve disease control. • Disease control can be determined by the use of a questionnaire or by patient/ family interviews. • Disease control should be assessed at every visit. • When asthma is not controlled, providers should confirm proper diagnosis, proper treatment, adherence, inhaled medication technique, and trigger avoid ance. • Nonadherence is an issue in asthma. • Improving adherence is not a one-time effort but requires multiple strategies that are tailored to the individual patient and repeated over time. • Improving adherence can improve outcomes.

Asthma remains a serious health risk in the United States. There are 25 million asthmatics in the U.S. who have annual medical costs of $56 billion. Every day in America approximately 63,000 people miss school or work due to asthma, 5,000 people visit the emergency room due to asthma, 1,300 people are admitted to the hospital due to asthma, and 10 people die from asthma.1 Exhibit 1 outlines the goals of therapy from the National Asthma Education and Prevention Program Expert Panel Report.2 One of the goals of asthma therapy is control of daily and nocturnal symptoms, yet 30 percent of asthmatics report nocturnal awakenings at least once per week. Another goal is prevention of exacerbations. In one study, 32 percent of children with asthma required ER visits in a year and 41 percent of patients had unscheduled visits. There are many reasons for poor control in this

disease. Some include lack of access to quality care, nonadherence, and optimal medications not being prescribed. Underestimation of severity, overestimation of control, inadequate environmental control, stress, depression, and cultural issues are other significant issues. Small subsets of patients remain poorly controlled despite optimal therapy. The treatment guidelines recommend therapy based on severity (Exhibit 2). A patient is placed in the highest severity category where they meet a criterion. For example, a patient’s symptoms all fall within the mild category, but she is having more than one nighttime awakening weekly. Her disease severity should be classified as moderate persistent and Step 3 therapy should be initiated. Patients should be seen for follow-up two to six weeks after initiation of treatment. At that time, the provider should evaluate the level of control and adjust therapy.

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Exhibit 1: Goals of Asthma Therapy2 • Prevent chronic symptoms (day, night, and with exertion) • Minimize need for rescue inhaler (<2 days a week) • Maintain (near) “normal” pulmonary function • Maintain normal activity levels (including exercise and attendance at work or school) • Meet patients’ and families’ expectations • Prevent recurrent exacerbations • Minimize ER visits and hospitalizations • Prevent progressive loss of lung function • Provide optimal therapy with minimal adverse effects

There are many elements of asthma control which can be used to determine if therapy needs to be modified (Exhibit 3). Disease control can be determined by the use of a questionnaire or by a patient/ family interview. The Asthma Control Test™ is one type of questionnaire that can be utilized at visits or at home to monitor control. Disease control should be assessed at every visit. According to the EPR3 guidelines, a patient is well controlled if they have symptoms less than twice a week, nighttime awakening less than twice a month, short-acting beta agonist (SABA) use less than twice a month, and peak flow or forced expiratory volume in 1 second (FEV1) is greater than 80 percent of predicted.2 Patients may overestimate their disease control. In one community survey, 41 percent of patients with asthma were not well controlled based on a score of less than or equal to 19 on the Asthma Control Test™. Of those uncontrolled by their answers, 25 percent were using only a SABA and 85 percent considered their asthma somewhat or completely controlled. The use of SABA more than two days a week for symptom relief generally indicates inadequate control and the need to step up treatment.2 Daily albuterol use is a marker of poorly controlled asthma. Most albuterol inhalers have 200 puffs per canister, equaling 100 doses, thus four canisters per year could equal daily albuterol use. When asthma is not controlled, providers should confirm proper diagnosis, treatment, adherence, and inhaled medication technique. Environmental control strategies for known allergens should be reviewed or implemented. Unsuspected triggers such as medications (including eyedrops), pets, and mold need to be considered. Other issues that can make it difficult to control asthma include untreated gastroesophageal reflux and sinus disease. Patient education and treatment adherence support are two ways to help patients improve the control of

their disease. Patient education is vital for optimal disease control. Asthma education should cover basic facts about asthma, goals of asthma management, medications including proper inhaler technique and importance of adherence, risks of suboptimal treatment, environmental control measures, early recognition and management of worsening symptoms, when and where to seek care, and the need for regular follow-up. In addition to education, all patients with persistent asthma need an action plan detailing what to do daily to control their disease and what to do in case of deterioration of control. Action plans need to be simple to follow and minimize the number and frequency of medications. Medication timing needs to fit the patient’s routine so they can be adherent. Providers have to consider affordability, another aspect of adherence, when selecting a medication regimen. Health literacy and language barriers are two areas that need to be considered in providing verbal and written educational materials. Twenty-five percent of people cannot read and understand basic written material. Written materials should be at a fifth-grade reading level or below. Importantly, tailored education can overcome health illiteracy. Written materials also are best provided in the patient’s native language. To communicate asthma information effectively, providers need to learn basic phrases in the most common languages found in their practice. Nonadherence with therapy is a major reason for the lack of adequate disease control, which impacts morbidity and mortality. Regular use of inhaled steroids is associated with a decreased risk of asthma death, and excessive use of short-acting beta agonists is associated with a markedly increased risk of asthma death.3 Inhaled corticosteroids, when taken regularly, decrease the number of hospitalizations for asthma by up to 80 percent.4

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Exhibit 2: Classifying Severity and Initiating Treatment in Patients > 12 Years Not Currently Taking Long-Term Controllers2 Classification of Asthma Severity (Youths > 12 Years of Age and Adults)

Components of Severity Intermittent

Impairment

Persistent Mild

Moderate

Severe

Symptoms

< 2 days/week

> 2 days/week (but not daily)

Daily

Several times/day

Nighttime awakenings

< 2 times/month

3 to 4 times/month

> 1 time/week (but not nightly)

Often 7 times/week

Short-acting beta2-agonist use for symptom control

< 2 days/week

>2 days/week but not daily and not more than 1 time on any day

Daily

Several times/day

Interference with normal activity

None

Minor limitation

Some limitation

Extremely limited

• FEV1 <80% predicted

• FEV1 >60% but <80% predicted

• FEV1 <60% predicted

• FEV1/FVC normal

• FEV1/FVC reduced 5%

• FEV1/FVC reduced >5%

• Normal FEV1 between exacerbations Lung function

• FEV1 >80% predicted • FEV1/FVC normal

Risk

Exacerbations requiring OSC

Step 1 Recommended Step for Initiating Therapy*

> 2/year

0 - 1 year

SABA PRN

Step 2

Step 3

Step 4 or 5

Low-Dose ICS

Medium-Dose ICS or Low-Dose ICS + and consider short course of systemic corticosteroids

High-Dose ICS + LABA (+ oral steroids)

In 2-6 weeks, evaluate level of asthma control that is achieved, and adjust therapy accordingly. *Only preferred regimens given FEV1 = Forced expiratory volume; FVC = forced vital capacity; OSC = oral system corticorsteroid; beta agonist; ICS = inhaled corticosteroid; LABA = long acting beta agonist

The reasons for nonadherence are numerous and can include medication costs, inadequate education, fear of side effects such as steroid phobia, fear of dependency on medication, cultural and family issues, and depression. Underestimation of severity and overestimation of control by the patient are associated with decreased adherence. Providers should inform patients “where they stand” with their disease control. No single strategy for improving adherence has

SABA = short-acting

been found to be effective. Comprehensive interventions combining multiple strategies may be effective. It is important to tailor educational messages to individual patients. Self-management programs and direct physician to patient discussion may be useful. Additionally, feedback of adherence rates to the patient may help them recognize when they have an issue. The optimal frequency for intervening with patients to sustain adherence is unknown. It is known that

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Exhibit 3: How Can Asthma Control Be Measured?

Inflammation? Direct or indirect?

Lung function?

Daytime symptoms?

Utilization of healthcare resources?

Functional status?

Nighttime awakenings?

Asthma Control

Use of “quick relief” inhaler and/or nebulizer?

Missed work and/or school?

repetition of adherence messages and open communication are important. Open-ended questions such as “What worries you most about your asthma?” can help providers identify barriers in individual patients. Ethno-cultural factors can also play a role in disease control and medication adherence. Minorities often accept suboptimal control of asthma. Greater than 50 percent of low income/high risk, predominantly minority inner-city residents in one survey believed that they only had asthma when they were having symptoms.5 Adherence was one-third less in this group. The single question, “Do you think you have asthma all of the time, or only when you are having symptoms?” can efficiently identify patients who do not think about or manage their asthma as a chronic disease. Adequate education may alter this belief. Another example is Latinos often classify diseases as “hot” or “cold”. Asthma is “cold” and thus amenable to “hot” treatment. Recommending taking medications with hot tea or water may improve adherence. Dominicans believe medication is overused in the U.S. and many prefer folk remedies. Providers need to be aware of potential barriers posed by ethno-cultural beliefs and educate themselves about those common in their practice. They can ask “In your community, what does having asthma mean?” Incorporating harmless or potentially beneficial remedies can help improve adherence with

Patient self-report of control?

recommended treatment regimens. Conclusion

Despite well disseminated asthma treatment guidelines, many patients still are not well controlled. One major reason is medication nonadherence. Adherence, and thus disease control, can be improved with patient and family education and ongoing provider support. Robert Sussman, MD is a Pulmonologist with the Atlantic Health System Overlook Medical Center in Summit, NJ.

References 1. American Lung Association Epidemiology & Statistics Unit Research Program Services. Trends in Asthma Morbidity and Mortality. November 2007. Available at www.lungusa.org. 2. NIH, National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR–3 2007). NIH Item No. 08–4051. Available at http://www.nhlbi.nih.gov/guidelines/asthma/ asthgdln.htm. 3. Lanes SF, García Rodríguez LA, Huerta C. Respiratory medications and risk of asthma death. Thorax. 2002;57(8):683-6. 4. Suissa S, Ernst P. Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin Immunol. 2001;107(6):937-44. 5. Halm EA, Mora P, Leventhal H. No Symptoms, No Asthma. The acute episodic disease belief is associated with poor self-management among inner-city adults with persistent asthma. Chest. 2006; 129:573-80.

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Improving Patient Outcomes with Effective Treatment Strategies in the Management of Type 2 Diabetes Mellitus Timothy S. Reid, MD

Summary Failure to maintain good glycemic control increases the risk of long-term complications in type 2 diabetes mellitus (T2DM). Achieving glycemic control will improve treatment outcomes, but existing barriers to optimizing control must first be overcome, including any patient issues, the failure of physicians to intensify therapy in a timely manner, and inadequacies in the health care system itself. Although underutilized, insulin therapy may be the key to achieving adequate control. Key Points • There is an epidemic of T2DM in the U.S. • Many patients with T2DM are not treated to appropriate goals. • Clinical inertia is one reason. • Patient and provider reluctance to move to insulin therapy is a major reason for the lack of goal achievement. • There are many different insulin regimens that can be initiated and tailored to a patient’s lifestyle. • Providers can use various strategies to ensure patient success with insulin nitiation.

It has been said that diabetes is the most demanding chronic illness that “ challenges every fiber of a patient’s body and spirit and demands a system of care that ministers to the biological, social, and psychological aspects of the illness”.1 Thus, it takes a “village” to accomplish this task.1 The number of Americans affected by type 2 diabetes mellitus (T2DM) continues to grow. In 2011, 25.8 million (8.3% of population) people had this disease.2 The number of those affected has been increasing by 1.9 million cases every year. T2DM especially impacts older people in the United States; those over 65 account for 10.9 million cases. Several factors have been identified as drivers of the T2DM epidemic including the increasing age of

the U.S. population, physical inactivity, the obesity epidemic, and increases in the sub-populations prone to diabetes. Native Americans, African Americans, and Hispanics are disproportionately affected by the disease. The cost of T2DM is enormous. It has been estimated at $245 billion in the U.S. in 2012.3 This includes $176 billion in direct medical costs and $69 billion in lost productivity. Costs for those with T2DM are 2.3-fold more than someone without this disease. Overall, one in 10 health care dollars is used for diabetes and its complications. One in five health care dollars is spent on someone with diabetes. Of the estimated $13,700 annual per patient costs, 43 percent are for hospital inpatient care, 18

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Exhibit 1: Clinical Inertia Results in Prolonged Exposure to Hyperglycemia10

Mean Hb1C (%)

10

Diet/exercise

9

Sulfonylurea or metformin monotherapy

Combination therapy

Insulin 9.6%

9.0%

8.6%

8 7

7.2%

7.4%

7.7% ADA goal < 7%

Exhibit 2: Patient Barriers to Insulin Therapy11-15 Perceptions Physical Barriers • Severity of diabetes • Visual • Failure of therapy • Cognitive • Personal failure - Developmental delays • Toxicity (misconcptions - Errors with aging regarding insulin risk) • Manual dextrity • Costs - Arthritic - Neurologic Aversions • Injections Cultural Barriers • Scheduling • Increased psychological • Social stigma resistance among women and ethnic minorities Legacy • Family Members Mental Health • Friends • Depression • Schizophrenia • ADHD

percent are for medications to treat complications, 12 percent are for diabetes medications and supplies, 9 percent for physician office visits, and the remaining 8 percent for nursing home care. Many patients with T2DM are not treated to appropriate goals. In the United Kingdom Prospective Diabetes study (UKPDS), only 33 percent of those treated with the combination of metformin and sulfonylurea were at goal after three years of therapy.4 Intensification of therapy through the use of combinations of oral therapies or insulin initiation would achieve appropriate goals, but there are many different barriers to improving diabetes care by achieving appropriate glucose goals. There are physician, patient, structural, administrative and economic barriers. Some physician barriers are the perception of the time and personnel requirements to make improvements, concerns surrounding weight gain and hypoglycemia with insulin or intensified medication

regimens, and a sense of inadequacy or perceived inability to manage a patient’s disease with treatments other than insulin.5-7 Other barriers include multiple therapeutic options to choose from and the high volumes of patients with diabetes.7 One major barrier is both physician and patient resistance to insulin therapy. The cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study highlighted some of the cornerstones leading to the presence of psychological insulin resistance and clinical inertia regarding adequate initiation and intensification of insulin therapy. This study was designed to examine the correlates of patient and provider attitudes toward insulin therapy. Patients in the U.S. reported more self-blame for insulin therapy than all other countries examined in this study. The belief that insulin therapy should be delayed until absolutely necessary was strongly held in the U.S. among physicians and nurses. Fifty to 55 percent of general practitioners (including nurs-

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Exhibit 3: Recommended Targets for Patients with T2DM20,21

ADA

AACE

< 7.0%*

< 6.5% (Individualize)

Pre-prandial plasma glucose

70 - 130 mg/dL

< 110 mg/dL

Peak post-prandial glucose

< 180 mg/dL†

< 140 mg/dL

A1C

Exhibit 4: Elements of Decision Making22 Approach to management of hyperglycemia

Patient attitude and expected treatment efforts

More Stringent

Less Stringent

Highly motivated, adherent, excellent self-care capacities

Less motivated, non-adherent, poor self-care capacities

Risks potentially associated with hypoglycemia, other adverse events

Low

Disease duration

Newly diagnosed

Life expectancy

Long

Important comorbidities

Absent

Few/mild

Severe

Established vascular complications

Absent

Few/mild

Severe

Resourcs, support system

Readily available

es) delay insulin therapy until absolutely necessary.8 Specialists and opinion leaders are less likely to do so. Delaying insulin therapy was less likely when health care providers perceived their patients to be adherent with previous therapies. Another physician barrier, clinical inertia, also plays a role in the failure of glucose goal achievement. Clinical inertia is the failure to initiate or intensify therapy in a defined time among patients who have not attained clinical goals and who would likely benefit from intensification.9 Clinical inertia leads to prolonged exposure to hyperglycemia. In

High

Long-standing

Short

Limited

the study illustrated in Exhibit 1, at insulin initiation, the average patient had five years with hemoglobin A1C (A1C) greater than 8% and 10 years with A1C greater than 7%.10 Patient barriers to insulin therapy are significant and can be categorized as perceptions, legacy, aversions, physical, cultural, and mental health (Exhibit 2).11-15 Individuals who believe in the value of tight glucose control, have strong self-efficacy, and have better interpersonal relationships with their health care providers are less reluctant to use insulin treatment.14

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Exhibit 5: Insulin Regimens

– Basal-Plus Insulin

Meal

Meal

Meal

Long Acting Insulin Dosing

Insulin Activity

Insulin Activity

– Basal Insulin

Rapid acting insulin dosing Meal

– Multiple Daily Insulin Mixed Insulin Dosing

Mixed Insulin Dosing

Meal

Insulin Activity

Insulin Activity

– Pre-Mixed Insulin

Meal

Basal Insulin dosing

Meal

24 Hours

24 Hours

Meal

Meal

Meal

Meal

Long acting insulin Dosing

Meal

24 Hours

24 Hours

There are also structural, administrative and economic barriers. Structural barriers to improving diabetes outcomes include office systems such as staffing and scheduling that do not support optimal care. Office systems can be reorganized to overcome some barriers. The appropriate delegation of some tasks to the office staff increases the amount of time the clinician has to discover and address barriers.1 Staff members may also uncover barriers because patients may be more comfortable sharing information with them.1 Administrative barriers include insurance coverage issues or restrictions for various therapies, including insulin pens, glucose monitoring strips, and insulin initiation counseling. Financial considerations definitely play a role in the ability of patients to be adherent with therapy. Although not practiced by many general practitioners, there is significant rationale for early insulin therapy in T2DM. In type 1 diabetes, data from the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) trials showed long-term reduction in retinopathy and nephropathy risk with tight control with insulin therapy.16,17 The newer insulins more closely match normal physiology and

Rapid Insulin Dosing

newer evidence links glucose excursions to CV risk.18 Insulin may also protect against endothelial damage. Lastly, patients with T2DM will eventually need insulin therapy given the progressive nature of the disease. Insulin therapy of course will be necessary for all patients with type 1 diabetes but is also indicated for latent autoimmune diabetes of the adult. Latent autoimmune diabetes (LADA) is a slowly progressing form of T1DM. It accounts for roughly 10 percent of patients who think they have T2DM. The working criteria for its diagnosis are (1) the presence of auto­antibodies in the blood, (2) adult age at onset, and (3) no need for insulin treatment in the first six months after diagnosis.19 The recommended glucose goals, which can be individualized for a given patient, are shown in in Exhibit 3.20,21 The elements that may guide the clinician in choosing an HbA1c target for a specific patient are shown in Exhibit 4.22 Treatment guidelines recommend starting most patients with oral agents, unless they meet criteria for insulin as initial treatment. Insulin is indicated in patients with T2DM where presenting blood glucose measurements are greater than 250mg/dl, A1C greater than 9.0%, or

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where oral therapy has failed to achieve goal.18 There are many different insulin regimens that are suitable for managing patients with T2DM. The options for advancing therapy in those who have not reached goals on oral agents include addition of basal insulin to current oral therapy, basal-plus therapy, mixed insulin, and multiple daily injections (MDI) insulin therapy. Basal insulin is usually given in addition to oral anti-diabetic agents. Basal insulins are very long acting; insulin glargine and detemir are examples. The advantages of basal insulins include that they are administered once daily (typically), that they can be added to most existing oral agent regimens, that they have a long half-life with flat kinetic profile, and that they have low hypoglycemic risk. They also have some disadvantages including cost, requiring subcutaneous administration, and requiring glucose monitoring. Basal-Plus therapy is when basal insulin is given along with a rapid-acting insulin at the largest meal. Oral agents can also be continued with this regimen. This regimen is given as twice-daily administration, with basal insulin in the evening and rapid insulin before the largest meal. Each insulin can be independently titrated. In addition to the same disadvantages as basal insulin, this regimen has increased complexity with different insulins. Premixed insulin formulations can be given as stand-alone insulin or with continued oral agents. Various combinations of long- and short-acting insulins (70/30, 75/25, 50/50) are available for meeting individual needs. This regimen is typically given as twice-daily administration. Premixed insulin can be added to metformin but is typically not used with secretagogues because of risk of hypoglycemia. The dual kinetic profile of the mixed insulin formulations can meet both basal and prandial insulin needs. This type of regimen can work well for patients with predictable, consistent lifestyles. MDI insulin therapy can be given as stand-alone insulin or in addition to metformin. This type of regimen provides individualized dosing for meals as content and quality of meals change and independent basal coverage/control. It requires four injections daily – rapid acting insulin with meals and basal insulin at bedtime. This type of regimen is useful with varied lifestyle and meal timing. The disadvantages of MDI are complexity, the cost of two insulin preparations, and the need for more intensive glucose monitoring. Exhibit 5 compares the insulin profiles of these various insulin regimens. Numerous strategies can be used to help providers succeed in improving outcomes in patients with T2DM when initiating insulin.23 Providers need to

frame the need to move to insulin properly. Providers need to avoid blaming the patient for failing to achieve goals and requiring insulin. Providing supportive, individually tailored messages about insulin, including that insulin does not mean failure and it does not indicate that diabetes has worsened, will help patients accept this therapy. Before starting insulin, providers need to address emotional issues by asking patients about their thoughts or feelings about insulin. Providers need to uncover each patient’s obstacles by use of simple, respectful, open-ended questions. They can consider using a brief questionnaire to get at this information. When initiating insulin, the process of insulin use has to be demonstrated for the patient. When choosing an insulin regimen, providers should consider insulin pens; these are preferred by patients and providers, improve adherence, and enhance quality of life.12 All patients should be seen for follow-up two weeks after initiating insulin. Patients should be educated about the risks, symptoms, and treatment of hypoglycemia. To have the best outcomes, providers should be referring patients for diabetes self-management education and medical nutrition therapy. Diabetes self-management education is most effective when delivered by a multidisciplinary team.24 Providers can provide ongoing self-management support. Office staff can be especially helpful in supporting and reinforcing self-management. This support is especially important during early insulin experiences. Conclusion

Type 2 diabetes mellitus is a significant health issue that is facing our patients and society. There are difficult barriers to optimum care that our health systems and patients face. Earlier use of insulin to achieve appropriate glucose goals will significantly benefit patients. The transition to insulin and injection therapy, in general, is a sensitive issue that must be addressed carefully with patients. There are strategies that work and can help teams succeed in the care of their patients. Providers need to create collaborative relationships with patients and design systems to facilitate chronic disease care. Timothy S. Reid, MD is a Diabetes Specialist with the Mercy Diabetes Center in Janesville, WI.

References 1. Shahady EJ. Barriers to Effective Diabetes Care: How to Recognize and Overcome. Consultant 360. 2011. Available at http://www.consultant360.com/ content/barriers-effective-diabetes-care-how-recognize-and-overcome. 2. American Diabetes Association. Diabetes Statistics. Available at http://www. diabetes.org/diabetes-basics/diabetes-statistics.

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3. American Diabetes Association. Economic Costs of Diabetes in the U.S. in

lin resistance in individuals with type 2 diabetes. Diabetes Care. 2010;33(8):1747-9.

2012. Diabetes Care. 2013;36:1033-46.

15. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of

4. UKPDS Study Group. UKPDS 28: a randomized trial of efficacy of early

comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care.

addition of metformin in sulfonylurea-treated type 2 diabetes. Diabetes Care.

2001;24(6):1069-78.

1998;21:87-92.

16. [No authors listed]. The effect of intensive treatment of diabetes on the de-

5. Korytkowski M. When oral agents fail: practical barriers to starting insulin.

velopment and progression of long-term complications in insulin-dependent

Int J Obes Relat Metab Disord. 2002;26 Suppl 3:S18-24.

diabetes mellitus. The Diabetes Control and Complications Trial Research

6. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyper-

Group. N Engl J Med. 1993;329(14):977-86.

glycemia in type 2 diabetes: a consensus algorithm for the initiation and adjust-

17. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and

ment of therapy: a consensus statement of the American Diabetes Association

cardiovascular disease in patients with type 1 diabetes. N Engl J Med.

and the European Association for the Study of Diabetes. Diabetes Care.

2005;353(25):2643-53.

2009;32(1):193-203.

18. Hirsch IB, Bergenstal RM, Parkin CG, et al. A Real-World Approach to

7. Hayes RP, Fitzgerald JT, Jacober SJ. Primary care physician beliefs about insu-

Insulin Therapy in Primary Care Practice. Clinical Diabetes. 2005;23(2):78-86.

lin initiation in patients with type 2 diabetes. Int J Clin Pract. 2008;62(6):860-8.

19. Naik RG, Brooks-Worrell BM, Palmer JP. Latent autoimmune diabetes in

8. Peyrot M, Rubin RR, Lauritzen T, et al. Resistance to insulin therapy

adults. J Clin Endocrinol Metab. 2009;94(12):4635-44.

among patients and providers: results of the cross-national Diabetes Attitudes,

20. American Diabetes Association. Standards of medical care in diabe-

Wishes, and Needs (DAWN) study. Diabetes Care. 2005;28(11):2673-9.

tes--2013. Diabetes Care. 2013;36(Suppl 1):S11-S66.

9. Zafar A, Davies M, Azhar A, Khunti K. Clinical inertia in management of

21. Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of

T2DM. Prim Care Diabetes. 2010;4(4):203-7.

Clinical Endocrinologists medical guidelines for clinical practice for the man-

10. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2

agement of diabetes mellitus. Endocr Pract. 2007;13 Suppl 1:1-68.

diabetes. Diabetes Care. 2004;27(7):1535-40.

22. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia

11. Peyrot M, Rubin RR, Khunti K. Addressing barriers to initiation of insulin

in type 2 diabetes: a patient-centered approach: position statement of the Amer-

in patients with type 2 diabetes. Prim Care Diabetes. 2010;4 Suppl 1:S11-8.

ican Diabetes Association (ADA) and the European Association for the Study of

12. Magwire ML. Addressing barriers to insulin therapy: the role of insulin

Diabetes (EASD). Diabetes Care. 2012;35(6):1364-79.

pens. Am J Ther. 2011;18(5):392-402.

23. Polonsky WH, Jackson RA. What’s So Tough About Taking Insulin? Ad-

13. Heile MK, Reid TS. Integrating advances in insulin into clinical practice: Ef-

dressing the Problem of Psychological Insulin Resistance in Type 2 Diabetes.

fective utilization of insulin in patient management. J Fam Pract. 2013;62(9

Clinical Diabetes. 2004;22:147-50.

Suppl):S18-31.

24. Funnell MM, Brown TL, Childs BP, et al. National standards for diabetes

14. Nam S, Chesla C, Stotts NA, et al. Factors associated with psychological insu-

self-management education. Diabetes Care. 2008;31 Suppl 1:S97-104.

46 Journal of Managed Care Medicine | Vol. 17, No. 1 | www.namcp.org


Improving the Management of Severe Hemophilia Mark T. Reding, MD

Summary Although rare, hemophilia is an expensive condition to manage. Because it is also complex to manage, caring for those affected within a hemophilia treatment center provides the best treatment outcomes. Additional clotting factor products are on the horizon that will hopefully continue to improve management of this condition. Key Points • Although rare, hemophilia is complex and expensive to manage. • The complications of hemophilia cause significant joint destruction and disability. • Treatment is factor replacement. • Inhibitory antibodies against the replacement factors are a major treatment issue. • Better outcomes occur when patients are managed by a hemophilia treatment center.

Hemophilia is a congenital bleeding disorder due to the deficiency or absence of a coagulation cascade protein. In hemophilia A, there is a factor VIII deficiency and in hemophilia B there is a factor IX deficiency. As shown in Exhibit 1, this is a disorder that predominately occurs in males. Hemophilia affects all racial and socioeconomic groups equally. There are approximately 20,000 hemophiliacs in the United States and more than 500,000 hemophiliacs worldwide. Although it only affects a limited number in the U.S., hemophilia is an expensive and complex condition to manage.1 As shown in Exhibit 2, the mean annual cost of routine factor prophylaxis alone is significantly more costly than the annual medical costs for several other much more common conditions.2-5 The majority of hemophiliacs in the U.S. are young. Forty-eight percent are under age 19. Another 36 percent are between 20 and 44.6 The genetics for hemophilia are interesting. The

genes for factors VIII and IX are carried on the X chromosome. Thus, women are the carriers of the hemophilia gene. For each child a carrier has, there is a 50 percent chance that a son will have hemophilia and a 50 percent chance that a daughter will carry the gene. Women can only have hemophilia if their father has hemophilia and their mother is a carrier. This is very uncommon; therefore, as cited previously, males are predominately affected by this disorder. Approximately 30 percent of cases have no family history of hemophilia because there is a high rate of spontaneous mutations that can result in the disorder. People with a family history of the disorder should have testing to identify carriers. Women with a family history can defer testing until they are considering pregnancy. Carriers should get preconception counseling. All newborn males of carriers should have cord blood testing. Boys with bleeding secondary to birth trauma, circumcision, or immuniza-

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Exhibit 1: Clinical Phenotypes are Indistinguishable. Hemophilia A Hemophilia B • Factor VIII deficiency • Factor IX deficiency • Classical hemophilia

• Christmas disease

• 1 in 5,000 to 10,000 male births

• 1 in 30,000 male births

• 80% of total cases

• 20% of total cases

• Spontaneous mutations = 30%

• Spontaneous mutations = 20%

Exhibit 2: Magnitude of the Problem2-5

Diabetes (28 million)

Mean annual per patient medical expenditures

COPD (15 million)

Mean annual per patient COPD-relat$2,000 - $43,000 ed health care costs

MS (300,000)

Mean annual per patient specialty drug costs

$28,000 - $42,000

Hemophilia (20,000)

Mean annual cost for routine factor prophylaxis (74 kg adult)

$180,000 - $300,000

tions should be tested. Other indications for testing include joint bleeds or hematomas when a child is learning to walk. The severity of bleeding tendency in an individual with the disorder depends on the factor levels (Exhibit 3). Hemarthrosis, primarily involving the ankles, knees, and elbows, is the most common complication of hemophilia (Exhibit 4). Bleeding in joints leads to a vicious cycle of inflammation, synovitis, and further bleeding.7,8 Forty-five percent of patients experience their first joint bleed within the first year of life. Ninety percent have at least one joint bleed by age 4. Ninety percent of those with severe hemophilia have chronic degenerative changes involving at least one joint by age 25. Physical activity restrictions due to arthropathy are reported by 40 percent. Other complications of hemophilia include deep muscle bleeds, intracranial hemorrhage, and soft tissue hematoma. Recurrent joint bleeds in patients with severe deficiency and no access to factor replacement may lead to joint pseudotumors. Up until the 1940s, hemophilic life expectancy was 25 to 30 years and those affected were usually disabled by age 20. By 1960, life expectancy had

$7,900 - $13,700

increased to 40 years due to transfusions of whole blood and plasma, but most hemophiliacs were still severely disabled and unemployed. The first commercially available factor VIII concentrate became available in 1968. Life expectancy reached 60 years by 1980. Unfortunately, in 1982, the first reported cases of AIDS transmitted via factor replacement were reported. More than 50 percent of patients ultimately were infected with HIV, and more than 75 percent were infected with viral hepatitis. In 1985, virally inactivated factor concentrates were introduced. The most recent advances were the introduction of recombinant factor VIII in 1992 and recombinant factor IX in 1997. There are now first-, second-, and third-generation recombinant factor concentrates. There have been no documented cases of viral transmission in more than 25 years. The primary treatment for hemophilia is factor replacement with plasma-derived and recombinant factor VIII and factor IX concentrates. The goal is for every child with hemophilia to learn self-infusion of their factor replacement. Factor replacement can be done as on-demand or prophylactic therapy. On-demand replacement stops

48 Journal of Managed Care Medicine | Vol. 17, No. 1 | www.namcp.org


Exhibit 3: Severity of Hemophilia

Mild (> 5%)

Moderate (1 - 5%)

Severe (< 1%)

• Bleed only after severe injury, trauma or surgery • May not be diagnosed until adulthood

• Bleed after injury or surgery • May have occassional spontaneous bleeding

• Frequent spontaneous bleeding • Diagnosis made in early childhood

Exhibit 4: Process of Joint Damage from Hemophilia Blood in joint

Recurrent bleeding

Inflammation

Synovitis

bleeds after they occur, but progressive joint damage still develops. This is only appropriate for those with mild bleeding phenotypes. Prophylactic factor replacement prevents bleeds from occurring and protects joints from progressive arthropathy. It allows for more “normal” physical activities. Prophylaxis in children was pioneered in Sweden in the 1960s. This has been the standard of care since the introduction of recombinant factor concentrates in the 1990s and is effective in preventing long-term arthropathy.9 Prophylaxis is initiated after the first joint bleed or before age 3. There is much less data on prophylaxis in adults, but it is increasingly used. Adult prophylaxis has been shown to decrease bleeding frequency and improve QOL, but it is not yet known if it prevents

progression of arthropathy.10,11 The other issue that needs to be resolved is how to deal with children who enter adulthood on regular prophylaxis and with preserved joints. Currently, the most serious complication of factor replacement therapy is the development of inhibitory antibodies. Some hemophilia patients’ immune systems identify infused factor VIII or IX as a foreign protein. Infusion of factor concentrate to prevent or treat bleeding triggers an immune response and the development of antibodies. Antibodies directed against factor VIII or IX neutralize the procoagulant effect and render standard treatment useless. These occur following treatment with both plasma-derived and recombinant factor products. Antibodies to factor VIII are relatively common

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(~25%) and are well-studied and characterized. Factor IX antibodies are rare, occurring in less than 5 percent of hemophiliacs. These patients also often develop allergic reactions to factor infusion. The risk factors for development of inhibitory antibodies are poorly defined. Typically, they are seen in those with severe hemophilia. It may occur in those with mild or moderate hemophilia, usually after intense factor exposure related to trauma or surgery. Luckily, antibody development is no longer associated with increased mortality. However, bleeding is more difficult to control and devastating joint disease and disability occurs because bleeds cannot be prevented. Because of disability and pain, the severely damaged joints will many times need replacement. This is a major clinical and economic challenge. Treatment of patients with inhibitory antibodies is complicated, extremely expensive, and requires hemophilia treatment center (HTC) expertise. These patients are rare and the treatment options have significant limitations. Immune tolerance induction (ITI) therapy and bypass agents are the only options. With ITI therapy, factor concentrate is given regularly over a period of time until the body is trained to recognize the treatment product without reacting to it. When ITI is successful, the inhibitors disappear and the patient’s response to factor concentrates returns to normal. The majority of people who undergo this therapy will see an improvement within 12 months, but more difficult cases can take two years or longer. Unfortunately, this therapy costs approximately $1 million per patient and is only 70 percent effective overall. Conversely, the effects of long-term inhibitor antibodies can be devastating. Different dosing schedules are currently being used for ITI therapy, and the best one for eliminating inhibitory antibodies has not yet been defined. Daily high doses of factor concentrates may induce tolerance faster, but this type of regimen is more expensive and carries different risks than do schedules that involve giving less factor concentrate, less frequently. Bypassing agents, such as activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa), are used to treat acute bleeding in people with high titers of antibodies. These agents also have incomplete (75% to 90%) and unpredictable efficacy. No standard laboratory monitoring for this therapy exists and thrombosis is a real risk. Both long-acting factor VIII and IX products are in development. The first approval of one of these agents is expected in early 2014. These long-acting products have longer half-lives and less frequent dosing. It is hoped that they will provide more ef-

fective prophylaxis and better adherence. The costs are yet unknown for these agents. Gene therapy in hemophilia has been an area of active investigation for 20 years. Clinical trials in animal models have shown it can work but the scale up to humans has been challenging. Gene therapy is still expected to be a clinical reality, but not anytime soon. The management of those with severe hemophilia can be improved by ensuring access to safe and effective factor replacement therapy. A major step in improving care would be to ensure that all severe hemophiliacs are cared for in a HTC. Approximately 30 percent of hemophilia patients in the U.S. receive care outside of an HTC. HTCs offer a multidisciplinary team approach to care of these complex patients. There is a significant benefit for severe hemophiliacs being cared for at an HTC; there is a 40 percent reduction in mortality among those who receive HTC care versus those who do not.12 Similarly, people who used a treatment center were 40 percent less likely to be hospitalized for bleeding complications.13 Patients, community providers, and managed care organizations need to be educated about the benefits of HTC-based care and about which patients would most benefit from these centers. Another vital step in improving care is increased support and collaboration among academia, industry, and managed care. Clinical trials need to be conducted to answer key questions and fill in knowledge gaps. Major areas of clinical trials needed are prophylaxis in adults, managing comorbidities of aging, optimal clinical use of long-acting agents, and improved treatments for inhibitor patients. One collaborative effort under way is development of a secure national database that will be used to support clinical outcomes analysis, research, advocacy and public health reporting in the hemostasis and thrombosis community by the American Thrombosis and Hemostatis Network (ATHN). ATHN is a nonprofit organization committed to advancing and improving care for individuals affected by bleeding and thrombotic disorders. A last step to improving care is addressing cost issues. Factor replacement accounts for 45 to 93 percent of the total health care cost of hemophilia, depending on severity and treatment regimen.1 The federal 340B program lowers the cost of acquiring covered outpatient drugs, including factor replacement products, for selected health care providers, including HTCs, so that they can stretch their resources in order to serve more patients or improve services. 340B pricing of factor replacement is generally 20 to 40 percent lower than non-340B pric-

50 Journal of Managed Care Medicine | Vol. 17, No. 1 | www.namcp.org


ing. Barriers to accessing HTC 340B programs need to be eliminated. This is also going to require support and collaboration among academia, industry, and managed care.

4. Gleason PP, Alexander GC, Starner CI, et al. Health plan utilization and costs of specialty drugs within 4 chronic conditions. J Manag Care Pharm. 2013;19(7):542-8. 5. Fischer K, Steen Carlsson K, Petrini P, et al. Intermediate-dose versus highdose prophylaxis for severe hemophilia: comparing outcome and costs since the

Conclusion

1970s. Blood. 2013;122(7):1129-36.

Hemophilia is a rare condition, with a large economic burden on our health care system. There is great progress already in place for the management of hemophilia, but many important unanswered questions remain. HTC-based care is key to the optimal management of this complex condition, particularly for those with severe hemophilia. In addition, there needs to be more collaboration across the boundaries of academia, industry, and managed care.

6. Centers for Disease Control and Prevention. Summary Report of UDC Activity (National). Report Date – May 30, 2011 7. Valentino LA, Hakobyan N, Enockson C. Blood-induced joint disease: the confluence of dysregulated oncogenes, inflammatory signals, and angiogenic cues. Semin Hematol. 2008;45(2 Suppl 1):S50-7. 8. Lafeber FP, Miossec P, Valentino LA. Physiopathology of haemophilic arthropathy. Haemophilia. 2008;14 Suppl 4:3-9. 9. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-44.

Mark T. Reding, MD is an Associate Professor of Medicine in the Divi-

10. Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of

sion of Hematology, Oncology, and Transplantation and Director, Cen-

two prophylaxis regimens and a paired comparison of on-demand and prophylaxis

ter for Bleeding and Clotting Disorders at the University of Minnesota

treatments in hemophilia A management. J Thromb Haemost. 2012;10(3):359-67.

Medical Center in Minneapolis, MN.

11. Manco-Johnson MJ, Kempton CL, Reding MT, et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment

References

with sucrose-formulated recombinant factor VIII in adults with severe hemo-

1. Johnson KA, Zhou ZY. Costs of care in hemophilia and possible implications

philia A (SPINART). J Thromb Haemost. 2013;11(6):1119-27.

of health care reform. Hematology Am Soc Hematol Educ Program. 2011;2011:413-8.

12. Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia:

2. American Diabetes Association. Economic costs of diabetes in the U.S. in

relations with source of medical care. The Hemophilia Surveillance System

2012. Diabetes Care. 2013;36(4):1033-46.

Project Investigators. Blood. 2000;96(2):437-42.

3. Dalal AA, Christensen L, Liu F, Riedel AA. Direct costs of chronic obstruc-

13. Soucie JM, Symons J, Evatt B, et al. Home-based factor infusion therapy and

tive pulmonary disease among managed care patients. Int J Chron Obstruct Pul-

hospitalization for bleeding complications among males with hemophilia. Hae-

mon Dis. 2010;5:341-9.

mophilia. 2001; 7:198-206.

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New Treatment Paradigms in the Management of Metastatic Breast Cancer Sara A. Hurvitz, MD, FACP

Summary As more underlying drivers of breast cancer cell growth have been discovered and therapies targeted against these drivers developed, the treatment paradigm of breast cancer has changed to an individualized approach. Therapy is selected based on the presence or absence of tumor markers such as human epidermal growth factor receptor 2 (HER2) and hormone receptors (HR). Significant advances are being made in this disease, even in the metastatic setting, which are allowing patients to live longer. Key Points • HER2+ metastatic breast cancer (MBC) – Dual blockade of HER2 is synergistic. – First-line therapy is triple therapy with pertuzumab/trastuzumab/taxane. – Second- and third- line therapy is TDM1. – Continuing HER2-blockade in the face of trastuzumab-resistance is beneficial. • HR+/HER2- MBC – Endocrine therapy should be used until options are exhausted. – Chemotherapy is indicated in some cases. – In postmenopausal women whose disease has progressed on nonsteroidal aromatase inhibitors, exemestane combined with everolimus is an excellent option but toxicity needs to be closely managed. • TNBC – Only current treatment is chemotherapy. – Research ongoing on targeted therapy. • Although MBC is considered incurable, many patients are living a very long time (5+ years) with well-controlled disease because of targeted therapy.

Breast cancer is the most common cancer among women and the second leading cause of death with almost 40,000 annual deaths.1 Incidence and prevalence of Stage IV breast cancer are not formally collected, but it is estimated that over 160,000 women are living with MBC in the United States. Breast cancer has traditionally been classified by histology, but this classification tells you nothing about the prognosis of a particular case.2 Treatment decisions are now being based on the molecular basis of the tumor cells rather than histologic appearance. The molecular type gives clues about the genes that may be mutated or turned on and thus can be targeted with therapies. As shown in Exhibit 1, basal-

like disease has the worst prognosis and luminal A type has the best.3 Luminal A tumors tend to have high HR expression, be HER2 negative, and tend to be slower growing. Basal-like tumors tend to be triple negative – no estrogen receptors, progesterone receptors or HER2 expression. HER2 positive breast cancer encompasses about 20 to 25 percent of cases.4 In normal cells, HER2 mediates signaling for cell proliferation and survival.5 When HER2 is overexpressed, the amount of HER2 protein on the cell surface increases 10- to 100-fold. This may lead to excessive cellular division and formation of tumors.6 There can be as many as 2,000,000 HER2 molecules per cell in

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Exhibit 1: Breast Cancer is Not All One Disease3

B

Censored

1.0

Luminal A Luminal B

Probability

0.8

Basal ERBB2+

0.6 0.4 0.2

0

P < .01 24

48

72

96

Overall Survival (months) ERBB2+ = HER2+

malignant tissues, instead of the normal 20,000 to 50,000 molecules per cell.4 Before the discovery of targeted therapy, patients with HER2 + tumors had lower survival than patients without, even when the disease was detected early. Trastuzumab [Herceptin®], approved in 1998, has changed the natural history of HER2+ breast cancer. This monoclonal antibody binds to the outside of cells that overexpress HER2 and prevents the unregulated growth of these cells. Patients with HER2+ MBC treated with trastuzumab now have comparable or better outcomes than HER2 negative MBC.7 An interesting analysis found that approximately 154,000 life-years have been saved over the past 15 years attributable to first-line trastuzumab therapy in HER2+ MBC.8 This study found an estimated median overall survival (OS) of 36 months with trastuzumab/chemotherapy versus 16 months for chemotherapy alone. The NCCN guidelines include numerous different chemotherapy regimens that have been studied in combination with trastuzumab.9 About 12 percent of breast cancer cases express both HER2 and estrogen receptors. HER2-targeted agents plus hormonal therapy can be used to treat these patients. Trastuzumab and lapatinib have both been studied in combination with aromatase inhibitors (letrozole, anastrozole).10-11 These trials have shown improvements in progression-free survival (PFS) and response rate. One lesson learned from trials in HER2+/HR+ disease is that HER2 must be targeted or the outcomes are not ideal. Hormone

therapy alone is not enough in HER2+/HR+ disease. HER2 is activated by binding to itself, epidermal growth factor receptor (EGFR), HER1, or HER3. Its preferred binding partner is HER3. The HER2/ HER3 dimer turns on the intracellular signaling pathways through transphosphorylation, resulting in cell growth, proliferation and survival via mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways. A better understanding of how HER2 gets activated led to the development of additional agents targeting HER2 overexpression. Pertuzumab [Perjeta®], which targets a different part of the HER2 receptor than trastuzumab, was approved in 2012. It is a humanized monoclonal antibody designed to be a HER dimerization inhibitor.12,13 It binds to the dimerization domain of HER2 and may inhibit the ability of HER2 to pair with other HER receptors. By blocking the formation of HER2–HER3 dimers, pertuzumab may prevent the activation of intracellular signaling cascades, including the P13 and MAPK signaling transduction pathways, which are key biological processes that mediate cancer cell proliferation and survival. Pertuzumab has been shown to decrease tumor growth in preclinical models that do not overexpress or have gene amplification of HER2. Pertuzumab has been studied in combination with trastuzumab and chemotherapy in women with previously untreated HER2+ MBC. The triple combination improved PFS by six months.14,15 Overall

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Exhibit 2: Effect of Pertuzumab on OS14,15 1 year 94%

100 90

89%

80 Overall Survival (%)

2 years 3 years

81%

70

66%

69%

60 50

HR = 0.66 95% Cl 0.52 - 0.84

50%

40

P = 0.0008

30 20

P + T + D: 113 events; median not reached P + T + D: 154 events; median 37.6 months

10 0

0

5

10

15

20

25

30

No. at Risk P + T + D 402 387 371 342 317 230 143 P + T + D 406 383 350 324 285 198 128

35

40

45

50

55

84 67

33 22

9 4

0 0

0 0

Time (months)

P, pertuzumab; T, trastuzumab; D, docetaxel

survival in this study was also significantly improved (Exhibit 2).14,15 Benefit was shown even in the patients who had previously received trastuzumab. Thus, pertuzumab also works in patients who have developed resistance to trastuzumab. This triple combination is now FDA approved and has become the first-line therapy for HER2+ MBC. The next new agent for MBC is trastuzumabemtansine [TDM1, Kadcyla®] which is an antibodydrug conjugate consisting of trastuzumab linked to the cytotoxic agent mertansine (DM1). By binding to HER2, trastuzumab enters cells and takes the emtansine with it. Once in the cancer cell, the emtansine is cleaved of the molecule and destroys the cell by binding to tubulin. Because the monoclonal antibody targets HER2, and HER2 is only overexpressed in cancer cells, the conjugate delivers the toxin specifically to tumor cells.16 This allows minimal systemic adverse effects. Trials have shown that trastuzumab-emtansine has an advantage over regular chemotherapy plus trastuzumab because it is better tolerated. Patients are able to complete more cycles of this therapy.17 TDM1 has not yet been approved for the first-line setting but is under study for this indication. Once a patient progresses on first-line therapy, continuing HER2-blockade in trastuzumab-resistant disease improves outcomes. The options include lapatinib plus capecitabine, lapatinib plus trastuzumab, trastuzumab plus capecitabine, and TDM1.

There are also emerging data on using pertuzumab combined with trastuzumab or everolimus. There is a benefit in PFS and OS.18-20 Lapatinib [Tykerb®], which hits the HER2 receptor on the inside of the cancer cell, was approved in 2007. It has shown benefit in combination with trastuzumab for PFS (four weeks) and OS (56% vs 41% at 12 months) in heavily pretreated patients (Exhibit 3).21 Thus, dual blockade of HER2 is synergistic. The issue with lapatinib is a 60 percent rate of diarrhea when combined with trastuzumab. This can be life-threatening diarrhea. EMILIA is a Phase III, randomized, multicenter, international, two-arm, open-label clinical trial designed to compare the safety and efficacy of TDM1 with that of capecitabine + lapatinib for HER2+ advanced BC following progression on trastuzumab. The PFS and OS were longer in the TDM1 group compared to capecitabine/laptinib (9.6 vs. 6.4 months; 25.1 vs. 30.9 months, respectively).22 There was a modestly lower rate of significant adverse events in the TDM1 treated group. Dose limiting toxicities that can occur with TDM1 are thrombocytopenia and elevated liver function tests. Based on the results of this trial, TDM1 is becoming the therapy of choice in the second-line setting over lapatinib plus capecitabine. For HER2+ MBC, several regimens are under investigation for second-line therapy. One of the pathways that has implicated in trastuzumab resis-

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Exhibit 3: Effect on Overall Survival21

L

100

Survival (%)

60

N = 146 105 (72)

Median, months

9.5

14

Hazard ratio (95% Cl)

0.74 (0.57, 0.97)

Log-rank P value

56%

70%

.026

6 Month OS

40

41%

20

0

N = 145 113 (78)

Died, N (%)

80%

80

L+T

L+T L 0

5

12 Month OS

10

15

20

25

30

35

Time for Randomization (months) Patients at Risk L+T 148 L 148

121 102

88 65

64 47

43 28

25 13

1 0

L, lapatinib; T, trastuzumab

tance is mTOR. When HER2 is blocked, sometimes the pathways below can turn themselves on so the cell continues to grow. The theory is that blocking both HER2 and mTOR might halt the process. Everolimus, currently FDA approved in ER+ breast cancer, is being studied in combination with trastuzumab for trastuzumab resistance in heavily pretreated HER2+ MBC.23 A Phase III study has been presented with a modest improvement in PFS (four weeks) but the publication of the overall survival data is awaited.24 Approximately 60 to 75 percent of invasive breast cancers are HR+ because they express estrogen receptors (ER) or progesterone receptors (PR). HR+ breast cancers depend on estrogens for growth. Estrogen receptor signaling increases the proliferation rate of normal breast epithelia, and by doing so, reduces the time available for DNA repair, leading to an increased risk of mutation. In the first, second, and probably third lines, hormonal therapies will be used. Importantly, HR+ breast cancers are sensitive to treatment with endocrine therapy (i.e., interventions that impair ER signaling). Increased ER expression correlates with improved response to endocrine therapy. In the small proportion of HR+ and HER2+ tumors, combined treatment with endo-

crine and HER2-targeted therapy has been shown to be efficacious. There are multiple mechanisms within the ER pathway that allow for the development of resistance to endocrine therapy. Treatments that overcome resistance are crucial, especially for women with advanced disease that has progressed on previous endocrine therapy. Exhibit 4 shows a timeline of approval of endocrine and chemotherapies. Selective estrogen receptor modulators (SERMs), such as tamoxifen, competitively bind to estrogen receptors. In the late 1990s, nonsteroidal aromatase inhibitors (NSAIs), such as anastrozole and letrozole, were approved for the first-line or later-line treatment of postmenopausal women with HR+ breast cancer. The steroidal AI, exemestane, was also approved for the later-line treatment of postmenopausal women with HR+ breast cancer. Aromatase inhibitors block the activity of the enzyme aromatase, which is responsible for estrogen synthesis in peripheral tissues and is the main source of endogenous estrogen in postmenopausal women. More recently in the 2000s, the estrogen receptor downregulator, fulvestrant, was approved for the treatment of postmenopausal women with HR+ advanced breast cancer whose disease has progressed

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Exhibit 4: Historical Timeline of Therapies for HR+ Advanced Breast Cancer

Anthracyclines • Doxorubicin • Epirubicin

Taxanes • Paclitaxel • Docetaxel

1980s

1990s

2000s

Chemotherapy

Endocrine Therapy

Others • Capecitabine • Gemcitabine • Ixabepilone • Eribulin • Nab-paclitaxel

1896

1977

1990s

2002

2010

Oophorectomy

SERMs • Tamoxifen • Toremifene

AIs • Anastrozole • Letrozole • Exemestane

ERDs • Fulvestrant

ERDs • High-dose Fulvestrant*

2012

Targeting mechanisms of endocrine resistance

Abbreviations: AI, aromatase inhibitor; ERDs, estrogen receptor down regulator; HR+; hormone receptor positive; SERMs, selective estrogen receptor modulators. * Marginal improvement over lower dose fulvestrant.

on previous endocrine therapy. This agent acts as a pure antagonist to the estrogen receptor with no known agonist effects, and has been shown to bind, block, and increase the degradation of the estrogen receptor. Regardless of the specific mechanism of action, all endocrine therapies ultimately inhibit ER-mediated signaling to prevent growth of tumor cells dependent on the ER pathway. The NCCN recommends different treatment approaches depending on the length of time since prior endocrine therapy.9 For postmenopausal women who have received endocrine therapy within the last year, subsequent treatment approaches should include up to three rounds of endocrine therapy regimens. Chemotherapy is only recommended in postmenopausal women who have failed three consecutive regimens of endocrine therapy or who develop symptomatic visceral disease. For postmenopausal women who have not received endocrine therapy within the last year, subsequent treatment approaches include additional endocrine therapy with aromatase inhibitors or anti-estrogens. Continuing to use hormonally-targeted approaches in the face of resistance is better tolerated by the patients than chemotherapy and avoids the significant effects of chemotherapy as long as possible. Aromatase inhibitors have become the standard of care for initial treatment of postmenopausal women with hormone-receptor–positive (HR+) advanced

breast cancer. Results from several studies demonstrate that aromatase inhibitors have improved efficacy compared with tamoxifen. Fulvestrant has demonstrated similar efficacy compared with tamoxifen as initial treatment for advanced disease. Results from combination endocrine therapy trials with anastrozole and fulvestrant for the initial treatment of treatment-naive postmenopausal women with HR+ advanced breast cancer are inconclusive and results demonstrate marginal clinical benefit.25-28 These trials used half the dose of fulvestrant, which is currently approved and is the more effective dose.29 Despite several endocrine therapy options, the majority of patients with advanced breast cancer eventually develop resistance. This could manifest as disease recurrence during or within a short interval after completing adjuvant endocrine therapy, or progression during endocrine therapy for advanced disease. Therefore, it is important that current treatment approaches for HR+ advanced breast cancer target mechanisms of endocrine resistance. The definition of endocrine resistance in advanced breast cancer is evolving. The most recent definition of primary resistance is progressive disease within six months of starting treatment. The most recent definition of secondary or acquired resistance is initial response to treatment with relapse six months or later. It should be noted that the definition for endocrine resistance in the adjuvant breast

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cancer setting is different from that in the advanced breast cancer setting. Approximately 50 percent of patients with HR+ advanced breast cancer have primary resistance and do not respond to initial endocrine therapy. The response rate declines to 30, 25, and 15 percent respectively as one progresses from second-line through fourth-line therapy.31 Even for patients who do respond to initial therapy, the majority will progress despite endocrine therapy. Much research is ongoing to discover ways to circumvent hormonal resistance. There are many avenues of hormonal resistance, one of which is the mammalian target of rapamycin (mTOR) pathway. Everolimus [Afinitor ®] is an mTOR inhibitor and is approved, in addition to several other indications, for use in postmenopausal women with advanced HR+, HER2-negative cancer, in conjunction with exemestane. Everolimus in combination with exemestane results in a better PFS in the third-line setting. The analysis of PFS based on independent central radiological assessment was very consistent and showed a 2.6-fold prolongation in median PFS (10.58 months versus 4.14 months), resulting in a 64 percent risk reduction of progression or death (HR 0.36).32 Importantly, the adverse effects of everolimus must be understood and managed. It has chemotherapy-like adverse effects, including stomatitis, fatigue, dyspnea, and pneumonitis. In postmenopausal women whose disease has progressed on nonsteroidal AI, exemestane/everolimus is an excellent option, but toxicity needs to be anticipated and closely managed. An exciting compound, palbociclib, which is under development, is a cyclin-dependent kinase (CDK) 4/6 inhibitor. Inhibiting CDK blocks luminal type cancers from dividing.30 It is being studied in combination with letrozole for first-line treatment of HR+, HER2 negative advanced breast cancer. Preliminary data from a Phase II trial are very positive, with an almost 19-month increase in PFS compared with letrozole alone. Additionally, this oral agent appears well tolerated. It is hoped the Phase III data will be as positive and that this agent will receive FDA approval. Triple negative breast cancer (TNBC) is where there are significant unmet needs. It is the most poorly defined type of breast cancer. This type of cancer lacks expression of ER, PR and HER2. It is identified in 10 to 18 percent of all breast cancer. It is not synonymous with basal-like breast cancer; 10 to 30 percent of TNBC cases are not basal-like. The underlying drivers of growth for this type of cancer are unknown. TNBC tends to be more aggressive and high grade

with a high relapse pattern (especially in first five years). The sites of relapse with TNBC are different from luminal type. This type of breast cancer tends to metastasize to organs and the central nervous system. It tends to be responsive to chemotherapy but quickly regrows. TNBC typically occurs in younger women, particularly African Americans. BRCA1 mutations and P53 mutations may play a role in promoting this type of cancer. There are little data regarding molecular characteristics and associated signaling for TNBC. Targeted therapy does not exist, but many different targets are under investigation. At this time, chemotherapy is the only treatment option for TNBC. Based on treatment guidelines from the first International Consensus Conference for Advanced Breast Cancer (ABC1), when chemotherapy is warranted, sequential single-agent chemotherapy is preferred over combination chemotherapy for most patients.33 Combination chemotherapy should be reserved for patients with rapid clinical progression, life-threatening visceral metastases, or need for rapid symptom and/or disease control. The duration of each regimen and number of regimens should be tailored to each individual patient. Additionally, each regimen should be given until progression of disease or unacceptable toxicity, the latter of which should be defined together with the patient. Conclusion

These are exciting times for those who treat patients with breast cancer. Significant strides in improving survival are being made in all types of this cancer. There are significant unmet needs in triple negative breast cancer, and it is hoped these needs will be addressed in the near future. Sara A. Hurvitz, MD, FACP is an Assistant Professor of Medicine and Director of the Breast Oncology Program at UCLA. She is also CoDirector of the Outpatient Oncology Clinics at SM-UCLA and Medical Director of the Clinical Research Unit at Jonsson Comprehensive Cancer Center/UCLA.

References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30. 2. Li CI, Uribe DJ, Daling JR. Clinical characteristics of different histologic types of breast cancer. Br J Cancer. 2005;93(9):1046-52. 3. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869-74. 4. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82. 5. Pegram MD, Konecny G, Slamon DJ. The molecular and cellular biology of

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HER2/neu gene amplification/overexpression and the clinical development of her-

Oncol. 2009;27(12):1999-2006.

ceptin (trastuzumab) therapy for breast cancer. Cancer Treat Res. 2000;103:57-75.

21. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of Lapa-

6. Ross JS, Fletcher JA. ER-2/neu (c-erb-B2) gene and protein in breast cancer.

tinib alone or in combination with trastuzumab in women with ErbB2-positive,

Am J Clin Pathol. 1999;112(1 Suppl 1):S53-67.

trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124-30.

7. Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic

22. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-pos-

breast cancer by HER2 status and trastuzumab treatment: an institutional-based

itive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91.

review. J Clin Oncol. 2010;28(1):92-8.

23. Morrow PK, Wulf GM, Ensor J, et al. Phase I/II study of trastuzumab in

8. Danese M, Lalla D, Brammer M, et al. Estimated life years saved with trastu-

combination with everolimus (RAD001) in patients with HER2-overexpress-

zumab in first-line HER2+ metastatic breast cancer from 1999 to 2013. J Clin

ing metastatic breast cancer who progressed on trastuzumab-based therapy. J

Oncol 2013;31 (suppl):abstract 625.

Clin Oncol. 2011;29(23):3126-32.

9. National Comprehensive Cancer Network. NCCN Clinical Practice Guide-

24. O’Regan RM. Phase 3, Randomized, Double-Blind, Placebo-Controlled

lines in Oncology: Breast Cancer. V.1.2014.

Multicenter Trial of Daily Everolimus Plus Weekly Trastuzumab and Vinorel-

10. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole ver-

bine in Trastuzumab-Resistant, Advanced Breast Cancer (BOLERO-3). 2013

sus anastrozole alone for the treatment of postmenopausal women with human epidermal

ASCO Annual Meeting. Oral Abstract 505.

growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: re-

25. Bonneterre J, Buzdar A, Nabholtz JM, et al. Anastrozole is superior to

sults from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27(33):5529-37.

tamoxifen as first-line therapy in hormone receptor positive advanced breast

11. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole

carcinoma. Cancer. 2001;92(9):2247-58.

versus letrozole and placebo as first-line therapy for postmenopausal hormone

26. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole

receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538-46.

versus tamoxifen as first-line therapy for postmenopausal women with advanced

12. Agus DB, Akita RW, Fox WD, et al. Targeting ligand activated ErbB2 sig-

breast cancer: results of a phase III study of the International Letrozole Breast

naling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-37.

Cancer Group. J Clin Oncol. 2001;19(10):2596-606.

13. Baselga J. A new anti-ErbB2 strategy in the treatment of cancer: prevention of

27. Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane

ligand dependant ErbB2 receptor heterodimerization. Cancer Cell. 2002;2:93-5.

with tamoxifen as first-line hormonal treatment of metastatic breast cancer in

14. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus

postmenopausal women: the European Organisation for Research and Treatment

docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-19.

of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26(30):4883-90.

15. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetax-

28. Howell A, Robertson JF, Abram P, et al. Comparison of fulvestrant versus

el for HER2-positive metastatic breast cancer (CLEOPATRA study): overall

tamoxifen for the treatment of advanced breast cancer in postmenopausal wom-

survival results from a randomised, double-blind, placebo-controlled, phase 3

en previously untreated with endocrine therapy: a multinational, double-blind,

study. Lancet Oncol. 2013;14(6):461-71.

randomized trial. J Clin Oncol. 2004;22(9):1605-13.

16. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique

29. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo

antibody-drug conjugate in development for human epidermal growth factor

controlled trial of fulvestrant compared with exemestane after prior nonsteroi-

receptor 2-positive cancer. Clin Cancer Res. 2011;17(20):6437-47.

dal aromatase inhibitor therapy in postmenopausal women with hormone re-

17. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastu-

ceptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol.

zumab emtansine versus trastuzumab plus docetaxel in patients with human

2008;26(10):1664-70

epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin On-

30. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D ki-

col. 2013;31(9):1157-63.

nase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen re-

18. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for

ceptor-positive human breast cancer cell lines in vitro. Breast Cancer Res.

HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-43.

2009;11(5):R77.

19. Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women

31. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer.

with HER-2-positive advanced breast cancer: final survival analysis of a phase

Annu Rev Med. 2011;62:233-47.

III randomized trial. Oncologist. 2010;15(9):924-34.

32. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hor-

20. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond pro-

mone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9.

gression in human epidermal growth factor receptor 2-positive advanced breast

33. Cardoso F, Costa A, Norton L, et al. 1st International consensus guidelines

cancer: a German breast group 26/breast international group 03-05 study. J Clin

for advanced breast cancer (ABC 1). Breast. 2012;21(3):242-52.

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Optimizing the Treatment and Management Strategies of Pulmonary Arterial Hypertension Yon K. Sung, MD

Summary Pulmonary arterial hypertension (PAH) causes significant morbidity and mortality. Survival has improved in recent years with effective medications. Optimizing treatment requires an accurate diagnosis, the appropriate treatment selection and escalation, and medication adherence. Two new medications were approved by the FDA in 2013 and more are on the horizon. Key Points • PAH, although rare, has significant impact on a patient’s morbidity and mortality. • Overall survival has improved significantly in recent years. • Appropriate treatment of PAH begins with identifying the disease and making an appropriate diagnosis. • There are effective treatments for PAH, but the regimens can be complicated and require close monitoring. • Optimizing treatment will help improve outcomes. • Care is best provided for these patients by PAH experts.

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arterioles that causes increases in pulmonary artery pressures and eventual damage to both lungs and heart. It is probably triggered by some vascular endothelial injury coupled with vasoconstriction. Early in the disease process, PAH is characterized by normal pulmonary vasculature but with vasoconstriction and vascular injury, and increasing pulmonary pressures. Initially, the right ventricle of the heart can maintain cardiac output. As time goes on, there is more pulmonary vascular remodeling with vascular smooth muscle hypertrophy and endothelial cell proliferation, which leads to further increases in pulmonary artery pressures and vascular resistance. This leads to right ventricle dilatation and hypertrophy to overcome the pressure issues. Eventually, cardiac output begins to decline with right ventricle compromise (heart failure). Symptoms begin to progress once

the disease progresses to the point that cardiac output declines significantly. As the disease continues to progress, complete occlusion of the pulmonary arteries can occur. In end-stage disease, pulmonary pressures actually begin to decrease as cardiac output continues to also decrease. Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (mPAP) of greater than or equal to 25 mmHg determined with a right heart catheterization. PAH, a subset of PH, is defined as the same mPAP, a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg and pulmonary vascular resistance of less than 3 Wood units. The symptoms of PAH are very nonspecific and can be misidentified as many other conditions. The symptoms are from right heart failure and include dyspnea, decreased exercise tolerance, fatigue, chest pain, palpitations, edema, and syncope. PH is classified into four subgroups based on the

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Exhibit 1: Key Pathways Targeted in PAH Therapy6

etiology - idiopathic, genetic, drug- and toxin-induced, or associated with another disease (connective tissue disease, HIV, portal hypertension, congenital heart disease, or schistosomiasis). One of the most common drug-induced causes is methamphetamine abuse. Historically, PAH has been thought of as a disease of younger women.1 One-year survival was less than 70 percent and five-year survival was 38 percent.2 Newer registry data suggest that patients are older than the previous cohorts and there are more men affected. PAH prevalence is estimated as 15 cases per one million people.3 The prevalence of idiopathic PAH is six cases per one million.4 Survival data from the REVEAL registry, which covers 50 PAH centers throughout the U.S., show that overall survival has improved significantly in recent years.5 One-year survival is now 84.7 percent and five-year is 57 percent. The improvements in survival are primarily thought to be due to new medications. Earlier diagnosis is not an explanation because it still takes an average of 14 months for patients to get diagnosed. Many patients still present with New York Heart Association (NYHA) class 3 or greater symptoms. Although physical exam, patient symptoms and history, electrocardiogram, chest x-ray, and echocardiography can be suggestive of PAH, the definitive diagnosis is made with a right heart catheterization.3 This is the most accurate way to measure all

the different pulmonary pressures. A battery of tests will be done to rule out other types of PH. Establishment of a baseline and the patient’s prognosis will be done with a six-minute walk distance test and possibly cardiopulmonary exercise testing. During the right heart catheterization, vasoreactivity testing will also be done to determine response to vasodilator medication. Someone who has a significant reduction in mPAP and sustained or improved cardiac output when exposed to a vasodilator is considered vasoreactive. These patients have a good prognosis compared with someone who is not vasoreactive and are treated with calcium channel blockers. Their overall survival is close to 90 percent at five years. There are several general treatment measures that apply to all patients with PH. Exercise programs or pulmonary rehabilitation are incredibly effective for improving symptoms, quality of life, and exercise tolerance. Low-grade aerobic exercise is usually recommended. Patients should avoid heavy exertion and isometric exercises. Routine immunizations to prevent influenza and pneumonia are very important. Sodium restriction is also recommended in some patients. Women with PH need to avoid pregnancy because there is a 30 to 50 percent mortality. Comorbidities that can worsen symptoms such as anemia or thyroid disease need to be managed. Patients with PH do need to take some precautions when traveling. High altitudes may not be toler-

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Exhibit 2: What Is the Optimal Treatment Strategy?3

Anticoagulate + Diuretics + Oxygen + Digoxin

Acute Vasoreactivity Testing Positive

Oral CCB

Negative

Lower Risk

Higher Risk

1) ERAs or PDE-5i 2) Prostacyclins

1) Prostacyclins 2) ERAs or PDE-5i

No Sustained Response Yes Continue CCB

Reassess: Consider combination therapy Investigational protocols

ated, and they may need supplemental oxygen for air travel. Traditional supportive therapies used before specific medications were developed included supplemental oxygen, diuretics, inotropic support with digoxin, anticoagulation, and calcium channel blockers. Anticoagulation at a low INR target of 1.3 has been shown to improve survival. Calcium channel blockers are only indicated for patients who meet criteria for vasoreactivity. The agents used include nifedipine, diltiazem, and amlodipine. Patients with PAH need to avoid verapamil due to potential negative inotropic effects. Supportive therapies will be used in many patients along with more specific therapies that target vasoconstriction. Currently, three key pathways related to PAH pathogenesis are targeted with medications (Exhibit 1).6 Targeting these pathways leads vasodilation and antiproliferation. The phosphodiesterase 5 (PDE-5) inhibitors target the nitric oxide pathway. These agents block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels. Two agents (taldenafil [Adcirca®] and sildenafil [Revatio®]) are available in the U.S. These agents are given orally, either once a day or three times a day and no specific monitoring is needed. Additionally, there are minimal side effects and they are less expensive than other agents. Unfortunately, the side effects that do occur can be bothersome for some patients. The most common problematic ones

Atrial Septostomy Lung Transplant

are systemic hypotension, headache, and flushing. Endothelian is produced by endothelial cells and binds to endothelin receptors which causes vasoconstriction and cell proliferation. Endothelin receptor antagonists (ERA) block these receptors. Those available in the U.S. include bosentan [Tracleer ®], ambrisentan [Letairis®], and macitentan [Opsumit®]. Advantages of these agents are they are given orally once or twice a day, and there is evidence for reduction in time to clinical worsening. This class can cause several significant adverse effects including liver toxicity, anemia, and fluid retention. Monthly liver enzymes and quarterly CBC monitoring are required with bosentan use. These agents are teratogenic so treated women are required to have monthly pregnancy tests and use two forms of birth control. Macitentan, an active metabolite of bosentan, was FDA approved in October of 2013. This nonselective ERA has sustained receptor binding and enhanced tissue penetration compared to bosentan. In one trial of this agent, there was a 45 percent reduction in morbidity and mortality compared to placebo, a 33 percent reduction in risk of PAH- related death, and a 50 percent reduction in PAH- related hospitalization.7 This agent also improved the sixminute walk distance by 23 meters at six months and 37 meters for WHO functional class III/IV patients. Headache, nasopharyngitis, and anemia occurred more frequently in those treated with macitentan. Prostacyclins are agents that lead to vasodilation

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Exhibit 3: Prognostic Factors for Risk of PAH Disease Progression3

Lower Risk

Higher Risk

No

Yes

Gradual

Rapid

WHO Functional Class

II, III

IV

6-minute walk distance

>400 m

<300m

Peak VO2 > 10.4 ml/kg/min

Peak VO2 < 10.4 ml/kg/min

Minimally elevated

Significantly elevated

Echo findings

Minimal RV dysfunction

Precardial effusion; significant RV dysfunction RA enlargement

Hemodynamics

Normal/near normal RAP and CI

High RAP (> 20mmHg) Low CI (< 2.0 L/min/m^2)

Evidence of RV failure Progression

Cardiopulmonary exercise testing Brain natriuretic peptide (BNP)

RV = right ventricle:

VO2 = oxygen consumption:

RAP = right atrial pressure:

in the pulmonary vasculature. Three prostacyclin analogs with differing administration techniques are available - epoprostenol (continuous intravenous or subcutaneous (SQ) infusion [Flolan®, Veletri®]), treprostinil (continuous intravenous or subcutaneous infusion [Remodulin®], inhaled [Tyvaso®]), and iloprost (inhaled [Ventavis®]). These are by far the most effective medications for PAH but they have some significant difficulties. When prostacyclins are used intravenously, patients require indwelling lines. Also because these are given at home, the patient must be able to mix medications at the correct concentration. Epoprostenol must be kept cold with ice packs even while being infused. These agents also have very short half-lives; therefore, if the infusions are interrupted, patients will become extremely sick very quickly and may even die. Trials of the infused or subcutaneous agents have shown survival benefit and improvement in hemodynamics, exercise tolerance, and quality of life. Cons include complications with intravenous catheters such as line infections, accidental removal, or thrombosis; site pain with SC catheters, and adverse effects. Adverse effects include flushing, headaches, jaw pain, nausea, and diarrhea. The inhaled prostatcyclins require very frequent administration. Iloprost is given as one inhalation six to nine times per day and each inhalation takes six to 10 minutes. Treprostinil is given as three to nine inhalations four times per day. There is evidence for improvement in functional status with the inhaled agents and they are noninvasive. The cons

CI = cardiac index

are difficulty with adherence with the dosing and adverse effects that are similar to intravenous formulations. Cough is the one unique adverse effect of the inhaled prostatcyclins. Exhibit 2 outlines the treatment algorithm for PAH.3 All patients should be considered for anticoagulation, diuretics, and digoxin. Treatment selection primarily depends on vasoreactivity and risk for disease progression. Exhibit 3 shows the factors that can make a person high or low risk for disease progression. The subtype of PAH also has to be considered in selecting treatment. In patients with PAH secondary to congenital heart disease, benefit has been shown in reports of treatments with prostacyclins. Caution has to be taken with intravenous therapy in patients with right/left shunts because of increased stroke risk. Bosentan has the best documented level of efficacy and safety in this group. In patients with PAH secondary to HIV infection, there are significant interactions between highly active antiretroviral therapy and the PDE-5 inhibitors so these may need to be avoided. Optimizing treatment will help improve outcomes. Clinical response should be assessed three to four months after therapy is initiated. Escalation of therapy should be considered in patients who are still having symptoms or who have high-risk features. Patients who are considered low risk should be seen every three to six months. Those who are high risk need more frequent follow-up. Functional assessment and the six-minute walk distance should

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be done at each visit. Echocardiography and brain natriuretic peptide (BNP) should be measured periodically. BNP is a marker of right ventricular dysfunction. Levels of BNP correlate with mPAP and pulmonary vascular resistance in patients with PAH. Elevated plasma BNP levels are associated with increased mortality and a fall in BNP levels after therapy is associated with improved survival. There are several emerging therapies for PAH. Riociguat [Adempas®] is a soluble guanylate cyclase stimulator that was FDA approved in October 2013. In one trial, this agent led to improvement in the six-minute walk distance of 30 meters at 12 weeks versus a six meter decrease in the placebo treated group.8 Improvements were seen in both treatment naïve patients and those on background therapy. Significant improvements in functional class, clinical worsening, quality of life, and symptoms were also seen. This agent is given orally three times per day and has an adverse effect profile similar to placebo. The one major issue with this agent is teratogenicity. Women taking this agent should use two forms of contraception and have monthly pregnancy tests. This agent has not yet been included in the treatment guidelines. Agents under investigation include selexipag, a prostacyclin 2 receptor agonist. This is an oral, non-prostacyclin that binds to receptors on vascular smooth muscle cells. Early research with this agent is promising. Conclusion

ate treatments, and assess for comorbid conditions that also require treatment. Treatment regimens can be complex and should be tailored to the severity of disease and patient characteristics. These patients would best be treated at an expert center. Yon K. Sung, MD is a Clinical Instructor in the Division of Pulmonary/ Critical Care at the Vera Moulton Wall Center for Pulmonary Vascular Disease at Stanford University School of Medicine.

References 1. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343-9. 2. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023-30. 3. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-619. 4. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216-23. 5. Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448-56. 6. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425-36. 7. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-18.

A complete workup for pulmonary hypertension is needed to properly classify PH, prescribe appropri-

8. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-40.

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Improving Treatment Strategies in the Management of Castrate-Resistant Prostate Cancer Maha Hussain, MD, FACP, FASCO

Summary Many men with prostate cancer will develop hormonal resistance. There are now multiple treatment options that have been shown to modestly improve overall survival in the metastatic castrate-resistant prostate cancer (mCRPC) setting. There are numerous other exciting agents that will likely reach the market in the next few years. Key Points • Newer agents that improve survival in mCRPC include docetaxel, cabazitaxel, sipuleucel-T, abiraterone, enzalutamide, and radium-223. • Improvements in median overall survival with the above agents are modest (two to five months). • Denosumab and zoledronic acid are both approved for mitigating skeletal events related to bone metastasis but do not impact overall survival. • Many more agents are in clinical trials. • Biomarkers to predict outcomes and select therapy are on the horizon.

In years past, prostate cancer was considered a disease of old men and when patients presented many already had metastatic disease. The introduction of prostate specific antigen (PSA) measurement identified patients with much earlier disease. As shown in Exhibit 1, there are many pathways the disease can take, but the disease does not always result in the patient’s death. The five-year relative survival rates are nearly 100 percent with 98 percent at 10 years and 93 percent at 15 years. Thus, prostate cancer is a relatively chronic disease. Relative survival rates are much higher than any other cancer. However, metastatic prostate cancer is still the second leading cause of death after lung cancer. Metastatic prostate cancer results in an estimated 30,000 deaths annually. Currently, about 4 percent of men present with metastatic disease. The major-

ity of patients with metastatic disease are those who have progressed after local therapy. Prostate cancer is one of the hormone-dependent solid tumors. It begins as a hormone-dependent disease, which has been both a blessing and a curse. Nine out of 10 men will respond initially to antihormone agents. The curse comes in that therapy for prostate cancer has not moved much beyond hormone treatments in many years. Treatment strategies over the past seven decades have focused on surgical and medical castration with various antihormonal agents. Over the last seven decades, improvements have been made in antihormonal treatment is delivered, but there have not been major improvements in median survival. Despite a high initial response rate, most patients will progress to castration resistance (i.e., hormonal resistance) There are several mechanisms by which a patient

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Exhibit 1: Prostate Cancer Disease States Death from other causes Clinically Localized Disease

Rising PSA

Clinical Metastatic Hormone sensitive Non Metastatic Rising PSACastrate

may develop castration resistance.1-3 These include changes in the androgen receptor through gene amplification or mutations or alteration in survival by using pathways that bypass the androgen receptor.3 Androgen ablation creates a host environment in which the androgen-independent tumor cells have a selective growth advantage over the androgen-dependent cells.2 Eventually, with time, this selective growth advantage results in a tumor that is primarily composed of androgen-independent cells. Proliferation of these androgen-independent tumor cells is one path to castration resistance.2 Several different ways of targeting metastatic castrate-resistant prostate cancer (mCRPC) have been developed or are being studied, including androgen signaling, tumor cell apoptosis, DNA repair, and immune modulation. Several new agents have been FDA approved for mCRPC. Some that improve survival (two to five months) include docetaxel [Taxotere®], cabazitaxel [ Jevtana®], sipuleucel-T [Provenge®], abiraterone [Zytiga®], enzalutamide [Xtandi®, formerly MDV3100] , and radium-223 [Xofigo®, formerly Alpharadin]. Others do not specifically treat the cancer but reduce bone-related events – denosumab [Xgeva®] and zoledronic acid [Zometa®]. Each of these agents is discussed briefly. The first agent shown to make a difference in survival in the mCRPC setting was docetaxel, a cytotoxic agent that binds to microtubules in cancer cells leading to apoptosis. When compared with mitoxantrone (the only other chemotherapy agent that was approved for prostate cancer), docetaxel treatment every three weeks resulted in a 3.4 month difference in median overall survival (OS).4 A second chemotherapeutic agent that was approved in the post-docetaxel setting was cabazitaxel, another semi-synthetic taxane. In the trial compar-

Clinical Metastatic Castrate prechemo

Clinical Metastaic Castrate Post Chemo

Death of Disease

ing this new agent to standard therapy, median OS was improved by 2.4 months, from 12.7 months with mitoxantrone to 15.1 months with cabazitaxel.5 On the basis of these results, the FDA has approved the use of cabazitaxel together with prednisone for men with mCRPC who have been previously treated with docetaxel. The field of immunotherapy is growing rapidly in the treatment of several different types of cancer. Sipuleucel-T is the first immunotherapy approved specifically for prostate cancer. It is autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic mCRPC. In the pivotal trial of this agent against a placebo, the vaccine resulted in a four-month increase in median survival (25.8 months versus 21.7 months).6 The only issue with this agent is there is no objective way to measure response. It does not change PSA or slow progression. Because of the inability to measure response, many patients elect not to pursue this therapy. Previously it was thought that when prostate cancer became castrate resistant it was refractory to all hormonal intervention. This theory was disproved with the development of abiraterone. Because androgen receptor signaling does continue in most cases of mCRPC, the tumor cells can produce their own androgens. About 5 percent of androgens in men comes from the adrenal gland. Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues (Exhibit 2).7 Because abiraterone suppresses both androgen and corticosteroid synthesis, prednisone is given along with it to prevent adrenal insufficiency. Abiraterone was compared to placebo in patients who had progressed on docetaxel. The study dem-

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Exhibit 2: Steroid Hormone Synthesis Pathway7 ACTH gonadotropin

Abiraterone Cholesterol 17-hydroxylase

17,20-lyase Androgens

Pregnenolone

17-OH-progesterone

DHEA Estrogens

Progesterone

17-OH-progesterone

Androstenedione

Estrone

Corticosterone

Cortisol

Testosterone

Estradiol

Aldosterone ACTH = adrenocorticotropic hormone DHEA = dehydroepiandrostenedione

onstrated a 35 percent improvement in survival from 10.9 months with placebo/prednisone to 14.8 months with abiraterone and prednisone.8 Based on this data, abiraterone was initially FDA approved for use for men with mCRPC who have been previously treated with docetaxel. In addition, secondary endpoints of time to PSA progression (10.2 months v. 6.6 months, P<0.001), PFS (5.6 months v. 3.6 months, p<0.001), and PSA response rate (29% v. 6%, p<0.001) were all significantly improved with abiraterone.8 Enzalutamide was also recently approved for treating mCRPC. Enzalutamide is an androgen receptor inhibitor that acts on multiple steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. In a trial comparing it to placebo in mCRPC post-chemotherapy, the median overall survival was 18.4 months in the enzalutamide group versus 13.6 months in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001).9 Compared with placebo, this agent was superior in reducing PSA level by 50 percent or more (54% vs. 2%, P<0.001), soft-tissue response rate (29% vs. 4%, P<0.001), quality-of-life response rate (43% vs. 18%, P<0.001), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25;

P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001).9 Several agents that were initially approved for treatment of patients who had progressed on docetaxel have now been studied in the pre-chemotherapy space. Abiraterone that has been studied in the pre-docetaxel setting results in a radiographic progression-free survival advantage of 8.2 months, and has been FDA approved for use before chemotherapy.10 Differences in overall survival have not yet been demonstrated. Many patients prefer to take a pill like abiraterone rather than have chemotherapy. One of the things very unique to prostate cancer is that in roughly 80 to 90 percent of the time when prostate cancer metastasizes, it goes to the bone. The clinical manifestations of bone metastasis include pain, spinal cord compression, fractures, myelophthisis (infiltration of bone marrow with cancer cells), and constitutional symptoms. Two medications, denosumab and zoledronic acid, have been shown to decrease skeletal-related events (SREs) in metastatic prostate cancer but not alter survival. In the approval studies, skeletal-related events were defined as pathologic fracture, spinal cord compression, surgery to bone, pain requiring radiation to bone, or change in antineoplastic therapy. Zoledronic acid reduces the incidence of SREs

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Exhibit 3: Standards for mCRPC in 2013 Clinical trial mCRPC Progressing on Hormonal Therapy

Abiraterone/Prednisone Sipuleucel-T Doctaxel/Prednisone Alpharadin Clinical Trial Abiraterone/Prednisone

mCRPC Progressing on Docetaxel/Prednisone

Enzalutamide Cabazitaxel/Prednisone Mitoxantrone

compared to placebo but does not totally eliminate such events.11 Denosumab, a RANK ligand inhibitor, was the second agent approved to reduce prostate cancer-related skeletal events and has been compared with zoledronic acid.12 These agents have clinical benefit but, as noted previously, do not change survival or disease progression. In clinical practice, many providers prefer denosumab because it is an injection that can be given in the office rather than an infusion like zoledronic acid that requires an infusion room. Osteonecrosis of the jaw is an issue with both of these agents. Before they are started, the patient needs to have a dental check-up and have any issues such as extractions handled. Until the approval of Radium-223 [Alpharadin] in 2013, the bone targeted drugs were considered supportive care because they did not impact disease progression or overall survival. Radium-223, a targeted alpha emitter, is a bone-seeking calcium mimetic that selectively binds to areas of increased bone turnover, especially within the microenvironment of osteoblastic or sclerotic metastases. It is not clear if this agent has a direct tumor effect but in a Phase 3 trial, compared to placebo, there was about a 3.6 month survival advantage and reduced skeletal events.13 In this trial the assessment of skeletal events was a secondary outcome measure. Targeting bone alone is not enough in metastatic prostate cancer. The bulk of disease will be in the bone but the lungs, liver, and lymph nodes can also be significant sites of disease. It is important to target

all the areas of disease and not just bone. Exhibit 3 presents an overview of the possible treatment options for mCRPC. Choosing therapy can be difficult because no trials have compared the various treatment options to each other. Clinical considerations in choosing therapy include performance status, symptoms, extent of metastatic disease, comorbidities, patient preferences, cost and insurance coverage, and logistics such as the ability to travel to get chemotherapy. Exhibit 4 also lists some of the treatments and combinations that are currently in Phase 3 trials. There have been some exciting preliminary results with some of these agents and hopefully they will make it to market. Ten years ago, the median survival for mCRPC was nine months and now it is over two years. The impact on survival with the available therapies is relatively modest individually but with multiple options, patients can be treated with sequential therapies. Continued challenges include determining how to maximize the therapeutic efficacy of the various treatments and how to best sequence currently approved agents. Unfortunately, all the new agents have been tested primarily against placebo and not each other. Additionally, a “one-size-fitsall” treatment approach is still used. Unlike other cancers, there are no predictive biomarkers or personalized therapeutics in this arena. There is not an androgen receptor test analogous to estrogen receptor testing in breast cancer for use in predicting response to treatment in prostate cancer.

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Exhibit 4: Pending Phase III Trials

Chemotherapy-Naïve

First-Line Chemotherapy

• Enzalutamide

• Docetaxel/Prednisone +/Zibotentan

• TAK-700/Prednisone

• Docetaxel/Prednisone +/- Custersen • Docetaxel vs Cabazitaxel

Post-Docetaxel • TAK-700/Prednisone

• Ipilimumab • Cabozantrone vs Mitoxantrone

• Ipilimumab • Tasquinimod

At this time, the only widely used biomarker in prostate cancer is PSA. It is a prognostic marker that correlates with outcome, independent of treatment effects. It is used for detection, diagnosis, prognosis, and monitoring of disease activity. PSA decline has been used as an “efficacy” indicator and PSA increase has been associated with disease “progression”. To date, there are no prospectively validated data correlating response to treatment or progression of disease based on PSA values. Post hoc analyses have shown patients can be stratified based on PSA.14 One biomarker that has been FDA approved for use in decision making is circulating tumor cells.15 Levels can be used for determining response to therapy. At this point, it is not used frequently because of the slow turnaround time and issues with level of detection. Studies are ongoing trying to find predictive biomarkers in prostate cancer. One being investigated is gene fusions. Approximately 50 percent of prostate cancers have ETS gene fusions. The predominant fusion is TMPRSS2: ERG, which occurs in 80 to 90 of ETS gene fusions in prostate cancer. The gene fusion is between two genes – one codes for androgen sensitivity and the other for a transcription factor that promotes cancer cell growth. This gene fusion is thought to be a major driver in the formation of prostate cancer. A National Cancer Institute study examining the effects of abiraterone and a poly (ADP-ribose) polymerase (PARP) inhibitor in ETS fusion positive and negative patients is ongoing. The PARP inhibitor is aimed at preventing the cancer cell from repairing itself. It is hoped that in the very near future biomarkers for predicting therapy response will be

available. This will likely also lead to personalized therapy for prostate cancer. Conclusion

Patients with metastatic CRPC are living longer, but metastatic prostate cancer is still the second leading cause of death after lung cancer. Because of screening with PSA, patients are presenting earlier and are in better physical health, which makes them eligible for more aggressive treatment. Death rates do continue to decline. Due to the amount of ongoing research, the best is yet to come. Maha Hussain, MD, FACP, FASCO is the Cis Maisel Professor of Oncology, Associate Director for Clinical Research and Co-Leader of the Prostate Cancer Program at the University of Michigan Comprehensive Cancer Center.

References 1. Noble RL. The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Res. 1977;37(6):1929-33. 2. Isaacs JT, Coffey DS. Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res. 1981;41(12 Pt 1):5070-5. 3. Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;351(15):1488-90. 4. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12. 5. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-54. 6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-22. 7. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated

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castration-resistant prostate cancer. J Clin Oncol. 2010;28(9):1496-501.

treatment of bone metastases in men with castration-resistant prostate cancer: a

8. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased sur-

randomised, double-blind study. Lancet. 2011;377(9768):813-22.

vival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

13. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and sur-

9. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in

vival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-23.

prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-97.

14. Hussain M, Goldman B, Tangen C, et al. Prostate-specific antigen progres-

10. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate

sion predicts overall survival in patients with metastatic prostate cancer: data

cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-48.

from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and

11. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled

9916. J Clin Oncol. 2009;27(15):2450-6.

trial of zoledronic acid in patients with hormone-refractory metastatic prostate

15. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells pre-

carcinoma. J Natl Cancer Inst. 2002;94(19):1458-68.

dict survival benefit from treatment in metastatic castration-resistant prostate

12. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for

cancer. Clin Cancer Res. 2008;14(19):6302-9.

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GBEMTI Perspectives – Impact of Accountable Care Organization Models on Biopharmaceuticals and Specialty Products Eric Faulkner, Joshua Ransom, Jeffery Taylor, RPh, MS and Geneva Briggs, PharmD, BCPS

Summary Accountable care organizations (ACOs) are poised to play a central role in shaping tomorrow’s U.S. health care marketplace. How and to what extent biopharmaceuticals and other specialty product management and access will be integrated into ACOs is yet to be determined. To assess this impact, a survey of managed care medical directors was conducted. Those surveyed agreed ACOs will have moderate impact on the management of new biopharmaceutical and specialty medications. The survey highlighted the importance of solid value demonstration strategies for new biopharmaceuticals to ensure appropriate acceptance, inclusion in evolving clinical pathways and management strategies and the potential to secure advantageous contracting in certain cases. The majority of survey participants were optimistic that ACO approaches and payment bundling would not markedly reduce innovation in the drug, device, biologics and genomics industries

Introduction

Accountable care organizations (ACOs) are poised to play a central role in shaping tomorrow’s U.S. health care marketplace as the financial burden for cost management increasingly shifts to providers and patients. The Patient Protection and Affordable Care Act (PPACA) of 2010 specifies payment reform provisions for the Medicare program, including initial reforms around ACOs, value-based purchasing mechanisms, expanding bundled payments and medical home approaches, and targeting improvements in quality and efficiency at a time when health care costs comprise 23 percent of the federal budget.1 The PPACA requires establishment of the Medicare Shared Savings Program intended to encourage the development of ACOs for Medicare beneficiaries. The Shared Savings Program is a key component of the Medicare delivery system reform initiatives included in the Affordable Care Act and is a new approach to the delivery of health care aimed at: (1) better care for individuals; (2) better health

for populations; and (3) lower growth in Medicare Part A and B expenditures.3 Although the reforms specified in the PPACA are for the Medicare program, many of them are also being adopted by commercial payers, who in some cases are going well beyond Medicare’s ACO requirements in terms of developing new management mechanisms around accountable care concepts. The term “accountable care organization” was first used by Elliott Fisher, Director of the Center for Health Policy Research at Dartmouth Medical School, in 2006 during a discussion at a public meeting of the Medicare Payment Advisory Commission.2 According to the Centers for Medicare and Medicaid Services (CMS), an ACO is “an organization of health care providers that agrees to be accountable for the quality, cost, and overall care of Medicare beneficiaries who are enrolled in the traditional fee-for-service program.”3 A group of coordinated health care providers form an ACO, which then provides care to a group of patients. The ACO may use a range of payment models (capitation, fee-

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for-service with asymmetric or symmetric shared savings, etc.), but is ultimately accountable to the patients and the third-party payers for the quality, appropriateness, efficiency and affordability of the health care provided. Improving coordination and communication among physicians and other providers and suppliers through ACOs is anticipated to help improve the care Medicare beneficiaries receive, while also helping lower costs. According to one analysis of the proposed regulation for ACOs, Medicare could potentially save as much as $960 million over three years.4 Of course, others have suggested that the savings will not be significant.5 Some evolving models, which include ACO components, also shift significant financial management burden to provider organizations (e.g., integrated delivery networks – IDNs), forcing providers to be much more cognizant of value for money than in traditional fee-forservice models. As a result, U.S. providers operating under such business models will emerge as key drivers of value-based health care along with payers. As of January 2013, CMS is contracting with more than 250 organizations participating in Medicare shared savings initiatives, serving over four million Medicare patients across the country.6 However, commercial payers have not limited themselves to the requirements under PPACA, and many have pressed for expanded models that involve a broader array of evidence-based and business financial metrics. There were an estimated 428 private and public ACOs in the U.S. as of January 2013.7 Some are sponsored by hospital systems and independent practice associations, others by insurance companies, and yet others by community-based organizations. How and to what extent medication management and access will be integrated into ACOs is yet to be determined. Because of varied distribution and reimbursement paradigms, integration of biopharmaceuticals and specialty products into ACO models is a particularly complicated issue. Express Scripts has estimated that by 2014, specialty products will account for 40 percent of total drug spending (medical and pharmacy benefits) in the United States.8 Currently, about half of specialty pharmaceuticals are covered under the medical benefit and half under the pharmacy benefit.9 In general, ACO models may not explicitly limit access to any therapeutic option, be it a conventional medication or a biopharmaceutical. In the execution of these models, however, financial incentives or disincentives could affect the utilization of biopharmaceuticals or clinical pathway management (via either the payer or risk-based provider) may influence sequencing of access. In the ACO model, which

is budget-based, biopharmaceuticals will be under scrutiny because their acquisition costs are high and, therefore, they will be actively managed.10 ACOs must look at total costs and must capture shared savings to succeed. Some biologics might have a favored position in these models because early intervention with certain biologics to treat conditions like RA has been shown to reduce the risk of disease progression and complications. Failing to use such a product could be financially counterproductive if the agent reduces overall costs. Biologics with proven value will likely have an important place in the new care delivery models. To ensure that happens, manufacturers must communicate the value of their products to ACOs and develop new products that align with the emerging incentives of the healthcare providers – in a manner that goes beyond historical provider value communication.10 In order to gain a better understanding of the issues surrounding the impact of ACOs on specialty medications, medical devices, and other medical technologies, a targeted Internet-based survey was conducted by the Genomics, Biotech, and Emerging Medical Technologies Institute (GBEMTI) of the National Association of Managed Care Physicians (NAMCP) member medical directors. Methods

The GBEMTI was established in 2011 as an institute of the NAMCP. The NAMCP represents medical directors from payer, purchaser (employers), and provider systems such as IPAs, ACOs, PHOs, and medical groups. The goal of GBEMTI is to support and characterize the value of genomics, biotechnology, regenerative medicine, and medical technologies as these new modalities enter and impact the health care system. The GBEMTI seeks to support collaborative stakeholder engagement around emerging health technologies to consider their potential to improve patient outcomes, impact on managed care management practices and value to the health care marketplace. The Institute is guided by an Executive Leadership Council (ELC) composed of over 85 payer and manufacturer members. The GBEMTI is unique in that it is a multi-stakeholder group centered on bringing medical director decision makers and manufacturers together to address key trends and topics that are transforming U.S. health care and explore means to improve managed care decision making and patient access to emerging health technologies. The GBEMTI is divided into four key technology divisions: • Biopharmaceuticals and Specialty Products • Diagnostics and Personalized Medicine

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Exhibit 1: On a scale from 1-10, respondents ranked the following options for care management in terms of greatest potential to impact quality & cost of care, where 1 = lowest impact and 10 = highest impact. 80%

1-2

60%

3-4

40%

5-6

20% 0%

7-8 CER ACO

Value Based Risk-sharing Health IT Purchasing

CED

9-10

(n = 20; CER, comparative effectiveness research; ACO, accountable care organization; IT, information technology; CED, coverage with evidence development)

• Emerging Medical Devices • Regenerative Medicine To address the objectives of the Institute, each division is focusing on questions unique to that respective division and developing a series of perspective papers. The goal of these papers is to evaluate payer/managed care perspectives and implications for improving managed care processes, policies, and patient outcomes for each core emerging technology area. Under the Biopharmaceuticals and Specialty Products division, the impact of ACOs on products in this area was chosen as the second topic. This paper and all other perspective papers published by the Institute have been peer reviewed by the GBEMTI ELC. The survey questions addressed the impact and integration of biopharmaceuticals and specialty medications with ACOs. The survey was randomly disseminated to medical director members of NAMCP and 40 total responses were obtained. Of the total respondents, approximately 70 percent identified themselves as medical directors at commercial MCOs and 30 percent identified themselves as medical directors of health system and provider organizations (e.g., academic medical centers, hospital and other health systems, large physician practices). The sample also included payer decision makers from leading U.S. MCOs (i.e., Aetna, Cigna, WellPoint, United Healthcare), which collectively represent more than 115 million covered lives in the U.S. Survey findings were also supplemented by input from the GBEMTI ELC at regular meetings to discuss findings and add additional perspectives on feedback beyond the limitations of conventional survey approaches. Results

The survey participants were asked to rank several options for care management in terms of greatest

potential to impact quality and cost of care on a scale of 1 to 10, with 10 being highest impact (Exhibit 1). The care management options included comparative effectiveness research (CER), ACOs, value-based purchasing programs, risk-sharing, health information technology, and coverage with evidence development (CED). Based on average ratings, CER, health information technology, and risk sharing were considered to have the greatest impact on quality and cost of care. The other items rated slightly below these three in terms of potential impact, suggesting that payer and provider respondents selected multiple of these options in the quest to rebalance quality and costs of health care management. Participants were also asked which types of health technologies were poised to have the greatest impact on quality and cost of care in a more value and financially-focused environment. While survey participant responses were heterogeneous, vaccines, small molecules and biologics, personalized medicine and molecular diagnostics were viewed as having the greatest potential impact (Exhibit 2). Emerging areas such as cell and gene therapies and medical technologies were also viewed favorably. Respondents were less certain about nascent areas like nanotechnology, perhaps because vanguard or demonstration product entries that leverage nanotechnology have been limited to date. Overall, the respondents saw ACOs as having moderate impact on the management of new pharmaceuticals (i.e., 5.6 average on scale of 1 = business as usual/little change and 10 = profound impact), perhaps because ACO methods have not yet clearly focused on pharmaceutical access and instead have focused on broader quality metrics around key financial drivers or areas of efficiency in care delivery. Aside from ACOs, comparative effectiveness research, clinical pathways, and revised formulary

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Exhibit 2: On a scale from 1-10, respondents ranked the following technology types in terms of greatest potential to impact quality & cost of care, where 1 = lowest impact and 10 = highest impact.

Nanotech Cell and Gene Therapy Personalized Medicine

1-2

Molecular Dx

3-4

Medical Device

5-6

Vaccine

7-8

Biologic

9-10

Small Molecule 0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

(n = 20, DX, diagnostics)

Exhibit 3: Aside from ACOs, respondents ranked the THREE of the following that will have the greatest impact on efficient access management of biopharmaceuticals.

47%

36%

40%

Cost shifting to providers and patients

Formulary structure/ models

Clinical pathways

0%

CER

20%

26%

21%

16%

16%

Evolving management practices

57%

60%

Increasing right of HTA

83%

Internal analysis of treatment alternatives

80%

Coverage provisions changes

100%

(n = 20; CER, comparative effectiveness research; HTA, health technology assessment)

structure/models were anticipated as the top three management strategies having the greatest impact on managed care for biopharmaceuticals (Exhibit 3). The survey participants were asked to identify how likely certain key outcomes were for new health technologies as a result of introduction of ACO models (1 = highly unlikely and 10 = highly likely). These tested outcomes were (a) increased provider scrutiny of value, (b) carve outs for certain health technology assessments, (c) clinical pathways for more efficacy, (d) clinical pathways for greater cost savings, (e) preclusion of some new health technologies, (f ) new contracting requirements, and (g) higher access hurdles targeting quality and/or pay

for performance. Of these categories increased scrutiny of value, clinical pathways and new contracting requirements were viewed as being the most likely outcomes of introducing ACO approaches (Exhibit 4). Carve outs for certain technologies with high potential or precluding access to some health technologies deemed to be insufficiently beneficial or overly costly were viewed as mechanisms less likely to be applied in the ACO environment. This suggests the importance of solid value demonstration strategies for new biopharmaceuticals and devices to ensure appropriate acceptance, inclusion in evolving clinical pathways and management strategies and the potential to secure advantageous contracting in

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Exhibit 4: Indications on a scale of 1-10 the extent to which respondents think the following outcomes are likely for new health technologies as a result of ACO models, where 1 = highly unlikely and 10 = highly likely.

Higher access hurdles targeting quality and/ or for performance New contracting requirements 1-2

Preclude some new health tech

3-4

Clinical pathways for greater cost savings

5-6

Clinical pathways for more efficacy

7-8

Carve outs for certain HTAs

9-10

Increased provider scrutiny of value 0%

20%

40%

60%

80%

100%

(n=20, HTAs, health technology assessments)

Exhibit 5: Respondents indicate the effect of ACOs to noticeably reduce innovation in the drug, device, biologics and genomics industries.

Strongly Disagree

7.7%

Somewhat Disagree

7.7%

Disagree

61.5%

Agree

7.7%

Somewhat Agree Strongly Agree 0%

15.4% 0.0% 10%

20%

30%

40%

50%

60%

70%

(N = 19)

certain cases – assuming the product value proposition is competitive, differentiating and clearly aligns with efficiency and cost metrics of payers and riskbased provider systems. Geisinger and Kaiser were two organizations identified in the survey as being representative of two effective ACO models, based on their systematic approach to integrate care and role our successful programs focusing on balancing quality and costs across the enterprise. In general the patient-centered medical home programs were also identified as an effective component of evolving ACO models, with emphasis on linking patient care to efficient champions and gatekeeper physicians, provided that in-

centive structures in the system sufficiently reward provision of cost-effective care and responsible care decisions in a manner that does not unnecessarily impede appropriate or timely access. Several participants noted in open responses that they could not identify specific effective ACO models, potentially because the models remain new, are rapidly evolving and details of “best practices” are not yet widely understood. The majority of survey participants were optimistic that ACOs approaches and payment bundling would not markedly reduce innovation in the drug, device, biologics and genomics industries (Exhibit 5). Twenty-three percent of the respon-

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Exhibit 6: Respondents indicating “This time it’s different.” ACO approaches will succeed where HMO’s failed in the 1980s and early 1990s.

Strongly Disagree

0.0%

Somewhat Disagree

7.7%

Disagree

30.8%

Agree

23.1%

Somewhat Agree

15.4%

Strongly Agree 0%

23.1% 5%

10%

15%

20%

25%

30%

35%

(N = 19)

Exhibit 7: Respondents expecting the quality measures associated with ACO models to reduce health care costs. Strongly Disagree

0.0%

Somewhat Disagree

0.0%

Disagree

23.1%

Agree

38.5% 23.1%

Somewhat Agree Strongly Agree 0%

15.4% 5%

10% 15%

20%

25%

30%

35% 40% 45%

(N = 20)

dents did expect a noticeable reduction in innovation, though market pressure may channel toward areas of high unmet need and/or high breakthrough potential. This would be consistent with recent industry restructuring efforts to more proportionally include niche and specialty indications to adapt to global pressures on health technology reimbursement and access. There were variable perspectives among the survey participants as to whether ACOs and/or bundled payment systems would succeed where health maintenance organizations (HMOs) failed in the 1980s and early 1990s (Exhibit 6). Sixty percent of respondents thought that ACOs would succeed because financial incentives would correct “gaps” influencing the ineffectiveness of prior HMO models. Alternatively, almost 40 percent thought that new

ACO models would not achieve anticipated goals of care efficiencies and cost savings. When asked about implications for biopharmaceuticals, ELC members indicated that models were still emerging and impacts were presently unclear, but that management approaches would not specifically single out biopharmaceuticals only and instead focus on broader efficiencies. However, the ELC viewed that the degree of focus on novel biopharmaceutical management is still evolving and may vary significantly from ACO to ACO. Despite this variability, some themes around biopharmaceuticals and devices appear to be emerging, including: tightening of prior authorizations, development and enforcement of clinical pathways, provider “engagement” to enhance consistency of care around pathways, and incentives to support

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Exhibit 8: If the ACO model becomes the dominant system for payment for health care in the U.S. respondents indicating that patients will have to become better informed consumers of health care.

Strongly Disagree

0.0%

Somewhat Disagree

7.7%

Disagree

7.7%

Agree

38.5%

Somewhat Agree

7.7%

Strongly Agree 0%

38.5% 5%

10% 15%

20%

25%

30%

35% 40% 45%

(N = 20)

use of lower cost or high-value alternatives.11 The ELC also suggested that areas such as cardiovascular disease, metabolic syndrome and oncology, which represent significant financial impact, are “fair game” for additional focus as they represent potential for significant gains in efficiency and costs. Some specific models focusing on costly biopharmaceuticals are emerging, and these pilots may set the stage for future management strategies.12 However, details on how financial incentives will be structured – e.g., bundled vs. episode of care payment for certain service groupings – are still being piloted and may have different implications in terms of (a) difficulty in administration, (b) drivers and incentives for technology selection, and (c) provider role with the greatest influence (e.g., primary care. specialist, administrative manager).13 The quality measures integrated into ACO and performance-based provider “dashboards” are expected by the vast majority of respondents (approximately 80%) to help reduce health care costs – this is apart from reducing the overall volume of services provided (Exhibit 7). It was unclear from responses whether the greatest efficiencies would result in use of evidence-based quality metrics or whether other factors being integrated into ACOlike models such as requiring providers to manage to a capitated budget for certain bundles of services or increasing patient medical home and disease management were viewed as primary drivers of savings. One challenge associated with use of evidence-based quality metrics is that existing metrics may not sufficiently address key areas where care efficiencies and cost savings are feasible.14 This may mean that health technologies linked to quality metrics may experience differential impacts on use and access versus other care areas that are “off

the grid” and where quality metrics have yet to evolve – requiring that manufacturers consider the impact of ACO dashboards on products by a caseby-case basis. It also presents an opportunity for payer-provider-manufacturer collaboration around important areas where quality of care improvements could be anticipated and addressed. If the ACO model becomes the dominant system for payment for health care in the U.S., patients will have to become better informed consumers of health care. Again, an overwhelming majority of those surveyed felt this was true (Exhibit 8). This would include consumers developing an informed perspective on the benefits and risks associated with particular treatment choice decisions, particularly those for which the patient has a significant financial stake in the decision. Because of this, channeling information on the comparative value to treatment alternatives will need to extend beyond focus on payers and providers to include the patient. Survey Limitations

Limitations of this analysis may include respondent bias, as it was not possible to determine whether respondents held a particular interest in ACOs or were active participants in developing such programs. Based on the limited number of respondents, the survey findings may not be fully representative of U.S. medical director perspectives, but do point to trends in payer views on the impact of ACOs. Next Steps and Future Directions

As initial ACO models have advanced in the U.S. over the past several years, catalyzed by U.S. health reform mandates of PPACA, this survey helps to capture the current thinking of health plan and provider Medical

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Directors to understand implications of this evolving model of health care delivery. Overall, respondents viewed ACOs as having a moderate impact on technology access, and are one of several approaches/ mechanisms (e.g., clinical pathways, comparative effectiveness, new formulary structure and benefit management schemes) that will be used to improve efficiency and quality of care and moderate costs. Key themes from this research in regard to the implications of ACOs on biopharmaceuticals and emerging health technologies include the following: • Mechanisms for ACO management of biopharmaceuticals and devices are still fairly nascent and the blanket of coverage of some therapeutic areas (e.g., oncology) remains highly heterogeneous and uncertain across these models. • Financial incentive “win themes” and best practices also remain uncertain due to the novelty and limitations of available information on ACOs in the public domain. • ACOs will focus increasing scrutiny on those technology types that call into heavily managed areas on ACO dashboards, while other technologies “off the grid” may not be as subject to this scrutiny and resultant management/utilization decisions. • Evolving models may result in preclusion of access to some technologies that do not demonstrate sufficient differentiation versus alternatives, where fit in clinical pathways is unclear or which have marked cost disadvantages. • The environment is still evolving and remains open for payer and provider negotiation of carve outs, special contracting considerations, and formulary positioning discussions for technologies with a differentiated value story. This would support collaborative engagements among manufacturers, payers and provider organizations to further pilot and measure impact of ACO models overall or component approaches focused on target disease areas or technology types.

of financial-at-risk provider models on technology uptake, patient access, (b) understand implications and outcomes for provider performance, and (c) identify best practices and further refine these models over time. Eric Faulkner, Co-Director, NAMCP Genomics Biotech and Emerging Medical Technologies Institute, Director Global Market Access, Quintiles, Professor, University of North Carolina at Chapel Hill Joshua Ransom, Co-Director, NAMCP Genomics Biotech and Emerging Medical Technologies Institute, Principal Consultant, Quintiles, Jeffery Taylor, RPh, MS, Pharmacy Director, Aetna Geneva Briggs PharmD, BCPS, Briggs & Associates Acknowledgements: Our thanks and acknowledgements to the Genomics, Biotech, and Emerging Medical Technology Institute of the National Association of Managed Care Physicians, representing over 90 commercial payers, provider executives, and health care technology manufacturers, for your thoughtful review.

References 1. The Patient Protection and Affordable Care Act of 2010 (Public Law 111148), as amended by the Health Care and Education Reconciliation Act of 2010. 2. Fisher E, et al. Fostering accountable health care: Moving forward in Medicare. Health Affairs. 2009;28:w219-231. 3. Centers for Medicare & Medicaid Services (CMS), HHS. Medicare program; Medicare Shared Savings Program: Accountable Care Organizations. Final rule. Fed Regist. 2011;76(212):67802-990. 4. Accountable Care Organizations: Improving Care Coordination for People with Medicare. Available at www.healthcare.gov. 5. Eddy DM, Shah R. A Simulation Shows Limited Savings from Meeting Quality Targets under the Medicare Shared Savings Program. Health Aff (Millwood). 2012;31(11):2554-62 6. CMS Press Release. More doctors, hospitals partner to coordinate care for people with Medicare. January 10, 2013. Available at www.cms.gov. 7. Muhlestein D.C. Continued Growth Of Public And Private Accountable Care Organizations. February 19, 2013. Available at http://healthaffairs.org/ blog/2013/02/19/continued-growth-of-public-and-private-accountablecare-organizations/. 8. Nease R, Miller S, Frazee SG. 2010 Specialty Drug Trend Report. St Louis: Express Scripts Specialty Benefit Services; 2011. Available at www.curascript. com/bin_web/documents/10DrugTrendReportCuraScript.pdf. 9. Mccain J. Part 1: Distribution models for biologics and other specialty pharmaceutical products. Biotechnol Healthc. 2012 Summer; 9(2):8–13. 10. Peskin SR. New Care Delivery Models: Where Do Biologics Fit? Biotechnol

While ACO models hold promise as one mechanism to improve health care delivery, the early stage of evolution of existing models leaves many uncertainties regarding how and in what ways benefits will bear out in practice. It will also be important to understand whether there are unintended consequences of these models that may adversely impact patient access to appropriate technologies. Further study of the impact of ACO models would be important to (a) more robustly characterize influence

Healthc. 2012 Summer; 9(2): 19–20. 11. Weber S. Five Trends Emerge in Payer Management of Oncology. Am J Manag Care. 2013 Mar-Apr;19(3 Spec No.):SP. 12. Mehr S. Applying Accountable Care to Oncology: Developing an Oncology ACO. Am J Manag Care. 2013 Mar-Apr;19 Spec No. 3:E2. 13. Ullman K. Bundled Payment: Practice Savior or Killer? Am J Manag Care. 2013 Mar-Apr;19(3 Spec No.):SP. 14. Blayney DW, Severson J, Martin CJ, et al.. Michigan Oncology Practices Showed Varying Adherence Rates To Practice Guidelines, But Quality Interventions Improved Care. Health Aff (Millwood). 2012; 31(4):718-28.

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Epidemiology and Economic Burden of Conjunctivitis: A Managed Care Perspective John E. Schneider, PhD, Cara M. Scheibling, Darron Segall, MHS, Robert Sambursky, MD, Robert L. Ohsfeldt, PhD and Laura Lovejoy, MA

Summary Conjunctivitis is a common condition of the eye that occurs worldwide and affects all ages and social strata, affecting more than 2 percent of the population. It is caused by a variety of bacterial or viral pathogens but may also be caused by allergies, irritants or medications. Most types are self-limiting, but some may progress and cause serious complications. Health care providers have low clinical accuracy at differentiating the various etiologies of acute conjunctivitis. In this paper we review the epidemiology and economic burden of conjunctivitis. The main methods are a comprehensive review of the literature supplemented by analysis of medical claims data. A health plan with one million covered lives will see approximately 22,000 cases of conjunctivitis each year. At an average cost of $218 per case, the same plan will spend close to $5 million to treat those cases. Extrapolated to the national population of the commercially insured, these costs sum to nearly $800 million per year in the U.S. This is an underestimate of the total societal costs, which include the indirect costs associated with work loss days, school loss days, the costs of disease spread associated with inaccurate diagnosis, and the costs of antibiotic resistance. Improvements in the accuracy and timeliness of the diagnosis may improve the management and treatment of acute conjunctivitis and result in an overall reduction in prescription drug costs, the number of follow-up visits, and the spread of disease.

Introduction

Conjunctivitis is a common condition of the eye that occurs worldwide and affects all ages and social strata.1,2 Conjunctivitis can be caused by a number of different bacterial or viral pathogens but may also be caused by allergies, irritants or medications. Most types of conjunctivitis are self-limiting, but some may progress and cause serious ocular and extra-ocular complications.1 Health care providers have a low clinical accuracy at differentiating the various etiologies of acute conjunctivitis.2-7 The costs of conjunctivitis are substantial. Bacterial conjunctivitis, which comprises about 50 percent of all cases of conjunctivitis, costs an estimated $377 million to $857 million annually in the U.S.8 From a payer perspective, diagnostic uncertainty results in unnecessary antibiotic costs. Poor diag-

nostic accuracy can lead to further spread of disease, which can in turn lead to additional medical costs. The main objective of this paper is to describe the epidemiology and economic burden of conjunctivitis, focusing on the subset of the population with private commercial health insurance. The main sources of data are a comprehensive review of the literature and descriptive analyses of a large database of U.S. commercial health insurance medical care claims. Methods

The literature review was conducted using PubMed, restricted to works published from January 1975 through November 2013. However, given how the body of knowledge on conjunctivitis has evolved, and the existence of several comprehensive literature

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reviews published in the 1990s, the emphasis of this review is from January 2000 to November 2013. Keywords used included the disease and condition terms “conjunctivitis” or “pink eye” combined with content terms “epidemiology,” “prevalence,” “incidence,” “cost#,” economic#,” “burden.” After conducting preliminary searches and data analysis, the content terms “diagnosis” and “misdiagnosis” were added to account for the relationship between diagnostic uncertainty and epidemiologic research. Articles were retained based on the following inclusion criteria: (1) published in English; (2) abstract included; (3) human study population; and (4) original research. The “original research” requirement was defined by reviewers as any published paper excluding letters, commentaries and case studies. For the purposes of this research, literature reviews were considered original research if the authors conducted calculations (e.g., meta-analyses or population cost estimates) based on the information gathered in the review. The MarketScan Commercial Claims and Encounters Database (from Truven Analytics) was used to supplement the findings from the literature review. MarketScan data included the enrollment, claims (paid and adjudicated), and encounter records for employees and dependents who received coverage from primarily large self-insured employers. Patients are selected for this study if they had any claims with a conjunctivitis diagnosis in the 2005 calendar year. A more detailed description of the data and data analysis is provided in Appendix A. Epidemiology

A previous survey reported that conjunctivitis in the U.S. occurs annually in 13 of every 1,000 people between the ages of one and 74, an overall prevalence of 0.13 percent.9 The prevalence in the commercially insured population, based on the MarketScan claims analysis, was 2.2 percent. Thus, for a health insurer with one million covered lives, the expected number of conjunctivitis cases per year would be approximately 22,000. Extrapolated to the whole population of the commercially insured in the U.S. (approximately 165 million in 2011),10 we would expect approximately 3,630,000 cases of conjunctivitis cases per year in the commercially insured population. Approximately 3 percent of all emergency department visits are ocular related, and of these, conjunctivitis is indicated in 30 percent of cases.11 Among patients visiting primary care physicians, 2 percent of all visits are for eye complaints with 54 percent of these cases being diagnosed as conjunctivitis or corneal abrasion.12 Several studies have reported that

the majority of these cases-- as much as 2 percent of all general practice consultations-- are cases of acute infective conjunctivitis.13-18 An analysis of several clinical studies suggests that the U.S. prevalence of adenoviral conjunctivitis ranges from 20 to 62 percent of all cases of acute conjunctivitis and adenovirus is thought to represent 80 to 90 percent of all viral conjunctivitis.19-24 Variation in how patients experience and tolerate the symptoms of conjunctivitis is likely the main contributor to the wide variation in prevalence estimates. However, another important factor is clinical uncertainty in differentiating the various etiologies of acute conjunctivitis. Studies have found that health care providers have a clinical accuracy of only 40 to 72 percent in differentiating acute conjunctivitis.2-7,25,26 Data from a questionnaire administered to British general practitioners, for example, reveal that only a third of physicians are confident in differentiating viral from bacterial conjunctivitis.27 These findings may be reflected in the claims analysis-- the vast majority of cases (90%) are recorded as one of the four categories of “unspecified” (see Appendix B). According to the claims analysis, this diagnosis pattern holds for patients over age 65 as well. The literature suggests that adenoviral conjunctivitis represents 40 to 50 percent of all cases of conjunctivitis but was only found to represent 0.37 percent of coded cases in the claims analysis. While the clinical diagnosis remains uncertain, most clinicians empirically treat patients with acute conjunctivitis despite the availability of a rapid immunoassay4,28 and rarely perform conjunctival cultures.5 The claims analysis shows that less than 1 percent of conjunctivitis patients received a bacterial or virus culture. Economic Burden

Due to its common occurrence, contagiousness, and potentially debilitating morbidities, conjunctivitis is a global economic burden.2 The bulk of conjunctivitis-related costs include physician consults, supportive care, prescription drugs, diagnostic tests, and productivity losses associated with time away from work or school.29 Misdiagnosed cases (which constitute approximately 50% of all cases24,30 ) typically have substantially higher costs, including repeat physician visits, additional diagnostic testing, referrals to specialists, and other medical costs associated with inappropriate treatment.31,32 Misdiagnosis may also imply that precautions were not taken to prevent the spread of infection (especially in the case of viral conjunctivitis), thereby adding additional cases and costs. Moreover, misdiagnosis of the causative agent of conjunctivitis may lead to

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misdiagnoses of associated morbidities or underlying systemic diseases. Misdiagnosis is also likely to result in the prescribing of antibiotics, a substantial proportion of which are likely unnecessary. Studies have shown that as many as 95 to 99 percent of physicians prescribe antibiotics empirically for all cases of acute conjunctivitis.27,33 Prescription antibiotic utilization constitutes a large proportion of conjunctivitis costs. Unnecessary or inappropriate antibiotic prescribing is in part attributable to clinical challenges in the differential diagnosis of viral and bacterial conjunctivitis.4,34 Consequently, the standard of care for conjunctivitis, regardless of causative agent, continues to be antibiotics prescribed empirically.35,36 However, routine use of antibiotics in bacterial conjunctivitis is often unnecessary as bacterial infections are self-limiting and complications are rare.37,38 Overutilization of antibiotics is likely to result in substantial unnecessary costs, contribute to antibiotic resistance, and expose patients to drug-related topical allergies and toxicity. Antibiotic resistance is a growing problem.34 Several studies have shown high rates of broad antibiotic resistance among ocular pathogens,39-41 and one study suggests that topical treatment for conjunctivitis may lead to systemic antibiotic resistance.42 A recent study out of Japan demonstrates antibiotic resistance occurring in the newest generation of antibiotics.43 Older topical antibiotics, though less expensive, have more resistance associated with them,39-41 increased risk of toxicities, and higher rates for allergic reactions that may lead to confounding clinical pictures. Based on our analysis of claims, average net payments for 60-day episodes of conjunctivitis were $612. Excluding inpatient visits, which are likely to be the result of comorbid conditions, average net payments for 60-day episodes of conjunctivitis were $218 per episode. Based on the previously calculated conjunctivitis prevalence for a health plan with one million covered lives (n = 22,000), the average annual expected costs of conjunctivitis would be $4,796,000. Extrapolated to the whole population of the U.S. commercially insured, annual costs sum to nearly $800 million. This amount is consistent with the findings of Smith and Waycaster (2009), though their analysis focused only on bacterial conjunctivitis and included all ages.44 Were their analysis to have included viral conjunctivitis, their estimates would have been substantially higher given that at least 50 percent of all infective cases are viral. Moreover, given that patterns of misdiagnosis extend to patients over age 65, extrapolated to the whole popu-

lation these costs would be substantially higher. The bulk of outpatient episode costs (81%) consisted of physician office visits. The mean number of physician office visits per episode was 2.4 per year. Typically, a properly diagnosed and managed case of infectious conjunctivitis does not require a followup clinic visit.3,45-47 Thus, these findings suggest that for many cases the initial treatment to some extent failed, thereby warranting at least one additional outpatient visit. Given the relatively low costs of other outpatient services occurring during the episode (e.g., prescription drugs and lab tests), the additional visits to providers explain most of the $218 per case. Although prescription drug costs were only $11 per episode, 57 percent of episodes included at least one prescribed antibiotic. Given the relatively high prevalence of conjunctivitis in the U.S., the number of lost days of school and work attributable to the disease has been a concern.3,7,8,25,48,49 Unfortunately, formal analysis of work and school absenteeism represents a gap in the literature. A simple analysis using conjunctivitis incidence rates and U.S. Census population data demonstrates the extent of the burden of lost work and school days. If all patients were to follow recommended “stay home” days for adenoviral conjunctivitis,5 the condition would cause approximately 8.5 million missed work days and 3.5 million missed school days in the U.S. annually. Based on prevailing average hourly wages in the U.S., estimated lost wages associated with missed work days is approximately $1.9 billion. Conclusions

Consistent with the literature on difficulties in properly diagnosing conjunctivitis, we find that a surprisingly high 90 percent of the conjunctivitis cases in the MarketScan database were coded as “unspecified.” Challenges in differentiating viral and bacterial conjunctivitis have several important implications for managed care plans, including the overprescription of antibiotics, which adds to the direct costs of drugs, the indirect costs of misdiagnosis (such as repeat physician visits), and the indirect costs of increased antibiotic resistance. Moreover, much of the research on conjunctivitis has focused on bacterial rather than viral, in spite of the relatively high prevalence of viral cases. A health plan with one million covered lives will see approximately 22,000 cases of conjunctivitis each year. At an average cost of $218 per case, the same plan will spend close to $5 million to treat those cases. Extrapolated to the national population of the commercially insured, these costs sum to nearly $800 million per year in the U.S. This is

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an underestimate of the total societal costs, which include the indirect costs associated with work loss days, school loss days, the costs of disease spread associated with inaccurate diagnosis, and the costs of antibiotic resistance. Improvements in the accuracy and timeliness of the diagnosis may improve the management and treatment of acute conjunctivitis and result in an overall reduction in prescription drug costs, the number of follow-up visits, and the spread of disease. John E. Schneider, PhD, Avalon Health Economics LLC Cara M. Scheibling, Avalon Health Economics LLC Darron Segall, MHS, Rapid Pathogen Screening, Inc Robert Sambursky, MD, Rapid Pathogen Screening, Inc Robert L. Ohsfeldt, PhD, Department of Health Policy and Management, Texas A&M Health Science Center Laura Lovejoy, MA, Saranova Consulting Funding/Acknowledgements This project was funded in part by an unrestricted grant from Rapid Pathogen Screening, Inc. The views expressed in the article are not necessarily those of the funding organizations or the institutional affiliations of the authors. We would like to thank Zack Mower, Megan Roy and Janet Benton for valuable research assistance.

Appendix A

This Appendix describes in greater detail the methods used to analyze the MarketScan® Commercial Claims and Encounters Database. In order to assess the extent to which misdiagnosis adds costs, we conducted a 60-day episode-of-care analysis. The episode-of-care approach captures repeat visits to care providers, lab tests, and prescription drug costs. It only looks at outpatient costs and excludes inpatient hospitalizations. The MarketScan data included the enrollment, claims (paid and adjudicated), and encounter records for employees and dependents who received coverage from primarily large self-insured employers. Patients are selected for this study if they had any claims with a conjunctivitis diagnosis in 2005. Patients who had this diagnosis on a laboratory claim (CPT Procedure 80000-89999) and no other claims were not included, as these are likely to be rule-out diagnoses. In addition, patients were required to have been enrolled in the MarketScan database for the entire 2005 calendar year (n = 10.5 million). Patient counts were reported by ICD-9 diagnosis codes and by place of service (ER, urgent care, physician office, inpatient hospital), provider specialty, and receipt of culture (CPT procedure 87070 and 87252). For a patient to be counted, the medical claim must have included the appropriate procedure, specialty, or setting, plus the diagnosis code

of interest. Patients with more than one type of diagnosis will appear in multiple rows of the tables. These counts were weighted to reflect the national distribution of 165.1 million individuals with employer-sponsored health insurance, as captured by the most recent year of the Medical Expenditure Panel Survey (MEPS).* The MarketScan commercial insurance weights were constructed using the Household Component of the MEPS. This survey, conducted by the Department of Health and Human Services’ Agency for Healthcare Research and Quality (AHRQ), provided the national estimates of the number of people with employer-sponsored private health insurance (ESI). These estimates were used to weight individuals in MarketScan to reflect the national ESI distribution. Weighted counts and averages appear in most tables in brackets beneath the raw counts. To construct national weights, MEPS respondents were stratified using combinations of demographic variables that account for substantial differences in utilization and expenditures. These variables were: region (north east, north central, south, west); age (three groups: 0-17, 18-44, 45-64); sex (male, female); Metropolitan Statistical Area (MSA) classification (urban, rural); and insurance policy holder status (policy holder, spouse / dependent). The weight was the ratio of MEPS-based national estimates in the different age/gender/region categories to the MarketScan number of persons in the same categories. (i.e., the numerator is the MEPS estimate of the size of the cell population and the denominator is the number of covered lives in the MarketScan data). Sixty-day episodes were constructed for patients identified in the patient counts. Each episode began with a claim that had a diagnosis of interest and ended 60 days thereafter. Episodes were based on a 60-day episode as viral conjunctivitis may frequently lead to the development of corneal deposits, otherwise known as sub-epithelial infiltrates, chronic tearing, or the development of an acute dry eye state for approximately 30 days after the resolution of symptoms.50-58 The majority of the corneal infiltrates resolve over six weeks.50-52,56-58 While the patient count tables stratified patients by ICD-9 diagnosis code, the episode-of-care analysis reports on all conjunctivitis diagnoses as one group. Multiple diagnoses may occur within each episode. The analysis summarized each episode by number of visits/admissions, number of laboratory tests (CPT codes 87070 and 87252), number of prescription drugs and total costs. Utilization, laboratory tests, and costs were summarized only if a conjunctivitis diagnosis appeared on the claim. Costs were reported as net payments (i.e.,

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Appendix B: National Estimates for Patients by Diagnosis, 2006 (1) ICD-9 Code

Total Patients

Description

Percent

077.3

Adenovirus

844

0.37%

077.8

Other virus

724

0.32%

077.98

Chlamydiae

61

0.03%

077.99

Other viral diseases of conjunctiva

5,220

2.29%

372.30

Unspecified or follicular conjunctivitis

114,905

50.44%

372.00

Acute conjunctivitis, unspecified

85,063

37.37%

372.01

Non-viral conjunctivitis, unspecified

5,050

2.22%

372.02

Acute follicular conjunctivitis (3)

4,751

2.09%

372.03

Mucopurulent

11,472

5.04%

372.04

Pseudomembranous

225

0.10%

372.10

Unspecified

3,098

1.36%

372.11

Simple

2,381

1.05%

372.12

Follicular

1,687

0.74%

372.39

Other conjunctivitis

2,954

1.30%

Total

227,787

100.00%

Sources and Notes: (1) Based on continuously enrolled members with Rx benefit; MarketScan Commercial Claims and Encounters and Medicare COB and Supplemental Databases, 2006; (2) CPT 87070, 87252 with appropriate diagnosis; (3) excludes adenovirus, EKC, pharyngoconjunctival fever

amount the primary health plan/insurer paid to the provider, excluding patient out-of-pocket and coordination of benefits). Total costs were the sum of inpatient, outpatient and prescription drug costs and are reported as the overall total payments (regardless of diagnosis code).* Episode-level data were summarized as mean per patient per episode. To avoid right and left censoring of episode length, only episodes that begin on or after March 1, 2005 or end before November 1, 2005 were reported. References

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