Journal of Managed Care Medicine Volume 16, Number 1 by Jeremy Williams

Vol.16, No.1, 2013

Journal of Managed Care Medicine

The Importance of Stroke Prevention in the Management of Atrial Fibrillation Overactive Bladder Under-Diagnosed and Under-Treated: Breaking the Cycle Practice and Funding Gaps Existing in HIV Management: Will Managed Care Bridge the Two? Advances in GLP-1 Based Therapy in the Treatment and Management of Type 2 Diabetes Emerging Treatment Options in the Management of Multiple Myeloma Individualizing Treatment Strategies in the Management of Advanced NSCLC New Developments in the Treatment and Management of Metastatic Melanoma Optimizing the Screening, Diagnosis, and Treatment of Hepatitis C in Managed Care Clinical and Economic Utility of a New Noninvasive Prenatal Test Using Massively Parallel Sequencing A Lifestyle Approach for the Control of Diabetic Hyperglycemia A Budget Impact Model to Estimate the Cost Dynamics of Treating High-Risk Heart Failure Patients with Advanced Percutaneous Cardiac Assist Devices: The Payer Perspective

COMING SOON FROM BIOGEN IDEC

DIMETHYL FUMARATE Sign up at www.DMFcomingsoon.com to receive more information upon approval.

ÂŠ2012 Biogen Idec. BIOGEN IDEC and the BIOGEN IDEC logo are registered trademarks of Biogen Idec. 07/12 7-8003-01

JMCM Journal of Managed care medicine 4435 Waterfront Drive, Suite 101 Glen Allen, VA 23060 (804) 527-1905 fax (804) 747-5316

Editor-In-Chief

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. 16, No. 1, 2013

J. Ronald Hunt, MD

publisher

TABLE OF CONTENTS

Katie Eads

director of communications Jeremy Williams

Journal management Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 658-4253 fax (703) 997-5842

Managing Editor Barry Barnum barry.barnum@douglasmurphy.com

Graphic Design Douglas Murphy Communications, Inc.

Custom Article Reprints High quality, custom article reprints of individual articles are available in print and electronic formats. Contact Katie Eads, keads@namcp.org, 804-527-1905 for reprints.

ISSN: 1094-1525. 1094-1525. The TheJournal JournalofofManaged ManagedCare Care is published Medicine isbypublished Association by Association Services Inc. Services Corporate Inc. and Corporate Circulation and Circulation offices: 4435offices: Waterfront 4435 Drive, Waterfront Suite 101, Drive, Glen SuiteAllen, 101, Glen VA 23060; Allen, VA Tel 23060; (804) 527-1905; Tel (804) 527Fax (804) 1905;747-5316. Fax (804)Editorial 747-5316. and Editorial Production and offices: Production P.O. Box offices: 71895, P.O.Richmond, Box 71895, VARichmond, 23255-1895; VATel 23255-1895; (804) 6584253; Tel (804) Fax 387-7580; (703) 997-5842. Fax (703) 997-5842. Advertising Advertising offices: Sloane offices: Reed, Sloane4435 Reed, Waterfront 4435 Waterfront Drive Ste Drive 101, Glen Ste Allen, 101, Glen VA 23060 Allen, Tel VA 23060 (804) 527-1905, Tel (804) Fax 527-1905, (804) 747Fax 5316. (804) 747-5316. All rights reserved. All rights Copyright reserved. Copyright 2012. No part 2012. of this No part publication of this publication may be reproduced may be reproduced or transmitted or in transmitted any form or inby anyany form means, or byelectronic any means, orelectronic mechanical, or mechanical, including photocopy, including recording, photocopy,orrecording, any informaor tion any information storage or storage retrievalor system, retrieval without system, without written consent written consent from thefrom publisher. the publisher. The publisher The publisher does not guarantee, does not guarantee, either expressly either expressly or by implication, or by implicathe factual tion, theaccuracy factual accuracy of the articles of the and articles descriptions and deherein, scriptions norherein, does the norpublisher does the guarantee publisher guarantee the accuracy the accuracy of any views of any or views opinions or opinions offered by offered the authors by the of authors said articles of said or articles descriptions. or descriptions. POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060.

The Importance of Stroke Prevention in the Management of Atrial Fibrillation Noel G. Boyle, MD, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Overactive Bladder Under-Diagnosed and Under-Treated: Breaking the Cycle Pamela Ellsworth, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Practice and Funding Gaps Existing in HIV Management: Will Managed Care Bridge the Two? William A. Oâ&#x20AC;&#x2122;Brien, MD, MS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Advances in GLP-1 Based Therapy in the Treatment and Management of Type 2 Diabetes Tom A. Elasy, MD, MPH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Emerging Treatment Options in the Management of Multiple Myeloma Robert L. Schlossman, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Individualizing Treatment Strategies in the Management of Advanced NSCLC Sandeep Reddy, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 New Developments in the Treatment and Management of Metastatic Melanoma Ragini Kudchadkar, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Optimizing the Screening, Diagnosis, and Treatment of Hepatitis C in Managed Care David H. Winston, MD, FACP, AGAF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Clinical and Economic Utility of a New Noninvasive Prenatal Test Using Massively Parallel Sequencing Anthony O. Odibo, MD, MSCE and Susan Garfield, Dr.PH . . . . . . . . . . . . . . 50 A Lifestyle Approach for the Control of Diabetic Hyperglycemia Will Clower, PhD and Bradley Pifalo, MD, FACC. . . . . . . . . . . . . . . . . . . . . . . 55 A Budget Impact Model to Estimate the Cost Dynamics of Treating High-Risk Heart Failure Patients with Advanced Percutaneous Cardiac Assist Devices: The Payer Perspective David Gregory, MPA, FACHE and Dennis J. Scotti, PhD, MBA, FACHE, FHFMA. . . 61

BPA Audited Publication

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 3

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 10

53%

15.0 8.6

6.2

7.0

0 Baseline

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 Q-Med AB. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. MCOSOL 12/12-1

• 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. 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 (eg, diet, fiber therapy, antimotility 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 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.

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 24 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 (ie, 136 subjects from the blinded phase and 61 subjects from the open phase). 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. 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. 06/11

*Safety information presented in the Package Insert only includes data up to 18 months.

Printed in the USA.

SOL12/57

Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross Madeleine Biondolillo, MD Director, Healthcare Safety and Quality Massachusetts Department of Public Health Paul Bluestein, MD Chief Medical Officer Connecticare Anthony Bonagura, MD Medical Director Aetna Inc. Philip M. Bonaparte, MD Chief Medical Officer Horizon NJ Health D. Kete Cockrell, MD Medical Director International Medical Group Pat Deverka, MD, MS, MBE Senior Research Director Center for Medical Technology Policy Stan N. Finkelstein, MD Co-Director, Program on the Pharmaceutical Industry Director, Harvard-MIT Division of Health Sciences & Technology Massachusetts Institute of Technology Howard Garber, MD, MPH Medical Director Johns Hopkins Health Care Mary Parish Gavinski, MD Chief Medical Officer Community Care Annetine Gelijns, PhD Co-Director International Center for Health Outcomes and Innovation Research (InCHOIR) Columbia University Uwe G. Goehlert, MD, MSC, MPH, MBA, FAAFP Staff Physician Northwestern Medical Center Department of Emergency Medicine Steven E. Goldberg, MD, MBA VP and Chief of Medical Affairs Express Scripts Atul Grover, MD, PhD Associate Director Association of American Medical Colleges Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer United Healthcare Community PlanDelaware

Leo M. Hartz, MD, MHM VP Clinical Advocacy/Chief Medical Officer Blue Cross of Northeast PA

Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions Inc.

Barry K. Herman, MD, MMM Executive Medical Director Clinical Research and Medical Affairs Sunovion Pharmaceuticals, Inc.

John W. Richards Jr., MD, MMM, CPE President/CEO Innovative Health Strategies

Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University Thomas Kaye, RPh, MBA, FASHP Senior Pharmacy Director Passport Health Plan Stephen Keir, DrPH Co-Director Center for Quality of Life/Supportive Care Research Robert Preston Tisch Brain Tumor Center Duke University Medical Center Fernando C. Larach, MD, FACR, MBA President A-Bay Area Medical Clinics, PA Catherine Marino, MD Chief Medical Officer MagnaCare Jeff Martin, PharmD Clinical Account Director Innoviant Inc. Peter W. McCauley Sr., MD, CPE Medical Director Gottlieb/West Towns PHO Inc. Wesley Mizutani, MD Talbert Medical Group Thomas Morrow, MD Director Genentech Lawrence Mullany, MD, MBA Medical Director United Healthcare Ray Mummery, MD, CMCE Chief Medical Officer, Dimension Health Denis O’Connell, MD Regional Medical Director Blue Cross Blue Shield of NC A. Mark Parker, MD, MBA Medical Director Quality Assessment Systems Inc.

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

Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc. Aran Ron, MD, MBA, MPH President and Chief Operating Officer Group Health Inc. Mark R. Rosenberg, MD, PhD President/CEO BHM Healthcare Solutions Jay Schechtman, MD, MBA Senior VP, Chief Medical Officer Healthfirst Nancy Single, PhD Assistant Director for Strategic Planning and Program The Ohio State University Comprehensive Cancer Center Robert H. Small, MD Behavioral Health Medical Director TriWest Healthcare Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPF, ACOI VP Medical Affairs/Chief Medical Officer Group Health Plan Bruce Steffens, MD Market Medical Director Iowa– Central Illinois United Healthcare William D. Strampel, DO, FACOI Dean, Michigan State University College of Osteopathic Medicine Jeff Taylor, RPh, MS Pharmacy Director Aetna Prentiss Taylor Jr., MD Regional Medical Center Director Advocate Health Care Pam Thomas, MD, MPH, FACOEM Consulting Medical Director Wellness, Health and Productivity Management Strategies

The Importance of Stroke Prevention in the Management of Atrial Fibrillation Noel G. Boyle, MD, PhD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Thromboprophylaxis to prevent stroke is an important aspect of atrial fibrillation (AF) management. All patients with AF should be assessed for stroke and bleeding risk to select the most appropriate therapy. Dabigatran, a new anticoagulant, is available with more new agents to come. Although warfarin continues to be the anticoagulant of choice for most patients, the place of dabigatran in therapy is evolving. Key Points • Fifteen percent of all strokes are attributable to AF. • Outcomes from AF-related strokes are significantly worse than outcomes of strokes from other causes. • Thromboembolism prevention must be considered in all patients with AF. • Risk scoring systems provide a practical clinical way to assess stroke risk and determine appropriate thromboembolism prevention therapy. • Dibigatran is a new anticoagulant with equivalent efficacy to warfarin without drug interactions but has its own disadvantages. • Warfarin continues to be the therapy of choice for most patients.

Atrial fibrillation (AF) was a neglected disease until about 20 years ago and is now a topic receiving much attention. It was neglected because it was not a life-threatening arrhythmia. Results from the Framingham study in the 1970s provided the first population data to show a fivefold increased risk of stroke with AF. In the 1990s, the major anticoagulation in AF trials were published which led to our current standard of care of thromboembolism prevention. AF is an atrial myopathy characterized by disordered atrial electrical activation and contraction and often a rapid ventricular rate. AF can be divided into three types – paroxysmal, persistent, and permanent. Because many patients are initially asymptomatic, the first detected episode of AF can be any of the types. The typical natural history of AF is to go from paroxysmal to persistent to permanent, but this may take many years. In addition to rate and rhythm control, management of AF requires thromboembolism prevention. Thromboembolism prevention is needed because AF is the predominant cause of strokes from cardiac origins.1 In AF, the majority of strokes are due to

emboli from the left atrial appendage that form as the result of blood statsis from inefficient atrial emptying. Overall, 15 percent of all strokes are attributable to AF.2 In the over 70 age group, AF accounts for 25 percent of all strokes. Preventing strokes related to AF is important because the outcomes after stroke are significantly worse when AF was the cause. In one study, the three-month death rate was much higher in the AF group compared to those patients without AF (33 percent vs. 20 percent).3 The AF group also had an increased likelihood of remaining disabled (OR=1.4) or handicapped (OR=1.5). Preventing strokes, from any cause, is important because of their significant direct and indirect costs. The total annual national cost for strokes is estimated at $45.3 billion.4 The cost of an acute stroke in a patient less than 65 is estimated at $18,244 with an average hospital length of stay of 6.7 days. The long-term cost of a moderate to severe event averages $18,000. Many studies published since 1989 have shown that strokes in AF patients can be prevented using antiplatelet agents and anticoagulation. When war-

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 7

Exhibit 1: CHA 2DS2VASc Score and Stroke Rate10 (a) Risk factors for stroke and thrombo-embolism in non-valvular AF Major’ risk factors

Clinically relevant non-major’ risk factors

Previous stroke, TIA, or systemic embolism Age >75 years

Heart failure or moderate to severe LV systolic dysfunction (e.g. LV EF < 40%) Hypertension - Diabetes mellitus Female sex - Age 65-74 years Vascular diseasea

(b) Risk factor-based approach expressed as a point based scoring system, with the acronym CHA 2DS2-VASc (Note: Maximum score is 9 since age may contribute 0,1, or 2 points) Risk factor

Score

Congestive heart failure/LV dysfunction

Hypertnsion

Age >75

Diabetes mellitus

Stroke/TIA/thrombo-embolism

Vascular diseasea

Age 65-74

Sex category (i.e. female sex)

Maximum score

farin is compared with a placebo, the relative risk reduction is 67 percent; if the patient’s individual risk is 3 percent, warfarin use would reduce it to 1 percent.5 Warfarin therapy in AF patients could prevent up to 40,000 strokes annually at a cost savings of $600 million. Aspirin reduces relative stroke risk by 21 percent; if a patient’s individual risk is 5 percent, aspirin would reduce it to 4 percent.5 Warfarin provides the most benefit in those patients with moderate to high risk of stroke (greater than 3 percent annual risk) but the risk of major adverse effects (i.e., bleeding) must be balanced against risk of stroke. Two different meta-analyses of data have shown that the risk of intracranial hemorrhage and major bleeding (i.e., requires hospitalization, blood transfusion, or surgery) is not statistically different between patients treated with warfarin and those not.6,7 Minor bleeding does occur significantly more often in patients treated with warfarin. There are several consensus guidelines for AF-related thromboembolism prevention.8-10 All patients with AF need to be considered for thromboprophylaxis. Because the most benefit from warfarin occurs in those at highest annual risk for stroke, several scales have been developed to predict annual risk for having a stroke and are used to determine which type of therapy an AF patient should receive. The

CHADS2 or CHA 2DS2VASc score can be used to estimate the annual stroke risk.10,11 In the CHADS2 scoring system, one point is given for presence of congestive heart failure, hypertension, age greater than 75, and diabetes. Two points are given for a history of stroke or transient ischemic attack. The CHA 2DS2VASc score includes additional risk factors not included in CHADS2 and is recommended by the most recent European Society of Cardiology guidelines to determine therapy (Exhibit 1 and Exhibit 2).10 The higher the score on either scale the higher the annual stroke risk. For example, a CHA 2DS2VASc score of 2 estimates an annual risk of 2.2 percent and a 9 as 15.2 percent. These are easy scales to use in the clinical setting. Because of the issues with the narrow therapeutic range of warfarin, many clinicians avoid prescribing warfarin even when indicated. Alternative anticoagulants have been developed, but before moving to these newer more expensive alternatives the advantages of warfarin need to be considered. There are many advantages with warfarin including it is effective, familiar, and inexpensive. Its effect can be measured easily and is rapidly reversed with vitamin K. Procedures, such as pacemaker and defibrillator placement and radiofrequency ablations, can be can be performed safely in the patients receiving warfarin

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

Exhibit 2: Approach to Thromboprophylaxis in Patients with AF10

Risk category

CHA 2DS2-VASc score

Recommended antithrombotic therapy

One major risk factor or >2 ‘clinically relevant non-major’ risk factors

OAC

One ‘clinically relevant non-major’ risk factor

Either OAC or aspirin 75-325 mg daily. Preferred: OAC rather than aspirin

Either aspirin 75-325mg daily or no antithrombotic therapy. Preferred: No antithrombotic therapy rather than aspirin

No risk factors OAC, oral anticoagulant

Exhibit 3: Clinical Characteristics Comprising the HAS=BLED Bleeding Risk Score10 Letter

Clinical characteristic

Points awarded

Hypertnsion

Abnormal renal and liver function (1 point each)

1 or 2

Stroke

Bleeding

Labile INRs

Elderly (e.g. >65 years)

Drugs or alcohol (1 point each)

1 or 2

High Risk: score > 3

Maximum 9 points

as long as the INR is less than 3.5. Apart from bleeding, there are only rare side effects. There is also the social aspect of the warfarin clinic for patients. There are also many disadvantages of warfarin. It interacts with many medications, alcohol, and dietary vitamin K. The effect must be measured and dose adjusted frequently, resulting in trips to a laboratory and clinic that may be inconvenient or impractical and expensive. It has a slow onset and offset of action. A prothrombotic state also occurs initially through decreased protein S levels. Fear of warfarin by clinicians and patients is a major disadvantage. Warfarin is used in only half of eligible patients with AF. Under-use of warfarin is greatest in elderly patients who are at the highest risk of stroke and also have the highest rate of contraindications.12 In the patients who actually get placed on warfarin, approximately 40 percent are not maintained at an appropriate level of anticoagulation.13 Patients at high risk for bleeding from anticoagulants can be identified using the HAS-Bled score (Exhibit 3).10 A score of three or greater indicates high risk for bleeding. The HAS-Bled score can be

documented to explain why warfarin was not prescribed for patients at high risk for stroke. Many new anticoagulants have been introduced in recent years to try to overcome the disadvantages of warfarin; many more of these are in clinical trials. The first new oral anticoagulant indicated for stroke prevention secondary to AF is dabigatran (Pradaxa®), a direct thrombin inhibitor. In a large trial, dabigatran administered at a dose of 150 mg twice a day, as compared with warfarin, was associated with lower rates of stroke and systemic embolism.14 Major bleeding was equivalent between the two treatment groups; gastrointestinal bleeding risk was increased with dabigatran and intracranial bleeding risk was increased with warfarin. In this trial, there was a higher rate of myocardial infarction in the dabigatran group. There was a higher discontinuation rate in the dabigatran group compared with the warfarin group, primarily as the result of dyspepsia. An advantage of dabigatran might be when the patient has AF and also requires clopidogrel and aspirin after cardiovascular stent placement. There is a lower bleeding rate with triple therapy when dabigatran is used instead of warfarin.15

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 9

Initiating dabigatran is easy. In patients currently on warfarin, it is discontinued and the dabigatran initiated once the INR is less than 2. Clinically significant anticoagulant effect occurs within two hours of the first dose. Dabigatran 150 mg bid should be used unless the patient is greater than 80, has significant renal dysfunction, or has an increased risk of bleeding. A reduced dose (75 mg bid) is recommended in the package labeling for patients with reduced renal function, but there is no evidence of efficacy with this dose. Dabigatran should be stopped two days before an elective procedure and reinitiated the day after if there are no bleeding complications. There is a major fear that if a bleeding complication occurs that there is no antidote to reverse effects. Case reports of severe bleeding have led the FDA to issue a safety advisory related to dabigatran.16 Dabigatran is given twice a day compared with once a day warfarin. Adherence with twice a day medications can be less than with once a day and because of the shorter activity of dabigatran, missing doses may cause a greater negative effect on overall anticoagulation. Additionally, dabigatran does interact with several medications and cannot be used in patients with significantly reduced renal function (CrCl < 30 ml/min). Renal function should be tested yearly in patients on dabigatran. Unfortunately, there is not any easy laboratory measure to know if the patient is taking the medication. To determine the anticoagulant effect, activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and thrombin time (TT) may be measured but routine use is not recommended. Another disadvantage of dabigatran is its acquisition cost, which is approximately $2,000 per year. In one analysis, the incremental cost-effectiveness ratios for dabigatran 150mg bid compared with warfarin was $45,372 per quality adjusted life year (QALY).17 This is within the accepted range of cost per QALY to be considered cost effective. Overall, there is no additional benefit of dabigatran in patients who are well controlled and stable on warfarin. The question of whether to change a patient to dabigatran should be determined on a case-by-case basis. Other new anticoagulants will likely be approved for thromboembolism prevention in AF in the near future. The place for dabigatran and these other anticoagulants relative to aspirin and warfarin will need to be determined.

be considered in all patients with AF. Risk scoring systems provide a practical, clinical way to assess stroke risk and are now widely used. Direct thrombin inhibitors are now available and appear equivalent to warfarin without drug interactions but have their own disadvantages. Warfarin is likely to be the therapy of choice for most patients for some time to come. Efforts to improve warfarin utilization, compliance and INR monitoring remain important. Noel G. Boyle, MD, PhD is a Cardiologist at the UCLA Cardiac Arrhythmia Center in Los Angeles, CA.

References 1. Cerebral Embolism Task Force. Cardiogenic brain embolism. Arch Neurol. 1986;43:71-84. 2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-8. 3. Hart RG, Halperin JL. Atrial fibrillation and stroke : concepts and controversies. Stroke. 2001;32:803-8. 4. American Heart Association. 1999 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association. 1999:1-29. 5. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131:492-501. 6. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449-57. 7. Atwood JE, Albers GW. Anticoagulation and atrial fibrillation. Herz. 1993;18:27-38. 8. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:104-23. 9. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 ;133(6 Suppl):546S-592S. 10. European Heart Rhythm Association; European Association for CardioThoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-429. 11. Fuster V, RydĂŠn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-354. 12. Go AS, Hylek EM, Borowsky LH, et al.Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors

Conclusion

Approximately 15 percent of all strokes are attributable to AF, thus thromboembolism prevention must

in atrial fibrillation (ATRIA) study. Ann Intern Med. 1999;131:927-34. 13. Ansell J, Hollowell J, Pengo V, et al. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with

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

chronic non-valvular atrial fibrillation: the international study of anticoagula-

16. FDA Drug Safety Communication: Safety review of post-market reports of

tion management (ISAM). J Thromb Thrombolysis. 2007;23:83-91.

serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate

14. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in

mesylate). Available at http://www.fda.gov/Drugs/DrugSafety/ucm282724.

patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.

htm.

15. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2

17. Freeman JV, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran

doses of dabigatran compared with warfarin in older and younger patients with

compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern

atrial fibrillation: an analysis of the randomized evaluation of long-term antico-

Med. 2011;154:1-11.

agulant therapy (RE-LY) trial. Circulation. 2011;123:2363-72.

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 11

Overactive Bladder Under-Diagnosed and Under-Treated: Breaking the Cycle Pamela Ellsworth, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Overactive bladder (OAB) is an exceedingly common condition that has significant impact on a person’s well-being and can result in noteworthy and costly consequences such as falls and fractures. Providers need to screen patients for OAB and provide appropriate treatment. Medications and behavioral therapy combined provide the best efficacy in managing symptoms. Key Points • OAB is characterized by urgency. • Frequency, nocturia, and urgency urinary incontinence can also occur. • This is a common but under-diagnosed and under-treated condition. • Untreated OAB results in significant quality of life and financial costs. • Behavioral therapy and medication should be used together to control symptoms. • Alternative therapy includes neurostimulation, botulinium toxin injections, and surgery.

Overactive bladder (OAB) is not a disease; it is a constellation of symptoms that need to be treated. OAB is primarily characterized by urgency – the sudden compelling desire to void that is difficult to defer. Patients will commonly have frequency (eight or more micturitions per day) and nocturia. Many will also have urgency urinary incontinence (UUI). Frequency or nocturia themselves do not make OAB; the patient must also have urgency. Patients with idiopathic OAB do not have other reasons for their urinary issues such as infection, stroke, spinal cord injury, or bladder cancer. It is important to note that urgency is not the same as urge, a sensation that everyone feels when their bladder is full. Urge can be deferred until there is a socially acceptable time or place to void, but urgency cannot be easily deferred. Patients with OAB may experience an urgency episode early in the bladder filling phase. This usually results in a void, whether voluntary or involuntary.1 Incontinence from OAB (UUI) has to be distinguished from stress incontinence and mixed incontinence. A simple symptom assessment can differen-

tiate between OAB, stress incontinence, and mixed incontinence. UUI is associated with urgency and a large amount of urinary leakage. Urine leakage associated with physical activity is a typical symptom of stress incontinence. Patients with OAB can have mixed incontinence from both their OAB and stress incontinence. There are some contributing mechanisms to OAB (Exhibit 1).2 In the detrusor muscle of the bladder, increased afferent nerve activity may result from an enhanced reaction to stretching of the detrusor cells or by an increase in urothelial signaling to suburothelial nerves. In the central nervous system (CNS), there may be a tonic inhibition of afferent signals. A decrease in this tonic inhibition could result in the initiation of detrusor activity during the bladder filling phase. Several disorders associated with detrusor overactivity, whether neurogenic damage, aging, bladder outflow obstruction, or idiopathic detrusor overactivity, may result in increased sensitivity of the bladder smooth muscle to contraction-mediated neurotransmitters. The lining of the bladder may also contribute to the pathology of OAB.

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

Exhibit 1: Multiple Etiologies Involved in OAB: The Role of Afferent Pathways1 Pathophysiology of detrusor overactivity and OAB

Decreased capacity to handle afferent information

Decreased suprapontine inhibition

Increased affrent activity

Increased sensitivity to released contractionmediating transmitter

The most common risk factor for OAB is increasing age. Other common risk factors include obesity, Caucasian race, depression, and use of hormone replacement therapy. Neurogenic OAB may be secondary to multiple sclerosis, Parkinson’s disease, dementia, spinal cord injury, stroke, or diabetes.3 Symptoms of an overactive bladder are highly prevalent in the general population. In the largest United States prevalence study of OAB, over 33 million Americans were found to suffer from OAB.4 This is 16.6 percent of the population. Of those identified in this study, 37 percent of OAB sufferers had UUI. The typical patient with OAB has a long journey before being appropriately diagnosed and treated. Most women wait long periods after symptom onset to seek treatment; more than half wait greater than a year (mean = 3.1 years).5 While UUI is the primary reason for seeking help, many still do not consult about their OAB symptoms with a health care provider. Less than half of patients with probable overactive bladder discussed the symptoms with a health care provider. Only a small proportion of patients with symptoms of OAB are diagnosed (~ 6 million) or prescribed medication (~ 3 million).6,7 There is considerable scope for improvement in terms of how physicians diagnose and treat this condition. There are many reasons so few OAB sufferers are diagnosed and treated. Physicians often do not ask because they are too busy with so many other screenings. Practitioners do not always understand the impact. In addition, many physicians and patients do not view this as life threatening. In many instances, the attitude of the physician is that the

patient will bring it up if bothered. A simple screen for OAB that can be incorporated into primary care practice is asking two questions: 1) “Is your bladder causing you any problems?” 2) “Do you have trouble controlling your urine?” OAB can negatively affect various components of quality of life (QOL) including physical, occupational, sexual, psychological, domestic, and social aspects. OAB can affect physical QOL by restricting the amount of physical activity the patient will or can perform. Occupationally, OAB can lead to absence from work and, therefore, decreased productivity. Socially, OAB can reduce social interaction and limit travel, or at least hinder travel so it must be planned around accessibility to a toilet. Hygienically, specialized underwear (pads) and bedding may be required. OAB can also affect sexual QOL because it might lead to avoidance of sexual contact and intimacy. Psychologically, OAB can negatively affect the patient by causing guilt or depression; loss of self-esteem; and fear of being a burden, of lack of bladder control, or of an odor of urine.8 There is a strong association between OAB and depression; 60 percent of individuals with OAB suffer from depression.9 QOL scores among people with OAB are worse than those of people with diabetes in several domains including physical functioning, vitality, social functioning, and emotional and mental health.10 Additionally, OAB places people at greater risk for sleep disturbances, urinary tract infections (UTIs), perineal dermatitis, and falls and fractures.4,11 OAB increases risk of falls by 26 percent and fractures 34 percent. Early diagnosis and treatment of OAB can potentially prevent or decrease falls and fractures.

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 13

Exhibit 2: Treatment of OAB

Management Strategies

Education

OAB Treatment Behavioral Modification

Medications Surgical Procedures

Having incontinent episodes increases risk of hospitalization (30 percent for women, 50 percent for men) and risk of being admitted to nursing homes.12 OAB results in significant total costs. This annual costs have been estimated at $65.9 billion, with $49.1 billion for direct medical, $2.3 billion direct nonmedical, and $14.6 billion indirect.13 Treating OAB decreases costs as the result of fewer UTIs, less skin breakdowns/infections, and fewer falls/fractures. Many OAB patients can be identified and managed in primary care. The initial evaluation will include a focused history, a focused physical examination, a urine analysis, and a bladder diary. Patients should be referred to a urologist if they have microscopic or gross hematuria, significant pelvic organ prolapse, recurrent UTIs, increased post void residual, failure to improve with medical therapy, or have had prior pelvic surgery. With a bladder diary, the patient records the number of urgency episodes, UUI episodes, and voided volume over at least three days. They also track how much fluid and what types they are consuming. Many times the bladder diary will identify easy behavior modification interventions that will preclude the need for medication or other intervention. An example would be a person who consumes two cups of coffee in the morning and typically has an episode of severe urgency around 11 a.m. She could preemptively urinate before 11 a.m. or decrease coffee consumption. Exhibit 2 outlines the treatments for OAB. Patients do need realistic expectations from treatment. With OAB, the likelihood of cure is low but the symptoms of patients can be significantly improved. Various forms of behavioral modification can be helpful in the management of OAB. 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 to suppress urgency. Patients can be taught to manage their fluid intake and to use coping strategies such as defensive voiding, toilet mapping, and pads. There are also some beverages and foods which can irritate the bladder lining â&#x20AC;&#x201C; examples include alcohol, caffeine, citrus fruits, tomato-based products, and highly spiced foods. Behavior modification can be combined with medications and results in greater efficacy (Exhibit 3).14 The current medications for OAB are antimuscarinics. In the detrusor, the postjunctional muscarinic (M3) receptor is the predominant subtype mediating contraction. M3 receptor antagonism stabilizes the detrusor muscle, increases bladder capacity, diminishes frequency of involuntary bladder contractions, and delays the initial urge to void. All antimuscarinics are effective for treatment of OAB symptoms. There is insufficient evidence to suggest that any one agent has better efficacy than another. However, individual differences do exist in the pharmacologic profiles of the antimuscarinics. Although the efficacy profile of these agents is similar, the side effect profiles differ significantly and are dependent on the molecular characteristics of each agent. When selecting the ideal antimuscarinic agent for a particular patient type, one must consider the pharmacokinetic and pharmacologic profiles of each agent. The major differences are the delivery route (oral, transdermal patch, gel) and the dose flexibility (Exhibit 4). There are several management pearls to maximize patient outcomes. The patientâ&#x20AC;&#x2122;s most bothersome symptom should be identified and managed. Medi-

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

Exhibit 3: Additive Effect of Combining Behavioral And Drug Therapies14

Mean Reduction in UI, %

Behavioral Therapy

Combined Therapy

Drug Therapy

Combined Therapy

0 -20 -40 -60

-57.5% -72.7%

-80

-84.3%

-88.5%

-100

P < .05

P = .001

Exhibit 4: Comparison of Agents DRUG

DOSE

DELIVERY

COMMENTS

Darifenacin (Enablex®)

7.5mg, 15mg

Tablet

Can’t cut, crush, chew

Fesoterodine (Toviaz ®)

4mg, 8mg

Tablet

Can’t cut, crush, chew

Oxybutynin

3.8mg, 30mg

Tablet, liquid, patch, gel

Patch 2x/wk, gel QD

Solifenacin (Vesicare®)

5mg, 10mg

Tablet

Can’t cut, crush, chew

Tolterodine LA (Detrol LA®)

2mg, 4mg

Tablet

Can open

Trospium chloride XR (Sanctura®)

60mg

Tablet

Can’t cut, crush, chew can’t evening dose

cation should be started at the lowest dose and titrated upward as needed. Most patients will see some benefit within two weeks, but it will often take at least four weeks for maximum response. Patients also need to use behavior modification. Medications provide faster relief, but behavior modification can provide long-term relief. Providers also need to be proactive in preventing and treating side effects. Medications can result in up to 90 percent reduction in UUI and reduction in micturition frequency. The endpoint for frequency is two to three less voids per day. Dry rates achieved with medication will vary with baseline severity; typically 50 to 64 percent of patients will have no episodes of incontinence. This will be less with more severe baseline UUI and greater with less severe UUI. The primary medication side effects that bother patients and can result in discontinuation are dry mouth and constipation. Nighttime dosing may help decrease adverse effects but should not be used with tropsium chloride. Expectations about treatment efficacy and side ef-

fects are the most important considerations in discontinuing OAB medications for most patients.15 Interventions to promote realistic expectations about medication efficacy and side effects may enhance adherence. Most patients will need continuous or periodic therapy to manage their symptoms. In a study of women with OAB who responded to a one-month trial of tolterodine, 53 percent of patients had symptoms return and requested retreatment after being off therapy for one month.16 After three months off therapy, another 22 percent requested retreatment. Risk factors for retreatment were symptom duration and baseline health related QOL. When an antimuscarinic agent fails, a switch between agents can be made. Many times another agent will be effective. Also, if behavioral interventions are not optimized, that should be done at this time. When medications and behavioral therapy fail, alternative therapies include neuromodulation, botulinum toxin injection, and bladder augmentation. Neuromodulation is approved for treating OAB. It

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 15

can be done with an implanted sacral nerve stimulator or a percutaneous tibial nerve stimulator. Botulinum toxin injection (BTX) is investigational for idiopathic OAB but is FDA approved for neurogenic OAB. It is administered via cystoscopic injection into the detrusor muscle. Patients will require re-treatment although effects often last six months. Bladder augmentation is a therapy of last resort. The cost effectiveness of sacral nerve neuromodulation and BTX for idiopathic OAB has been compared in one study. Starting with sacral nerve neuromodulation resulted in a higher quality life year gain and a higher cost difference compared to starting with BTX. Sacral nerve neuromodulation starts to be cost effective after four years. It is not cost effective when BTX is administered under local anesthesia.17 Beta agonists are being investigated for treating OAB. Mirabegron and solabegron are selective beta-3 adrenoceptor agonists. They activate beta-3 adrenoceptors on the detrusor muscle to facilitate filling of the bladder and storage but do not affect detrusor contractility. Mirabegron is currently approved for OAB in Japan. Trials with these agents look promising with low rates of adverse effects.

9. Zorn BH, Montgomery H, Pieper K, et al. Urinary incontinence and depression. J Urol. 1999;162(1):82-4. 10. 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. 11. Wagner TH, Hu TW, Bentkover J, et al. Health-related consequences of overactive bladder. Am J Manag Care. 2002;8(19 Suppl):S598-607. 12. Brown JS, Vittinghoff E, Wyman JF, et al. Urinary incontinence: does it increase risk for falls and fractures? Study of Osteoporotic Fractures Research Group. J Am Geriatr Soc. 2000;48(7):721-5. 13. Ganz ML, Smalarz AM, Krupski TL, et al. Economic costs of overactive bladder in the United States. Urology. 2010;75(3):526-32. 14. Burgio KL, Locher JL, Goode PS. Combined behavioral and drug therapy for urge incontinence in older women. J Am Geriatr Soc. 2000;48(4):370-4. 15. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2009;105(9):1276-82. 16. Lee YS, Choo MS, Lee JY, et al. Symptom change after discontinuation of successful antimuscarinic treatment in patients with overactive bladder symptoms: a randomised, multicentre trial. Int J Clin Pract. 2011;65(9):997-1004. 17. Leong RK, de Wachter SG, Joore MA, van Kerrebroeck PE. Cost-effectiveness analysis of sacral neuromodulation and botulinum toxin A treatment for patients with idiopathic overactive bladder. BJU Int. 2011;108(4):558-64.

Conclusion

OAB remains an under-diagnosed and undertreated condition. Providers have a responsibility to identify and treat patients with this condition. There are effective treatments which can significantly reduce the quality of life impact. Pamela Ellsworth, MD is an Associate Professor of Urology/Surgery at Brown University.

References 1. Chapple CR, Artibani W, Cardozo, LD, et al. The role of urinary urgency and its measurement in the overactive bladder syndrome: current concepts and future prospects. BJU Int. 2005;95:335-41. 2. Andersson KE. Antimuscarinics for the treatment of overactive bladder. Lancet Neurol. 2004;3:46-53. 3. DuBeau CE. Interpreting the effect of common medical conditions on voiding dysfunction in the elderly. Urol Clin North Am. 1996;23(1):11-8. 4. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20(6):327-36. 5. Dmochowski RR, Newman DK. Impact of overactive bladder on women in the United States: results of a national survey. Curr Med Res Opin. 2007:23(1):65-76. 6. Rovner E, Wein A. Incidence and prevalence of overactive bladder. Curr Urol Rep. 2002;3:434-8. 7. 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(9):760-6. 8. Tubaro A. Defining overactive bladder: epidemiology and burden of disease. Urology. 2004;64(suppl 6A):2-6.

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

Practice and Funding Gaps Existing in HIV Management: Will Managed Care Bridge the Two? William A. O’Brien, MD, MS For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary With the advent of highly active antiretroviral therapy, HIV (human immunodeficiency virus) is no longer a death sentence. Treatment continues to evolve with newer agents that makes adherence easier for patients. There are still issues with identifying infected individuals, preventing spread of the infection, and most significantly with public funding of care for the HIV population, which is predominately indigent and underinsured. Key Points • The mortality rate from HIV infection has significantly declined with the advent of highly active antiretroviral therapy. • Treatment of HIV infection is now effective, reasonably well tolerated, and easy for patients to take. • There are challenges to paying for HIV/AIDS care with ongoing reductions in public funding. • Generic antiretrovirals are now entering the marketplace.

Human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS), attacks white blood cells (CD4+ T cells). The virus is transmitted to uninfected people through infected body fluids. The treatment of HIV infection has evolved dramatically since the first active agent, AZT, was introduced in 1987. This is now a manageable, chronic disease that patients do not have to die from. As shown in Exhibit 1, the mortality rate has significantly declined with the advent of highly active antiretroviral therapy (HAART).1 Patients are not infected with a single type of HIV; they have a population of viruses that are constantly mutating. The goal of therapy is to keep levels of virus so low there is no replication and thus no mutations or the development of medication resistance. Suppressing viral levels to very low levels requires multiple medications and a high level of adherence. The recommended regimens for treatment-naïve patients are given in Exhibit 2.2 Medication management has significantly improved with the introduction of medications that are less toxic and require fewer doses than older agents.

A great example of the simplification of therapy is the introduction of a triple combination product containing efavirenz, tenofovir, and emtricitabine (Atrilipa®) that can be taken as one tablet, once a day. With a single, once daily combination product, even patients with challenging social issues can be adherent and achieve viral suppression. The keys to successful therapy are numerous. The provider must connect with the patient and provide information about the importance of a high level of medication adherence (90 percent or greater) that prevents resistant virus. The provider needs to make sure the patient is prepared for therapy. Other keys to successful outcomes include optimizing antiretroviral therapy with a simple, tolerable regimen and appropriate monitoring of the viral load and CD4 counts. The viral load should be undetectable after a couple of months of therapy. If it is not, compliance issues and medication resistance need to be assessed. Antiretroviral therapy (ART) is recommended for all HIV-infected individuals.2 Although there is some controversy on whether to treat patients with CD4 counts above 500, most clinicians will choose to treat if the patient is willing to take therapy. Re-

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 17

Exhibit 1: Mortality and HAART Use Over Time1 HIV Outpatient Study, CDC, 1994-2003 0.9

14 Deaths per 100 PY

Patients on HARRT

Deaths per 100 PY

0.7 0.6 0.5 0.4

0.3

0.2

Patients on HAART

0.8

0.1 0

0 1994 1995

1996

1997

1998

1999

2000 2001 2002 2003

Year

Exhibit 2: DHHS Guidelines â&#x20AC;&#x201C; 2012 Recommendations for Treatment-NaĂŻve Patients â&#x20AC;&#x201C; Preferred Regimens2 Two NRTIs plus either 1 NNRTI or 1 PI + ritonavir or 1 Integrase Inhibitor NNRTI-Based Regimen

efavirenz /tenofovir /emtricitabine

PI-Based Regimens

atazanavir /ritonavir + tenofovir /emtricitabine darunavir /ritonavir + tenofovir /emtricitabine

INSTI-Based Regimen

raltegravir

Pregnant Women

lopinavir /ritonavir

gardless of CD4 count, initiation of ART is strongly recommended for individuals with a history of an AIDS-defining illness, HIV-associated nephropathy, or HIV/hepatitis B virus (HBV) coinfection.2 ART is also recommended regardless of CD4 count for pregnant women. There are many different potential benefits and risks to starting therapy early which must be considered. The potential benefits of starting therapy early include maintaining higher CD4 count, preventing potentially irreversible damage to the immune system, decreasing risk for HIV-associated complications, and decreasing risk of HIV transmission. There are potential risks associated with early therapy including treatment-related side effects and toxicities, increased total time on medication, less time for patient adjustment to disease and treatment requirements, development of drug resistance because of incomplete viral suppression, and transmission of drug-resistant virus in patients who do not maintain full virologic suppression. Even with all these potential risks, there is increasing evidence demonstrating that the benefits outweigh the risks of early therapy. 3 New evidence shows increased survival with early treatment. Also patients are more likely to have immune system re-

+ tenofovir /emtricitabine + zidovudine /lamivudine

constitution when therapy is started with higher CD4 counts. HIV Screening

In 2006, there was a dramatic change in the approach to HIV testing. Prior to that time, the testing requirements were cumbersome. The CDC recommends that HIV testing and HIV screening be part of routine clinical care in all health care settings.4 HIV screening is recommended for patients in all health care settings after the patient is notified that testing will be performed unless the patient declines (opt-out screening). Adults in communities with a high prevalence of HIV may need to be tested multiple times. Screening for HIV is becoming easier. Rapid point-of-contact testing is being developed and represents an opportunity to advance care and clinical decision-making. Confirmation of an HIV infection currently requires sending the test to a laboratory that results in a long turnaround time. Confirmation may ultimately be achieved through a second rapid test. In the next few years, it will be possible to detect the virus and confirm the infection in the same office visit. This improvement is needed because our testing has been occurring too late to prevent the development of AIDS in many

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

Exhibit 3: Cost-effectiveness of Commonly Employed Tests and Treatments Cost per Quality Adjusted Life-Years (QALY) HIV testing, 1% prevalence

$15,078

HIV testing, 0.1% prevalence

$57,138

Mammography and breast exam

$35,500

Implantable cardio-defibrillators

$34,000-$70,200

Treatment of hypercholesterolemia

$47,000

HIV treatment

$19,000-$57,000

Coronary artery bypass surgery

$88,087

Kidney dialysis

$147,000

patients. Another reason to improve screening for this virus is that one-fourth of infected patients who are unaware of their infection account for over 50 percent of all newly transmitted infections.5 Treatment as a Public Health Issue

Prevention of HIV transmission is important in limiting the number of new cases. There are several components of prevention. One is behavioral. This is a disease that can be prevented by behavioral actions including medication adherence, condoms, and limiting sexual partners. Another aspect of prevention is guiding infected individuals to care to prevent spread of the virus. There is biological plausibility for prevention through effective treatment. There are at least a dozen trials showing this. The concentration of HIV1 in blood and genital tract correlates with sexual transmission. Dramatic reductions in vertical transmission have been shown with viral load reduction in HIV+ pregnant women. Most observational reports indicate ART reduces transmission of HIV-1 in couples. A study of discordant couples (one infected/one not) found that treating the patient early (CD4 > 350) resulted in significantly fewer cases of transferred infection (1 versus 25) than delayed treatment (CD4 < 250).6 In this study, treatment reduced transmission by 96 percent. Many people are advocating treating everyone with the virus to stop the epidemic. Population-based prevention of HIV infection depends on durable and reliable HIV suppression, preventing transmitted resistance, and detecting and treating acute HIV infection. There are numerous implementation issues with a prevention program. Treating everyone infected with HIV is an added burden to the health care system in terms of capital and human resources that may not be possible. There are definitely cost benefits of prevention

and early treatment. Patients treated at the later stages of HIV disease required 2.6 times more health care dollars annually than those receiving earlier treatment. Preventing one infection would save approximately $355,000. Investing in HIV prevention as well as early and ongoing care and treatment have been shown to be cost effective (Exhibit 3). HIV/AIDS Funding

There are definitely challenges to paying for HIV/ AIDS care. Funding for HIV/AIDS was significantly cut in the federal budget in 2012. Because people are no longer dying from the disease, the number of people living with HIV infection is increasing while funding has been decreasing. The Ryan White Program has had tremendous impact on covering costs of HIV/AIDS care. This program was established in 1992 after an HIV-infected child was prevented from attending classes at a local school. This program provides funds for AIDS care, medication and support services to approximately 577,000 low-income, underinsured individuals and families affected by HIV/AIDS each year. For 2012, this program received $2.1 billion in funding. The AIDS Drug Assistance Program (ADAP) provides tremendous help in providing HIV/AIDs coverage for medications. It is a federally funded program delivered by states. Each state develops rules and policies for use of funds. This program led to good control of the epidemic as effective treatments became available. Over 165,000 people are served by the ADAP program, accounting for more than a third of people on AIDS treatment in the U.S. Another third receive care through Medicaid. Although successful, funding of the ADAP program is inadequate to meet need. Most states now have waiting lists for this program. In August of 2011, there were 8,785 low-income AIDS patients in 10

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 19

states on waiting lists. Because of funding cuts, states are implementing restrictions on eligibility for some of the more expensive treatments. Recently, overall eligibility was reduced by lowering the Federal Poverty Level (FPL)-eligible income. As with other types of medical care, studies can help to guide HIV/AIDS policy by establishing costeffective practices as standard of care. The science to drive policy for treating HIV is well established. Our health care system has to address standards of adequate versus optimal therapy. At this time, the only way an HIV-infected patient can get good care is to not work and live well below the poverty line so they can qualify for Medicaid. There is no incentive for patients to work. Because the antiretroviral medications are just now beginning to come off patent, medication cost controls are not yet widespread in HIV care but will be increasing over the next few years with the availability of more generics. Zidovudine became generic in 2005 but is not extensively used in the U.S. because of adverse effects and resistance. Saquinavir is an effective protease inhibitor with low levels of toxicity that went generic in 2011. The major disadvantage with this agent is the number of tablets required per day. Efavirenz will be going off patent in 2013.

AdolescentGL.pdf. 3. Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr. 2007;45:183-92. 4. CDC. Revised recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings. MMWR Morb Mortal Wkly Rep. 2006:55(NO. RR-14): 1-17. 5. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV from persons aware and unaware that they are infected with the virus in the USA. AIDS. 2006;20:1447-50. 6. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505.

Conclusion

Treatment of HIV infection has dramatically improved over the years and is now effective, reasonably well tolerated, and easy for patients to take. Recommendations and studies support treating everyone who is infected if they are willing to take medications. Expanded HIV testing and referral to treatment will help in prevention and community health. Reductions in public funding for HIV/AIDS care now and expected reductions in the future are threatening the continued success of conquering this epidemic. There is an uncertain future because so many people with HIV infection are poor, uninsured, and marginalized. It is not clear whether the current system can continue treating them. William A. Oâ&#x20AC;&#x2122;Brien, MD, MS is a Clinical Professor of Medicine in the Division of Infectious Diseases at Emory University School of Medicine in Atlanta, GA.

References 1. Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43:27-34. 2. CDC. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/Adultand-

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

Advances in GLP-1 Based Therapy in the Treatment and Management of Type 2 Diabetes Tom A. Elasy, MD, MPH For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Newer agents that target the incretin system are now available for managing type 2 diabetes. These agents are good choices as add-on medications to metformin because they result in low rates of the adverse effects of concern with other secondline medications such as hypoglycemia and weight gain. Although more expensive than older agents, the incretin agents may be worth the cost given the low rate of significant and costly adverse effects. Key Points • Incretin agents are good choices as add-on medications to metformin. • These agents cause very low risk of hypoglycemia. • The lack of weight gain or, for GLP-1 agonists, sustained weight loss are significant advantages for these agents. • DPP-IV inhibitors are less potent in lowering A1C than other second-line medications but are a safe and easy choice especially in patients with renal insufficiency or who are elderly.

An understanding of the natural history of type 2 diabetes is helpful to understanding the use of medication and lifestyle therapy for managing the disease (Exhibit 1). Early in the disease process, pancreatic beta cells are able to compensate for insulin resistance related primarily to excess weight. As the beta cells are unable to compensate, insulin resistance predominates and fasting glucose begins to rise. Therapeutic strategies include altering insulin resistance and altering the slope of the beta cell decline. We may not be able to prevent the development of type 2 diabetes but may be able to forestall the process. Losing weight and controlling glucose can alter this slope. The relationship between being overweight and obese and the development of type 2 diabetes is very strong, and the relationship is about more than just carrying extra weight. The management of weight has to be considered when managing diabetes. Also the medications used to treat diabetes can have weight consequences. Age is also an important factor in the development

of type 2 diabetes. It is a disease that disproportionately impacts people as they age. It is the best predictor of development. As we age the consequences of therapy also become more relevant. Hypoglycemia is more difficult to deal with in the older patient. Because of adverse effects shown in recent trials of tight control in type 2 disease, recommended glycemic targets have changed. The most recent American Diabetes Association (ADA) glucose goals are shown in Exhibit 2.1 A hemoglobin A1C (A1C) around 7 is now considered a reasonable goal in most patients rather pushing to achieve near normal values. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that pushing patients to achieve near normal values, particularly in the elderly with cardiovascular disease, may lead to worse outcomes.2 Higher targets may be appropriate if the patient is a frail elder with risk of falls or other consequences from hypoglycemia, has lifethreatening co-morbid illness, has hypoglycemia unawareness, or has limited cognitive function or severe psychiatric disease. Tighter control (less than

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 21

Exhibit 1: Natural History of Type 2 Diabetes Obesity IFG Diabetes Uncontrolled Hyperglycemia Relative Function (%)

300 250 Insulin Resistance

200 150 100

Insulin level

Ă&#x;-Cell Failure

50 0 -10

-5

Years of Diabetes

Exhibit 2: ADA Glycemic Targets1

Normal

Goal

HbA1c

4-6%

<7%*

Pre-prandial Blood Sugar

70-100mg/dl

90-130mg/dl (70-120)

Post-prandial Blood Sugar

<140 mg/dl

<180 mg/dl (<160)

*No longer as close to 6.0% as possible

7) may be appropriate for young patients without evidence of disease complications. Oral monotherapy will lower A1C, but the overall effect depends on the baseline A1C â&#x20AC;&#x201C; the higher the baseline A1C, the greater the reduction. On average, oral monotherapy results in a 1 to 2 percent reduction in A1C (i.e., 9% to 8% or 7%). According to the ADA guidelines, the medication of first choice is metformin.1 Metformin is started at the time of diagnosis along with lifestyle therapy. Monotherapy fails in the majority of patients either initially to achieve an A1C less than 7% or in the long term given the progressive nature of the disease. When monotherapy fails, the addition of a second agent generally has an additive effect with a net additional decline in A1C of 1 to 2 percent. The way diabetes medications are combined has changed in recent years. Several years ago, injectables and orals were not combined. Now, this is common and accepted practice. At the time of monotherapy failure, there are several options to add to metformin; all of them have disadvantages which must be considered. The addi-

tion of insulin as a second agent or third agent is often done by adding bedtime NPH or glargine or detemir insulins. All are effective in reducing A1C by at least an additional 2%. There are significant barriers to insulin use including hypoglycemia, weight gain, and patient fears. Because of adverse effects, alpha glucosidase inhibitors and thiazoladindiones (glitazones) are not used very frequently. The sulfonylureas also lead to weight gain and hypoglycemia. Episodes of hypoglycemia can be very disturbing to patients and can result in additional health care costs for management. Weight gain with medications (insulin, sulfonylureas, and glitazones) can also worsen glucose control. New agents that target postprandial glucose control are now available for managing type 2 diabetes. These agents target the incretin system. Incretins are gut hormones that enhance insulin secretion in response to food; they lead to glucose-dependent insulin secretion. Glucagon-like peptide (GLP-1) is the best characterized incretin. It is secreted from L cells in the intestines. Exhibit 3 illustrates the various actions of GLP-1.3-6 The secretion of GLP-1 is

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

Exhibit 3: GLP-1 Modulates Numerous Functions in Humans3-6

GLP-1: Secreted upon the ingestion of food

Promotes satiety and reduces appetite

Alpha cells: Postprandial glucagon secretion

Liver: Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying

diminished in type 2 diabetes resulting in high postprandial glucose. There are two ways to target the diminished GLP-1 secretion – by delaying the metabolism of endogenous GLP-1 or by giving a GLP-1 mimic (agonist). The agents that delay the metabolism are the dipeptidyl peptidase 4 (DPP-4) inhibitors and are oral agents. Three DPP-4 inhibitors are available [sitagliptin ( Januvia®), saxagliptin (Onglyza®), linagliptin (TradjentA®)] and many more are on the horizon. Exenatide (Byetta®) and liraglutide (Victoza®) are available GLP-1 agonists, which are injectables. These agents can be used as monotherapy or in combination with a sulfonylurea or metformin. These agents distinguish themselves, not on efficacy, but on side effects, cost, and complexity of use, and role of comorbid conditions. These are no more effective than other second-line agents; the DPP-4 inhibitors are somewhat less effective in lowering A1C. A1C will typically decrease 1 to 2% with GLP1 agonists and less than 1% with DPP-4 inhibitors. Because they only work in the face of food intake, these agents do not cause hypoglycemia when used alone. When added to metformin, the incidence of hypoglycemia does not significantly increase. If added to a sulfonylurea, the dose of the sulfonylurea needs to be reduced to prevent hypoglycemia. The GLP-1 agonists increase satiety and can lead to modest weight loss. The DDP-4 inhibitors tend

to be weight neutral. Nausea is a common adverse effect with the GLP-1 agonists. Because they slow gastric emptying, these agents are not useful and can worsen problems in patients with gastroparesis. Based on acquisition costs, these agents are more expensive than older agents. But, the total cost of using a medication must be considered. If the cost of managing hypoglycemia attacks and the glucose consequences of weight gain are considered, these agents may not be more costly. Although managing glucose is important and is the focus of this article, consideration of the whole patient and all their concomitant diseases and risk factors must also occur. Clinicians must also remember to manage blood pressure and lipids because cardiovascular disease is the most common cause of death in patients with diabetics. Conclusion

The newer agents that target the incretin system are good choices as add-on medications to metformin, especially when hypoglycemia is a concern. The lack of weight gain or, for GLP-1 agonists, sustained weight loss are another significant advantage for these agents. The DPP-IV inhibitors are less potent in lowering A1C than other second-line medications but are a safe and easy choice especially with patients with renal insufficiency or who are elderly. These agents are more expensive than older agents

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 23

but so are the complications of diabetes.

glycemic treatment in the ACCORD trial. Diabetes Care. 2010;33:983-90.

Tom A. Elasy, MD, MPH is an Associate Professor of Medicine at Van-

tiety and suppresses energy intake in humans. J Clin Invest. 1998;101:515-20.

3. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes saderbilt University Medical Center.

4. Larsson H, Holst JJ, AhrĂŠn B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physi-

References

ol Scand. 1997;160:413-22

1. American Diabetes Association. Standards of Medical Care. Diabetes Care.

5. Nauck MA, WollschlĂ¤ger D, Werner J, et al. Effects of subcutaneous gluca-

2012;35(suppl 1):511-563.

gon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetolo-

2. Riddle MC, Ambrosius MT, Brillon DJ, et al. Epidemiologic relationships

gia. 1996;39:1546-53.

between A1C and all-cause mortality during a median 3.4-year follow-up of

6. Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47:159-69.

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

Emerging Treatment Options in the Management of Multiple Myeloma Robert L. Schlossman, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary The arrival of the novel agents, thalidomide, lenalidomide, and bortezomib, has significantly changed the approach to the management of multiple myeloma and, importantly, patient outcomes have improved. Although this is not yet a curable disease, various combinations of the novel agents with and without older agents are effective for initial therapy and for relapsed/refractory disease. There are many additional agents in the research pipeline that will continue to improve disease response and patient survival. Key Points • Multiple myeloma cannot be cured and patients will relapse eventually after initial treatment. • The greater the degree of cytoreduction initially, the longer the patient will go before needing further treatment. • The newer agents have revolutionized treatment. • Three-drug regimens (bortezomib/lenalidomide/dexamethasone or bortezomib/ thalidomide/dexamethasone) are much more effective than two drugs and less toxic than four-drug regimens. • Maintenance therapy after treatment leads to a modest survival advantage. • Relapsed/refractory MM is difficult to treat, but the novel agents can be used. • Many more novel agents are under study.

Although the newer treatments for multiple myeloma (MM) are commonly referred to as novel agents, they have been used for some time now. These newer agents include bortezomib, lenalidomide, and thalidomide. The use of these agents has significantly changed the landscape of MM treatment. These agents target MM in the bone marrow microenvironment to overcome conventional drug resistance in vitro and in vivo. They are effective as induction/first-line therapy, effective in relapsed/refractory MM, and have an emerging role in transplant and maintenance. Before these agents, the goal of therapy was to get the MM patient to stem cell transplant and then experiment with various agents once they inevitably relapsed post-transplant. As shown in Exhibit 1, nearly all patients with MM will experience relapse and will require several lines of therapy.1 The understanding of the biology of MM and risk stratification

and new medications have led to a change in how treatment of this disease is viewed. There are two major forks in the road of choosing treatment. The first decision that must be made is whether the patient is a stem cell transplant candidate. Generally, patients under physiologic age of 70 and reasonably fit with a cancer type responsive to chemotherapy are going to be considered a transplant candidate. Older patients with medical problems or who have primary refractory disease are not candidates. The other fork in the road is how aggressive the patient wants to be. If the patient wants to be aggressive in treating their disease, aggressive therapy can be used whether they are a transplant candidate or not. If someone has low-risk disease and doesn’t want to be so aggressive, less aggressive therapy (two-drug combination) would be used with three-drug combinations being saved for treating relapse.2

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 25

Exhibit 1: Natural History of Multiple Myeloma: Nearly All Patients Experience Relapse1

Asymptomatic

Symptomatic

100 2. RELAPSE

ACTIVE MYELOMA 50 M Protein (g/L)

REFRACTORY RELAPSE

1. RELAPSE MGUS or smoldering myeloma Plateau remission

First-line therapy Second-line

Third-line

Exhibit 2: Response to Bortezomib + TD Induction/Consolidation After Double ASCT 3 100 90 CR/nCR Rate (%)

*P<0.0001 †P<0.0024 ‡P<0.0002

70 50 30 20 10

‡ 62

† 55

* 52

60 40

VTD TD

* 31

31 11

0 Induction First Second Consolidation ASCT ASCT

Treatment Stage

For many years, a two-drug regimen of thalidomide and dexamethasone was the standard of care for induction therapy for stem cell transplant candidates. The addition of bortezomib (Velcade®) to thalidomide/dexamethasone (VTD) dramatically increases the complete and near complete response rates. The three-drug regimen is superior for induction and at first stem cell transplant, second stem cell transplant, and for consolidation therapy (Exhibit 2).3 These data are a strong argument for using aggressive three-drug regimens for transplant candidates. Aggressive therapy selects for patients with chemotherapy sensitive disease and thus they will be at a low disease state at the time of stem cell harvesting. When stem cells are harvested in the patient at a low disease state, the amount of contamination with

disease cells is limited. No matter how well patients initially respond, these are not curative treatments. VTD has been shown to be a very good combination, but lenalidomide (Revlimid®) is the next evolution in therapy. Lenalidomide is a more active agent than thalidomide and has a different and favorable side effect profile. It induces caspase 8–mediated apoptosis of MM cells in the bone marrow; as with thalidomide, dexamethasone enhances the response. Synergistic MM cell toxicity (dual apoptotic signaling) occurs when lenalidomide is combined with bortezomib. Phase I trials showed that the majority (60 percent) of patients’ refractory to either agent alone responded to the combination. Lena l idom ide/dexa metha sone/ bor tezom ib (RVD) is highly effective for previously untreated

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

Exhibit 3: Combinations in the Upfront Treatment of MM7

100 90

Percent Response

ORR, overall response rate; VGPR, very good partial response; CR/nCR, complete response/near complete; VAD, vincristine/adriamycin/dexamethasone; RD, lenalidamide/dexamethasone; PAD, bortezomib/doxirubicin/dexamethasone; VTD, bortezomib/thalidomide/dexamethasone (VTD); CVD, cyclophosphamide/bortezomib/dexamethasone; RVD, lenalidamide/bortezomib/dexamethasone; CVRD, cyclophosphamide/bortezomib/dexamethasone/lenalidamide

ORR VGPR CR/nCR

70 60 50 40 30 20 10 0

VAD

TD RD

PAD VTD CVD RVD CVRD

Induction Regimen

MM. It is the first regimen to result in a 100 percent response rate (â&#x2030;Ľ partial response) without bone marrow transplant and results in remarkably high rates of complete and near complete response.4,5 The studies have shown promising outcomes data with estimated 24-month progression-free survival of 68 percent and overall survival of 95 percent with combined RVD and stem cell transplant. This three-drug regimen has a favorable tolerability over a lengthy treatment period with manageable toxicities. Importantly, in studies, stem cell mobilization was feasible and successful in almost all patients treated with this three-drug regimen. There has been some concern that lenalidomide impairs the ability to collect stem cells. This may be due to the agents used for mobilization or to continuing the lenalidomide until the time of harvesting. Some sites allow a one-month washout from lenalidomide before stem cell harvest. Peripheral neuropathies and deep vein thrombosis (DVT) are the most common adverse effects. Lenalidomide causes DVTs; full anticoagulation needs to be used if the patient has risk factors for clotting. Patients need to be educated about peripheral neuropathy risk with bortezomib. Clinicians rely on the patient to report any neuropathy symptoms in order to make changes to therapy. These peripheral neuropathies are reversible if identified early. The addition of a fourth drug (cyclophosphamide or doxorubicin) to the standard regimens has been investigated. Unfortunately, the fourth drug adds toxicity and does not seem to dramatically improve clinical results.6 Exhibit 3 compares two-, three-, and four-drug regimens in terms of efficacy.7

Carfilzomib (Kyprolis) is a new proteasome inhibitor like bortezomib. It has two benefits â&#x20AC;&#x201C; it is not associated with neuropathies, and it is different enough that patients who have stopped responding to bortezomib will likely respond. It is a good choice in patients where there is concern about neuropathy or if the patient has developed neuropathy that is limiting the use of bortezomib. The standard of care in the non-study setting for transplant eligible patients who want to be aggressive or have high-risk disease by staging and cytogenetics is becoming RVD for induction followed by high-dose cyclophosphamide followed by autologous stem cell transplant. Consolidation therapy is given with RVD after the transplant. Maintenance therapy with lenalidomide follows for one year. Maintenance therapy after treatment is still somewhat controversial. There have been many studies examining the best way to conduct maintenance. These studies show a progression-free survival benefit, but it has been difficult to show an overall survival benefit. Lenalidomide and bortezomib have both been studied as maintenance therapies and can likely be used interchangeably for maintenance. In one study, independent of patient age, lenalidomide maintenance resulted in a 65 percent reduced risk of progression. There is a survival benefit trend. In a motivated patient who has had an excellent response to induction, there are data to support continuing medications as maintenance. Several trials have raised an issue of increased risk of secondary malignancy with treatment of MM. As shown in Exhibit 4, the risk of second malignancy in

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 27

Exhibit 4: Second Primary Malignancies8 SPM, n (IR per 100 per year)

MPR-R (n = 150)

MPR (n = 152)

MP (n = 153)

Total Invasive SPMs

12 (3.04)

10 (2.57)

4 (0.98)

Hematologic

7 (1.75)

6 (1.54)

1 (0.24)

Solid tumors

5 (1.26)

5 (1.28)

3 (0.74)

Non-melanoma skin cancer

2 (0.50)

5 (1.29)

6 (1.50)

IR, incidence rate; MP, melphalan,prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melaphalan, prednisone, lenalidomide with lenalidomide maintenance; PD, progresive disease; PY, person-year; SPM, second primary malignancy

patients receiving a transplant followed by lenalidomide maintenance is higher compared to patients who did not receive lenalidomide maintenance.8 In addition to the usual myelodysplastic syndromes, the secondary malignancies include solid tumors, T cell lymphomas, and other non-Hodgkinâ&#x20AC;&#x2122;s lymphomas. These tend to occur earlier than historically seen with secondary cancers. There is disagreement on about how to incorporate the secondary malignancy risk with lenalidomide into treatment recommendations. The French limit lenalidomide maintenance to one to two years post- transplant. In the U.S., it is still recommended to continue the lenalidomide till disease progression. In the past, MM patients did not live long enough to develop a second cancer. The risk of myelodysplastic syndrome is much lower than after treatment of other hematologic cancers such as lymphoma. There is a thought that patients with MM are inherently at risk for other cancers, but this has not been proven. Patients need to understand the risk in continuing with maintenance therapy. No matter how well a patient with MM responds to initial therapy, they will relapse. There are a number of ways to approach relapsed disease. Therapy is individualized to the patient and the aggressiveness of the disease. There are several considerations in choosing therapy. These include the disease characteristics at relapse and response to prior therapy. Participation in clinical trials for relapsed MM is a priority. Toxicity of the therapy options and toxicities from prior therapies must also be considered. For example, a patient may already have peripheral neuropathies from bortezomib, which would limit further use of this agent. Clinical considerations include comorbid conditions, previous therapy, time since last therapy, mode of drug administration, disease risk profile, and the potential role of a second autologous or allogenic stem cell transplant. The novel agents can be used in the relapse setting in same or different combinations

which have been used previously. A transplant can be considered at relapse. Patients will get about 50 percent of the mileage out of a second autologous transplant. For patients who are relapsing within a couple of years of initial treatment, it probably does not make sense to offer another autologous transplant. Allogenic transplant might be an option. Patients with disease refractory to all the novel agents are particularly challenging. They often have very short event-free survival (i.e., approximately five months).9 Ideally, the patients should be enrolled in clinical trials where the novel agents will be combined with investigational agents. There are many ongoing studies combining novel agents with investigational agents for synergy. Among the numerous agents under study for relapsed/refractory MM, three are histone decetylase inhibitors - vorinostat, panobinostat, and romidepsin. Vorinostat and romidepsin have already been FDA approved for the treatment of cutaneous T cell lymphomas. The combination of one of these agents with bortezomib may offer a new treatment option for heavily pretreated, refractory myeloma patients. Vorinostat is an oral agent that has been studied in combination with bortezomib in patients who had become refractory to bortezomib therapy. A 30 percent response rate has been seen with a median progression-free survival of about three months and overall median survival of 11.2 months. Panobinostat is also being studied in patients refractory to bortezomib. It is also being explored in combinations with other agents for MM treatment, including RVD, pomalidomide, carfilzomib, and thalidomide. Pomalidomide is an investigational immune modulator in the same class as lenalidomide and thalidomide. It is another oral agent with significant activi-

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

ty against MM in combination with dexamethasone and has been studied in patients refractory to multiple prior therapies including novel agents.10 Two proteasome inhibitors like bortezomib are under study. MLN9708, an oral proteasome inhibitor, is being studied in patients with relapsed and/ or refractory MM. This is essentially an oral form of bortezomib. Marizomib (NPI-0052) exhibits high levels of proteasome inhibition without toxicities associated with bortezomib. It is active preclinically and clinically in bortezomib and lenolidamide resistant myeloma.11

References 1. Durie BGM. Concise review of the disease and treatment options. Multiple myeloma. 2011-2012 Edition. Available from: http://myeloma.org/pdfs/ CR2011-Eng_b1.pdf 2. Ludwig H, Beksac M, BladĂŠ J, et al. Multiple myeloma treatment strategies with novel agents in 2011: a European perspective. Oncologist. 2011;16(4):388-403. 3. Cavo M, Pantani L, Petrucci MT, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120(1):9-19. 4. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009;27(34):5713-9. 5. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and

Conclusion

Novel therapy combinations in MM have resulted in a new treatment paradigm targeting both the tumor cell and its microenvironment. These agents have already markedly improved overall response rates, complete response rates, progression-free survival and overall survival. Combinations of novel agents induce even higher overall response rates. Thus, novel agents are the treatments of choice for high-risk patients. These agents can also be used in patients with relapsed/refractory disease. Numerous next generation novel agents are under study for both initial induction and management of the inevitable relapse that occurs with this so far incurable disease.

dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-86. 6. Jakubowiak AJ, Griffith KA, Reece DE, et al. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial. Blood. 2011;118(3):535-43. 7. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114(27):5436-43. 8. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366(19):1759-69. 9. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149-57. 10. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004 Aug 15;22(16):3269-76.

Robert L. Schlossman, MD is an Assistant Professor at Harvard Medi-

11. Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor

cal School and the Jerome Lipper Multiple Myeloma Center at Dana-

induces apoptosis in multiple myeloma cells with mechanisms distinct from

Farber Cancer Institute in Boston.

bortezomib. Cancer Cell. 2005;8(5):407-19.

Sharpen your skills and broaden your knowledge with our varying CME/CE educational offerings

1. Conferences

2. Live Webinars

3. Archived Webcasts

Earn up to 14 hours of CME/CE at one of our live conferences.

Don't have time or budget for a live conference this year?

The Spring and Fall Managed Care Forums feature presentations in business, oncology, population health management and genomics, biotechnology and medical technologies. Get the most up to date information on what is happening in the world of managed care!

Our series of live webinars features topics on chronic illnesses, oncology, medical technology and more! Follow along as our expert speakers update you on the latest in managed care. Our webinars feature one hour of continuing education!

Our online continuing education page features over 50 archived webcasts that you can take at your leisure. Each webcast provides one hour of continuing education on topics from all of NAMCP's Institutes. Visit www.namcp.org/ cmeonline.htm to begin your online educational experience!

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 29

Individualizing Treatment Strategies in the Management of Advanced NSCLC Sandeep Reddy, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary An improved understanding of the biology of lung cancer, particularly non-small cell, is leading to improvements in therapy selection and subsequent patient outcomes. As data on various genetic markers evolve, therapy can be applied to only those patients likely to respond. Overall, this should improve response rates, decrease unnecessary exposure in those not likely to respond, and improve overall survival. Key Points • Understanding the underlying biology of lung cancer is leading to personalized therapy. • More than 50 percent of adenocarcinomas have genetic mutations or rearrangements that have been identified. • Some of the genetic anomalies can predict response to therapy. • Molecular testing has to be conducted to identify the genetic mutations, but the best test for each marker has yet to be determined. • Examples of markers and the connected medications are EGFR and gefitinib, ERCC1 and MSH2 and cisplatin, RRM1 and gemcitabine, and EML-ALK4 and ROS1 and crizotinib. • The value of these markers is in applying this information to early stage patients to determine potentially curative therapy.

Conceptually, the understanding of advanced non-small cell lung cancer (NSCLC) has changed profoundly and continues to evolve because of molecular biology. In the 1990s, all lung cancers were thought of as the same, and everyone was treated with the same regimens. No differences in survival were shown between the various chemotherapy regimens because all patients with lung cancer were lumped together. Beginning in 2008, researchers began to change how lung cancer was approached by recognizing that the underlying biology of the different types of lung cancer impact response to therapy. The first data showing differences in response to different treatment were with pemetrexed in non-squamous cell lung cancer.1,2 The labeling for the agent was changed to reflect the efficacy of this agent in nonsquamous disease only.

As Exhibit 1 shows, it is now known that over 50 percent of adenocarcinoma lung cancers exhibit various genetic mutations or rearrangements for which targeted therapies have been or are being developed. For the other 50 percent, the mutations have not yet been discovered. Instead of choosing therapy based on grouped patient outcomes, with personalized medicine, therapy is chosen based on predictors of individual outcomes (Exhibit 2). Some of these predictors such as biomarkers are known and can be used clinically to choose the most appropriate therapy. To identify the genetic mutations present in a tumor, testing must be conducted because predictions based on patient characteristics such as race, smoking status and gender are not always accurate. Most molecular testing is currently performed with tumor tissue samples. The goal with the evolution of

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

Exhibit 1: An Evolving View of Adenocarcinoma

KRAS

Pending

Adenocarcinoma

EGFR BRAF PIK3CA MEK FGFR4 EML4-ALK HER2

Exhibit 2: Molecular-Based Therapy for Individual NSCLC Patients Grouped Patient Outcomes

Individual Patient Outcomes

1.0

1.0 Low Mg440 high mg440

0.8

0.9

Survival Probability

0.9

0.7 0.6 0.5 0.4 0.3

0.8 0.7 0.6 0.5 0.4 0.3

0.2

0.1

Months

Months Chemotherapy Anti-EGFR Therapy Anti-Angiogenic Therapy

testing is to be able to use blood samples for much of the testing. It is difficult to convince patients to get serial tissue biopsies. Additionally, many times the tissue samples are not large enough for molecular testing. For an individual genetic mutation, there are multiple ways to identify and measure this mutation. For example, techniques currently used to identify epidermal growth factor receptor (EGFR) mutation status, gene copy number, and protein expression include gene sequencing, fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC), respectively. All these techniques require the

use of patient tumor tissue. Gene sequencing can be performed by different methods, including DNA polymerase chain reaction (PCR) and RNA reverse transcription PCR. Such techniques can help identify abnormal EGFR DNA sequences within the genome of the tumor cells. FISH analysis measures fluorescent-labeled probes hybridized to specific gene sequences within a cell. Gene amplification can be determined effectively by fluorescence microscopy visualization. FISH results are a quantitative score of the level of gene amplification. IHC is a method of identifying the presence of a protein in cells or tissues via specific antibodies. IHC staining

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 31

is a qualitative approach to detect protein expression levels. The best method for determining EGFR status or any of the other mutations has not been determined and may vary by therapy. Gefitinib (IressaÂŽ) is an EGFR inhibitor. In the IPASS study, targeted therapy with gefitinib was compared with paclitaxel-carboplatin.3 Patients with EGFR mutation positive status did statistically significantly better on gefitinib for progression-free survival but not overall survival. The results are flipped in patients without the mutation. This trial established gefitinib as the new standard of care for the ďŹ rst-line treatment of patients with NSCLC and activating EGFR mutations. The nucleotide excision repair gene, excision repair cross-complementation group 1 (ERCC1), is a well-validated biomarker for predicting response to cisplatin chemotherapy. ERCC1 plays a key role in DNA repair after cisplatin-induced damage. The balance of DNA damage to DNA repair dictates tumor cell death or survival after cisplatin therapy. Basically, if tumor cells have high levels of ERCC1, they can repair themselves after chemotherapy and do not die. Cells with low levels are unable to self-repair and die as a result of the chemotherapy. ERCC1 mRNA levels are predictive of improved response (58 percent versus 37 percent, p=0.03) and overall survival (p=0.009) after cisplatin therapy.4,5 About one-third of patients will not respond to cisplatin because of high levels of ERCC1. In the Genotypic International Lung Trial (GILT), patients with high levels of ERCC1 received docetaxel and gemcitabine (Gemzar ÂŽ), whereas those with low levels received docetaxel and cisplatin.6 Selecting therapy based on ERCC1 levels improved response compared with all patients receiving the same therapy. Mut S homolog 2 (MSH2) is another downstream DNA repair marker that can trump low ERCC1 levels. Patients with low MSH2 treated with chemotherapy have a significantly longer survival than those with high levels. Combining MSH2 and ERCC1 improves predictability of response to cisplatin. Patients who are low for both markers have the best overall survival when treated with cisplatin. Those with a low ERCC1 level and high MSH2 level do not receive a survival benefit from chemotherapy. RRM1 is a regulatory subunit of ribonucleotide reductase that provides deoxyribonucleotides for DNA-synthesis and also for DNA-repair. This is a marker of gemcitabine response. Low levels of RRM1 predict response, whereas high levels suggest resistance.7 The MADeIT trial examined using ERCC1 and

RRM1 for making individualized therapy decisions.8 Testing for ERCC1/RRM1 status improved response to 44 percent with cisplatin and noncisplatin regimens compared with a 19 percent response in unselected patients. EML4-ALK is the most recently identified genetic marker for selecting therapy in lung cancer. Multiple variants of this gene fusion protein have been identified. The variants can be identified by PCR or FISH. FISH is the FDA approved companion diagnostic even though PCR identifies 100 percent of the variants. EML4-ALK positive NSCLC occurs in about 4 percent of cases overall and 8 to 10 percent of adenocarcinoma cases. On August 26, 2011, the Food and Drug Administration (FDA) granted accelerated approval to crizotinib (Xalkori) for treatment of EML4-ALK positive lung cancer. The approval was based on two, singlearm trials. Crizotinib, 250 mg, was administered orally twice daily to a total of 255 patients with locally advanced or metastatic ALK-positive NSCLC who were heavily pretreated. The primary endpoint of both trials was objective response rate (ORR) as assessed by the investigator. In the first study, the ORR was 50 percent (95 percent CI: 42 percent, 59 percent) with a median response duration of 42 weeks. In the second study, the ORR was 61 percent (95 percent CI: 52 percent, 70 percent) with a median response duration of 48 weeks. These were amazing responses that had never been seen before with lung cancer treatments. The bad news is people are already developing resistance to crizotinib. ROS is a receptor tyrosine kinase of the insulin receptor family. ROS1 is a relatively rare gene rearrangement that appears to occur in less than 2 percent of lung cancers. Crizotinib is a more potent inhibitor of ROS than EML4-ALK. It is expected that crizotinib will be used in these cases until agents under development make it to market. Many other biomarkers have been identified. The interactions between all these markers are not yet understood. In the past, one of the barriers to doing this type of analysis was computing power limitations which are improving. A huge collaborative effort is needed to determine the interaction and importance of all the markers and which markers should be tested for in which patients. The value of these markers is not in treating patients with advanced stage disease because at that point a major difference in overall survival has not been seen. The value is in applying this information to early stage patients getting potentially curative therapy. Knowing the right drug to use as adjunctive therapy after surgery could shift the balance to saving more patients from death. Even if this only

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

saved 2 to 3 percent of the patients, that would account for thousands of patients in the U.S. annually.

3. Wu YL, Chu DT, Han B, et al. Phase III, randomized, open-label, first-line study in Asia of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer: evaluation of patients recruit-

Conclusion

ed from mainland China. Asia Pac J Clin Oncol. 2012;8(3):232-43.

The cost of caring for patients with advanced NSCLC is expensive. If we could utilize biomarkers to identify the best therapy early in disease, it should be cost effective and likely will save lives. Data on biomarkers and best therapies based on these markers continue to evolve.

(ERCC1) in platinum-based treatment of non-small cell lung cancer with spe-

Sandeep Reddy, MD is a Senior Medical Director with CARIS Life Sci-

2009;64(2):131-9.

4. Zhou W, Gurubhagavatula S, Liu G, et al. Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2004;10:4939-4943. 5. Vilmar A, Sørensen JB. Excision repair cross-complementation group 1 cial emphasis on carboplatin: a review of current literature. Lung Cancer.

ences and a Clinical Instructor at Harbor/UCLA Medical Center.

6. Cobo M, Isla D, Massuti B, et al. Customizing Cisplatin Based on Quantitative Excision Repair Cross-Complementing 1 mRNA Expression: A Phase III

References

Trial in Non–Small-Cell Lung Cancer. J Clin Oncol. 2007;25(19):2747-54.

1. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of peme-

7. Rosell R, Scagliotti G, Danenberg KD, et al. Transcripts in pretreatment bi-

trexed according to NSCLC histology: a review of two phase III studies. On-

opsies from a three-arm randomized trial in metastatic non-small-cell lung can-

cologist. 2009;14:253-263.

cer. Oncogene. 2003;22(23):3548-53.

2. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus

8. Feasibility and Efficacy of Molecular Analysis-Directed Individualized Ther-

best supportive care versus placebo plus best supportive care for non-small-cell

apy in Advanced Non–Small-Cell Lung Cancer. Simon G, Sharma A, Li X, et

lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-40.

al. J Clin Oncol. 2007;25(19):2741-46;

saving millions Health Diagnostic Laboratory, Inc. (HDL, Inc.) is saving lives and healthcare dollars through advanced testing for cardiovascular disease, diabetes, and related diseases.

Visit myhdl.com to learn more.

737 N. 5th Street, Suite 103 | Richmond, VA 23219 | 1.877.4HDLABS (1.877.443.5227) | www.myhdl.com

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 33

Announcing: J-code

J9042

CD30-directed therapy

effective 1/1/13

CT SCANS confirmed responses in relapsed patients

120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/Lin:DCM/id:ID W:200 L25

2011 August 19 Acq Tm: 14:05:52

512x512 B

Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9

A R

L Vp

855.4SEAGEN (855.473.2436) SeaGenSecure.com

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104j

After multiple failures,

single-agent response Indicated for the treatment of:

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

sALCL: 86% ORR (95% CI: 77%-95%)

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS® (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

Important Safety Information BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• P rogressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS® (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • S tevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • U se in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS® (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

General dosing information

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS and its logo, SeaGen Secure and its logo, Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2013 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2011/0150c

New Developments in the Treatment and Management of Metastatic Melanoma Ragini Kudchadkar, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although more people are developing melanoma, newer therapies are revolutionizing the treatment of this disease in the later stages. Therapies targeting the immune system and specific genetic mutations within tumors are now available. These therapies are modestly improving overall survival compared with historical treatments. Key Points • The lifetime risk for developing melanoma has dramatically increased in recent years. • Melanoma is a common cancer in young people, particularly women. • Chemotherapy does not improve survival when the disease is metastatic. • Ipilimumab and vemurafenib are two new agents for metastatic melanoma that target T cells and BRAF mutations respectively. • As understanding of underlying mechanisms for melanoma growth are better understood, additional therapies that improve survival will hopefully come to market.

Melanoma is now in the list of top cancers from the American Cancer Society. Overall, it is the fifth most common cancer in males and seventh in females. What makes melanoma unique is that it is common in young people. It is the most common tumor in women ages 25 to 29. Melanoma is second to breast cancer in women 30 to 35. In 2012, 131,810 new cases and 9,180 deaths were predicted. As shown in Exhibit 1, the lifetime risk for developing melanoma has dramatically increased in recent years.1 One factor in this dramatic increase is the prevalence of tanning. The mortality from this cancer is also increasing. For many years, there were no effective therapies for this disease. It is now a model for new drug development. From 1975 until 1995, decarbazine was the only approved therapy for Stage IV melanoma, but it was not really effective. In 1995, interferon was approved for Stage II and III disease. Interleukin-2 was approved for Stage IV disease in 1998. This agent was not widely adopted because of toxicity but is still used at some institutions. Dramatic changes in available therapies occurred in 2011 with approval of ipilimumab (Yervoy ®), pegylated-IFN

for adjuvant therapy, and vemurafenib (Zelboraf ®). Historically, the one-year overall survival rate for metastatic melanoma was only 25 percent with 10 percent of people still alive at two years. Until the new medications, there were no changes in the survival curves. Ipilimumab reinvented immunotherapy for metastatic melanoma. This agent literally takes the brakes off of T cell activation. Previous attempts at immunotherapy tried to stimulate the immune system. This agent, a CTL-4 antibody, prevents inactivation of T cells. In a comparison with a melanoma vaccine, ipilimumab therapy resulted in a 46 percent 12-month survival compared with 25 percent for the vaccine, which was comparable to the historical survival.2 Based on this trial, the agent was approved for Stage IV metastatic melanoma. This agent does not significantly shrink tumors or change progressionfree survival interval but does result in a survival benefit. The overall improvement in survival is about four months at a cost of approximately $120,000. It has also been studied in combination dacarbazine in treatment-naïve patients. Again, an improvement in overall survival was shown, but this agent is not approved for use in combination.3

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 37

Exhibit 1: Lifetime Risk of Developing Cutaneous Melanoma in the U.S.1 0.025 1:50

Lifetime Risk

0.020 0.015

1:74 1:100

0.010

1:150

0.005 1:1500

1:250

1:600

0.000 1935

1960

1980

1985

1993

2000

2010

Overall Survival (%)

Exhibit 2: Vemurafenib Improves Overall Survival in Previously Untreated Stage IV BRAF V600 Mutant Melanoma9

100 90 80 70 60 50 40 30 20 10 0

Estimated 6-month survival 84% vs 64% Vemurafenib (N=336)

Dacarbazine (N=336)

Hazard ratio, 0.37 P<0.001 0

6 7 Months

No.at Risk Dacarbazine

336

283

192

137

Vemurafenib

336

320

266

210

162

111

An interesting thing happens with use of this agent. A patient’s tumors can actually enlarge initially because of the inflammation related to stimulation of the immune system. Blockade of CTLA-4 can lead to the development of immune adverse effects. Treatment results in T cells losing tolerance to self-antigens. The common autoimmunities in patients treated with anti–CTLA4 include dermatitis, enterocolitis, and endocrinopathies. Toxicity does not always equal response, but there does appear to be an association.4-6 Dermatologic reactions are the most common immune reactions. These are mostly low- grade rash, pruritus, and vitiligo. These typically resolve with symptomatic therapy (antihistamines) or corticosteroids. The dermatologic reactions are frequently associated with T cell infiltrates in the skin.

Inflammation caused by T cells can occur anywhere in the gastrointestinal tract (e.g., mucositis and gastritis, but most commonly colitis). Diarrhea is a frequent immune symptom with most cases being mild or moderate. Being immune mediated, this diarrhea is more like Crohn’s disease than diarrhea from other causes. Treatment with loperamide, oral budesonide, predisone, or even infliximab may be necessary. Most cases respond to either symptomatic treatment or steroids, but it can rarely lead to gastrointestinal perforation (<1%) requiring surgery.7-8 Endocrine immune-mediated adverse effects, including hypophysitis and hypothyroidism, can also occur with ipilimumab therapy. Symptoms of these may be nonspecific, including fatigue, nausea, amenorrhea, impotence, hypotension, hyponatremia, hypoglycemia, and eosinophilia.

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

Patient education for early recognition of immune-mediated adverse effects is important. The overall rate of adverse effects is about 30 percent. Patients who have significant adverse effects should not be retreated with ipilimumab. When used in combination with chemotherapy, the adverse effect profile worsens. At this time, combination therapy is not recommended. In recent years, it was discovered that some melanoma tumors have genetic mutations. The most common is a V660 mutation that occurs in approximately 50 percent of cutaneous melanoma tumors; the mutation leads to unchecked cell proliferation. Vemurafenib is a BRAF inhibitor that halts this unchecked cell proliferation. Although FDA approved for V600E mutation only, the response to this agent in other V600 mutations is similar. It is not effective in patients who do not have a V600 mutation. In the treatment-naĂŻve patient, vemurafenib results in an estimated 84 percent six-month survival compared with a 64 percent survival with dacarbazine.9 The overall response rate (complete and partial response) was 48.4 percent compared with 5.5 percent with dacarbazine. Patients treated with vemurafenib had a median progression-free survival of 5.3 months versus 1.6 months in the dacarbazine group. The response in patients who have failed previous treatment is a median progression-free survival of 6.8 months and median overall survival of 15.9 months.10 This is significantly better than historic controls. Few people get a complete response. The major difference of vemurafenib from ipilimumab is the speed of response. Patients can get a very rapid response with this agent. This can help patients feel significantly better, but the response is short-lived. The average cost for six months of this oral agent is $55,000. The adverse effect profile of this agent is also different from ipilimumab. The most common adverse events are arthralgias, fatigue, elevated liver function tests, and nausea. This agent causes a significant amount of skin toxicity with rash and photosensitivity. A SPF 30 sunscreen must be used daily to prevent severe sunburns. Additionally, it carries a significant risk for keratoacanthoma-type squamous cell carcinoma; these occur in about 30 percent of treated patients. The median time to development of squamous cell carcinoma is eight weeks with a reported range of two to 36 weeks. Patients should be seen frequently by a dermatologist when started on this agent. The overall treatment options in metastatic melanoma are a clinical trial, chemotherapy (but no known survival response), high-dose interleukin, vemurafenib, or ipilimumab. The response to

ipilimumab is slow; for patients with large tumor burden and rapidly progressive disease, chemotherapy may be used. Vemurafenib also can rapidly shrink tumors. There are several novel agents on the horizon, including programmed death ligand (PD-1) antibodies, adoptive cell therapy, and combination BRAF and MEK inhibitors. PD-1 antibodies essentially revive exhausted T cells. PD-1 is another checkpoint protein expressed on cells. Early phase trials are finding similar toxicity to ipilimumab but lower incidence. Response rates and durability of response may be even higher than with ipilimumab. The goals of combining BRAF inhibitors with other agents are synergy in combination, prevent/ overcome potential monotherapy resistance, and potentially decrease incidence of BRAF inhibitorinduced hyper-proliferative skin lesions. The next chapter of melanoma therapy is studying these newer agents as adjuvant therapy and how to overcome acquired resistance to BRAF inhibitors. The population of patients that benefits from immunotherapy needs to be better defined. Conclusion

Amazing progress in the treatment of melanoma is being made, but there is still a long way to go. Two new agents â&#x20AC;&#x201C; ipilimumab and vemurafenib â&#x20AC;&#x201C; target different issues in the disease process. As more genetic mutations are discovered, additional targeted therapies will likely come to market. Ragini Kudchadkar, MD is an Assistant Member at the H. Lee Moffitt Cancer Center in Tampa, FL.

References 1. Rigel DS, Carucci JA. Malignant melanoma: prevention, early detection, and treatment in the 21st century. CA Cancer J Clin. 2000;50(4):215-36. 2. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-23. 3. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-26. 4. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic Tlymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043-53. 5. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13(22 Pt 1):6681-8. 6. Weber JS, O'Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26(36):5950-6. 7. Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58(5):823-30. 8. Ledezma B. Ipilimumab for advanced melanoma: a nursing perspective. Oncol Nurs Forum. 2009;36(1):97-104. 9. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-16. 10. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-14.

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 39

I NT RODUC I NG A new mechanism of action for OAB

The first and only FDA-approved b3-adrenergic agonist A new OAB therapy that targets a different pathway— the b3-adrenergic receptor pathway

Find out more at myrbetriqHcp.com

IndIcAtIOnS And USAge

Myrbetriq™ (mirabegron) is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. ImpOrtAnt SAfety InfOrmAtIOn

Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in severe uncontrolled hypertensive patients (defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg). Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB. Since Myrbetriq is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with Myrbetriq. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone. Most commonly reported adverse reactions (>2% and >placebo) for Myrbetriq 25 mg and 50 mg vs placebo, respectively, were hypertension (11.3%, 7.5% vs 7.6%), nasopharyngitis (3.5%, 3.9% vs 2.5%), urinary tract infection (4.2%, 2.9% vs 1.8%), and headache (2.1%, 3.2% vs 3.0%).

Printed in USA

012K-057-6780

November 2012

BRIEF SUMMARYOF PRESCRIBING INFORMATION The following information is a brief summary only. See full prescribing information for MYRBETRIQ.

The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.

MYRBETRIQTM (mirabegron) extended-release tablets

Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.

INDICATIONS AND USAGE Myrbetriq is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. ---------------------CONTRAINDICATIONS----------------------None ----------------WARNINGS AND PRECAUTIONS---------------Increases in Blood Pressure Myrbetriq can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg) [see Clinical Pharmacology].

Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with Myrbetriq 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Myrbetriq patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache. Table 1: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported by 1% or More Patients Treated With Myrbetriq 25 mg or 50 mg Once Daily in Studies 1, 2, and 3 Placebo (%)

Myrbetriq 50 mg

(%)

1380

432

1375

Hypertension*

7.6

11.3

7.5

Nasopharyngitis

2.5

3.5

3.9

Urinary Tract Infection

1.8

4.2

2.9

Headache

3.0

2.1

3.2

Constipation

1.4

1.6

Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB

Upper Respiratory Tract Infection

1.7

2.1

1.5

Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should be administered with caution to patients with clinically significant BOO. Myrbetriq should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB [see Clinical Pharmacology].

Arthralgia

1.1

1.6

1.3

Diarrhea

1.3

1.2

1.5

Tachycardia

0.6

1.6

1.2

Abdominal Pain

0.7

1.4

0.6

Fatigue

1.0

1.4

1.2

Patients Taking Drugs Metabolized by CYP2D6

*Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension.

In two, randomized, placebo-controlled, healthy volunteer studies, Myrbetriq was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg greater than placebo. In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mmHg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in Myrbetriq patients.

Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when coadministered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone [see Drug Interactions and Clinical Pharmacology]. -----------------------ADVERSE REACTIONS-----------------------

Number of Patients

Myrbetriq 25 mg

Other adverse reactions reported by less than 1% of patients treated with Myrbetriq in Studies 1, 2, or 3 included: Cardiac disorders: palpitations, blood pressure increased [see Clinical Pharmacology] Eye Disorders: glaucoma [see Clinical Pharmacology]

Clinical Trials Experience

Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Investigations: GGT increased, AST increased, ALT increased, LDH increased

In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), Myrbetriq was evaluated for safety in 2736 patients [see Clinical Studies]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received Myrbetriq 25 mg, 1375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years). Myrbetriq was also evaluated for safety in 1632 patients who received Myrbetriq 50 mg once daily (n=812 patients) or Myrbetriq 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received Myrbetriq in a previous 12 week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.

Infections and Infestations: sinusitis, rhinitis Renal and urinary disorders: nephrolithiasis, bladder pain Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Myrbetriq 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of Myrbetriq patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.

Table 2: Percentages of Patients with Adverse Reactions, Derived from all Adverse Events, Reported by Greater Than 2% of Patients Treated With Myrbetriq 50 mg Once Daily in Study 4 Myrbetriq 50 mg

Active Control

The following are drug interactions for which monitoring is recommended: Drugs Metabolized by CYP2D6 Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Myrbetriq is coadministered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions and Clinical Pharmacology]. Digoxin

(%)

Number of Patients

812

Hypertension

9.2

9.6

Urinary Tract Infection

5.9

6.4

Headache

4.1

2.5

Nasopharyngitis

3.9

3.1

Back Pain

2.8

1.6

Constipation

2.8

2.7

When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Clinical Pharmacology].

Dry Mouth

2.8

8.6

Warfarin

Dizziness

2.7

2.6

Sinusitis

2.7

1.5

Influenza

2.6

3.4

Arthralgia

2.1

2.0

Cystitis

2.1

2.3

The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Clinical Pharmacology].

In Study 4, in patients treated with Myrbetriq 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking Myrbetriq 50 mg, and these markers subsequently returned to baseline while both patients continued Myrbetriq. In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.

-----------------USE IN SPECIFIC POPULATIONS--------------PREGNANCY Pregnancy Category C There are no adequate and well-controlled studies using Myrbetriq in pregnant women. Myrbetriq should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq treatment are encouraged to contact their physician. Risk Summary

In a separate clinical study in Japan, a single case was reported as StevensJohnson syndrome with increased serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).

Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximal recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.

Postmarketing Experience

Nursing Mothers

Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.

It is not known whether Myrbetriq is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Myrbetriq on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Myrbetriq is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The following events have been reported in association with mirabegron use in worldwide postmarketing experience: Urologic: urinary retention [see Warnings and Precautions] -----------------------DRUG INTERACTIONS----------------------Drug interaction studies were conducted to investigate the effect of coadministered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives) [see Clinical Pharmacology]. No dose adjustment is recommended when these drugs are coadministered with mirabegron. Although no dose adjustment is recommended with solifenacin or tamsulosin based on the lack of pharmacokinetic interaction, Myrbetriq should be administered with caution to patients taking antimuscarinic medications for the treatment of OAB and in patients with clinically significant BOO because of the risk of urinary retention [see Warnings and Precautions].

Pediatric Use The safety and effectiveness of Myrbetriq in pediatric patients have not been established. Geriatric Use No dose adjustment is necessary for the elderly. The pharmacokinetics of Myrbetriq is not significantly influenced by age [see Clinical Pharmacology]. Of 5648 patients who received Myrbetriq in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies. Renal Impairment Myrbetriq has not been studied in patients with end stage renal disease (CLcr <15 mL/min or eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.

In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2) [see Clinical Pharmacology]. Hepatic Impairment Myrbetriq has not been studied in patients with severe hepatic impairment (ChildPugh Class C), and therefore is not recommended for use in this patient population. In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of Myrbetriq should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology]. Gender No dose adjustment is necessary based on gender. When corrected for differences in body weight, the Myrbetriq systemic exposure is 20% to 30% higher in females compared to males. OVERDOSAGE Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended. Pharmacodynamics Urodynamics

In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of Myrbetriq for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mmHg for Myrbetriq exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively. In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving Myrbetriq 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 - 1 mmHg were observed. Morning SBP increased by at least 15 mmHg from baseline in 5.3%, 5.1%, and 6.7% of placebo, Myrbetriq 25 mg and Myrbetriq 50 mg patients, respectively. Morning DBP increased by at least 10 mmHg in 4.6%, 4.1% and 6.6% of placebo, Myrbetriq 25 mg, and Myrbetriq 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/ day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/ kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose. Mutagenesis Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.

The effects of Myrbetriq on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of Myrbetriq once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, Myrbetriq should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions].

Impairment of Fertility

Cardiac Electrophysiology

Inform patients that Myrbetriq may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. Myrbetriq has also been associated with infrequent urinary tract infections, rapid heart beat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking Myrbetriq.

The effect of multiple doses of Myrbetriq 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo- and activecontrolled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg Myrbetriq dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec). For the Myrbetriq 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the Myrbetriq 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec). In this thorough QT study, Myrbetriq increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for Myrbetriq 50 mg was approximately 1 bpm. In this thorough QT study, Myrbetriq also increased blood pressure in a dose dependent manner (see Effects on Blood Pressure ). Effects on Blood Pressure In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of Myrbetriq for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mmHg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mmHg at Myrbetriq doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.

Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men. PATIENT COUNSELING INFORMATION

Patients should read the patient leaflet entitled “Patient Information” before starting therapy with Myrbetriq. Rx Only PRODUCT OF JAPAN Manufactured by: Astellas Pharma Technologies, Inc. Norman, Oklahoma 73072 Marketed and Distributed by: Astellas

Pharma

Northbrook,

US,

Illinois

Inc. 60062

Optimizing the Screening, Diagnosis, and Treatment of Hepatitis C in Managed Care David H.Winston, MD, FACP, AGAF For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Hepatitis C is a curable infection; however, in order to be cured, infected patients must be identified and treated. The primary care provider is the most important link in identifying these patients. Assessment of hepatitis C risk factors needs to be incorporated into routine care. Once identified, infected individuals need to be educated and treated in order to prevent the spreading and the devastating longterm consequences of this infection. Key Points • HCV is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. • A significant increase in the cases of cirrhosis and hepatocellular carcinoma is predicted if currently infected patients are not identified and treated. • Primary care providers need to screen, diagnose, and refer these mostly asymptomatic patients. • Screening for HCV should be conducted based on risk factors, not symptoms or lab tests. • All baby boomers should be considered for HCV screening. • Triple therapy is currently the best way of achieving sustained virologic response in genotype 1 patients. • Response-guided therapy permits a shorter duration of treatment without reducing the sustained virologic response rate.

Hepatitis C virus (HCV) is a singlestranded RNA virus and the only member of genus Hepacivirus in the Flaviviridae family. Humans are the only known natural host for this virus. Importantly, unlike the DNA viruses human immunodeficiency virus (HIV) and hepatitis B virus (HBV), the cure of HCV infection is possible. HBV infection cannot be fully eradicated because of the persistence of viral DNA in host cells. The major reason HIV infection cannot be cured is the virus can persist in a latent form in resting memory CD4 cells through integration of the HIV genome with the nuclear DNA of the host cell, which can survive for many years and may be reactivated at a later time to produce the virus again. In contrast to HIV and HBV, a sustained virologic response (SVR) can be achieved for HCV because it has an entirely cytoplasmic life cycle and does not have a

known form of persistence or latency in host cells.1 The World Health Organization (WHO) estimates that 170 million persons or 3 percent of the world’s population are infected with HCV, and 3 to 4 million persons are newly infected each year.2 The prevalence of HCV in some countries in Africa, the Eastern Mediterranean, South East Asia and Western Pacific is high compared to some countries in Europe and North America. According to the National Health and Nutrition Examination Survey of 1999 to 2002 and other population-based surveys, nearly 2 percent of Americans test positive for the hepatitis C antibody.3,4 This prevalence corresponds to an estimated four million Americans infected with HCV. The prevalence of HCV infection in the United States is highest in African American and male populations.4 Importantly, the prevalence is highest among baby boomers born between 1945

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

Exhibit 1: Prevalence of HCV in the U.S. (NHANES 1999-2002)4 Overall prevalence: 1.6% (4.1 million) Born ~ 1945-1965

Prevalence of anti-HCV

8% 7%

Men

Women

5% 4% 3% 2% 1%

55+

50-54

45-49

40-44

35-39

20-34

6-19

All

Age Group (years)

Exhibit 2: Natural History of Hepatitis C7

Acute HCV Infection 85%

15%

Anti-HCV + HCV-RNA -

Anti-HCV + HCV-RNA +

Chronic HCV Infection

Recovery

20%

80%

75% Stable

Cirrhosis

Stable 25% Decompensation

4% Hepatocellular CA

Death or Liver Transplantation

and 1965 (Exhibit 1).4 There are six major genotypes (1 to 6) and more than 50 subtypes (e.g., 1a, 1b, 2a) of HCV. The genotypes differ from each other by 31 to 34 percent in their nucleotide sequences. The different HCV genotypes have marked geographic variation. In the U.S., genotypes 1a and 1b account for approximately 75 percent of cases of chronic HCV, genotypes 2a and 2 b account for 13 to 15 percent, and genotype 3a accounts for 6 to 7 percent.5,6 Genotypes 1b, 2a, and 2b have worldwide distributions. Genotype

4 is the most common genotype of Africa and the Middle East, genotype 5 is found in South Africa, and genotype 6 is found in Southeast Asia.7 Exhibit 2 illustrates the natural history of hepatitis C.7 The majority of patients who have an acute HCV infection will go on to develop chronic HCV. An estimated 3.4 million Americans have chronic disease.4 A significant number of people with chronic infection will develop cirrhosis and hepatocellular carcinoma (HCC). HCV is the most common cause of HCC in the U.S., accounting for 60 percent of

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 45

Exhibit 3: Genotype and Viral Load in U.S. Patients 5,6 Genotype 4,5,6 HVL 2.7% Genotype 2,3 LVL Genotype 4,5,6 LVL 7.3% 1.3% Genotype 2,3 HVL 14.7%

Genotype 1 HVL 49.5%

Genotype 1 LVL 24.5%

HIGH VIRAL LOAD:>800,000 IU/ML LOW VIRAL LOAD:<800,000 IU/ML

cases. HCV increases the risk for HCC probably by promoting fibrosis and cirrhosis. Based on data from the third National Health and Nutrition Examination Survey (NHANES), as well as data from a large cohort of patients with chronic HCV reported by Blatt and colleagues, almost 50 percent of patients have genotype 1 and high viral load (>2 million copies/mL) â&#x20AC;&#x201C; the most challenging virological profile to treat (Exhibit 3).5,6 About 25 percent of patients have genotype 1 and low viral load (<2 million copies/mL). It is estimated that only 30 percent of those with chronic HCV have been diagnosed. Of those diagnosed with chronic hepatitis C, it is estimated that only 41 percent have received treatment, thus 59 percent who have been diagnosed have not received treatment. It is estimated that only 12 percent of those with chronic hepatitis C have received treatment. 8,9 In the U.S., acute HCV infections peaked between 1970 and 1990. With better education on risk factors, acute infections have declined. The peak of chronic HCV prevalence was in 2001. However, the true epidemic from HCV infections is yet to come. Because of the time delay in developing cirrhosis, the highest prevalence of cirrhosis is projected to be between 2010 and 2030.10 Using a model to project future HCV infection prevalence, disease severity, and burden on the health care system, the continued maturation of current cases will result in: 61 percent increase in cirrhosis, 279 percent increase in decompensated patients, 68 percent increase in HCC, 528 percent increase in the need for liver transplantation, and 223 percent increase in liver-related deaths.

Thus, despite the decreasing incidence of HCV infection, the future health care burden attributable to HCV-related liver disease will be significant. There are several factors associated with progression from chronic HCV infection to cirrhosis. These include ETOH consumption (>30 g/day in males, >20 g/day in females), disease acquisition at greater than 40 years, male gender, HIV or HBV co-infection, concomitant hepatic steatosis, and daily cannabis use.11 Patients who are initially exposed to HCV when they are older than 40 years of age generally have a higher degree of fibrosis regardless of how long they have had the disease, compared with individuals who are infected at a younger age. Hepatic steatosis is relatively common in the U.S. because of our rates of obesity. Other factors have been shown to not affect progression. These include transaminase level (ALT), viral load, mode of transmission, and genotype.12 The costs of untreated HCV infection have been estimated for a 10-year period from 2010 to 2019 at $10.7 billion in direct medical cost. The societal costs are estimated at $75.3 billion from premature disability and mortality for a total of $86 billion in direct and indirect costs.13 The costs of treating complications of untreated HCV are also significant. A single case of decompensated cirrhosis costs approximately $160,000 per year. The first year of treatment of HCC and liver transplant can cost $62,000 and $267,000, respectively.14 The insurance costs for untreated HCV will more than double between 2012 and 2027 (Exhibit 4).14 The per-patient costs for people with chronic

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

Exhibit 4: Estimated Insurance Costs Related to Untreated HCV Will More Than Double14 100 Medicare Uninsured VA Medicaid Commercial

90 80

$ (billions)

70 60 50 40 30 20 10 0 2009

2012

2015

2018

2021

2024

2027

Year

HCV infection increase rapidly as their disease progresses. Early diagnosis and treatment of HCV infection is important because viral eradication leads to improved outcomes, including decreases in cirrhosis, decompensation, HCC, liver transplants, and liverrelated deaths.15,16 Primary care providers (PCP) have a unique window of opportunity to make a diagnosis of HCV and refer for treatment prior to the development of cirrhosis and its complications. This will result in improved survival, quality of life, and will reduce the economic burden of HCV. HCV screening is the first step on a long road to a cure. Once screening has identified patients at risk for HCV infection, HCV testing must be performed. Then, among persons found to be positive, counseling must be provided to prevent transmission to others and to prevent further harm to that particular individual. The need for treatment is then assessed, along with the benefits and risks of treatment. At the end of this long process, some patients can be cured. Therefore, HCV screening is important because it is the very first step of this process of engaging someone in management and treatment. Unfortunately, approximately 70 percent of HCV patients are undiagnosed because of screening barriers.8,9 There are both patient and provider barriers to screening. Persons infected with HCV are usually asymptomatic and unaware of their infection. Fifty-six percent of infected people are asymptomatic. For those who are symptomatic, the most common symptom is nonspecific fatigue.17 Additionally, many people infected with HCV are unaware of the risk factors for HCV (Exhibit 5).18 For those who are aware of the risk factors, there is a concern about

admitting to having a risk factor. In general, PCPs do not include routine HCV risk factor assessment in their practice. Although elevated ALT is a marker for ordering a liver panel, as noted previously, persons infected with HCV are often asymptomatic.18 Additionally, ALT levels are an insensitive way of determining disease severity and indication for treatment. In one survey, only 28 percent of PCPs said they would refer an HCV patient with normal ALTs for treatment.19 Only 15 percent of patients with chronic HCV infection have persistently elevated ALTs, whereas 55 percent have intermittent elevations and 30 percent have persistently normal values.20 Greater than 75 percent of patients with chronic HCV and normal LFTs have evidence of damage on liver biopsy.20 Thus, normal ALT HCVinfected patients should be evaluated and treated the same as those with increased ALTs. It is up to the PCP to identify and screen all their patients with risk factors for HCV, including those with a normal ALT. A good time to conduct this screening is at the same time as alcohol and smoking screening. Once diagnosed with HCV infection, patients will need to be educated about their disease and how to minimize its damage and spread. They should be advised to avoid all alcohol consumption; to not donate blood, body organs, or semen; to not share personal items that might have blood on them; and to cover cuts and open skin lesions. They also need to understand how to prevent sexual transmission. Immunization against hepatitis A and B is needed to prevent further assault on the liver. The primary goal of HCV treatment is permanent eradication of virus from serum. This is defined as a

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 47

Exhibit 5: Risk Factors for HCV18 Common • IV drug use

Less Common

• Needle Sticks

• Sharing of household items that could carry infected blood: razors, toothbrushes, manicure implements

• Intranasal cocaine with shared implements

• Traumatic contact with blood: cuts, nose- bleeds, menstrual blood

• Body piercing with contaminated needles

• Perinatal transmission

• Tattooing with contaminated needles or ink

• Sexual transmission

• Received blood or blood products or solid organ transplant before 1992 • Hemodialysis patients before 1992

sustained virologic response (SVR) which is an undetectable HCV RNA six months after completion of treatment. An SVR is synonymous with “cure”. Cure rates have significantly improved since the early 1990s from 5 percent of patients to 70 or 75 percent with improved regimens. Interferon (IFN) was the first medication approved in the 1990s for HCV infection. IFN alone produces about a 5 percent cure rate. Interferon has a dual mechanism of action of viral inhibition and immune modulation. Ribavirin was the next innovation in therapy. This is a synthetic nucleoside analogue, which as monotherapy has no antiviral effect (i.e., does not reduce HCV RNA). Its mechanism of action in HCV infection is unknown, but it appears to upregulate interferon activity. Pegylated IFN was developed to improve the safety and efficacy of interferon. The efficacy of pegylated IFN differs based on HCV genotype. Therapy using pegylated IFN-alfa combined with ribavirin leads to SVR in 40 to 52 percent of patients infected with HCV genotype 1, the predominant genotype in the U.S.21-23 For patients with HCV genotype 2 or 3 infection, SVR rates are 80 to 93 percent.21-24 The discovery and understanding of the life cycle of HCV allowed for the identification of targets for antivirals that directly interrupt HCV replication. Direct acting antivirals (DAAs) which are protease inhibitors are the latest addition to the HCV treatment regimen. Two protease inhibitors [telaprevir (Incivek®), boceprevir (Victrelis®)] are available for treating HCV. Neither is effective when used as monotherapy and, therefore, should never be used alone. They are only approved for treating genotype 1. They are not ap-

proved for use in post-transplant recurrent HCV, coinfected HIV or HBV, nor in children. Both telaprevir and boceprevir are inhibitors of liver metabolism through CYP3A, resulting in significant drugdrug interactions. If the affected contraindicated drugs cannot be stopped or substituted, protease inhibitors cannot be used. The current standard of care for HCV genotype 1 treatment in the treatment-naïve patient is peginterferon, ribavirin, and telaprevir or boceprevir.25 For genotypes 2 and 3, which are easier to eradicate, only peginterferon and ribavirin are recommended. The duration of therapy will vary by response and presence of cirrhosis. Treatment algorithms are available for naïve, previous treatment, relapsers, and partial responders.25 Response-guided therapy is treatment tailored based upon virologic response. Not all patients with the same genotype respond to treatment in the same way. With response-guided therapy, the regimen and treatment duration is based on individual response to therapy. Adjusting therapy based on individual virologic response permits a shorter duration of treatment without reducing the SVR rate. Numerous clinical trials are ongoing to refine treatment regimens. The future of treating HCV will likely be the combination of multiple oral drugs without interferon for shorter treatment duration. Conclusion

HCV is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. The PCP is the important link for screening, diagnosing, and referring these mostly asymptomatic patients. Screening for HCV should be conducted based on risk factors, not symptoms or lab tests. Because of their high rate

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

of infections, all baby boomers should be considered for HCV screening. Triple therapy is currently the best way of achieving SVR in genotype 1 patients.

2001;8(5):377-83.

David H. Winston, MD, FACP, AGAF is Section Head, Gastroenterol-

hepatitis C virus in patients with elevated or persistently normal serum alanine

ogy and Hepatology at CIGNA Healthcare of Arizona, in Sun City.

aminotransferase levels: comparison of hepatic histology and response to inter-

19. Shehab TM, Sonnad SS, Lok AS. Management of hepatitis C patients by primary care physicians in the USA: results of a national survey. J Viral Hepat. 20. Shiffman ML, Stewart CA, Hofmann CM, et al. Chronic infection with

feron therapy. J Infect Dis. 2000;182(6):1595-601.

References

21. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and

1. Chevaliez S, Pawlotsky JM. HCV Genome and Life Cycle. In: Tan SL, editor.

ribavirin combination therapy in chronic hepatitis C: a randomized study of

Hepatitis C Viruses: Genomes and Molecular Biology. Norfolk (UK): Horizon

treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346-55.

Bioscience; 2006. Chapter 1.

22. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus riba-

2. World Health Organization. Weekly Epidemiological Record. No. 49, 10

virin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-82.

December 1999.

23. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus

3. Rustgi VK. The epidemiology of hepatitis C infection in the United States. J

ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of

Gastroenterol. 2007;42(7):513-21.

chronic hepatitis C: a randomised trial. Lancet. 2001;358(9286):958-65.

4. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C

24. Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon alfa-2b plus

virus infection in the United States, 1999 through 2002. Ann Intern Med.

ribavirin for treatment of chronic hepatitis C in previously untreated patients

2006;144(10):705-14.

infected with HCV genotypes 2 or 3. J Hepatol. 2004;40(6):993-9.

5. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis

25. AASLD. Practice Guideline on Treatment of Genotype 1 Chronic Hepatitis

C virus infection in the United States, 1988 through 1994. N Engl J Med.

C. Hepatology. 2011;54:1433-44.

1999;341(8):556-62. 6. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States. J Viral Hepat. 2000;7(3):196-202. 7. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002:36(Suppl. 1):S21-S29.6 8. Centers for Disease Control and Prevention. Hepatitis C FAQs for Health Professionals. Available at: http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed November 14, 2012. 9. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC. 2010. 10. Davis G, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-21. 11. Ishida JH, Peters MG, Jin C, et al. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol. 2008;6(1):69-75. 12. Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol. 2004;40(3):484-90. 13. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health. 2000;90:1562-9. 14. Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009. 15. Wong JB. Hepatitis C: cost of illness and considerations for the economic evaluation of antiviral therapies. Pharmacoeconomics. 2006: 24(7);661-72. 16. McAdam-Marx C, McGarry LJ, Hane CA, et al. All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective. J Manag Care Pharm. 2011;17(7):531-46. 17. Smith BD, Jorgensen C, Zibbell JE, Beckett GA. Centers for Disease Control and Prevention initiatives to prevent hepatitis C virus infection: a selective update. Clin Infect Dis. 2012;55 Suppl 1:S49-53. 18. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19(3):1-46.

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 49

Clinical and Economic Utility of a New Noninvasive Prenatal Test Using Massively Parallel Sequencing Anthony O. Odibo, MD, MSCE and Susan Garfield, DrPH

Summary As new, highly accurate noninvasive prenatal tests continue to be developed, the need for invasive tests such as amniocentesis will continue to decline. One new test uses plasma to identify fetal chromosomal abnormalities using massively parallel sequencing. As these types of tests are added to the current screening paradigms, not only will fewer invasive procedures be needed, but also there will be a concomitant decline in the adverse events caused by those procedures. Key Points • All pregnant women, regardless of age, should be offered prenatal screening before 20 weeks' gestation. • Prenatal screening can identify the most frequent chromosomal abnormalities. • Invasive tests and new noninvasive DNA sequencing tests are the most accurate and specific. • The high sensitivity and specificity for the detection of trisomies 21, 18, 13 and monosomy X suggest that MPS can be incorporated into existing aneuploidy screening algorithms to reduce unnecessary invasive procedures.

Prenatal screening is available for various diseases or conditions in a fetus. The common chromosomal abnormalities screened for during pregnancy are Trisomy 21, 18, and 13, and monosomy X (Turner’s syndrome). Of all of these, Trisomy 21 (Down syndrome) occurs most commonly (Exhibit 1). Of those women who are offered prenatal screening, only 60 to 70 percent accept. Those who accept undergo some combination of protein marker based serum screen testing that provides risk information for genetic abnormalities. Serum test results can be nonspecific and sometimes confusing. Only invasive tests (chorionic villus sampling (CVS) and amniocentesis) currently provide definitive genetic information; however, these invasive tests involve risk to the fetus and mother. The market for prenatal screening tests is large. Of four million births annually, about 2.6 million

pregnancies are screened. Sixteen percent of the screenings are conducted in the first trimester and 84 percent in the second. Approximately 200,000 invasive tests are performed yearly with 88 percent being amniocentesis and the rest CVS.1 According to the ACOG guidelines, all pregnant women, regardless of age, should be offered prenatal screening before 20 weeks' gestation.5 Physicians should assess which test best meets the needs of the patient and provide information on detection and false positive rates, disadvantages and advantages, limitations, and the risks and benefits of each screening test and diagnostic procedure so that the patient can make an informed decision. As shown in Exhibit 2, there are numerous nonspecific screening options to identify chromosomal abnormalities.2 Testing is done in either the first trimester, second trimester, or a combination of both. Nuchal translucency (NT) uses ultrasound to

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

Exhibit 1: Incidence of common chromosomal abnormalities Chromosomal disorder

Incidence

Trisomy 21

1:660

Trisomy 18

0.3:1000

Trisomy 13

1:5500

Turners Syndrome

1:5000

Other sex chromosomal disorders, e.g. XXY

1:500 males

Exhibit 2: Numerous Prenatal Screening Options2 1st Trimester

2nd Trimester NT Ultrasound

1st Trimester Blood Screen

NT Ultrasound Triple Blood Screen Quadruple Blood Screen

Integrated Screen

1st Trimester Blood Screen

Serum Integrated

NT Ultrasound

1st Trimester Blood Screen

NT Ultrasound

2nd Trimester Blood Screen

Interim Decision

2nd Trimester Blood Screen

Contingent or Sequential > NT, Nuchal Translucency

measure the translucent space in the tissue at the back of the fetusâ&#x20AC;&#x2122;s neck. Fetal NT thickness is measured between 10 to 13 weeks gestation with an increased thickness indicative of chromosomal abnormality. NT performance as a screening marker declines with advancing gestational age and is subjective as well as operator dependent. NT use is limited by the availability of certified providers who are clustered in populated states. The majority of NT scans are performed by an estimated 2,000 certified sonographers at prenatal diagnostic clinics. NT can be combined with a first trimester blood screen which measures human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A). Triple and quad screens are the two blood screens

which are used in the second trimester. The triple screen test is a maternal blood screening test that looks for three specific substances: alpha-fetoprotein (AFP), hCG, and estriol. Low levels of AFP and abnormal levels of hCG and estriol may indicate a chromosome abnormality. The quad screen examines the same markers as triple screen plus inhibinA, a protein produced by the placenta and ovaries. The likelihood of identifying pregnancies at risk for Down syndrome is higher through the evaluation of inhibin-A levels. As shown in Exhibit 2, the integrated screen and serum integrated screens use combinations of first and second trimester screens. With these two screening options, the results are not given to the patient until the second trimester, which many pa-

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 51

Exhibit 3: Sensitivity and Specificity of Various Options Trimester - Test

Sensitivity*

1st - Combined (serum plus NT) screen for T21

81.00%

Specificity* 94.10%

1st - Combined (serum plus NT) screen for T18

89.00%

99.00%

1st - CVS

99.25%

98.65%

2nd - Serum screen for T21 in women < 35 years old

76.64%

95.15%

2nd - Serum screen for T21 in women > 35 years old

91.14%

88.90%

2nd - Serum screen for T18 in women < 35 years old

55.00%

99.00%

2nd - Serum screen for T21 in women > 35 years old

55.00%

99.00%

2nd - Ultrasound T21

79.90%

93.30%

2nd - Ultrasound T18

83.00%

99.00%

2nd - Ultrasound T13

91.00%

99.00%

2nd -Amniocentesis

99.40%

99.50%

Exhibit 4: MELISSA Study Final Results Classified

Sensitivity (%)

Specificity (%)

Trisomy 21 (n=493)

100.0 (89/89)

100.0 (404/404)

Trisomy 18 (n=496)

97.2 (35/36)

100.0 (460/460)

Trisomy 13 (n=499)

78.6 (11/14)

100.0 (485/485)

Monosomy X (n=433)

93.8 (15/16)

99.8 (416/417)

Female (n=433)

99.6 (232/233)

99.5 (199/200)

Male (n=433)

100.0 (184/184)

100.0 (249/249)

tients find unacceptable. Many practitioners use the contingent or sequential process where depending on the initial screening results, an interim decision during the first trimester can be made. Screening results offer estimates of risk. The risk cutoff level is pre-determined based on the individual test. A positive test result means the patient's risk of having a baby with a chromosomal abnormality is at or above a chosen cutoff level (e.g., Down syndrome risk â&#x2030;Ľ1 in 250). Assessment includes risk of a given chromosomal abnormality based on maternal age. A normal or negative result may be misinterpreted to mean the fetus is normal. False positive screens can lead to unnecessary invasive procedures. Exhibit 3 shows the sensitivity and specificity of the various options.3 If a patient has a positive serum or ultrasound

screen, they are offered additional, invasive testing. CVS and amniocentesis provide more definitive answers (Exhibit 3), but are invasive methods that come with risks to the patient. Approximately one miscarriage occurs with every 100 procedures for CVS and between one in 300 to one in 500 procedures for amniocentesis. Other risks include infection and infection transmission, Rh sensitization, spotting, leaking amniotic fluid, needle injury, cramping and pain at puncture point. An area of much concern is the issue of maternal anxiety while awaiting the results.4 Most of the invasive procedures performed every year are likely unnecessary due to the high rate of false positives in noninvasive screening. The newest type of noninvasive prenatal testing is genome-wide fetal aneuploidy detection by mater-

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

Exhibit 5: MPS NIPT as Secondary Screen First Trimester Track -- weeks 10 - 14 1st Trimester Blood Screen

NT Ultrasound

MPS test (if primary screen positive)

CVS (if needed)

MPS test (if primary screen positive)

Amniocentesis (if needed)

Second Trimester Trac k -- weeks 15 - 26 2nd Trimester Ultrasound

2nd Trimester Blood Screen

MPS, massive parallel sequencing NIPT, noninvasive prenatal testing

Exhibit 6: Incorporating MPS NIPT Dramatically Reduces the Use of Invasive Procedures Use of Diagnostics Following a Positive Prenatal Screen 12,000 10,000 8,000 6,000 4,000 2,000 0 Standard of Care Total Amnios

With verifi™ Testing

Total CVS procedures

nal plasma DNA sequencing using massively parallel sequencing (MPS). This testing (verifi® and MaterniT21™ ) is identifying abnormalities from the small amounts of fetal DNA fragments that can be found in a mother’s blood. The diagnostic accuracy of MPS to detect whole chromosome fetal aneuploidy was assessed in the MELISSA trial.6 As shown in Exhibit 4, this type of testing has very high sensitivity and specificity, especially for trisomy 21. Several other trials have been published on this type of testing.7-11 These studies demonstrate the efficacy of MPS of maternal plasma DNA to detect fetal aneuploidy for multiple chromosomes across the genome. A health economic model has been developed to look at the paradigm shift from invasive (CVS and amniocentesis) to noninvasive MPS testing. Using

Total verifi™ tests

U.S. census data on births by maternal age and published trisomy incidence by maternal age, the model stratified subjects into normal risk and high risk for fetal trisomies. The model assumed that 100,000 pregnancies would come from a membership of five million and that 81 percent of pregnancies would begin prenatal care in the first trimester, with the remainder initiating care in the second trimester. In order to estimate the likely reimbursement from private payer organizations, Medicare 2012 reimbursement rates plus 20 percent were used for the costs of prenatal testing. The model assumes a total view of costs, including physician fees, facility fees and laboratory fees. The model captures only direct costs to payer organizations and does not include costs for lost productivity or emotional distress. The model used sensitivity and specificity data and costs for the

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 53

verifi® MPS test. The model estimated that nine percent more pregnancies would receive prenatal diagnostic testing because of the noninvasive nature of the MPS testing (Exhibit 6). Most importantly, the model results demonstrated a 72 percent reduction in invasive procedures and 66 percent reduction in diagnosticinduced miscarriages with use of MPS testing. Due to the high accuracy of the verifi® test used in this model, an invasive procedure may not be necessary to confirm results. When an invasive procedure is not used following a MPS positive, diagnostic-induced miscarriages are further reduced. According to this model, despite increases in uptake of prenatal diagnostics, overall cost savings can be achieved. This cost savings is approximately 500,000 dollars for a population of 5 million covered lives with 100,000 annual pregnancies. This cost savings is achieved when a positive MPS test is followed by a confirmatory procedure. A greater savings can be achieved once an invasive procedure is no longer needed following a noninvasive positive result. Results of the model are sensitive to rates of uptake for prenatal screening and invasive procedures. The use of noninvasive MPS testing is in the early stages of clinical implementation. MPS for chromosomes 21, 18, and 13 can be incorporated into current screening paradigms as shown in Exhibit 5. It can be offered to patients who want to avoid the invasive procedures. In certain clinical scenarios (e.g., advanced maternal age and infertility), pregnant women will want to avoid an invasive procedure; they may request this test as an alternative to the primary screen or invasive procedure or both. The use of MPS will reduce unnecessary invasive procedures with a concomitant reduction in procedure-related adverse events. Invasive procedures would then be limited to confirmation of a positive result from MPS. Several large payers have decided that NIPT is medically necessary, subject to the criteria in the ACOG/SMFM Committee Opinion 545 issued in December of 2012. The presented economic model does not address questions of the emotional distress caused by diagnostic-induced miscarriage or the potential positive liability implications of moving to a lower-risk approach to prenatal diagnosis of fetal trisomies. These will be important considerations for payers and clinicians in follow-up research

procedures. With increasing experience with more samples, MPS may replace current screening protocols and become a primary screen. This economic model suggests that tests with sensitivity and specificity equal to or approaching 100% have the potential to improve outcomes and reduce costs. The availability of highly sensitive and specific tests for fetal aneuploidy and the rapid coverage of these tests by many of the country’s largest payers is likely to support rapid practice change in pre-natal testing. Anthony O. Odibo, MD, MSCE is an Associate Professor and Vice Chair of Women’s and Fetal Imaging at Washington University School of Medicine. Susan Garfield, DrPH is Vice President of Bridgehead International.

References 1. Thompson Reuters MarketScan 2009 Commercial Claims Database. 2. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109(1):217-27. 3. Wapner R, Thom E, Simpson JL, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med. 2003; 349(15):1405-13. 4. Sarkar P, Bergman K, Fisk NM, Glover V.Maternal anxiety at amniocentesis and plasma cortisol. Prenat Diagn. 2006;26(6):505-9. 5. ACOG Committee on Practice Bulletins. Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109:218. 6. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012;119(5):890-901. 7. Chiu RW, Chan KC, Gao Y, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008;105(51):20458-63. 8. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011;204(3):205.e1-11. 9. Sehnert AJ, Rhees B, Comstock D, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem. 2011;57(7):1042-9. 10. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011;13(11):913-20. 11. Palomaki GE, Deciu C, Kloza EM, et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012;14(3):296-305.

Conclusion

The high sensitivity and specificity for the detection of trisomies 21, 18, 13 and monosomy X suggest that MPS can be incorporated into existing aneuploidy screening algorithms to reduce unnecessary invasive 54 Journal of Managed Care Medicine | Vol. 16, No. 1 | www.namcp.org

A Lifestyle Approach for the Control of Diabetic Hyperglycemia Will Clower, PhD and Bradley Pifalo, MD, FACC

Summary A rise in treated disease prevalence is the most important determinant in the growth of private insurance spending.1,2 Diabetes and related chronic health conditions – hypertension, dyslipidemia, obesity, and sedentism – are increasing in prevalence and factor heavily in the 70 percent of direct, annual, health care costs that are spent on chronic diseases. Thus, strategies for improving glycemic control can reduce overall medical costs for patients with diabetes.3 Presented here is a lifestyle curriculum associated with long-term glycemic control in two case studies. Key Points • The first case study presented is an individual who participated in a behavioral adaptation of the Mediterranean diet, resulting in immediate and long-lasting control of hyperglycemia. • Nutritional analysis of the food record indicates sharp decreases in sodium consumption associated with the alleviation of previously uncontrolled hyperglycemia. • A follow-up study demonstrated similar and significant reductions in hyperglycemia after participating in the Mediterranean Wellness curriculum. This group participated in the program through a remote delivery model.

A Modified Mediterranean Diet

The Mediterranean diet has been widely acknowledged as being a healthy approach for residents of this region, associated with many aspects of a healthy lifestyle including glycemic control,5 heart health,6 and cancer prevention.7 However, the elements most commonly associated with the Mediterranean diet include the specific foods eaten, as diagrammed in the Mediterranean Food Guide pyramid. Eating behaviors of this diet are equally important and must be included into any effective lifestyle approach. In these trials, we have modified the traditional Mediterranean diet in two essential ways: in the method of food selection, and in the behavioral habits of healthy eating. • Food selection is principles-driven, meaning that this curriculum does not specify exact food elements or amounts. Participants do not have to eat according to an accounting of calories, fats, carbohydrates, or proteins. Rather, they are coached according to general principles that accord with the Mediterranean approach. Regarding food selection, partici-

pants may choose from anything from the Mediterranean food guide pyramid, as long as it does not include artificial or synthetic ingredients. The principle here is to “eat real food”. • In addition to the foods themselves, the behavioral retraining of healthy eating habits is essential to a lifestyle approach to food selection and controlled consumption.10 To this end, the modification of the traditional Mediterranean diet here incorporates the retraining of healthy eating habits. These include procedures for retraining the microstructure of eating behavior: at the fork, at the bite, portioning, plating, pacing, drinking control, and coaching for specific daily life situations. Curriculum Delivery Structure

Participants met weekly to receive PowerPoint lectures in the Mediterranean Wellness curriculum, delivered either in person or remotely via webcast. Each week included ancillary supporting materials such as homework, recordings of each lecture for ondemand review offline, recipes, instructional videos,

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 55

Exhibit 1: Daily Glycemic Control

Program Begins Here Daily Glucose Readings August 1, 2007 - January 3, 2008 600 400 200 0 -41

-21

-1

Day Pre Program/Post Program

daily audio coaching, and a weekly participant manual. These materials were available in physical form as well as in electronic form on a website platform. Weekly Curriculum Content

• Week 1: The first week teaches the Mediterranean food guide pyramid, emphasizing the importance of eating natural foods, rather than synthetic processed food products. Participants complete this week capable of making healthy food choices at conventional grocery stores. Homework includes specific lists for replacing poor food choices with healthy food choices and ingredients to include/exclude, along with a method for the habituation of individual tastes for sweetness in foods. • Week 2: The second week begins training participants in the eating habits and routines that curtail excess consumption. This behavioral protocol includes the use of eating implements, hand-held foods, portioning, drinking, and specific coaching for consumption in a restaurant and home environment. Homework includes behavioral practice routines at each meal, with instructions to compare their volume of consumption to pre-program levels. • Week 3: The third week reinforces the personal habits learned in Week 2 by teaching participants to control overconsumption through individualized pacing techniques. Emphasized here are the physiological mechanisms of satiety, and their practical manipulation within specific circumstances. Homework includes a quantitative measure of each participant’s current appetite levels, with the ability to track changes over time.

Program Ends Here

• Week 4: The fourth week introduces the eating routines required to control between-meal consumption, and emphasizes a daily three-meal standard for meal consumption. Homework includes at-home trials to quantify and affect phasic hunger in response to these routines. • Week 5: The fifth week informs participants on the links between stress and weight gain, with emphasis on the reduction of stress-induced overconsumption. Practical methods to integrate destressing techniques into daily lives are emphasized. Homework includes strategies to practice stress reduction activities, along with long-term measures for stress reduction. • Week 6: The sixth week instructs participants on the necessity of daily activity as a fitness strategy. Emphasis is placed on everyday movements rather than exercises one must perform within a gym environment. Specific encouragement is given to the performance of low weight, high repetition muscle toning activities. Homework includes the performance of muscle toning exercises daily, as specified by a written plan created by the participant. • Week 7: The seventh week instructs participants on the proper selection of object goals and process goals in the identification of targeted goal planning. Behavioral chaining is discussed in the context of individuals coaching themselves. Homework includes the participants identifying and completing their own goals statements, along with the identification of specific personal behavioral chains that lead to poor eating choices and actions. • Week 8: The eighth week is highly personalized

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

Exhibit 2: A1c Values A1c Values Measured from Program Onset (T=0) 10

10.0

8.4

8.2

8 7 6.2 6 0 wks

6 wks

10 wks

18wks

Program Start Date T=0 wks Program End Date T=8 wks

to each individual. The atmosphere diverges from the typical didactic format, to facilitate a support group environment focused on troubleshooting specific situations. • Program follow-up: Following Week 8, participants receive interactive feedback with the registered dieticians in two formats: over the telephone or online. The telephone support is scheduled in coordination with participants’ schedules, and consists of weekly 30-minute calls. The online support consists of email communications from participants asking information from the registered dietician, and receiving specific answers. Individual Case Study

These data were obtained from a 33-year-old female (MF, weight 235, height 5’7”, type 1 diabetes) with severely uncontrolled hyperglycemia (see Exhibit 1), who participated in the Mediterranean Wellness curriculum as a component of a corporate wellness initiative at ALCOA, Inc. in Pittsburgh, PA. Data Acquisition: MF was instructed to collect and record the following data before, during, and after the curriculum: • Blood glucose level (five times/day), beginning 40 days prior to curriculum onset • Glucose readings were provided electronically through an implanted glucose monitor • Detailed food record one week prior, and one week following the curriculum, to be recorded following each meal • Medical bills for the six months before and after the curriculum

Glycosylated hemoglobin levels (HbA1c) were acquired by the subject’s endocrinologist at program initiation, after 6 weeks, 10 weeks, and 18 months (all units in mg/dl).

Results:

The prior graph (Exhibit 1) represents the timeline of glycemic changes before, during, and following the Mediterranean Wellness curriculum. The vertical line represents the onset of the curriculum. The patient’s glucose record documents a substantial and rapid reduction in mean glucose from 309.94 to 98.32 mg/dl by Week 8 of the program, along with a similar decrease in the glucose excursions from (+/-)107.8 to (+/-)29 mg/dl. To date, these results have been sustained (over four years, post-program). The standard deviation of the pre-program mean = 120.17 The standard deviation of the post-program mean = 32.42 Differences between means (pre-program vs postprogram) were assessed using a two-tailed T-test with two samples of unequal variance (p < 3.7*10 -7,6). Dietary Food Record:

MF provided a detailed food record for one full week prior to the start of the program, and one full week following the completion of the program. The food record included the kind and amount of food eaten at each meal, and at each snack. Each record was analyzed for calories, fat, total cholesterol, carbohydrates, fiber, and sodium. Each of these elements was then compared to assess the percent change in consumption following the curriculum (Exhibit 3). Weight changes:

MF experienced a gradual weight reduction during the curriculum and following its completion. After

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 57

Exhibit 3: Nutrient Analysis of Food Record Dietary Comparison Before/After Med Diet 1.20

1.05

1.00 0.80

0.86 0.76 0.50

0.60

0.61 0.30

0.40 0.20 0.00 Calories Fat

Cholest

Carb Fiber Sodium

Percent Change in Average Daily Consumption

six weeks, the weight had fallen by 10 pounds and by 13 pounds at 10 weeks. Activity levels were not assessed.

tion since program onset. Given these changes in health care utilization, the net cost savings during the first year after program completion totaled $51,360.

Nutrient Analysis of Food Record

The nutrient analysis in Exhibit 3 demonstrates the percent change in average daily consumption of nutrients, following the completion of the curriculum. MF consumed 24 percent fewer calories overall, with a slightly higher overall fat content, and reductions in cholesterol, carbohydrates, and fiber. The largest change was seen in the sodium content, which was reduced by 70 percent. Interestingly, despite the reduction in calories, MFs tendency to require a mid-morning and midafternoon snack abated, and she adopted a threemeal per day eating pattern. Health Care Utilization and Cost Savings:

MF provided detailed hospitalization and medical expenses that had been incurred before and after the curriculum. Prior to the Program MF had been hospitalized for diabetic ketoacidosis (DKA) four times in the twelve months prior to the curriculum. The uncontrolled nature of the condition required monthly endocrinologist visits with extensive testing. Insulin usage typically reached four vials per month. Following the Program Insulin use was reduced by half. The requirement to visit the endocrinologist was reduced from twelve to two times per year. MF has not required hospitaliza-

Follow-Up Study:

Patient Selection: Subjects (n=8, diabetic, type 1) were recruited from the patient pool of the diabetes clinic at the Diabetes Research Institute (DRI) at the University of Miami, under the supervision of Dr. Luigi Meneghini. Remote Delivery Model: All subjects participated in the Mediterranean Wellness curriculum through a remote delivery model according to the following protocol. Subjects met weekly at a specified common area to receive web-based information and coaching. These weekly seminars were conducted by Mediterranean Wellness via webcast delivery and moderated by the patient education team at the DRI. In addition to the live sessions, participants could also review the weekly lectures, on demand, through a recorded version of the weekly session on the website platform. Subjects were provided with physical and electronic versions of the participant manual to assist in the implementation of the Mediterranean dietary approach. Data Acquisition: All participants were fitted with a continuous glucose monitor for three days before, and three days after the intervention. Glucose levels were recorded in an analog fashion, and analyzed according to the amount of time the readings were “Above Normal Range” (>180 mg/dl), “Below Normal Range” (<70 mg/dl), or “Within Normal Range” (70 – 180 mg/dl).

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

3-D Extrude & Bevel 53 14 -10

Perspective: 0

Extrude & Bevel: 20 pt.

Plastic Shading

Exhibit 4: Glycemic Changes Resulting From Remote Delivery Model

Glucose Readings: Before the Mediterranean Diet

Glucose Readings: After the Mediterranean Diet

44% 33%

60%

54%

Within Normal Range Above Normal Range Below Normal Range

Because the continuous glucose monitor was used only as an assessment tool prior to, and following, the program, information from the monitor was not used to adjust insulin utilization by the patients during the intervention itself. Results:

In Exhibit 4, the data show the average time the subjects’ glucose values were: • within normal range – The average time these patients spent with glycemic levels Within Normal Range significantly increased, from 44 percent to 60 percent (p<0.02). • above normal range – The average time these patients spent with glucose levels Above Normal Range significantly decreased, from 54 percent to 33 percent (p< 0.03). • below normal range - The average time these patients spent with glucose levels Below Normal Range increased, although not significantly (p<0.08).

Mean individual weight loss was 6.4 pounds (range: 2 pounds gained to 15 pounds lost). Activity levels were not assessed. Limitations:

• Small Sample Size: These data show stark short- term and long-term improvements in glycemic control within a single individual case study, and within a small group of type-1 diabetics. While compelling, the generalization of these results cannot be inferred until the study is replicated within a broader population. • Diabetic Type and Glycemic Control: These results were found with the type 1 diabetic condition. Although the issue of disordered glycemic control is common to both type 1 and type 2 diabetics, the etiology of these conditions are not similar. Thus, it is not a foregone conclusion that this lifestyle approach will produce similar effects on type 2 diabetics. However, these data do suggest that a similar investigation of this approach on the type 2 condition is warranted. Discussion:

Weight changes:

Participants experienced only slight weight reduction during the curriculum. Prior to the program, the mean weight of participants was 195.4 (range: 154 to 248 pounds). After nine weeks, mean weight was 189.0 (range: 150 to 233 pounds).

Uncontrolled blood sugar can produce devastating complications. Its prevalence is increasing in all segments of the population and driving increased insurance spending. The data presented here suggest that the control and management of hyperglycemia can be achieved through a lifestyle approach cen-

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 59

tered on food selection, based on Mediterranean dietary principles, in combination with behavioral control over the quantity of food eaten. This overall lifestyle approach was associated with the immediate and sustained management of hyperglycemia in these diabetic participants and patients. The importance of such a lifestyle approach to glycemic control is supported by the long-lasting improvements seen in MF, who experienced a large drop in A1c levels (from 10.0 to 6.2) in the weeks after the diet had already been completed. This subject, once trained in the new eating behaviors, also applied them for her family. After they were learned, these lifestyle behaviors were expressed unconsciously, as habits of healthy eating. Thus, even though the curriculum itself had been completed, the effect of the behavioral approach was sustained in MF. This potential for long-term benefits9 represents the power and promise of lifestyle behavioral strategies. As a managed care strategy, even modest reductions in the prevalence of diseases associated with lifestyle-related risk factors, such as hyperglycemia, can produce dramatic cost savings, particularly for private plans.4 In addition, the remote delivery model presented here offers the possibility to extend access to patients across a wide geography, while maintaining the effectiveness of the intervention.8 In this way, utilization of existing technology (through web-casting interventions) may help reduce the cost of care without compromising the effectiveness.

tion. Am J Public Health 2011; 101(1):157-64. 5. Esposito K, et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009 Sep 1; 151(5): 306-14. 6. Martinez-Gonzalez MA, et al. Mediterranean diet and the incidence of cardiovascular disease: a Spanish cohort. Nutr Metab Cardiovasc Dis 2011 Apr;21(4):237-44. 7. Giacosa A, et al. Cancer prevention in Europe: the Mediterranean diet as a protective choice.Eur J Cancer Prev. 2013 Jan; 22(1): 90-95. 8. Brindal E, et al. Features predicting weight loss in overweight or obese participants in a web-based intervention: randomized trial. J Med Internet Res 2012 Dec 12;14(6):e173. 9. Look AHEAD Research Group, Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med 2010 Sep 27;170(17);1566-75. 10. Hays NP et al. Eating behavior correlates of adult weight gain and obesity in healthy women aged 55–65 y. Am J Clin Nutr 2002 Mar 75(3); 476-483.

Will Clower, PhD is CEO of Mediterranean Wellness,LLC. He received his PhD in Neuroscience from Emory University in Atlanta and is the author of two books on the Mediterranean dietary lifestyle. Bradley Pifalo, MD, FACC is the Corporate Medical Director for Mediterranean Wellness, LLC. He received his MD from the University of Higher Studies at Bologna School of Medicine, and he has served as Medical Director for major medical plans (Highmark Blue Cross, Health America) over the course of 25 years.

References 1. Thorpe KE, Florence CS, Howard DH, Joski P. The rising prevalence of treated disease: effects on private health insurance spending. HealthAff 2005: Suppl W5-317-W5-325. 2. Thorpe KE. Factors accounting for the rise in health-care spending in the United States: the role of rising disease prevalence and treatment intensity. Public Health 2006;120(11):1002-7. 3. Newton CA, Young S. Financial implications of glycemic control: results of an inpatient diabetes management program. Endocr Pract 2006; 12 (Suppl 3):43-8. 4. Ormond BA, Spillman BC, Waidmann TA, Caswell KJ, Tereshchenko B. Potential national and state medical care savings from primary disease preven-

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

A Budget Impact Model to Estimate the Cost Dynamics of Treating High-Risk Heart Failure Patients with Advanced Percutaneous Cardiac Assist Devices: The Payer Perspective David Gregory, MPA, FACHE and Dennis J. Scotti, PhD, MBA, FACHE, FHFMA

Summary Treatment of heart disease is a major driver of health care spending in the United States. Temporary and timely use of hemodynamic support devices can be particularly beneficial to two high-risk patient populations: cardiogenic shock patients and those requiring hemodynamic support as an adjunct to high-risk coronary revascularization. The rate of adoption of advanced percutaneous cardiac assist devices (pVADs) for providing such support is steadily increasing. The objective of this study is to propose a budget impact model, from the third-party payer perspective, to estimate the separate and combined economic costs to health plans of covering this emerging trend in medical treatment. Clinical and financial inputs used to generate our results were obtained from a nationally recognized source of commercial claims data. Key Points • The prevalence rates of cardiogenic shock and high-risk percutaneous interventions are relatively low within the study population. • While medical costs to treat these patient subgroups is relatively high during the acute hospitalization period, post-discharge resource consumption does not suggest a pattern of chronic utilization. • Budgetary modeling of the combined impact of covering treatment costs for both clinical indications suggests a scenario in which health plans may experience meaningful savings, depending upon the assumed rates of migration from traditional circulatory support strategies to advanced pVAD therapy.

Introduction

More than one in three American adults have at least one type of cardiovascular disease1 and it is the leading cause of death in the U.S. for both men and women. Recent estimates of the total burden of cardiovascular disease equate to $312.6 billion in annual combined direct and indirect costs.1 Heart failure is one of the main causes necessitating acute hemodynamic support, and acute heart failure is the leading reason for medical readmissions in the Medicare population 2-4 and is likely a major readmission driver for private commercial health plans. These heart failure patients typically have unstable hemodynamic profiles, with left ventricular function and/or an ejection fraction frequently less than 30 percent, which has clinical and economic implications to payers and providers alike.

Temporary and timely use of percutaneous cardiac assist devices (pVADs) to provide hemodynamic support can be particularly beneficial to two highrisk patient populations: cardiogenic shock (CS) patients and those who require hemodynamic support as an adjunct to high-risk percutaneous coronary intervention (HR-PCI) procedures. For CS patients, pVADs urgently provide effective and systemic circulatory support, prevent additional cardiac damage and hypoperfusion-induced organ damage, thereby allowing acute cardiac recovery while the damaged heart is off-loaded and effectively perfused. Treatments have included surgical hemodynamic support from extracorporeal membrane oxygenation (ECMO) or extracorporeal left ventricular assist devices (LVADs), in combination with IABP as appropriate. However, despite advances in medicine,

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 61

Exhibit 1a: Commercial Payer Database Distribution of Age and Gender (in thousands)

Age Band

Female

Male

Total

% of Total

< 30

4,860

4,886

9,746

39%

30-49

3,964

3,831

7,795

31%

50-64

2,664

2,511

5,175

21%

65-79

746

777

1,523

6% 2%

80+

332

280

612

Total

12,566

12,285

24,851

Exhibit 1b: Age and Gender Distribution for CS by Treatment Cohort (2009 to first half of 2011) ECMO/LVAD1 Age Band

Female

Male

Total

< 30

31-49

50-64

65-79

80+

CS pVAD % of Total Cohort

Female

Male

26%

20%

34%

57%

16%

20%

23%

77%

TOTAL

% of Total Cohort

29%

71%

Total

% of Total Cohort

Notes: 1 Included in this classification are some cases that used IABP for ancillary circulatory support

the mortality rate for CS remains over 50 percent,5-8 and the effectiveness of these traditional therapies continues to be challenged.9,10 The annual incidence of CS stands at 40,000 to 50,000 cases per year, most often occurring with ST-elevation myocardial infarction (STEMI).1 It is estimated that 12,000 postSTEMI cardiogenic shock patients are in need of acute hemodynamic support.1 For other high-risk patients, pVADs are intended to ensure that percutaneous revascularization procedures and other interventions can be performed successfully; it can be an option for select patients who are turned down for complex, invasive surgical and cardiac procedures because of their clinical and coronary anatomy risk. Approximately 7 to 10 percent of the 600,000 PCI procedures performed annually are at high risk for hemodynamic collapse and may benefit from pVAD support.11 Further, it is estimated that there are approximately 8,000 commercially insured patients nationwide that would be considered to be HR-PCI (and therefore pVAD) candidates. The traditional treatment for HR-PCI patients has been the IABP, despite published data questioning

its value.9,12-15 In the recently published PROTECT II randomized clinical trial involving HR-PCI patients, pVAD therapy (using Impella 2.5, Abiomed, Inc., Danvers, MA) resulted in a 22 percent reduction (p = 0.023) in major adverse events compared to the IABP; this reduction increased to 56 percent (p = 0.002) post hospital discharge.16 Alternatively, these patients would face high-risk coronary artery bypass grafting (CABG) procedures with increased risk of morbidity and mortality. The shortcomings of the traditional therapies have led practitioners and their patients to express a desire for alternative therapeutic options. Advanced technologies, such as pVADs, are filling the gap created by unmet clinical and practitioner needs in the provision of circulatory support for treatment of CS and HR-PCI patients. Furthermore, while the economic impact of adopting this new technology has been explored from the provider perspective, the need for a payer impact assessment is now appropriate. The objective of this study was to develop a budget impact model, from the payer perspective, to estimate the annual direct medical costs of treatment for these two important patient populations and to estimate

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

Exhibit 1c: Age and Gender Distribution for HR-PCI by Treatment Cohort (2009 to first half of 2011)

High-Risk PCI IABP Age Band

Female

Male

High-Risk PCI pVAD

Total

% of Total Cohort

Female

Male

Total

% of Total Cohort

< 30

31-49

50-64

247

309

44%

39%

65-79

162

239

34%

38%

80+

14%

20%

700

18%

82%

TOTAL

191

509

% of Total Cohort

27%

73%

Exhibit 2: ICD-9 Diagnosis and Procedure Codes Used to Classify CS and HR-PCI Treatment Cohorts Cardiogenic Shock Classification Scheme Treatment Cohort

ICD-9 Diagnosis Codes

ICD-9 Procedure Codes

pVAD (Impella 2.5/TandemHeart

785.51

37.68

Surgical (ECMO / LVAD1)

785.51

37.65 or 39.65

Treatment Cohort

ICD-9 Diagnosis Codes

ICD-9 Procedure Codes

pVAD (Impella 2.5/TandemHeart)

401.x, 427.31, 428.x, 584.x, 414.8, 250.x, 443.x

00.66 and 37.68

IABP

401.x, 427.31, 428.x, 584.x, 414.8, 250.x, 443.x

00.66 and 37.61

High-Risk PCI Classification Scheme

Notes: 1 Included in this classification are some cases that used IABP for ancillary circulatory support

the combined incremental budgetary impact of introducing the innovative pVAD treatment option. Methods Study Population and Data Sources

Data for this study were obtained from a recognized database compiled by OptumInsight, Inc. (Eden Prairie, MN) comprising claims generated by a national commercial health plan consisting of approximately 25 million members. Included in the database were all members affiliated with fullyinsured entities as well as self-insured clients reliant on administrative services only. A demographic profile of the plan membership appears in Exhibit 1a. Overall, the database comprised approximately 25 million members nearly evenly divided between males and females. The majority of members were under 50 years of age and over two million were 65 years of age or older and thus likely to exhibit the utilization and cost characteristics of the Medicare population. In addition, Exhibits 1b and 1c detail

the demographics of the specific high-risk patients under review in this model. Specifically, for HRPCI, 49 percent of patients were 65 years of age or older, with another 44 percent between the ages of 50 to 64. With regard to CS patients, only 21 percent were 65 years of age or older, while 44 percent were between the ages of 50 to 64. Moreover, the cohort populations were heavily weighted toward males (71 percent to 82 percent across all cohorts under review). The time frame for the claims data used in the model was 2009, 2010, and the first half of 2011. Any patient that experienced CS or had a PCI in 2009 or 2010 was excluded from the 2010 or 2011 data set, respectively, to avoid double counting of cases. This accounted for approximately 5 percent of the potential cases. It is also worth noting that advanced pVADs have been cleared for use by the FDA only recently, and were not widely employed in clinical practice prior to 2009. Accordingly, the 30-month time interval selected for this study was

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 63

chosen to maximize the sample size available for entry into the budget impact model (BIM). The logic applied to identify cases for each BIM was derived from specific International Classification Disease 9th Version (ICD-9) diagnosis and procedure codes. Claims classified as CS cases included patients diagnosed with CS who received surgical cardiac support from ECMO or extracorporeal LVADs (with or without IABP support) or those receiving non-surgical cardiac support from a pVAD. Claims classified as HR-PCI cases included patients receiving a percutaneous coronary intervention supported by either IABP or pVAD; a complete description of the coding schemes used to create these patient classifications is presented in Exhibit 2. Model Development

A dynamic BIM was developed to show the effect of pVAD adoption on commercial claim costs for both high-risk (CS and HR-PCI) populations. The cost of an individual claim was defined as the payer’s maximum allowed amount in accordance with the payer’s provider network contracts. These allowed amounts subsume both the provider and patient components of financial responsibility and therefore removed member benefit differences as a confounding variable in the analysis. Specifically, the model for CS cases estimates the per member per month (PMPM) cost and, the overall cost of CS coverage, as well as the impact of increasing the percentage of the membership that receives pVAD therapy vs. current surgical alternatives for hemodynamic support, including ECMO or extracorporeal LVAD in combination with IABP as appropriate. The model for HR-PCI cases estimates the PMPM cost and the overall cost of HR-PCI coverage, as well as the impact of increasing the percentage of the membership that receives pVAD therapy vs. hemodynamic support via the IABP. For both models, pVAD therapy includes both major types of percutaneous cardiac assist devices, Abiomed’s Impella 2.5 and the TandemHeart system (CardiacAssist, Inc., Pittsburgh, PA) as defined by ICD-9 procedure code 37.68, with market share data from both companies indicating that Impella 2.5 comprises at least 80 percent of this category of devices. Both models included three relevant time intervals for these high-risk populations: the index hospital stay (up to 30 days), 31 to 90 days post-index hospital stay, and 91 to 365 days post-index hospital stay. Claims activity was limited and the existence of meaningful differences were not observed in the 90day time intervals comprising the final nine months of the tracking period. Consequently, we collapsed these data into a single time span for purposed of

estimating budget impact. In addition, the claim costs for each time period were collected for inpatient, outpatient, emergency room, physician, and pharmacy services. These three time intervals and five service components were aggregated for both cohorts (pVAD and surgical hemodynamic support alternatives) to derive an overall mean allowed costs for CS subpopulation of patients. Similarly, for the HR-PCI model, the same three time intervals and five service components were aggregated for both the pVAD and IABP cohorts to derive an overall HR-PCI coverage cost for the membership. In both models, these total costs were then converted into a PMPM for each cohort. Differences were first analyzed assuming no change in utilization for the interventions under review. Finally, the impact on PMPM and overall costs were analyzed with various utilization changes, specifically focusing on the expansion of pVAD therapy as a replacement for the identified surgical alternatives in the CS model and for IABP in the HR-PCI model. The percentage of pVAD therapy adoption in this sensitivity analysis was permitted to vary from 10 percent to 60 percent in both models. Statistical Analysis

Our ability to conduct formal statistical analyses of differences between study cohorts was limited by lack of availability of claim-level data beyond the index admission period (defined as the first 30 days including the index event). Statistical testing of mean differences in allowed costs for the various service components and length of stay that was observed during the index admission period was performed by SPSS Version 20 (IBM SPSS Statistics, USA). Differential comparisons for non-normally distributed variables were calculated by Mann-Whitney U-test; categorical variables were compared by Fisher’s exact test. Results Prevalence Rates

For the 30-month study period spanning from 2009 to the first half of 2011, the overall prevalence of CS requiring surgery and/or hemodynamic support was observed to be 0.0619 per 1,000 members. pVAD therapy prevalence in the CS population was 0.00225 index admissions per thousand members, while the prevalence of surgical hemodynamic support alternatives was 0.00282 index admissions per thousand members. For the two and a half year period from 2009 through the first half of 2011, the overall prevalence of HR-PCI was observed to be 0.0312 per 1,000 members. pVAD therapy prevalence in this cohort

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

Exhibit 3: Mean Allowed Costs Per CS Case by Treatment Cohort, Service Component and Time Period Mean Cost Per Case (Index Stay uo to 30 days)1

Mean Cost Per Case (31 - 90 days)

Mean Cost Per Case (91 - 365 days)

Mean Cost Per Case (12 month Tracking Period)

Service Component

Surgical

pVAD

∆

Surgical

pVAD

∆

Surgical

pVAD

∆

Surgical

pVAD

∆

Inpatient

$416,982

$262,347

$154,635

$5,128

$8,421

$(3,293)

$22,647

$13,971

$8,676

$444,757

$284,740

$159,835

Outpatient

2,735

3,202

(467)

3,929

6,728

(2,799)

18,232

9,560

8,672

24,896

19,490

5,406

Physician

35,925

20,077

15,848

12,247

4,788

7,459

8,422

5,925

2,497

56,594

30,790

25,804

Emergency Room

1,873

1,901

(28)

698

443

255

2,631

2,371

260

Pharmacy Total Alowed Cost Per Claim

215

203

1,285

718

567

2,906

2,728

178

4,406

3,649

757

$457,730

$287,730

$170,000

$22,649

$20,683

$1,966

$52,905

$32,627

$20,278

$533,284

$341,040

$192,244

Notes: 1Detail at the claim-level was available only for the Index admission (1 to 30 days) time period. The inpatient cost differential between surgical and pVAD treatment was statistically significant (p = .006 ). All other service component differences associated with the index admission period were not statistically significant. Although not reported in this exhibit, inpatient LOS for the Surgical Cohort was 10.5 days longer than for the pVAD cohort (30.9 days vs. 20.4 days, respectively), p = .053.

was 0.00306 index admissions per thousand members, while the prevalence of IABP was 0.0282 index admissions per thousand members. Budget Impact

In the CS budget impact analysis, comparisons of mean allowed costs were made between the pVAD and the surgical hemodynamic support cohort. Exhibit 3 shows the mean allowed costs per CS claim by treatment cohort and service component for each time period. The major difference in cost, both in percentage and absolute dollars, between the surgical cohort and the pVAD cohort was observed in the index hospital stay through 30 days. For the surgical alternative, the total mean cost was $457,731 compared with $287,731 for the pVAD cohort, a difference of $154,635, primarily driven by the major difference in costs associated with the inpatient service component. Statistical analysis, using the non-parametric Mann-Whitney test, indicates this difference is significant (p = 0.006). The mean length of stay (LOS) for the index hospitalization was 30.9 days for the surgical cases versus 20.4 for the pVAD cases (p = 0.053). While not quite achieving statistical significance at the p < 0.05 level (likely attributable to the small sample sizes involved), this differential in LOS certainly has operational implications and is worth noting. The 31- to 90-day time interval revealed a similar cost trend between the two cohorts, with the total mean cost per case for the surgical alternative cohort at $22,650 compared to $20,682 for the pVAD total mean cost. Further review of the cost categories shows a mixed trend with physician and pharmacy

services being higher for the surgical cohort, but lower for inpatient and outpatient services compared to the corresponding cost categories for the pVAD cohort. However, the magnitude of these post-index expenditures is relatively small for both cohorts. In the 91- to 365-day time interval, the total mean costs per case for surgical cohort and pVAD cohort were $52,904 and $32,627, respectively. The primary drivers of this cost differential are the inpatient and outpatient service components, which were higher in the surgical cohort. However, as with the 31- to 90-day time interval, the magnitude of these post-index costs is negligible compared to the index costs previously reported. Aggregating all costs across the 12-month tracking period for each qualifying case, the costs of surgical cases were considerably greater than those incurred by the use of pVADs ($533,285 vs. $341,040, respectively), driven largely by the index admission costs reported above. Both cohorts incurred approximately 85 percent of their total annual cost within the first 30 days. This demonstrates that while these patients are high-intensity resource utilizers during the acute phase of their condition, they do not display “chronic” utilization and cost patterns on a post-index basis. On a PMPM basis, the payer cost for surgical cases was $0.07 PMPM versus $0.03 PMPM for pVADs. In the HR-PCI budget impact analyses, comparisons were made between the pVAD and IABP device cohorts. Exhibit 4 shows the mean allowed costs per HR-PCI claim by treatment cohort and service component for each time period. As was the case for the CS budget impact analysis, the major difference in allowed cost, both in per-

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 65

Exhibit 4: Mean Allowed Costs Per HR-PCI Case by Treatment Cohort, Service Component and Time Period Mean Cost Per Case (Index Stay uo to 30 days)1 Service Component Inpatient

Mean Cost Per Case (31 - 90 days)

Mean Cost Per Case (91 - 365 days)

Mean Cost Per Case (12 month Tracking Period)

IABP

pVAD

∆

IABP

pVAD

∆

IABP

pVAD

∆

IABP

pVAD

∆

$73,308

$85,700

($12,392)

$3,820

$7,458

($3,638)

$4,912

$7,382

($2,470)

$82,040

$100,540

($18,500)

Outpatient

1,383

856

527

3,567

1,604

1,963

6,727

4,347

2,380

11,678

6,807

4,871

Physician

7,832

6,960

872

1,898

2,358

(460)

2,915

3,102

(187)

12,645

12,420

225

Emergency Room

2,135

714

1,421

233

160

621

379

124

2,990

1,167

1,823

Pharmacy Total Allowed Cost Per Claim

440

389

653

229

424

2,587

3,630

669

2,961

$85,048

$94,670

($9,622)

$10,172

$11,722

($1,550)

$17,762

$15,210

$2,552

$112,982

$121,602

($8,620)

Notes: 1Detail at the claim-level detail was available only for the Index Admission (1 to 30 days) time period. The Emergency Room cost differential between IABP and pVAD treatments was statistically significant (p < .000). All other service component differences associated with the index admission period were not statistically significant. Although not reported in this exhibit, inpatient LOS for the IABP cohort was 2.1 days longer than for the pVAD cohort (11.9 days vs. 9.8 days, respectively), p = 0.001.

Exhibit 5a: Sensitivity Analysis of the Impact on PMPM and Total Health Plan Cost Resulting from Incremental Migration from Surgical to pVAD Therapy in Treating CS Patients Percent Migration

PMPM

Total Allowed Dollars

10%

($0.0024)

($1,345,717)

20%

($0.0049)

($2,691,434)

30%

($0.0073)

($4,037,152)

40%

($0.0097)

($5,382,869)

50%

($0.0122)

($6,728,586)

60%

($0.0146)

($8,074,303)

centage and absolute dollars, between IABP cohort and the pVAD cohort was observed in the index hospital stay through 30 days. For IABP, the total mean cost was $85,048 compared with $94,670 for the pVAD cohort. This was an 11 percent increase overall, primarily driven by the major difference in inpatient costs. Statistical analysis of the cost data for the index stay, using the non-parametric MannWhitney test, indicates the difference in inpatient cost between the two cohorts of $12,392 was not statistically significant (p = 0.218). However, the 2.1 day differential in mean index admission LOS between IABP cases (11.9 days) and pVAD (9.8 days) was found to be a statistically significant (p = 0.001). The 31- to 90-day time interval showed a similar cost trend between the two cohorts, with the total mean cost for IABP cohort at $10,172 compared to $11,722 for the pVAD cohort. Further review of the cost categories shows a mixed trend with outpatient and ER costs being higher for the IABP cohort, but lower for inpatient and physician as com-

pared to those cost categories for the pVAD cohort. However, the magnitude of these post-index costs is equally not impressive for either cohort. In the 91- to 365-day time interval, the total mean cost per case for IABP cohort and pVAD cohort were $17,762 and $15,210, respectively. The primary drivers of this overall difference are the outpatient, ER, and pharmacy cost categories being higher in the IABP cohort. However, as with the 31- to 90day time interval the magnitude of these post-index costs is negligible compared to the index costs previously reported. Aggregating all costs across the 12-month tracking period, the mean allowed costs of pVAD were somewhat more than those of IABP ($121,602 vs. $112,982, respectively), driven largely by cost of the pVAD during the index admission. Both cohorts incurred approximately 75 percent of their total annual costs during the first 30-day interval. This again demonstrates that these patients, while highintensity resource utilizers during the acute phase of

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

Exhibit 5b: Sensitivity Analysis of the Impact on PMPM and Total Health Plan Cost Resulting from Incremental Migration IABP to pVAD Therapy in Treating HR-PCI Patients Percent Migration

PMPM

Total Allowed Dollars

10%

$0.0011

$603,415

20%

$0.0022

$1,206,830

30%

$0.0033

$1,810,245

40%

$0.0044

$2,413,660

50%

$0.0055

$3,017,075

60%

$0.0065

$3,620,490

their condition, do not display “chronic” utilization and cost patterns on a post-index stay basis. On a PMPM basis, the current costs for IABP were $0.14 PMPM versus $0.02 PMPM for pVADs; however, this simply reflects a utilization disparity driven by a mature adoption level for IABP and a slowly emerging adoption level for pVADs. Sensitivity Analysis

The BIM for CS cases computes the impact on PMPM as well as the total cost to the health plan if pVAD therapy had been administered to the surgical cohort on a sensitivity scale ranging from 10 percent to 60 percent. If 10 percent of the surgical cohort switched to pVAD therapy, the impact on the health plan costs would be negative $0.0024 PMPM, resulting in approximately $1.3 million in potential cost savings for a health plan of similar size to that associated with this study’s database. Moreover, if 60 percent of the surgical cohort switched to pVAD therapy, the impact on PMPM would be a negative $0.0146 PMPM, resulting in a potential savings in excess of $8 million for a similarly-sized health plan. Exhibit 5a illustrates the impact on PMPM, as well

as overall cost to the health plan, for the entire range sensitivity scenarios. Sensitivity analysis of the BIM for HR-PCI cases was also conducted to examine the impact on PMPM as well as the total cost to the health plan if pVAD therapy had been administered to patients in the IABP cohort on a sliding scale ranging from 10 percent to 60 percent. If 10 percent of the cohort switched to pVAD therapy, the impact on health plan costs would be a positive $0.0011 PMPM, resulting in approximately $603,000 in greater cost to the health plan under review. Moreover, if 60 percent of the IABP cohort switched to pVAD therapy, the impact on PMPM would be a positive $0.0065 and over $3.6 million in additional cost to the health plan. Exhibit 5b illustrates the impact on PMPM, as well as overall cost to the health plan, for the entire range of sensitivity scenarios. Overall Budget Impact

Given these independent results, the combined impact across both conditions yields net savings ranging from approximately $2.2 million to $3.7 million based on assumed pVAD migrations ranging from

Exhibit 6: Integrated Sensitivity Analysis for All High-Risk Patients (a)

HR-PCI PMPM

CS PMPM

PMPM Combined

TotalAllowed Amount (HR-PCI)

Total Allowed Amount (CS)

Total Allowed Amount Combined

10.00%

$0.0011

($0.0024)

($0.0013)

$603,415

($1,345,717)

($742,302)

20.00%

$0.0022

($0.0049)

($0.0027)

$1,206,830

($2,691,434)

($1,484,604)

30.00%

$0.0033

($0.0073)

($0.0040)

$1,810,245

($4,037,152)

($2,226,907)

40.00%

$0.0044

($0.0097)

($0.0054)

$2,413,660

($5,382,869)

($2,969,209)

50.00%

$0.0055

($0.0122)

($0.0067)

$3,017,075

($6,728,586)

($3,711,511)

60.00%

$0.0065

($0.0146)

($0.0081)

$3,620,490

($8,074,303)

($4,453,813)

(a)Represents changes in payer allowed amounts associated with a transition to pVAD from targeted standards of care

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 67

30 percent to 50 percent for both indications (refer to Exhibit 6). These migration levels are considered reasonable and achievable, particularly given some key pVAD marketplace dynamics including: • Clinical data demonstrating improved clinical outcomes for CS and HR-PCI patients16,17,18 • Inclusion in national clinical guidelines for cardiogenic shock as endorsed by professional societies • Minimally invasive deployment which facilitates expedited introduction in emergent and urgent cases • New Category I CPT codes effective January, 2013 • Steady insurance coverage expansion for pVAD use Discussion

The Affordable Care Act and its enabling of fullyintegrated “accountable care organizations” (ACOs) will accelerate fundamental transformation in the delivery of acute and chronic care, from the organization of the health care delivery system, the measurement of care outcomes, and importantly payment incentives to providers. The latter change will likely come in the form of shared savings models that will attempt to align the incentives of thirdparty payers and all provider types to work collaboratively toward positive patient-centered outcomes that also yield cost-mitigating benefits. Such economic benefits may include reduced adverse events, readmissions and resource consumption through new clinical protocols supported by new and improved technologies. As these incentives permeate the market through both the Centers for Medicare and Medicaid Services and private payer initiatives, new and innovative ways to deliver care to acutely ill patient populations will be important. To this end, high-risk heart failure patients that experience CS or require a high-risk PCI have historically been treated with technologies and protocols that were expensive and/ or produced poor outcomes.5-15 Updated clinical literature indicates the pVADs can improve clinical outcomes; this budget impact model seems to indicate that pVADs can do so at a minimal cost to the system. Furthermore, this technology offers a subset of high-risk patients a treatment option where one was not previously available.16,17 Importantly, this model tracked patients for a full year subsequent to the qualifying event to evaluate key cost items that the health care system often does not contemplate in severe cases. In doing so, it became clear that while these patients experience relatively infrequent but very resource-intensive in-

dex events (usually associated with high inpatient costs), they are not incurring significant costs in the post-index period. Thus, this new technology, while it represents an incremental cost to providers and payers in non-surgical cases, is producing favorable clinical outcomes at a relatively low PMPM cost to payers. The finding is primarily based on the low incidence of these high-risk cardiac patients, the high-cost of current surgical interventions for CS patients and the reduced variability of resource consumption in HR-PCI patients (extreme cost outliers were more prevalent in the IABP arm). Notably, traditional Medicare patients appear to track along a similar cost dynamic, in that HR-PCI cases cost more but CS cases cost significantly less, with a net impact that is less than $0.05 PMPM. Few studies are without limitations. While this study offers economic stakeholders a viable framework for evaluating new technologies like pVADs, several model challenges should be considered when evaluating this analysis and/or designing subsequent models. First, the retrospective nature of the study presented challenges with regard to the matching of “high-risk” patients across the cohorts, particularly in the HR-PCI model where “high-risk” assignment was limited to claims coding and not actual patient assessments. In addition, with regard to the CS model, patients that did not undergo a surgical intervention or receive pVAD therapy were not analyzed given that pVADs role in this population is undetermined. If this population (including those who receive IABP therapy without surgery) is determined to benefit from pVAD therapy, future models will need to contemplate the impact of these patients on payer costs as well. Moreover, the migration sensitivity analysis applied estimated case conversion rates to retrospective volumes given the difficulty in projecting targeted case volumes moving forward. With regard to the commercial claim set utilized, while the membership base was large and national in scope, the resulting model estimates may not be completely generalizable to smaller, regional plans. To this end, the authors encourage plans to use the structure of this model in conjunction with their own data to generate plan-specific results. Conclusion

In this era of health care reform, in which all stakeholders are ultimately preparing for population health management, models like this one will be useful in identifying the most effective and efficient ways to manage patients, particularly high-risk patients with the potential to generate significant costs if not managed properly. Moreover, this model

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

seems to indicate that technologies such as pVADs should be given careful consideration despite their initial incremental cost in non-surgical cases, as the incidence rates for target cases are relatively low and post-index resource consumption is unimpressive from a cost standpoint. This study demonstrates that pVAD technology has a minimal PMPM impact across very challenging heart failure patient populations and throughout a technology adoption curve.

12. Curtis JP, Rathore SS, Wang Y, et al. Use and effectiveness of intra-aortic balloon pumps among patients undergoing high risk percutaneous coronary intervention: insights from the National Cardiovascular Data Registry. Circ Cardiovasc Qual Outcomes 2012;5:21-30. 13. Patel MR, Smalling RW, Thiele H, et al. Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock. The CRISP AMI randomized trial. JAMA 2011;306:1329-1337. 14. Perera D, Stables R, Thomas M, et al. Elective intra-aortic balloon counterpulsation during high-risk percutaneous coronary intervention. A randomized controlled trial. JAMA 2010;304:867-874.

David Gregory, MPA, FACHE is Executive Vice President and Partner

15. Sjauw KD, Engström AE, Vis MM, et al. A systematic review and meta-

for Prescott Associates, a division of ParenteBeard LLC. His health care

analysis of intra aortic balloon pump therapy in ST-elevation myocardial infarc-

expertise includes economic value analysis, payment innovation, rev-

tion: should we change the guidelines? Eur Heart J 2009;30:459-468.

enue cycle optimization and provider integration. He received his MPA

16. O’Neill WW, Kliman KS, Moses J, et al. A prospective randomized clinical

from New York University and has published in MGMA’s Connexion,

trial of hemodynamic support with Impella 2.5™ versus intra-aortic balloon

HFMA’s HFM Journal and Life Science Leader outlets.

pump in patients undergoing non-emergent high risk percutaneous coronary intervention: the PROTECT II trial. Circulation 2012;126:1717-1727.

Dennis J. Scotti, PhD, MBA, FACHE, FHFMA is the Alfred Driscoll Pro-

17. Maini B, Naidu SS, Mulukutla S, et al. Real-world use of the Impella 2.5

fessor of Healthcare and Life Sciences at Fairleigh Dickinson Univer-

circulatory support system in complex high-risk percutaneous coronary inter-

sity, Teaneck, NJ. He received his PhD from Temple University. He is an

vention: the USpella registry. Catheter Cardiovasc Interv 2012;80:717-725.

ACHE and an HFMA Fellow.

18. Sjauw KD, Konorza T, Erbel R, et al. Supported high-risk percutaneous

References

Am Coll Cardiol 2009;54:2430-2434.

coronary intervention with the Impella 2.5 device. The Europella Registry. J 1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2013 Update: a report from the American Heart Association. Circulation 2013 127:c6-c245. 2. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010;121:948-954. 3. Jencks S, Williams MV, Coleman EA, et al. Rehospitalization among patient in the Medicare fee-for-service program. N Engl J Med 2009; 360:1418-1428. 4. Whellan DJ, Greiner MA, Schulman KA, et al. Costs of inpatient care among Medicare beneficiaries with heart failure, 2001 to 2004. Circ Cardiovasc Qual Outcomes. 2010;3:33-40. 5. Awad HH, Anderson FA Jr, Gore JM, et al. Cardiogenic shock complicating acute coronary syndromes: insights from the Global Registry of Acute Coronary Events. Am Heart J 2012;163:963-971. 6. Goldberg RJ, Spencer FA, Gore JM, et al. Thirty-year trends (1975 to 2005) in the magnitude of, management of, and hospital death rates associated with cardiogenic shock in patients with acute myocardial infarction: a populationbased perspective. Circulation 2009;119:1211-1219. 7. Babaev A, Frederick PD, Pasta DJ, et al. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005;294:448-454. 8. Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial infarction – Etiologies, management and outcome: a report from the SHOCK trial registry. J Am Coll Cardiol 2000;36 (Suppl A):1063-1070. 9. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:12871296. 10. Lamarche Y, Ignaszewski, A, Cheung A, et al. Comparative outcomes in cardiogenic shock patients managed with Impella microaxial pump or extracorporeal life support. J Thorac Cardiovasc Surg 2011;142:60-65. 11. Health Research Institute Report. US Opportunities in Acute Cardiac Assist. Report # 0514-1-US-1209-204. December 2009.

www.namcp.org | Vol. 16, No. 1 | Journal of Managed Care Medicine 69

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

now indicated in combination with carboplatin for the first-line treatment of advanced Non–Small Cell Lung Cancer

Scan with your mobile device to learn more at www.abraxane.com

Please see Important Safety Information for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages, and Brief Summary on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, and 15 for non-small cell lung cancer (NSCLC) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood

Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with single-agent use of ABRAXANE in the MBC study were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients with normal baseline 35%), fatigue/ asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%) • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note included vomiting (any 18%; severe 4%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis (any 7%; severe <1%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; severe 0%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In all ABRAXANE treated patients (n=366) ocular/visual disturbances were reported (any 13%; severe 1%). Dehydration and pyrexia were also reported • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non-Small Cell Lung (NSCLC) Cancer Study • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin in NSCLC were anemia (28%); neutropenia (47%); thrombocytopenia (18%), and peripheral neuropathy (3%) • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC were anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

Please see Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages.

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group) Post-marketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities • Monitor patients closely

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle, beginning immediately after the completion of ABRAXANE administration. 2.3 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin Levels ABRAXANE Dosea Levels MBC NSCLC Mild < 10 x ULN > ULN to ≤ 1.25 x ULN 260 mg/m2 100 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN 200 mg/m2 75 mg/m2 Severe < 10 x ULN 2.01 to 5 x ULN 130 mg/m2 b 50 mg/m2 c > 10 x ULN OR > 5 x ULN not eligible not eligible MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Increase dose to 75 mg/m2 in subsequent courses, as tolerated. 2.4 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to

Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose 2 (mg/m ) (AUC mg•min/mL) Neutropenic Fever (ANC less than 500/mm3 First 75 4.5 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC Second 50 3 less than 1500/mm3 OR Third Discontinue Treatment ANC less than 500/mm3 for more than 7 days First 75 4.5 Platelet count less than 50,000/mm3 Second Discontinue Treatment First 75 4.5 Severe sensory Neuropathy – Second 50 3 Grade 3 or 4 Third Discontinue Treatment 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC). Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.4)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.4)]. 5.3 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience

a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5.4 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.5 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.6 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.7 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (â&#x2030;Ľ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (â&#x2030;Ľ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 3 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer. Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 (continued)

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose

of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma,

43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 4 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 4: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) plus carboplatin plus carboplatin Grades Grade Grades Grade 1-4 (%) 3-4 (%) 1-4 (%) 3-4 (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 5 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin. Table 5: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups Paclitaxel Injection ABRAXANE (200 mg/m2 2 (100 mg/m weekly) every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) MedDRA Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 System Organ v 12.1 Toxicity Toxicity Toxicity Toxicity Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General Edema 10 0 4 <1 disorders and peripheral administration site conditions 7 0 2 0 Respiratory Epistaxis thoracic and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective 10 <1 19 2 tissue disorders Myalgia a Peripheral

neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord par esis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.4 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. There are no clinically important pharmacokinetic drug-drug interactions between carboplatin and ABRAXANE [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.7)]. • Patients must be informed of the risk of low blood cell counts and instructed to contact their physician immediately for fever or evidence of infection. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties, or signs of an allergic reaction. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE. • Patients must be informed that hypersensitivity reactions may occur, which could be severe and sometimes fatal. Manufactured for: Celgene Corporation Summit, NJ 07901 ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2012 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; 8,034,375; 8,268,348; and RE41,884. ABRPI.004/PPI.004 10/12

N EW

Now Available! Indications and Usage VASCEPA (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. • The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. • The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined. Important Safety Information for VASCEPA • VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components. • Use with caution in patients with known hypersensitivity to fish and/or shellfish. • The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia. • Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA.

Please go to www.VASCEPA.com for full Prescribing Information and more information on VASCEPA