Journal of Managed Care Medicine Volume 16, Number 3

Vol.16, No.3, 2013

Journal of Managed Care Medicine

COPD from a Managed Care Lens: Emerging Trends and Treatment Choices in COPD Diagnosis and Treatment

Effective Diagnosis, Treatment, and Management of Pulmonary Arterial Hypertension

Effective Treatment Strategies for Inflammatory Bowel Disease

Improving Outcomes with Novel Treatment Strategies in the Management of Type 2 Diabetes

Individualizing Treatment Strategies in the Management of Metastatic Breast Cancer

Metastatic Colorectal Cancer: Updates in Treatment Strategies and What’s in the Works

Optimizing Treatment Strategies in the Management of Metastatic Melanoma

Advances in the Treatment of Fecal Incontinence

Updated Strategies and Outcomes in the Diagnosis and Treatment of Major Depressive Disorder

GBEMTI Perspectives: Value-Based Reimbursement for Medical Devices in the U.S. – Where Do We Stand?

Physician Engagement is Critical to the Success of any Accountable Care Organization

How Behavioral Health Integration Can Reduce Health Care Costs

©2013 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. MM2030R0 June 2013

We Offer More Than Face Time.If you haven’t heard, GSK is moving forward by aligning our actions with managed care executives’ expectations. This means we are continuously investing in the strategic expertise of our account managers to understand your needs.

Diffi cult challenges, such as improving population outcomes, abound for managed care organizations—and that’s where the account managers at GSK can bring together experts who offer credible scientifi c and economic knowledge that can provide insights to inform your solutions.

True collaboration is more than face time—it’s moving forward with solutions that meet your needs.

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

ISSN: 1094-1525. The v is published by Association Services Inc. Corporate and Circulation offices: 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060; Tel (804) 527-1905; Fax (804) 747-5316. Edito-rial and Production offices: 2613 N. Parham Rd., Suite B, Richmond, VA 23294; Tel (804) 272-9100; Fax (804) 272-1694. Advertising offices: Jack Klose, 804 Broadway, W. Long Branch, NJ 07764; Tel (732) 229-8845; Fax (856) 582-9596. Subscription Rates: one year $95 in the United States; one year $105 in Canada; one year $120 international. Back issues are available for $15 each. All rights reserved. Copyright 2010. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photo-copy, recording, or any information storage or re-trieval system, without written consent from the publisher. The publisher does not guarantee, ei-ther expressly or by implication, the factual accu-racy of the articles and descriptions herein, nor does the publisher guarantee the accuracy of any views or opinions offered by the authors of said ar-ticles or descriptions.

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Journal of Managed Care MedicineThe Official Journal of the NaTiONal assOCiaTiON Of MaNaged Care PhysiCiaNsaMeriCaN assOCiaTiON Of iNTegraTed healThCare deliVery sysTeMsaMeriCaN COllege Of MaNaged Care MediCiNeaMeriCaN assOCiaTiON Of MaNaged Care Nurses

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TABLE OF CONTENTS

Journalof Managed care

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ISSN: 1094-1525. The Journal of Managed Care Medicine is published by Association Services Inc. Corporate and Circulation offices: 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060; Tel (804) 527-1905; Fax (804) 747-5316. Editorial and Production offices: P.O. Box 71895, Richmond, VA 23255-1895; Tel (804) 387-7580; Fax (703) 997-5842. Advertising offices: Sloane Reed, 4435 Waterfront Drive Ste 101, Glen Allen, VA 23060 Tel (804) 527-1905, Fax (804) 747-5316. All rights reserved. Copyright 2012. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage or retrieval system, without written consent from the publisher. The publisher does not guarantee, either expressly or by implica-tion, the factual accuracy of the articles and de-scriptions herein, nor does the publisher guarantee the accuracy of any views or opinions offered by the authors of said articles or descriptions.

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JMCM

BPA Audited Publication©2013 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. MM2030R0 June 2013

We Offer More Than Face Time.If you haven’t heard, GSK is moving forward by aligning our actions with managed care executives’ expectations. This means we are continuously investing in the strategic expertise of our account managers to understand your needs.

Diffi cult challenges, such as improving population outcomes, abound for managed care organizations—and that’s where the account managers at GSK can bring together experts who offer credible scientifi c and economic knowledge that can provide insights to inform your solutions.

True collaboration is more than face time—it’s moving forward with solutions that meet your needs.

687727_M03DR_GSK_launch_FullPageAd_AHDB.indd 1 7/17/13 4:34 PM

Vol. 16, No. 3, 2013

copd from a Managed care lens: emerging trends and treatment choices in copd diagnosis and treatmentJoseph Johnson, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

effective diagnosis, treatment, and Management of pulmonary arterial hypertensionyon K. sung, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

effective treatment strategies for inflammatory bowel diseaseJoel r. rosh, Md, faCg, agaf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

improving outcomes with novel treatment strategies in the Management of type 2 diabetesyehuda handelsman, Md, faCP, faCe, fNla . . . . . . . . . . . . . . . . . . . . . . . . 22

individualizing treatment strategies in the Management of Metastatic breast cancerMichael Naughton, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Metastatic colorectal cancer: updates in treatment strategies and What’s in the WorksTanios Bekaii-saab, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

optimizing treatment strategies in the Management of Metastatic Melanomaadil daud, MBBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

advances in the treatment of fecal incontinenceBeth Moore, Md, faCs, fasCrs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

updated strategies and outcomes in the diagnosis and treatment of Major depressive disorderKen hopper, Md . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

gbeMti perspectives: Value-based reimbursement for Medical devices in the u.s. – Where do We stand?eric faulkner, Joshua ransom, Natalie heidrich, Brad lucas, Md, geneva Briggs, Pharmd, BCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

physician engagement is critical to the success of any accountable care organizationanthony N. akosa, Md, MBa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

how behavioral health integration can reduce health care costsMark rosenburg, Md, Phd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

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.

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

Please see brief summary of full Prescribing Information on following page.

Find out more at solestainfo.com.

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

Num

ber

of e

piso

des/

14 d

ays

0

5

10

15

20

25

123Baseline

15.0

8.6

24

7.0 7.0

36

6.2

P=0.001

Months

n=136

53%

Durable efficacy with Solesta

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

A good day.

It’s no accident.

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).

SALSOP120033B Rv2 2pg ManagedMedicine 1 1/14/13 6:21 PM

Brief SummaryPlease consult Package Insert for full prescribing information.

Indication for UseSolesta 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).

ContraindicationsSolesta 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.

PrecautionsGeneral precautions• Solesta should only be administered by physicians experienced in performing anorectal

procedures and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure.

• The safety and effectiveness of Solesta have not been investigated in patients with complete external sphincter disruption or significant chronic anorectal pain.

• The safety and effectiveness of Solesta have not been investigated in patients with previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with rubber band within 3 months, anorectal implants and previous injection therapy, Stapled Transanal Rectal Resection (STARR) or stapled hemorrhoidectomy.

• The safety and effectiveness of Solesta have not been studied in patients under the age of 18 years.

• The safety and effectiveness of Solesta have not been studied in pregnant or breastfeeding women.

• The durability of Solesta has not been studied past 12 months.• The safety and effectiveness of Solesta have been studied in patients who received

one or two treatments. In the Pivotal study, the majority of patients received two treatments, four weeks apart.

Patient related precautions• Patients with bleeding diathesis or patients using anticoagulant or antiplatelet agents,

as with any injections, may experience increased bleeding at injection sites.• Patients should be counseled that a repeated Solesta injection procedure may be

required to achieve a satisfactory level of improvement in incontinence.

Procedure related precautions• Adequate bowel preparation of the rectum using enema is required prior to injection.

The enema should be given immediately prior to the procedure to ensure evacuation of the anorectum. It is recommended that additional cleansing of the injection area with an antiseptic be performed prior to injection. Use of prophylactic antibiotics is recommended.

• Solesta should be injected slowly to avoid undue stress on the Luer-lock connection which could cause leakage of the gel.

• After injection of Solesta, hold the needle at the injection site for an additional 15-30 seconds to minimize leakage of Solesta.

• Injections too close to the dentate line or too deep in the tissue might cause excessive pain.

• Injection should be stopped if excessive bleeding or pain occurs.• One sterile needle should be used per syringe and injection.

Device related precautions• The use of needles other than those supplied may impede injection of Solesta due to

the properties of the gel and may cause device malfunction.• Solesta is supplied ready to use in a prefilled syringe with a Luer-lock fitting. Carefully

examine the unit to verify that neither the contents nor the package has been damaged in shipment. Do not use if damaged.

• Solesta is supplied sterile and is intended for single use only. Do not re-sterilize, as this may damage or alter the product.

• In the event of accidental contamination of a needle, discard the needle.• Never mix Solesta with other products.• Solesta is to be stored at up to 25°C (77°F), and used prior to the expiration date

printed on the label. Do not expose Solesta to either sunlight or freezing, as this may damage or alter the product.

• Care should be taken when handling the glass syringes and disposing of broken glass to avoid laceration or other injury.

• After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements.

Adverse EventsPotential 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 UseSolesta 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 SuppliedSolesta 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.

StorageStore 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.

©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in the USA. SOL12/57

3259_Solesta_SE&OIT_Ad_M1.1.indd 2 5/23/12 3:30 PM

SALSOP120033B Rv2 2pg ManagedMedicine 2 1/14/13 6:21 PM

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

Editorial Review Boardalan adler, Md, MsMedical directorindependence Blue Cross

devena alston-Johnson, MdMedical directorCigNa

e. paul amundson, MdChief Medical Officerdakotacare

linda ash-Jackson, MdMedical directorhometown health

paul bluestein, MdChief Medical OfficerConnecticare

richard bock, Md, MbaChief Medical OfficerMolina health Care of California

anthony bonagura, MdChief Medical Officeraetna, inc.

philip M. bonaparte, MdChief Medical Officerhorizon NJ health

salil V. deshpande, MdMarket Medical Officerunited healthcare

Michael fine, MdMedical directorhealth Net

John K. fong, Md, MbaVice PresidentBlue Cross Blue shield of North Carolina

stephen friedhoff, Mdsenior Vice President, National Medical directoramerigroup/Wellpoint

ronald Y. fujimoto, do, faafpChief Medical Officerunited healthcare

howard garber, Md, MphMedical directorJohns hopkins health Care

uwe g. goehlert, Md, Msc, Mph, MbaPrinciplegoehlert & associates

steven e. goldberg, Md, MbaVice President of Medical affairsCoventry health Care of Kentucky

humberto guerra-garcia, Md, Mph, facpChief Medical OfficerMMM healthcare, inc./PMC Medicare ChoicePuerto rico

sarath gunatilake, Md, phdProfessor, health science departmentCalifornia state university, long Beach

John W. heryer, Md, facsMedical directorBlue Cross Blue shield of Kansas City

Kathy hudson, phddirector, genetics and Public Policy CenterJohns hopkins university

larry l. hsu, MdMedical directorBlue Cross Blue shield of hawaii (hMsa)

stephen Keir, drphCo-director, Center for Quality of life support Care researchrobert Preston Tisch Brain Tumor Center

John Knispel, Md, cpe, facogregional Medical Officerhumana

Karen Knowles, Mdinternal Medicine PhysicianhCa/emcare

catherine Marino, MdChief Medical OfficerMagnaCare

Jeff Martin, pharmdClinical account directorinnoviant, inc.

Monte Masten, Md, Mba, MphVice President, health guidancehumana

Wesley Mizutani, MdTalbert Medical group

thomas Morrow, Mdgenentech

ray Mummery, Md, cMceChief Medical Officerdimension health

barbara nabrit-stephens, Md, MbaMedical directorunited healthcare

tim newman, MdMedical directorfirstenergy

denis o’connell, MdMedical directorBlue Cross Blue shield of North Carolina

arik olson, Md, Mbasenior Medical directorChOiCe health Plans

gary owens, MdPrinciplegary Owens associates

philip painter, MdChief Medical Officerhumana

Mary h. pak, MdMedical directorunity health Plans insurance Corpora-tion

gary r. proctor, MdChief Medical Officer, federal divisionValueOptions, inc.

carlos ramirez, MdChief Medical OfficerValley Baptist health Plans

paul rein, doMedical directorPort Warwick ambulatory surgery Center

Kevin roache, Md, MMM, cpe, facpeVice President Medical affairsPeoples health, inc.

Mark r. rosenburg, Md, phdPresident/CeOBehavioral health Management

Joseph schappert, MdChief Medical OfficerPaMl

christine M. seals, MdMedical directorumpqua health alliance

Jacque J. sokolov, MdChairmanssB solutions

scott spradlin, do, facpf, acoiVice President Medical affairs/Chief Medical Officergroup health Plan

William d. strampel, do, facoidean, College of Osteopathic MedicineMichigan state university

prentiss taylor, MdCorporate Medical directoradvocate at Work at advocate health Care

pamella thomas, Md,Mph, facoeMConsulting Medical directorWellness health & Productivity strategies

robert a. Ziff, Md, Mba, facs, cpeeast Central region Medical director, senior Productshumana


ChroniC obstruCtive pulmonary disease (CopD) causes a significant health burden in the united states. an estimated 14.8 million adults in the u.s. are diagnosed with CopD and an additional 12 million adults are thought to have the disease but remain undiagnosed.1 it is generally diagnosed in adults aged 40 years or older.

CopD ranks as the third leading cause of death in the u.s.2 the death rate for CopD doubled from 1970 to 2002, while the death rates for other chronic illnesses such as stroke and heart disease markedly declined.3 From 1980 to 2007, the CopD death rate for u.s. women increased significantly compared with the rates in a number of other de-veloped countries.4

CopD also imposes a significant economic bur-den on the u.s. health care system. the annual cost of CopD in the u.s. exceeds $50 billion.5 in

2009, it resulted in 739,000 hospitalizations (average length of stay of 4.7 days) and 15,392,000 physician offices visits.5 hospital care accounts for the largest portion of direct costs of CopD (exhibit 1).6

Currently, there are several gaps in CopD care that should be addressed by managed care. the first is misdiagnosis despite availability of simple diag-nostic testing. misdiagnosis of CopD remains all too common when physician assessments are based on history and physical symptoms alone without utilization of spirometry. in one study, by Chapman et al, which investigated the gender bias in CopD diagnosis, approximately 35 percent of male patients who presented with CopD symptoms and 51 per-cent of female patients who presented with CopD symptoms were misdiagnosed when spirometry was not utilized.7

the second gap in CopD care is in the use of spi-

summarydespite advances in therapy, chronic obstructive pulmonary disease (COPd) con-tinues to result in significant morbidity, mortality, and economic costs. a new para-digm for COPd care, supported by updated management guidelines, is needed to address several significant gaps in care. Managed care can play a role in closing these known gaps in care.

Key points• COPd is a significant cost driver in managed care.• gaps in current care include misdiagnosis, low use of spirometry, low use of inhaled bronchodilators compared with corticosteroids, and high rates of 30-day hospital readmissions.• revised gOld patient classification system combines symptomatic assessment with spirometric classification and future risk of exacerbations.• Providers need to be educated on the updated guidelines.• a new paradigm for diagnosing, treating, and managing COPd is needed to ad dress gaps in care.

COPD from a Managed Care Lens: Emerging Trends and Treatment Choices in

Diagnosis and TreatmentJoseph Johnson, Md


rometry to confirm the diagnosis as recommended by the Global initiative for Chronic obstructive lung Disease (GolD) guidelines.8 as shown in exhibit 2, 2010 heDis data suggest low spirometry rates for CopD confirmation across plans.9

the third gap in care is the preferential use of in-haled corticosteroids instead of the guideline pre-ferred bronchodilators. in 2010, per member per year expenditure data for CopD medications by Commercial, medicare part D, and medicaid plans showed a three to sixfold higher spending on in-haled corticosteroids compared with bronchodila-tors.10 the GolD guidelines for initial pharmaco-logic management of CopD have bronchodilators as central to CopD management (exhibit 3).8 all

patients should be on either a long-acting beta ago-nist or anticholinergic agent. inhaled corticosteroids are recommended as a choice for patients who are at high risk for exacerbations.

lastly, CopD is a leading cause of readmissions to the hospital among medicare beneficiaries. a retrospective, medicare claims database analysis found that from 2003 to 2004 the 30-day readmis-sion rate among CopD is 22.6 percent, accounting for 4 percent of all 30-day readmissions.11 based on 2005 medicare discharge claims data, CopD ranks fourth on a list of seven conditions associated with the most costly readmissions.12

the GolD guidelines were updated in 2011. this major revision built on the strengths from the

exhibit 2: spirometry rates are low9

*healthcare effectiveness data and information set

hedis* Measure: estimates the number of members aged >40 years newlydiagnosed with COPd who received spirometry to confirm the diagnosis

50

40

30

20

10

0

patie

nts

rece

ivin

gsp

irom

etry

, %

hedis spirometry test rate(hMo averages, 2010)

Managed MedicaidCommercial Medicare

41.7%

33.9% 31.3%

exhibit 1: hospital stays drive direct copd costs for payers6

4035302520151050

adjusted Mean episode-level cost of copd-related Visits

Mea

n c

ost

(200

8 u

s$, t

hous

ands

)

OutpatientVisit

(n=19,641)

urgentOutpatient Visit

(n=13,833)

emergencydepartment

Visit(n=1,231)

standardhospital

admission(n=1,547)

iCu stay(n=837)

$305 $274 $327

$9,745

$33,440


original recommendations and incorporated new knowledge. in addition to presenting background information, these guidelines offer a new paradigm for assessment and treatment of CopD based on a review of current evidence.

the original strategy for classifying CopD was a simple system based upon spirometry and was called a staging system because it was believed, at the time, that the majority of patients followed a path of dis-ease progression in which the severity of the disease

exhibit 3: current gold pharmacologic treatment guidelinesa8

a Medications in each box are listed in alphabetical order and, therefore, not necessarily in order of preference.b Medications in this column can be used alone or in combination with medications in the first and second columns. sa, short-acting; la, long-acting; pde-4, phosphodiesterase type 4 inhibitor.

Patient group first Choice second Choice alternative Choiceb

a. low risk less symptoms

sa anticholinergic pm orsa beta2-agonist pm

la anticholinergic orla beta2-agonistorsa beta2-agonist and sa anticholinergic

Theophylline

B. low risk More symptoms

la anticholinergic orla beta2-agonist

la anticholinergic and la beta2-agonist

sa beta2-agonist and/orsa anticholinergic Theophylline

C. high risk less symptoms

iCs + la beta2-agonistorla anticholinergic

la anticholinergic and la beta2-agonist

Pde-4 inhibitor sa beta2-agonist and/orsa anticholinergic Theophylline

d. high risk More symptoms

iCs + la beta2-agonistorla anticholinergic

iCs and la anticholinergic oriCs + la beta2-agonist and la anticho-linergic oriCs + la beta2-agonist and Pde-4 inhibi-tor orla anticholinergic and la beta2-agonistorla anticholinergic and Pde-4 inhibitor

Carbocysteine sa beta2-agonist and/orsa anticholinergic Theophylline

exhibit 4: 2011 gOld grading Combines symptomatic assessment with spirometric Classification and/or exacerbation risk8

Patient Category

Characteristics spirometric Classificationa

exacerbations per year

mMrC CaT

a low risk, less symptoms

gOld 1-2 <1 0-1 <10

B low risk, More symptoms

gOld 1-2 <1 >2 >10

C high risk, less symptoms

gOld 3-4 >2 0-1 <10

d high risk, More symptoms

gOld 3-4 >2 >2 >10

a Postbronchodilator feV1: gOld 1, feV1 >80% predicted; gOld 2, 50% < feV1 < 80% predicted; gOld 3, 30% < feV1 < 50% predicted; gOld 4, feV1 <30% predicted.mMrC, Modified British Medical research Council Questionnaire; CaT, COPd assessment Test; feV1, forced expiratory volume in 1 second.


tracked the severity of the airflow limitation. the concept of staging based on spirometry alone has been revised to a new grading system that promotes an understanding of the impact of CopD on the patient by combining spirometry with symptomatic assessment and risk of exacerbations. patients are now classified into grades from a to D based on increasing risk of exacerbations, symptoms, and spi-rometric measurement. Group a patients have low risk and fewer symptoms, whereas Group D patients are high risk with more symptoms (exhibit 4).8

there needs to be a paradigm shift in how pro-viders diagnose, treat, and manage CopD patients to address the gaps (exhibit 5). managed care can play a role in closing these gaps by educating pri-mary care providers on the early use of spirometry for diagnosis and the recommended treatments in accordance with revised GolD guidelines. Closing the gaps will help plans prepare for medicare CopD quality requirements.

conclusionCopD is a costly disease in terms of both patient impact and economic costs. although easy diagnos-tic tests and effective therapies are available, these are not always applied correctly. providers need to be educated on the revised guidelines in order to close the gaps in care.

Joseph Johnson, Md is the Chief Medical Officer at arizona integrat-ed Physicians.

references1. national heart, lung, and blood institute. Chronic obstructive pulmonary

Disease. available at www.nhlbi.nih.gov/health/prof/lung/copd/copd_wksp.

pdf. accessed may 5, 2013.

2. hoyert Dl, Xu JQ. Deaths: preliminary data for 2011. Natl Vital Stat Rep.

2012;61(6):1-65.

3. Jemal a, Ward e, hao y, thun m. trends in the leading causes of death in

the united states, 1970-2002. JAMA. 2005;294(10):1255-9.

4. mannino Dm, homa Dm, akinbami lJ, et al. Chronic obstructive pulmo-

nary disease surveillance--united states, 1971-2000. MMWR Surveill Summ.

2002;51(6):1-16.

5. national heart, lung, and blood institute. morbidity and mortality: 2012 chart

book on cardiovascular, lung, and blood disease. available at http://www.nhlbi.nih.

gov/resources/docs/2012_Chartbook_508.pdf. accessed may 5, 2013.

6. Dalal aa, Christensen l, liu F, riedel aa. Direct costs of chronic obstruc-

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

mon Dis. 2010;5:341-349

7.Chapman Kr, tashkin Dp, pye DJ. Gender bias in the diagnosis of CopD.

Chest. 2001;119:1691-5.

8. Global initiative for Chronic obstructive lung Disease (GolD). Global

strategy for the diagnosis, management, and prevention of chronic obstructive

pulmonary disease. revised 2011. available at www.goldcopd.org. accessed

may 5, 2013.

9. national Committee for Quality assurance. the state of health Care Qual-

ity 2011. available at www.ncqa.org. accessed may 5, 2013.

10. emigh r, ed. the novartis pharmacy benefit report: 2011/2012 Facts,

Figures, & Forecasts. 19th edition. east hanover, nJ: novartis pharmaceuticals

Corporation; 2011.

11. Jencks sF, Williams mv, Coleman ea. rehospitalizations among patients in

the medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-28.

12. medicare payment advisory Committee. report to the Congress: promot-

ing Greater efficiency in medicare. Washington DC 2007.

exhibit 5: paradigm shift in how We diagnose, treat, and Manage copd patients

get ready forupcoming MedicareCOPd qualityrequirements

i ii iii

differentialdiagnosis of COPd

right Treatmentat the right Time

Managereadmissions

enhance earlyuse of spirometryin outpatientclinics by PCPs

use of varioustreatments inaccordance withrevised gOldguidelines

§ § §


the pulmonary vasCulature is a loW-pressure system with a normal mean pulmonary ar-tery pressure (pap) of 10 to 15 mmhg. pulmonary arterial hypertension (pah) is a disease specifically of the pulmonary arterioles as opposed to the veins resulting in increased pap. it is defined as a mean pap greater than 25 and a pulmonary capillary wedge pressure (pCWp) less than 15. pCWp is a surrogate for left ventricular end diastolic pressure (lveDp).

there are many causes of pah. these have been classified into five categories as shown in exhibit 1.1 this classification scheme is based on presumed mechanisms of disease and is useful in understanding the disease process and considerations for treatment.

early in the disease process there is pulmonary arteriopathy that leads to increased pap and pul-monary vascular resistance (pvr) (exhibit 2). For a long time, the right side of the heart is able to compensate for the increased pressures in the lung and maintain cardiac output through right ventricle dilation and hypertrophy. once the disease pro-gresses with remodeling of the pulmonary arteries,

proliferation of endothelial and smooth muscle cells and obstruction of the vessels, cardiac output begins to decline and the patient becomes symptomatic. the primary symptoms are dyspnea, decreased ex-ercise tolerance, fatigue, chest pain, and palpitations. right heart failure will eventually develop because of the continued stresses on the heart.

pah is a rare disease. the current prevalence is estimated as 15 cases per one million persons.2,3 the prevalence of idiopathic pah is six cases per one million. this disease was previously thought to af-fect primarily young or middle-aged women, but the age range is increasing and men are affected.

prior to the development of successful therapies, the survival rates in this disease were very poor. less than 50 percent of patients survived for three years after diagnosis.4,5 With pah specific therapies, sur-vival has improved to 78 percent of patients alive at three years, but this is still not optimal.6 surviv-al with pah is very dependent on the underlying cause.7 the best survival rate is in those with con-genital heart disease as the cause. the worst rates are in those with underlying collagen vascular disease

summaryalthough rare, pulmonary arterial hypertension (Pah) results in significant manage-ment costs and major morbidity and mortality. survival rates have improved with targeted therapies but are not optimal. Management of these patients requires complex, expensive regimens that are likely best managed by a pulmonary hyper-tension subspecialty center if available.

Key points• Pah is a rare disease. • diagnosis of Pah can be difficult and delayed.• a right heart cauterization is the test for definitive diagnosis and for obtaining hemodynamic measurements. • Current Pah specific therapies target three major pathways of vasoconstriction and appear to improve survival.• Treatment regimens should be tailored based on treatment guidelines to the severity of disease and patient characteristics.

Effective Diagnosis, Treatment, and Management of Pulmonary Arterial Hypertension

yon K. sung, Mdfor a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


or human immunodeficiency virus (hiv) infection.because the symptoms are nonspecific, pah diag-

nosis can be difficult. the average time to diagnosis is 18 to 24 months. presence of risk factors for pah, including family history, hiv risk factors, liver disease, or stimulant drug use, should suggest the need for more specific screening in a patient with symptoms suggestive of the disease. once patients are suspected of having pah, they undergo a bat-tery of testing to definitively diagnose and classify the disease and to assess their current baseline and prognosis.3 a right heart cauterization is the test for definitive diagnosis and for obtaining hemodynamic measurements.

an accurate diagnosis is important. patients can have multiple causes of ph. therapy is guided by the underlying cause. treating the underlying cause such as lupus or scleroderma may improve pul-

monary hypertension. additionally, treating some types of pah with pulmonary vasodilators may be harmful.

vasoreactive testing will usually be conducted at the time of the right heart cauterization to help guide medical therapy. a positive vasoreactive response is defined as a reduction in mean pap by at least 10 mmhg. the mean pap must also be reduced to less than 40 mmhg and cardiac output must be main-tained or improved as a result. patients with posi-tive vasoreactive responses have been shown to have better prognosis than those with negative response. these patients are likely to respond to vasodilators.

three groups of patients should be screened year-ly for pah with an echocardiogram. patients with known bone morphogenetic protein receptor type ii (bmpr2) mutation, scleroderma, or liver disease being considered for liver transplantation are all at

exhibit 1: pulmonary arterial hypertension: dana point 2008 classification1

1 pulmonary arterial hypertension 1.1 idiopathic Pah 1.2 heritable Pah 1.2.1 BMPr2 mutation 1.2.2 alK1, endoglin (with or without hereditary hemorrhagic telangiectasia) 1.2.3 unknown 1.3 drugs and Toxin - induced 1.4 associated with: 1.4.1 Connective Tissue diseases 1.4.2 hiV 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 schistosomiasis 1.4.6 Chronic hemolytic anemia 1.5 Persistent Pulmonary hypertension of the Newborn

exhibit 2: from early to symptomatic to severe pah

co, cardiac output; pap, pulmonary artery pressure; pVr, pulmonary vascular resistence;bnp, brain natriuretic peptide; nYha, new York heart association

early symptomatic severe

CO

PaP

pVr Nyha i ii iii iV

BNP

Time


high risk for developing pah or complications of transplant surgery.

traditional supportive care in pah includes supplemental oxygen, diuretics, inotropic agents, digoxin, anticoagulation, and calcium channel blockers. because pah is a prothrombotic state, an-ticoagulation has been shown to improve survival. Calcium channel blockers are only indicated for pa-tients who meet criteria for vasoreactivity. nifedip-ine, diltiazem, and amlodipine are the agents that can be used. verapamil has to be avoided in pah patients due to potential negative inotropic effects.

While current research has identified a myriad of pathways that are likely involved in the pathogenesis of pah, current pah specific therapies target three major pathways (exhibit 3).8 the phosphodiester-ase (pDe-5) inhibitors inhibit the activity of pDe, which breaks down cyclic Gmp. enhancing cyclic Gmp levels leads to pulmonary vasodilation. two pDe-5 inhibitors are available in the united states - sildenafil (revatio®) and tadalafil (adcirca®). mul-tiple clinical trials have shown the safety and benefit of pDe inhibitors in pah.

another area targeted with medication is endo-thelin, a potent vasoconstrictor. the endothelin receptor antagonists (era) block the receptors for endothelin, resulting in vasodilation. a nonselective agent, bosentan (tracleer®), and a selective agent, ambrisentan (letairis®) are currently available. al-though there are differences in selectivity, efficacy and adverse effects appear similar. several studies have shown these agents improve symptoms and reduce pvr. bosentan is the only medication that

has specifically been studied in patients with less se-vere disease [new york heart association (nyha) stage ii].

prostacyclins are potent vasodilators that can be given to reduce pap in pah. because these agents have very short half-lives, they have to be given by intravenous infusion or frequent subcutaneous in-jection or inhalation. the FDa approved agents in-clude epoprostenol (veletri®, Flolan® for injection), treprostini (remodulin® for infusion and tyvaso® for inhalation), and iloprost (ventavis® for inhala-tion). observational studies with epoprostenol show improved survival compared to historical controls.9,10

there are significant issues with giving prostacy-clins that can severely limit their use. intravenous prostacyclins are given by continuous infusion with a pump which limits the mobility of patients and carries the risk of infection and other complications of having intravenous access. inhaled prostacyclins are given six to nine times per day with each inha-lation taking six to 10 minutes each (treprostinil) or three to nine breaths four times per day taking 15 minutes each (treprostinil). the inhalers are very difficult for patients to use accurately. Compliance is a major issue with inhalation therapy. exhibit 4 compares with pros and cons of the various pah specific therapies.

because the current therapies target different pathologic pathways in pah, combination therapy is frequently considered. Combination therapy is utilized in treatment of many chronic diseases, but data are limited in regard to using combinations of pah specific therapies in this disease. many ques-

exhibit 3: Key pathways implicated in pah pathogenesis8


tions still need to be answered about combination therapy. these include which agent combinations should be used and in what order and when should treatment be escalated. there are pending data from clinical trials of combination sildenafil and bosen-tan. Combination therapy is frequently done in clinical practice because there are so few options for these patients.

Current therapy has some limitations. the avail-able treatments are not optimal and survival is still

abysmal. the available agents act as vasodilators, but vasoconstriction is only one minor component of increased pvr for most pah patients. endothelial cell proliferation is the major contributor to this dis-ease. it is not yet known if the available agents are significantly impacting endothelial homeostasis.

the current treatment guidelines suggest using indicators of progression risk to determine initial therapy. exhibit 5 shows the initial management algorithm.3,11 in addition to medications, support-

exhibit 5: What is optimal treatment? strategy?3,11

Positive Negative

ContinueCCB

investigationalprotocols

atrial septostomylung Transplant

No

Yes

anticoagulate + diuretics +Oxygen + digoxin

acute Vasoreactivity Testing

sustainedresponse

Oral CCB

reassess: Consider combinationtherapy

1) eras or Pde-52) Prostacyclins

lower risk higher risk

1) Prostacyclins2) eras or Pde-5

exhibit 4: comparing agents

agent Pros Cons

Pde-5 inhibitors • • • •

Oral once a day or three times a day dosing No specific monitoring needed Minimal side effects less expensive

• side effects - systemic hypotension, head-ache, flushing

era • •

Oral once a day or twice a day dos-ing evidence for reduction in time to clinical worsening

• • • •

liver toxicity - Bosentan requires monthly monitoring of liver enzymes anemia - Bosentan requires CBCq 3 months Teratogenic -requires monthly pregnancy tests side effects - fluid retention

Prostacyclins iV/sC •

•

Trials have suggested survival benefit improvement in hemodynamics, ex-ercise tolerance, and quality of life

• • •

Complications with iV catheters site pain with sC catheters side effects - flushing, headaches, jaw pain, nausea, diarrhea

Prostacyclins inhaled • Non- invasive • •

Compliance side effects - headache, flushing, diarrhea, cough


ive care for this disease includes pulmonary reha-bilitation and management of comorbidities that can worsen the disease. these include anemia and thy-roid disease. because of the complexity in managing these patients, they should be referred to pulmonary hypertension specialists for management.

pah can cause a significant financial burden. in one study of managed care costs, patients with pah had higher health care costs both before diagnosis ($2064 versus $1094 per month) and after diagnosis ($4021 versus $1533) compared with controls.12 the medication costs range from $18,000 to $160,000 per year for a single medication. in a cost-effective-ness study, treatment with sildenafil and bosentan was determined to be cost effective.13

conclusiona complete workup for pulmonary hypertension is needed to properly classify pah, prescribe appro-priate treatments, and assess for comorbid conditions that also require treatment. treatment regimens can be complex and should be tailored to the severity of disease and patient characteristics. because of the complexity of managing this disease, clinicians should consider referring patients to a pulmonary hypertension subspecialty center.

Yon K. sung, Md is a Clinical instructor in the division of Pulmonary/Critical Care at the Vera Moulton Wall Center for Pulmonary Vascular disease at stanford university school of Medicine.

references1. simonneau G, robbins i, beghetti m, et al. updated clinical classification of

pulmonary hypertension. J Am Coll Cardiol. 2009;54:s43-s54.

2. humbert m, sitbon o, Chaouat a, et al. pulmonary arterial hypertension in

France: results from a national registry. Am J Respir Crit Care Med.

2006;173(9):1023-30.

3. mclaughlin vv, archer sl, badesch Db, et al. aCCF/aha 2009 expert

consensus document on pulmonary hypertension a report of the american Col-

lege of Cardiology Foundation task Force on expert Consensus Documents and

the american heart association developed in collaboration with the american

College of Chest physicians; american thoracic society, inc.; and the pulmo-

nary hypertension association. J Am Coll Cardiol. 2009;53(17):1573-619.

4. rich s, Dantzker Dr, ayres sm, et al. primary pulmonary hypertension. a

national prospective study. Ann Intern Med. 1987;107(2):216-23.

5. D’alonzo Ge, barst rJ, ayres sm, et al. survival in patients with primary

pulmonary hypertension. results from a national prospective registry. Ann In-

tern Med. 1991;115(5):343-9.

6. mcGoon mD, miller Dp. reveal: a contemporary us pulmonary arterial

hypertension registry. Eur Respir Rev. 2012;21(123):8-18.

7. mclaughlin vv, presberg KW, Doyle rl, et al. prognosis of pulmonary

arterial hypertension: aCCp evidence-based clinical practice guidelines. Chest.

2004;126(1 suppl):78s-92s.

8. humbert m, sitbon o, simonneau G. treatment of pulmonary arterial hy-

pertension. N Engl J Med. 2004;351(14):1425-36.

9. mclaughlin vv, shillington a, rich s. survival in primary pulmonary hyper-

tension: the impact of epoprostenol therapy. Circulation. 2002;106(12):1477-82.

10. sitbon o, humbert m, nunes h, et al. long-term intravenous epoprostenol

infusion in primary pulmonary hypertension: prognostic factors and survival. J

Am Coll Cardiol. 2002;40(4):780-8.

11. mclaughlin vv, mcGoon mD. pulmonary arterial hypertension. Circula-

tion. 2006;114(13):1417-31.

12. said Q, martin bC, Joish vn, et al. the cost to managed care of managing

pulmonary hypertension. J Med Econ. 2012;15(3):500-8.

13. Chen yF, Jowett s, barton p, et al. Clinical and cost-effectiveness of epo-

prostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial

hypertension within their licensed indications: a systematic review and eco-

nomic evaluation. Health Technol Assess. 2009;13(49):1-320.


inFlammatory boWel Disease (ibD) appears to develop as the result of interplay of ge-netic predisposition, environmental triggers, and immune regulation in the bowel. more than 60 ge-netic loci have been identified as susceptibility genes for ibD. some of the environmental triggers that have been identified are infection, diet, smoking, stress, and allergens. the mechanism by which the immune-regulatory defect occurs in the mucosal immune system in the bowel is unknown, but the contribution of gut bacterial flora to immune re-sponse is a hot area of research.

ibD has traditionally been divided in ulcerative colitis (uC) and Crohn’s disease, although there are moves to abandon this classification system. uC is confined to the colon and is only a disease of the mucosal lining of the bowel. Crohn’s can oc-cur throughout the entire Gi tract. it begins in the bowel lining but can become a transmural disease if the inflammation breaks through the mucosa. the main complications of Crohn’s are fistula, stricture from bowel scarring, and abscess. With all forms of ibD, there is an increased risk of colorectal cancer.

the goals of ibD management – together with the corresponding clinical parameters and outcomes – have evolved from simply reducing symptoms to achieving a sustained true remission through muco-sal healing (exhibit 1). thus, the main therapeutic goal in ibD is the induction and maintenance of a true remission. other goals include maintaining quality of life, avoiding use of long-term cortico-steroids, adherence to therapy, and minimization of cancer risk. Keeping patients in a true remission will reduce the progression of the disease and the need for surgical procedures such as colectomy.

the american College of Gastroenterology (aCG) has published evidence-based guidelines for diagnos-ing and treating patients with ibD.1,2 these treatment guidelines should be followed to maintain response and remission in adult patients with ibD.

ulcerative colitisuC typically presents as persistent bloody diarrhea, rectal urgency, or feelings of incomplete defecation. because most patients with uC have bloody diarrhea, it is diagnosed earlier than Crohn’s disease, which

summaryThe treatment of inflammatory bowel disease (iBd) has changed significantly since the introduction of immune system altering biologics. using these agents in combi-nation with older agents can induce a sustained remission that will likely reduce the progression of the disease and the need for surgeries. evidence-based guidelines should be used to steer therapy to achieve and maintain sustained remissions.

Key points• evidence-based treatment guidelines should be used when diagnosing and creating a treatment plan for patients with iBd to maintain response and remission. • The evolution of iBd therapy has increased the likelihood of rapid remission with steroid-free, long-term maintenance. • risk stratification, drug monitoring and dose optimization are emerging as critical components to therapeutic durability. • strategies to assure adherence and health monitoring are likely to increase positive therapeutic effect and long-term wellness in the iBd patient.

Effective Treatment Strategies for Inflammatory Bowel Disease

Joel r. rosh, Md, faCg, agaf for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


can have more subtle symptoms. sigmoidoscopy or colonoscopy and biopsy are performed to confirm the presence of colitis. Characteristic endoscopic and histologic findings with negative infectious stool evaluation will suggest the diagnosis of uC.

population data suggest that most patients (70 percent) present initially with moderate to higher disease activity.3 moderate to higher disease activ-ity is defined as more than four bowel movements daily and/or presence of blood or pus with or with-out systemic symptoms. twenty percent of patients present with low activity and 10 percent with ful-minant disease.

in mild to moderate disease, disease remission can be induced with a variety of agents including oral aminosalicylates, topical mesalamine or corticoste-roids, or a combination (exhibit 2). Combination of oral and topical aminosalicylates is more effec-tive than either alone and results in a more rapid and sustained remission.4 patients refractory to all of the above agents in maximal doses, or who are systemically ill can be treated with oral prednisone (40 to 60 mg per day), infliximab (remicade®), or adilimumab (humira®). infliximab and adilimum-ab are both antibodies that bind to tumor necrosis factor (tnF), an inflammatory cytokine intimately involved in the ibD disease process.

For severe colitis, a decision whether to manage in the outpatient or inpatient setting must be made. patients with severe symptoms are not typically go-ing to respond to topical or oral agents. patients with less severe symptoms who are unresponsive to oral and topical agents will require intravenous corticosteroids. if the patient does not respond to intravenous therapy in three to five days, a second-

line agent is started. these include calcineurin in-hibitors, tacrolimus and cyclosporine, or infliximab. studies have found these second-line agents to have similar efficacy. higher doses of infliximab are re-quired to manage severe disease compared to lesser disease activity.

For patients who develop complications such as toxic megacolon, colectomy is the treatment op-tion. approximately 25 percent of uC patients will lose their colons to this disease after 10 years.5 exhibit 3 shows the predictors of having more se-vere disease requiring second- line treatment or colectomy.6-10

once remission is induced, the patient is con-verted to maintenance therapy (exhibit 2). about 50 percent of patients will remain in remission at one year.5 another 30 percent will have low disease activity and 20 percent will have high to moderate activity.5 therapy should be stepped up if the patient still has disease activity.

objective measures should be used to determine disease activity. unfortunately, sending patients for a colonoscopy at every visit is not practical. in-depth questions about bowel movements and surrogate markers of mucosal healing can be used to evaluate disease activity. some surrogate mark-ers for mucosal healing include serum C-reactive protein (Crp) and fecal markers, calprotectin and lactoferrin. low Crp values reflect minimal dis-ease activity. Fecal markers can be obtained from a stool sample. Calprotectin levels primarily indicate health of the colon, whereas fecal lactoferrin is bet-ter for measuring small bowel health. the use of fecal markers to assess mucosal healing is an area of the field that is emerging.

exhibit 1: evolving goals of therapy for ibd: sustained deep remission

susTaiNed

goal

response

remission

deep remission

clinical parameters

improved symptoms

No symptoms

Normal endoscopy

outcomes

improved quality of life

decreased hospitalization

avoidance of surgery


crohn’s diseaseCrohn’s disease (CD) diagnosis is based on a com-posite of endoscopic, radiographic, and pathologi-cal findings from mucosal biopsy. there needs to be documentation of focal, asymmetric, transmural, or granulomatous features. an endoscopy with biopsy is the gold standard for diagnosis. Genetic and se-rologic testing are not recommended at this time; however, in the future, this type of testing will like-ly be used.

because Crohn’s disease patients do require many tests over their lifetime that use radiation, there should be attempts to decrease the amount of radia-tion exposure in these patients to limit the risk of cancer. some advances in imaging to define the ex-tent of disease within the gastrointestinal tract and to reduce exposure to radiation include the use of video capsule endoscopy (vCe) and magnetic reso-nance enterography (mre). With vCe, a pill-sized video camera is swallowed. the camera has its own light source and takes pictures of the small intes-tine as it passes through. these pictures are sent to a small recording device worn on the body. mre is a minimally invasive imaging test that uses magnetic resonance and an oral contrast dye to also examine the small intestine.

patients are staged to determine the appropriate therapy to induce and then maintain clinical remis-sion with mucosal and transmural healing. exhibit 4 shows the schematic for induction and remission in CD. surgery may be necessary in some patients for neoplasia, obstruction, and suppuration.

induction in mild to moderate ileo-colonic CD is done with mesalamine, sulfasalazine, and corti-costeroids. mesalamine and sulfasalazine primarily

work on the muscosa and do not treat any trans-mural disease. because of this, the majority of pa-tients will require immune modification with cor-ticosteroids or biologics to effectively control their disease. Corticosteroids are first line, but the goal in CD is to use them as little as possible because studies have shown they do not work long term and they have significant adverse effects. in moderate to severe CD, 50 percent of patients become steroid de-pendent. Dependence on corticosteroids for disease control occurs especially in smokers and those with colonic disease.

interestingly, enteral therapy with liquid diets will induce remission in CD almost as effectively as ste-roids. it requires four to six weeks, but it is difficult for patients to comply with.

once a patient is in remission, maintenance ther-apy is started. thiopurines are used for maintenance therapy in CD. prior to use, patients should be tested for their metabolic ability. the thiopurines are con-verted to inactive metabolites by the phase ii drug-metabolizing enzyme thiopurine methyltransferase (tpmt). patients who are poor metabolizers are at high risk of developing hematopoietic toxicity after treatment with standard doses. Conversely, standard doses in patients with high tpmt activity may not achieve an optimal therapeutic effect. FDa labeling recommends testing before starting treatment with these agents and consideration of dosage reduction in patients who are heterozygous poor metabolizers and alternative treatment in patients with a homo-zygous poor metabolizer profile.

other therapies used in maintenance management of CD include methotrexate, anti-tnF biologics, and natalizumab. in the case of CD, three anti-tnF

exhibit 2: sequential therapies for uc

inductionMaintenance

disease severityat presentation

severe

Moderate

Mild

aminosalicylate aminosalicylate

Corticosteroid aminosalicylate Thiopurine

anti-TNf anti-TNfCyclosporine Thiopurine

Colectomy


agents are FDa approved -infliximab, adilimumab, and certolizumab (Cimzia®).

natalizumab, an anti-integrin agent, is typically reserved for anti-tnF agent intolerant or unre-sponsive patients. patients must be screened for John Cunningham ( JC) virus infection before therapy. the JC virus can cause progressive multifocal leu-koencephalopathy (pml), also known as progres-sive multifocal leukoencephalitis. this is a rare and usually fatal viral disease that is characterized by progressive inflammation of the white matter of the brain at multiple locations. the JC virus infection occurs in many people and is normally kept under control by the immune system. immunosuppressive drugs prevent the immune system from controlling the virus.

biologicsbiologic agents have changed the way ibD is treat-ed. these agents aggressively target the inflamma-tion without the adverse effect of corticosteroids. of course, they have their own unique adverse effects.

infliximab is FDa approved for treating adult and pediatric CD and uC, whereas adilimumab is ap-proved for use in adult CD and uC. Critolizumab and natalizumab are only approved for use in adult CD.

the indications for biologics in CD include fail-ure to induce remission despite steroids, failure to maintain remission despite optimized immune suppressants, and post-operative for prevention of recurrence after bowel resections. biologics should also be used early in CD patients with prognos-tic factors for rapid progression to complications - young age, fistula, steroid need, deep ulcerations, or smoking. in uC, the indications for biologics include failure to induce remission despite steroids, failure to maintain remission despite optimized aminosalicylates or immune suppressants, and se-vere hospitalized patients.

there are three areas to consider in maximizing benefit from biologics – combination therapy, dose optimization, and immunogenicity. Combining bi-ologics with azathioprine has been shown to result in higher steroid-free remission rates.11 patients do not do as well on an immune modulator alone com-pared with biologic alone.12 Current recommenda-tions are to start with a combination of biologic and azathioprine or 6-mercaptopurine when a biolog-ic is going to be used for induction. Combination therapy should be continued for six months. if the patient has a true remission (i.e., low Crp and no symptoms) and good blood levels of the biologic, the immune modulator can be discontinued. at this time, only infliximab levels can be measured.

approximately 50 percent of ibD patients will require biologic dose modification to achieve ad-equate levels.13 infliximab levels can be measured and should be checked to make sure the patient maintains an adequate trough level before infusion. For example, infliximab is given every eight weeks. Checking a level before the infusion ensures the pa-tient still has sufficient drug around at the end of eight weeks. the dose may need to be increased or the dosing interval decreased.

immunogencity is also important to response to biologics. patients can develop antibodies against these medications. patients with these antibodies have a lower rate of response and shorter duration of response.14 regularly scheduled therapy is the only known way to prevent antibody development. When treatment is interrupted, antibodies develop and the patient is likely to have an anaphylactic reac-tion. Concomitant immunomodulators help reduce antibody production which is the main reason for us-ing combination therapy for induction. monitoring antibody levels in addition to medication levels can indicate which patients can manage on monotherapy and which will require combination therapy.

exhibit 3: predictors of poor response or colctomy6-10

• serum albumin • stool frequency

• esr >30 mm/h • Percentage of bloody stools

• Bandemia • Body temperature >37.5°C

• Prolonged flare • heart rate >90 bpm

• active infection • incrased CrP

• hospitalization setting • Toxic megacolon

• severe endoscopic lesions • low hemoglobin <10.5 g/dl

• disease duration


in treating ibD, there must be a balancing of the risks of therapy versus the risks of the disease. there is a fourfold increased incidence of lymphoma in pa-tients with ibD who are treated with thiopurines versus those never treated with one of these agents.15 the contribution of significant exposure to radia-tion in these patients to the risk of developing lym-phoma is not known. stopping thiopurine therapy as people age decreases the risk of lymphoma to that of the general population. anti-tnF agents also in-crease the risk of lymphomas.16 the highest rates are in those who have received both tnF agents and thiopurines.

hepatosplenic t-cell lymphoma (hstCl) is the most concerning form of lymphoma that occurs in ibD patients. hstCl is a rare and usually fatal lym-phoma that primarily affects men younger than 35 years old. treatment of patients with inflammatory bowel disease (ibD) using anti-tnF agents in com-bination with thiopurines has been associated with hstCl. thirty-eight cases have been reported and all have been uniformly fatal.17 although lympho-mas occur, it is important to note that these are still rare adverse effects.

nonadherenceof course, all the ibD medications only work if the patient takes them. as with most chronic dis-ease, medication nonadherence is a major issue with ibD.18 the leading reason for a patient to fall out of remission is due to not continuing their mainte-nance medication. although many factors that lead to nonadherence are not modifiable, many are. some modifiable factors include out-of-pocket costs, dos-

ing regimen, treatable depression, and the patient-provider relationship. managed care can have a role in supporting patients to be adherent with therapy.

health Monitoringin addition to medication specific monitoring, pa-tients will need other long-term monitoring. those who require corticosteroids need to be monitored for osteoporosis. patients need to be up to date on vaccinations before starting on immunosuppressant therapy. live virus vaccines cannot be given to im-munosuppressed individuals. in addition, emotional wellness and quality of life should be monitored. all patients with ibD need colon cancer surveillance. if the disease is kept in remission, the risk of colon cancer falls to that of the general population.

conclusionthe evolution of ibD therapy has increased the likelihood of rapid remission with steroid-free, long-term maintenance. risk stratification, drug monitoring and dose optimization are emerging as critical components to therapeutic durability. strat-egies to assure adherence and health monitoring are likely to increase positive therapeutic effect and long-term wellness in the ibD patient.

Joel r. rosh, Md, facg, agaf is an associate Professor of Pediatrics at the university of Medicine and dentistry of New Jersey and is direc-tor of Pediatric gastroenterology at the goryeb Children’s hospital/atlantic health.

references1. Kornbluth a, sachar Da, practice parameters Committee of the american

exhibit 4: sequential therapies for crohn’s disease

inductionMaintenance

disease severityat presentation

severe

Moderate

Mild

Corticosteroid Thiopurine/MTX

anti-TNf anti-TNf +/- Thiopurine/MTX

Natalizumab

set-up according to severity at presentation or failure at prior step

aminosalicylate aminosalicylateBudesonide Budesonide/Thiopurine


College of Gastroenterology. ulcerative Colitis in adults. Am J Gastroenterol.

2010; 105:501–523.

2. lichtenstein Gr, hanauer sb, sandborn WJ, and practice parameters Com-

mittee of the american College of Gastroenterology. management of Crohn’s

Disease in adults. Am J Gastroenterol. 2009;104(2):465-83;

3. langholz e, munkholm p, nielsen oh, et al. incidence and prevalence of

ulcerative colitis in Copenhagen County from 1962 to 1987. Scand J Gastroen-

terol. 1991;26:1247-1256.

4. safdi m, Demicco m, sninsky C, et al. a double-blind comparison of oral

versus rectal mesalamine versus combination therapy in the treatment of distal

ulcerative colitis. Am J Gastroenterol. 1997;92:1867-71.

5. hendriksen C, Kreiner s, binder v. long term prognosis in ulcerative coli-

tis--based on results from a regional patient group from the county of Copen-

hagen. Gut. 1985;26(2):158-63.

6. lindgren sC, Flood lm, Kilander aF, et al. early predictors of glucocortico-

steroid treatment failure in severe and moderately severe attacks of ulcerative

colitis. Eur J Gastroenterol Hepatol. 1998;10(10):831-5.

7. Gonzalez-lama y, Fernandez-blanco i, lopez-sanroman a, et al. open-

label infliximab therapy in ulcerative colitis: a multicenter survey of results and

predictors of response. Hepatogastroenterology. 2008;55(86-87):1609-14.

8. suzuki y, yoshimura n, Fukuda K, et al. a retrospective search for predictors

of clinical response to selective granulocyte and monocyte apheresis in patients

with ulcerative colitis. Dig Dis Sci. 2006;51(11):2031-8.

9. Cacheux W, seksik p, lemann m, et al. predictive factors of response to cy-

closporine in steroid-refractory ulcerative colitis. Am J Gastroenterol.

2008;103(3):637-42

10. ananthakrishnan an, mcGinley el, binion DG. Does it matter where you

are hospitalized for inflammatory bowel disease? a nationwide analysis of hos-

pital volume. Am J Gastroenterol. 2008 nov;103(11):2789-98.

11. Colombel JF, sandborn WJ, reinisch W, et al. infliximab, azathioprine, or

combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-95.

12. louis e, mary Jy, vernier-massouille G, et al. maintenance of remission

among patients with Crohn’s disease on antimetabolite therapy after infliximab

therapy is stopped. Gastroenterology. 2012;142(1):63-70.

13. alzafiri r, holcroft Ca, malolepszy p, et al. infliximab therapy for moder-

ately severe Crohn’s disease and ulcerative colitis: a retrospective comparison

over 6 years. Clin Exp Gastroenterol. 2011;4:9-17.

14. Farrell rJ, alsahli m, Jeen yt, et al. intravenous hydrocortisone premedi-

cation reduces antibodies to infliximab in Crohn’s disease: a randomized con-

trolled trial. Gastroenterology. 2003;124(4):917-24.

15. Kandiel a, Fraser aG, Korelitz bi, et al. increased risk of lymphoma among

inflammatory bowel disease patients treated with azathioprine and 6-mercapto-

purine. Gut. 2005;54(8):1121-5.

16. siegel Ca, marden sm, persing sm, et al. risk of lymphoma associated

with combination anti-tumor necrosis factor and immunomodulator therapy

for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol.

2009;7(8):874-81.

17. Kotlyar Ds, osterman mt, Diamond rh, et al. a systematic review of fac-

tors that contribute to hepatosplenic t-cell lymphoma in patients with inflam-

matory bowel disease. Clin Gastroenterol Hepatol. 2011;9(1):36-41.

18. Kane sv, sumner m, solomon D, Jenkins m. twelve-month persistency

with oral 5-aminosalicylic acid therapy for ulcerative colitis: results from a large

pharmacy prescriptions database. Dig Dis Sci. 2011;56(12):3463-70.


more than 60 perCent oF u.s. aDults are overweight or obese. the obesity epidemic in america contributes to the diabetes and cardio-vascular disease (CvD) epidemics currently in the united states. obesity does this through the devel-opment of insulin resistance and the metabolic syn-drome as shown in exhibit 1.1

type 2 diabetes is a progressive disease that begins prediabetes.2 approximately 80 million americans have prediabetes and nearly 30 million people have clinical diabetes. twenty-five percent of the over 65 age group has this disease. the significant complica-tions of the disease are well known and include am-putation, blindness, renal failure, and cardiovascular disease. every day in the u.s., 5,205 new cases of diabetes are diagnosed, 230 people have a diabetes-related amputation, 133 people with diabetes prog-ress to end-stage renal disease, and 55 people with diabetes become blind.3

managing diabetes entails much more than just managing glucose; it requires managing all the

patient’s risk factors. unfortunately, 44 percent of patients with diagnosed diabetes are not at ac-cepted glucose target values.4 additionally, few patients reach target goals for hemoglobin a1C (a1C), lipids, and blood pressure (exhibit 2).5 We are far from achieving basic goals in patients with type 2 diabetes.

the inadequate management of diabetes not only impacts health outcomes, but also creates an enor-mous socio-economic burden. in the u.s., over $200 billion was spent on diabetes in 2011.6

the american association of Clinical endocri-nologists (aaCe) guidelines for diagnosis and target goals are shown in exhibits 3 and 4.7 Goals should be individualized based on co-morbidities, duration of disease, hypoglycemia risk, and life expectancy.

intensive glucose control leads to significant re-ductions in complications.8 From numerous studies, it is known that the lower the a1C the better, as long as it is achieved safely. standard therapy is to begin therapy with lifestyle changes and metformin.7,9 to

summaryType 2 diabetes, and resulting cardiovascular disease, continues to be an epidemic problem in the u.s. To fight this epidemic, prevention and treatment needs to be focused on all risk factors present in patients. The newer agents that target the incretin system have a role in managing glucose without significant adverse effects.

Key points• The obesity epidemic contributes to the diabetes and cardiovascular disease epidemics. • Providers need to utilize lifestyle modification for prevention and treatment and institute intensive treatment for glycemic control. • Patients need comprehensive care of all risk factors, with combination medications, to reduce CVd and other complications of diabetes.• incretin-based therapies target multiple defects of type 2 diabetes, including those not addressed by traditional medications without causing hypoglycemia while producing favorable effects on weight.

Improving Outcomes with Novel Treatment Strategies in the Management of Type 2 Diabetes

yehuda handelsman Md, faCP, faCe, fNla for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


achieve glycemic control, most patients will require combination therapy.

the american Diabetes association (aDa) pub-lished a treatment algorithm in 2008 that empha-sized the addition of insulin or sulfonylureas to met-formin if the patient was not at goal.9 there were several issues with this approach. primary was that it assumed all diabetes patients are the same. this type of approach ignored the risk of hypoglycemia, pos-sible risks of blood glucose fluctuation independent of a1C, and did not consider the impact of medi-cation choices on other complications of diabetes. thus, there were limited medication choices that might not apply to all patients. this algorithm also did not provide an alternative if metformin was con-traindicated and disregarded clinicians’ knowledge and preference.

in response to issues with the aDa algorithm, the aaCe developed its own algorithm.10 the princi-ples of this management algorithm were to mini-mize the risk of hypoglycemia, minimize the risk of weight gain and other drug-related adverse events, and to individualize the management plan by con-sidering both fasting and postprandial glucose levels and total cost of therapy, not just the acquisition cost of the drug. this algorithm includes all major classes of FDa approved glycemic medications and suggests therapy stratified by a1C level and lowering poten-tial of various medications.

the aaCe algorithm is stratified by a1C level.10

For a patient with an a1C level less than or equal to 7.5%, monotherapy should be started to achieve a goal a1C of 6.5%. if monotherapy fails, therapy can be increased to dual and then triple therapy. Finally,

insulin therapy should be initiated, with or without additional agents. For a patient with an a1C range of 7.6% to 9.0%, dual therapy should be started ini-tially because no single agent is likely to achieve the goal of 6.5%. if dual therapy fails, therapy should progress to three agents and then to insulin thera-py, with or without additional orally administered agents. For a patient with an a1C level greater than 9.0% who is asymptomatic, triple therapy is recom-mended. if, however, the patient is symptomatic, or therapy with similar medications has failed, it is ap-propriate to initiate insulin therapy, either with or without additional orally administered agents. the algorithm is available at the aaCe website www.aace.org.

since the publication of the aaCe algorithm, the aDa has published an updated approach that is similar but still puts metformin as first line.11 For pa-tients who metformin is contraindicated, clinicians have to go outside of this algorithm.

the shifting paradigm in diabetes management is incorporating the new incretin-based therapies into the diabetes treatment algorithm. hormones such as glucagon-like peptide (Glp-1) are secreted in the intestines after meals to prompt the release of insulin from the pancreas. patients with type 2 dia-betes have a blunted Glp-1 secretion in response to ingested foods and thus have elevated postprandial glucoses.

Glp-1 can be enhanced by giving an injectable Glp-1 agonist (exenatide [byetta®] or liraglutide [victoza®]) or an oral dipeptidyl peptidase 4 (Dpp-4) inhibitor (sitagliptin [ Januvia], saxagliptin [ong-lyza], and linagliptin [trajenta]) that prolongs the

exhibit 1: Metabolic-insulin resistance syndrome1

hypertension stroke

atherosclerosis PVd

high Tg Cadlow hdl

impaired glucose tolerance diabetes

factors Contributingto insulin resistance

sedentary lifestylelow physical activity

increased age

Central obesity

genetic factorsfamily history

Population groupsinsulin

resistance

hemostaticabnormalities

Vascularinflamation

abnormal vascularsMC, medical andendothelial function

abnormal ffa,Vldl and hdlmetabolism+ visceral fatdeposition

impairedhomeostasis

Metabolic and Vascular abnormalities

Clinical consequences


action of naturally secreted Glp-1. these agents can be used as monotherapy or in combination with metformin or insulin. unlike most other therapies for lowering glucose, patients can lose a modest amount of weight when started on a Glp-1 agonist. the Dpp-4 inhibitors appear to be weight neutral. hypoglycemia does not typically occur when the incretin agents are used as monotherapy because these are glucose-dependent agents. hypoglycemia can occur when used in combination with other agents that cause hypoglycemia.

in comparing the efficacy of the incretin agents, the long-acting formulations of Glp-1 agonists lower a1C more than the short-acting Glp-1 ago-nists and the Dpp-4 inhibitors. liraglutide, seem-ingly, has better weight loss properties and it results in greater a1C reduction than other Glp-1 ago-nists. long-acting exenatide has fewer adverse ef-fects than the other Glp-1 agonists. in general, the

Dpp-4 inhibitors cause fewer adverse effects than Glp-1-based therapy. the Glp-1 agonists are at least as efficacious as insulin in lowering a1C with no hypoglycemia and weight loss compared with the significant adverse effects that are possible with insulin therapy.

beyond glycemic control, management of diabe-tes requires targeting weight with lifestyle changes, exercise, and possibly obesity medication or surgery. Weight loss has been shown result in a 22 percent relative risk reduction of all-cause death and 24 per-cent decrease in death from CvD and diabetes.12 Weight loss will decrease glucose, a1C, low-density lipoprotein cholesterol (lDl-C), and triglycerides. it will also increase high-density lipoprotein choles-terol (hDl-C) levels.

Weight loss is not usually sufficient to achieve target lipid values. lDl-C is the primary target for therapy. aggressive lowering of lDl-C in patients

exhibit 2: We are far from achieving basic goals in patients with type 2 diabetes5

12.2

NhaNes 1999-2002 2003-2006

Patie

nts a

chie

ving

goa

l (%

)60

50

40

30

20

10

0 a1C <7.0% BP <130/80mm hg ldl-C <100 mg/dl achieved all 3 goals

43.1

57.1

39.245.5

36.1

46.5

7.0

exhibit 3: aace 2011 diagnosis of diabetes and pre dM7

NOrMal ifg or igT high risk for dM

diaBeTes

fPg < 100 mg/dl ifg fPg > 100 - 125mg/dl

fPg > 126 mg/dl

2-h Pg < 140 mg/dl igT 2-h Pg > 140 - 199 mg/dl

2-h Pg > 200 mgrandom Pg > 200 +symptoms

a1C 505% to 6.4% for screening*

> 6.5%secondary**

* requires testing fg or gTT ** Confirm with glucose when possible


with diabetes will reduce risk of CvD.13,14 statins are the treatment of choice in the absence of con-traindications. Combinations of statins with bile acid sequestrants, niacin, fibrates and/or cholesterol absorption inhibitors should be considered in situa-tions of inadequate goal attainment. the other lip-id-lowering agents may be used instead of statins in cases of statin-related adverse events or intolerance. non-hDl cholesterol is a secondary goal.

it is well known that intensive blood pressure low-ering reduces the risk of micro- and macrovascular complications of diabetes.15,16 therapeutic recom-mendations for hypertension should include lifestyle modification with the Dietary approaches to stop hypertension (Dash) diet, reduced salt intake and physical activity. patients should have consultation with a dietician or certified diabetes educator to implement these modifications. the evidence-based medications for lowering blood pressure in patients with diabetes are angiotensin converting enzyme inhibitors (aCe-i) and angiotensin receptor block-ers (arb) with subsequent addition of other agents as needed for control. thiazide diuretics and beta

blocker use should be limited because of their po-tentially adverse effect on glucose.

antiplatelet therapy should also be considered in all patients with diabetes. For primary prevention of CvD, aspirin use may be considered for high-risk patients (10 year risk > 10 percent). the use of low-dose (75 mg to 162 mg daily) aspirin is recom-mended for secondary prevention of CvD. in face of asa resistance, other antiplatelet agents may be considered.

overall, lifestyle modifications are essential for all patients with diabetes. achieving an a1C of 6.5% is the primary goal, but this goal must be cus-tomized for each individual patient. When com-bination therapy is prescribed, medications with complementary mechanisms should be used. the effectiveness of therapy needs to be evaluated fre-quently. safety and efficacy should be given higher priorities than the cost of medications. intensive control of any of the CvD risk factors has to be tempered with patient safety. if patients can reach target goals without significant adverse effects, that is an important goal.

exhibit 4: aace treatment goals7

Parameter Treatment goal for Non-Pregnant adults

glucose

a1C (%) individualize based on co-morbidities, duration of disease, hypogly-cemia risk, life expectancy < 6.5% for most, if can be done safely< 6% (5%) as close to normal for new, young relatively healthy; provided safely > 7% less stingent for “less healthy” - multiple comorbidities, labile, short life expectancy

fPg (mg/dl) < 110 mg/dl

2-hour PPg (mg/dl) < 140 mg/dl

inpatient hyperglycemia 140-180 mg/dl

lipids (mg/dl)

ldl-C < 70 highest risk; < 100 high risk

non-hdl-C < 100 highest risk; < 130 high risk

hdl-C > 40 in men; 50 in women

Triglycerides < 150

blood pressure (mm hg)

systolic < 130

diastolic < 80

anticoagulant therapy

aspirin for secondary CVd prevention or primary prevention for very high risk patients


conclusionthe obesity epidemic contributes to the diabetes and CvD epidemics. to begin to manage the dia-betes epidemic, providers need to target multiple conditions to reduce risk. it requires utilizing life-style modification for prevention and treatment and instituting intensive treatment for glycemic, lipid, and blood pressure control. incretin-based therapies target multiple defects of type 2 diabetes, including those not addressed by traditional medications with-out causing hypoglycemia, while producing favor-able effects on weight. patients need comprehensive care of all risk factors, with combination medica-tions, to reduce CvD and other complications of diabetes.

Yehuda handelsman, Md, facp, face, fnla is Medical director and Principal investigator at the Metabolic institute of america in Tarzana, Ca.

references1. Kendall Dm, harmel ap. the metabolic syndrome, type 2 diabetes, and

cardiovascular disease: understanding the role of insulin resistance. Am J Manag

Care. 2002;8(20 suppl):s635-53.

2. Garber aJ, handelsman y, einhorn D, et al. Diagnosis and management of

prediabetes in the continuum of hyperglycemia: when do the risks of diabetes

begin? a consensus statement from the american College of endocrinology and

the american association of Clinical endocrinologists. Endocr Pract.

2008;14(7):933-46.

3. Centers for Disease Control and prevention. 2011 national Diabetes Fact sheet:

Diagnosed and undiagnosed diabetes in the united states, all ages, 2010. atlanta.

4. hoerger tJ, segel Je, Gregg eW, saaddine Jb.is glycemic control improving

in u.s. adults? Diabetes Care. 2008;31(1):81-6.

5. Cheung bm, ong Kl, Cherny ss, et al. Diabetes prevalence and therapeutic

target achievement in the united states, 1999 to 2006. Am J Med.

2009;122(5):443-53.

6. iDF Diabetes atlas 4th ed. international Diabetes Federation, 2009.

7. american association of Clinical endocrinologists board of Directors;

american College of endocrinologists board of trustees. american association

of Clinical endocrinologists/american College of endocrinology statement on

the use of hemoglobin a1c for the diagnosis of diabetes. Endocr Pract.

2010;16(2):155-6.

8. ray KK, seshasai sr, Wijesuriya s, et al. effect of intensive control of

glucose on cardiovascular outcomes and death in patients with diabetes melli-

tus: a meta-analysis of randomised controlled trials. Lancet.

2009;373(9677):1765-72.

9. american Diabetes association. standards of medical Care in Diabe-

tes—2008. Diabetes Care. 2008;31(s1):s12-s54.

10. rodbard h, Jellinger p, Davidson Ja, et al. statement by an american as-

sociation of Clinical endocrinologists/american College of endocrinology

consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.

Endocrine Practice. 2009;15(6):540-559.

11. american Diabetes association. standards of medical Care in Diabe-

tes—2013. Diabetes Care. 2013;36(s1):s11-s66.

12. Williamson DF, thompson tJ, thun m, et al. intentional weight loss and

mortality among overweight individuals with diabetes. Diabetes Care.

2000;23(10):1499-504.

13. shepherd J, barter p, Carmena r, et al. effect of lowering lDl cholesterol

substantially below currently recommended levels in patients with coronary

heart disease and diabetes: the treating to new targets (tnt) study. Diabetes

Care. 2006;29(6):1220-6.

14. Colhoun hm, betteridge DJ, Durrington pn, et al. primary prevention of

cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative

atorvastatin Diabetes study (CarDs): multicentre randomised placebo-con-

trolled trial. Lancet. 2004;364(9435):685-96.

15. uKpDs Group. tight blood pressure control and risk of macrovascular and

microvascular complications in type 2 diabetes: uKpDs 38. uK prospective

Diabetes study Group. BMJ. 1998;317(7160):703-13.

16. aCCorD study Group, Cushman WC, evans GW, et al. effects of inten-

sive blood-pressure control in type 2 diabetes mellitus. N Engl J Med.

2010;362(17):1575-85.

Clearly the right choice for your formulary

VASCEPA® is an optimal TG-lowering agent for your formulary and your members with severe hypertriglyceridemia. VASCEPA® is the first FDA-approved, EPA-only omega-3-fatty acid that significantly lowers median placebo-adjusted TG levels by 33% without increasing LDL-C or HbA1c compared to placebo while also positively affecting a broad spectrum of lipid parameters.1

Consider VASCEPA® an affordable option for your members with severe hypertriglyceridemia (TG levels ≥ 500 mg/dL).

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

For the treatment of severe hypertriglyceridemia (TG levels ≥ 500 mg/dL)

Reference: 1. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, placebo-controlled, randomized, double blind, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol. 2011;108:682-690.

For more information on VASCEPA® see the brief summary or for the Full Prescribing Information please visit www.VASCEPA.com.

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®

Amarin Pharma Inc. Bedminster, NJ 07921 www.AmarinCorp.com © 2012 Amarin Pharmaceuticals Ireland Limited. All rights reserved. 130033 1/2013 Reprint Code: XXXXXX

1 INDICATIONS AND USAGEVASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving VASCEPA and should continue this diet and exercise regimen with VASCEPA.Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy.Limitations of Use: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.2 DOSAGE AND ADMINISTRATIONAssess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. [see Indications and Usage (1)].Patients should engage in appropriate nutritional intake and physical activity before receiving VASCEPA, which should continue during treatment with VASCEPA. The daily dose of VASCEPA is 4 grams per day taken as 2 capsules twice daily with food.Patients should be advised to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA.4 CONTRAINDICATIONSVASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.5 WARNINGS AND PRECAUTIONS5.1 Monitoring: Laboratory TestsIn patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA.5.2 Fish AllergyVASCEPA contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to VASCEPA. VASCEPA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause 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. Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with VASCEPA based on pooled data across two clinical studies are listed in Table 1.Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in Double-Blind, Placebo-Controlled Trials*

Adverse Reaction

Placebo(N=309)

VASCEPA(N=622)

n % n %Arthralgia 3 1.0 14 2.3

*Studies included patients with triglycerides values of 200 to 2000 mg/dL.An additional adverse reaction from clinical studies was oropharyngeal pain.

7 DRUG INTERACTIONS7.1 Anticoagulants Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether VASCEPA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. VASCEPA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13th reduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times

human systemic exposure following an oral dose of 4 g/day based on body surface area comparison.In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species.In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss).In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species. 8.3 Nursing MothersStudies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion is unknown; caution should be exercised when VASCEPA is administered to a nursing mother. In lactating rats, given oral gavage 14C-ethyl EPA, drug levels were 6 to 14 times higher in milk than in plasma.8.4 Pediatric UseSafety and effectiveness in pediatric patients have not been established.8.5 Geriatric UseOf the total number of subjects in clinical studies of VASCEPA, 33% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.9 DRUG ABUSE AND DEPENDENCEVASCEPA does not have any known drug abuse or withdrawal effects.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityIn a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation.In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).17 PATIENT COUNSELING INFORMATION17.1 Information for PatientsSee VASCEPA Full Package Insert for Patient Counseling Information.

Distributed by: Amarin Pharma Inc. Bedminster, NJ, USAManufactured by: Banner Pharmacaps, Tilburg, The Netherlands orCatalent Pharma Solutions, LLC, St. Petersburg, FL, USAManufactured for: Amarin Pharmaceuticals Ireland Limited, Dublin, Ireland

VASCEPA® (icosapent ethyl) Capsules, for oral useBrief summary of Prescribing InformationPlease see Full Prescribing Information for additional information about Vascepa.

Amarin Pharma Inc. Bedminster, NJ 07921 www.VASCEPA.com© 2012 Amarin Pharmaceuticals Ireland Limited.All rights reserved.12/2012 120707


breast CanCer is the most Com-mon solid tumor in women. there are an esti-mated 225,000 cases each year.1 there has been a slow, steady growth of breast cancer incidence that is probably related to population growth and aging.

importantly, breast cancer deaths have been de-clining steadily since the early 1990s. better treat-ment and early diagnosis are possible reasons for this decline. there are approximately 40,000 deaths an-nually from this disease.

breast cancer is interesting among solid tumors because it is typically diagnosed in its early stages. approximately 95 percent of women are diagnosed with potentially curable breast cancer. Currently, about three out of four are cured. unfortunately, about one in four women (~30,000 annually) who are treated for breast cancer will have metastatic recurrence and are no longer curable. every year about 10,000 women present with already meta-static disease.

Generally, metastatic breast cancer is a universally fatal disease with an overall median survival of 30 months. over the past 10 years, median survival has significantly increased. there is a wide spectrum of natural behavior based on tumor biology, including hormone sensitivity or human epidermal growth factor receptor 2 (her-2) status. hormone sensi-tive tumors tend to be less aggressive, while her-2 positive tumors are typically more aggressive. many effective therapies are available with variable effica-cy and toxicity. thus, decision making in advanced breast cancer is complicated.

the treatment goals in metastatic breast cancer are to prolong survival and decrease burden of disease. most patients will be on therapy for the majority of their expected survival. there are decisions to be made on which therapy to select and what to do when that therapy, inevitability, is no longer effec-tive. the risks and benefits of palliative therapy must be weighed. treatment is selected based on prob-

summaryThe treatment of metastatic breast cancer continues to evolve with better un-derstanding of the underlying biology and genetics and newer medications. al-though not yet curable, progress is being made with increases in overall median survival. several new medications are changing the treatment paradigm for ad-vanced disease.

Key points• Metastatic breast cancer is not curable.• Treatment is chosen based on tumor biology.• in premenopausal and postmenopausal patients with estrogen receptor positive disease, sequential endocrine agents are used until no longer effective.• everolimus is a new option in the postmenopausal, estrogen receptor positive patients.• ado-trastuzumab emtansine is a new option for her-2 positive disease.

Individualizing Treatment Strategies in the Management of Metastatic Breast Cancer

Michael Naughton, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm,

click on Oncology and then on Metastatic Breast Cancer 2012


ability of tumor response, probability of symptom-atic improvement, anticipated toxicity, and patient goals. patient goals will vary from “to get better” to “to live to see” a particular event. the reality is that patients cannot beat metastatic breast cancer so the individual has to understand this and have realistic goals. in general, the least toxic therapy to achieve disease control is selected.

because it is known that breast cancer is not one disease, therapy is selected based on tumor biology – hormone receptor-positive, her-2 positive, or tri-ple negative (exhibit 1). there are her-2 positive and estrogen receptor (er) positive specific thera-pies. approximately 20 percent of breast cancers are negative for er, progesterone receptor (pr), and her-2 markers. at this time, there are no specific therapies for triple negative disease. in the near fu-

ture, the group of patients with triple negative dis-ease will likely be further divided based on yet to be discovered tumor biology.

er positive tumors have er and/or pr receptors. this disease tends to have a more indolent course and is often bone predominant. it is more com-mon in postmenopausal patients and often responds to endocrine therapies. therapy is aimed at reduc-ing levels of estrogen in the body and will depend on whether the woman is premenopausal or post-menopausal (exhibit 2). in premenopausal women, ovarian production of estrogen can be shut off with surgical removal, radiation or hormonal therapy with gonadotropin releasing hormone (Gnrh) agonists. these put a woman into menopause. an-other avenue for blocking estrogen is the use of se-lective estrogen receptor modulators (serms) such

exhibit 1: Metastatic setting

er, estrogen receptor; Pr, progesterone receptor; Oa, ovarian ablation; ai, aromatase inhibitors

her2 ÷ disease

er or Pr + er or Pr -

Metastatic Breast Cancer diagnosed

Chemotherapy

Chemotherapy

No Visceral Crisis Visceral Crisis

aiTamoxifen+Oa

Pre-menopausal Post-menopausal

exhibit 2: hormone therapy

• Pre-menopausal – Ovarian ablation • surgery • radiation • hormonal - gNrh

– selective estrogen receptor Modulator (serM) • Tamoxifen • Toremifene

•Post-menopausal – serM • Tamoxifen • Toremifene – aromatase inhibitors (ai) • letrozole • anasrozole • exemestane – estrogen • estradiol – anti-estrogen • fulvestrant


as tamoxifen and toremifene (Fareston®). once a woman is made menopausal, she can be treated as postmenopausal.

postmenopausal women still have some estrogen because the adrenal glands make androgens that are converted to estrogen by aromatase. aromatase in-hibitors block this conversion. serms also work in postmenopausal women to block estrogen receptors.

in the metastatic setting, any agent the patient is treated with will eventually stop working. the pa-tient will then be switched to a second-line agent. second-line and subsequent agents produce fairly low response rates.

because women eventually run out of therapeutic options, novel agents are being investigated to man-age hormone responsive metastatic breast cancer. one novel agent that has been approved for treating metastatic disease is everolimus, an mtor (mam-malian target of rapamycin) inhibitor. mtor is a downstream signal for cancer cell growth and sur-vival. research has indicated that aberrant signaling through the mtor pathway is associated with re-sistance to endocrine therapies. everolimus has been studied in combination with estrogen blockage. the primary trial of this agent was in postmenopausal women with er positive tumors who had pro-gressed on an aromatase inhibitor. the combination of everolimus with exemestane led to an improve-ment in median progression-free survival (pFs, 7.4 months vs. 3.2 months). Fifty percent of patients did have some clinical benefit (no cancer growth) from the combination (exhibit 3).2 Compared with mov-ing on to chemotherapy, everolimus is a better toler-ated therapy. the addition of this agent has opened up a whole new area of treating the metastatic post-menopausal population.

her-2 positivity occurs in about 20 percent of

breast cancers. With the development of targeted therapies, median survival in these patients is now about four years. For patients with her-2 posi-tive disease, targeted therapy will be added to either hormone therapy or chemotherapy (depending on hormone receptor status). there are four currently available agents - trastuzumab (herceptin®), lapa-tinib (tykerb®), pertuzumab (perjeta®), and ado-trastuzumab emtansine (Kadcyla®, formerly known as tDm-1). trastuzumab prolongs survival when added to chemotherapy compared to chemotherapy alone in the her-2 positive first-line setting (25.1 months vs. 20.3 months).3 this agent has changed the natural history of this disease by truly improv-ing survival.

there are data supporting targeting the her-2 mechanism throughout the disease course. the tu-mor cells remain dependent on her-2, and this has been called her-2 addiction. her-2 resistance does occur in some patients, but the mechanism is not yet known.

the her-2 receptor has both an extracellular and intracellular site. trastuzumab blocks the extracel-lular site and lapatinib the intracellular (exhibit 4). by targeting both the extra and intracellular sites, efficacy is improved.

pertuzumab is a new agent that has a complemen-tary mechanism to trastuzumab. it interacts with a different part of the her-2 protein and prevents it from binding to another her protein (her-3). adding pertuzumab to trastuzumab and chemo-therapy prolongs pFs by about five months.4 median survival is almost 3.5 years with triple therapy.

the newest agent, approved by the FDa in 2013, is ado-trastuzumab emtansine. this is a combina-tion molecule of trastuzumab and a chemotherapy agent (emtansine) that delivers the chemotherapy

exhibit 3: bolero-2 (12 mo f/up): response and clinical benefit2

P <0.0001Pe

rcen

t

60

50

40

30

20

10

0response Clinical Benefit

everolimus + exemestanePlacebo + exemestane

12.0%

1.3%

P <0.0001

50.5%

25.5%


into the tumor cell thus minimizing damage to nor-mal cells. emtansine is an old agent that was never marketed because it was too toxic. ado-trastuzum-ab emtansine is indicated, as a single agent, for the treatment of patients with her-2 positive, meta-static breast cancer who previously received trastu-zumab and a taxane, separately or in combination. patients should have either received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy. this agent does appear to be improving pFs and os in the trials published so far.

triple negative disease does not have any clear therapeutic targets. there are many different che-motherapy options which are used as long as efficacy continues without excessive toxicity. patients can be given sequential single agents for lower toxicity or combination therapy with higher toxicity but high-er response rates. Combination therapy has not been shown to improve survival but is appropriate to use when a patient has a high disease burden.

conclusionas the understanding of the underlying biology of breast cancer has improved, so has therapy im-proved. agents are now selected based on the recep-tors found on the tumor. For patients with metastat-ic breast cancer who are estrogen receptor-positive, treatment will be sequential endocrine therapy pos-sibility with the addition of everolimus. there are several agents available now that target her-2 posi-tive tumors and these remain effective throughout multiple lines of therapy because of the tumor’s con-tinued reliance on the her-2 pathway. the next

advance in therapy will hopefully be the unraveling of targets for therapy in triple negative disease.

Michael naughton, Md is assistant Professor of Medicine, division of Oncology, at the Washington university school of Medicine in st. louis, MO.

references1. siegel r, naishadham D, Jemal a. Cancer statistics, 2012. CA Cancer J Clin.

2012;62(1):10-29.

2. beaver Ja, park bh. the bolero-2 trial: the addition of everolimus to

exemestane in the treatment of postmenopausal hormone receptor-positive ad-

vanced breast cancer. Future Oncol. 2012;8(6):651-7.

3. slamon DJ, leyland-Jones b, shak s. use of chemotherapy plus a monoclonal

antibody against her2 for metastatic breast cancer that overexpresses her2.

N Engl J Med. 2001;344(11):783-92.

4. swain sm, Kim sb, Cortés J, et al. pertuzumab, trastuzumab, and docetaxel

for her2-positive metastatic breast cancer (Cleopatra study): overall sur-

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

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

exhibit 4: dual targeting of her-2 receptor May have enhanced efficacy

Cell proliferationCell survival

Trastuzumab

lapatinib

downstream signaling pathways


the manaGement oF metastatiC Colo-rectal cancer (mCrC) has improved significantly since the late 1990s. until 1996, 5-fluorouracil (5-Fu) modulated by leucovorin was the only therapy available for the treatment of mCrC. since then, eight new agents have become available, adding to the armamentarium of therapies. overall survival has doubled with the newer agents compared to 5-Fu alone. there is now a 19- to 24-month medi-an survival in modern trials. response rates in large trials of the new agents are as high as 60 percent. improvements in the understanding of the genetics of this disease have also led to advances in targeted therapy.

irinotecan (Camptosar®), a topoisomerase i in-hibitor, was approved initially as a second-line treat-ment for patients with mCrC in 1996. in 2002, capecitabine (Xeloda®), an oral fluoropyrimidine prodrug converted into 5-Fu by thymidine phos-phorylase, was the first oral agent approved for the treatment of mCrC. oxaliplatin (eloxatin®), a

third-generation platinum analog that induces Dna crosslinks and results in apoptosis, was initially ap-proved for use in the united states in 2001 and is currently approved in both the first- and second-line settings.

the discovery of two key regulators of tumor cell growth, survival, metastasis, and angiogenesis, epidermal growth factor receptor (eGFr) and vas-cular endothelial growth factor (veGF), has led to the development of targeted biologic therapies for colorectal cancer. Cetuximab (erbitux®), a chimeric antibody to eGFr, and panitumumab (vectibix®), a recombinant human monoclonal antibody that binds to eGFr, are approved for the second-line treat-ment of mCrC in patients who overexpress eGFr. bevacizumab (avastin®), a humanized monoclonal antibody to the veGF was approved in February 2004 for the first-line treatment of mCrC.

in 2012, two additional agents were approved -- ziv-aflibercept (Zaltrap®) and regorafenib (stivar-ga®). Ziv-aflibercept is a recombinant fusion protein

summaryMetastatic colorectal cancer (MCrC) management has improved significantly in the past decade. several medications have been approved since the late 1990s, result-ing in significant improvements in overall survival. Therapy continues to evolve with the discovery of various genetic differences which predict response to individual targeted agents.

Key points• Metastatic colorectal cancer is still considered not curable.• Therapies approved in recent years have significantly improved median survival.• Biologics target key regulators of tumor cell growth, survival, metastasis, and angiogenesis.• The presence of genetic mutations, including Kras and Braf mutations, can be used to guide biologic agent selection.• improved health outcomes can be achieved by using genetic mutation testing to avoid ineffective chemotherapy and potential side effects and expedite access to the most effective treatment.

Metastatic Colorectal Cancer: Updates in Treatment Strategies and What’s in the Works

Tanios Bekaii-saab, Md for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.


consisting of veGF-binding portions from the ex-tracellular domains of human veGF and receptors 1 and 2 fused to the Fc portion of the human igG1. it is approved in combination with 5-fluorouracil, leucovorin, and irinotecan (FolFiri) for patients with mCrC that is resistant to or has progressed following an oxaliplatin containing regimen. the place of ziv-aflibercept in the treatment continuum is yet to be determined.

regorafenib is a new oral multikinase inhibitor targeting multiple tumor pathways (exhibit 1).1-3 its role, at this point, appears to be in refractory disease. studies are ongoing to identify markers that will predict which patients will respond best to this agent. additionally, there are studies ongoing to identify which medications it should be com-bined with.

Certain genetic mutations have been identified in colorectal cancer. one of these is in the Kras (v-Ki-ras2 Kirsten rat sarcoma viral oncogene ho-molog) gene. the protein product of the normal Kras gene performs an essential function in nor-mal tissue signaling, and the mutation of a Kras gene is an essential step in the development of many cancers. Kras mutation is predictive of a very poor response to anti-eGFr therapy (panitumumab and cetuximab). For the 40 percent of patients with colorectal cancer who are Kras mutation positive, chemotherapy plus a veGF inhibitor (bevacizumab) is the recommended treatment option. For the 60 percent who are not Kras mutation positive, there are multiple chemotherapy options. because studies have shown that anti-eGFr agents, especially when combined with bevacizumab, result in worse out-comes in patients with Kras mutations, patients

should be tested for Kras mutations before treat-ment.4-6

Kras mutation testing only has to be done once because the mutations are stable. the mutations do not change over time nor are primary tumors and metastases genetically different. they can actually be identified in pre-malignant tissues.

there has been some controversy as to whether all Kras mutations are equal in terms of progno-sis. two mutations are typically reported on testing – G13D and G12D. some data in a small number of patients have suggested that patients with G13D mutation may still respond to eGFr therapy with cetuximab.7 pooled analysis of panitumumab stud-ies showed no difference between codon 13 and co-don 12 Kras mutation response.8 based on cur-rent evidence, any patient with Kras mutations is unlikely to receive significant benefit from cetux-imab or panitumumab and has a very poor prog-nosis. they should not receive eGFr inhibitors. in patients without Kras mutation, bevacizumab or eGFr antibodies can be added to chemotherapy in first-line therapy.

braF is another possible marker of therapy re-sponse. braF is a primary effector of Kras sig-naling. braF mutations occur most frequently in exon 15 (v600e) and are found in approximately 10 percent of patients with colorectal cancer. this mutation is mutually exclusive with Kras muta-tions.9 the addition of cetuximab to chemotherapy regimens in patients with braF mutations has been shown to be beneficial in improving median pro-gression-free survival and overall survival.10

the findings from recent studies are allowing cli-nicians to better tailor therapy. For example, dual

exhibit 1: regorafenib targets Multiple tumor pathways1-3

VegfTie2

regorafenib

inhibition ofproliferation

inhibition of tumormicroenvironment

signaling

inhibition ofneoangiogenesis

KiTPdgfr

reT

Pdgfr-ßfgfr


eGFr and veGF inhibition does not improve outcome and may result in significant medication toxicity. the Coin and norDiC trials showed that oxaliplatin-based regimens should not be used in combination with cetuximab because of poorer outcomes.11,12

because mCrC is not curable, the treatment goal is palliation. although time to progression and sur-vival might be impacted, quality of life needs to be considered. sequential use of all active agents in ra-tional combination regimens does prolong survival. most patients tolerate a chemotherapy doublet, but not all need it. Data from europe suggest therapy can start with a single agent and then escalate to two agents when progression occurs. the addition of targeted therapy with biologics to chemothera-py has improved outcomes, but not as much as was hoped. both classes of targeted agents (anti-eGFr and anti-veGF) can be used here in principle as first line therapy. individualized therapy based on mo-lecular predictive factors will be the next evolution in therapy.

once patients progress on first-line therapy, they will move on to second-line therapy. this will typi-cally be agents they have not been exposed to previ-ously. anti-eGFr agents maintain efficacy in later lines of therapy. third-line studies with single agent cetuximab and panitumumab show improvement of outcomes, but bevacizumab is favored in the pallia-tive setting because of its favorable toxicity profile.

bevacizumab can be continued beyond progres-sion. if the patient progressed quickly (i.e., in less than three months), the bevacizumab should be dis-continued. if they progressed later, it can be contin-

ued. When continued, there is a modest improve-ment in overall survival (1.4 months).

because the agents used to treat mCrC cause sig-nificant toxicity, the prevention and management of adverse effects is vital to successful therapy and to maintaining quality of life. For chemotherapy, this can include appropriate antiemetics, antidiar-rheals, and dose adjustments. For example, several trials have demonstrated that scheduled oxaliplatin interruptions decrease neurotoxicity without im-pacting efficacy.

the biologic agents have different adverse ef-fect profiles than chemotherapy. the main toxici-ties for bevacizumab include hypertension and, less commonly, thromboembolic events, primarily in elderly patients with risk factors, and Gi perfora-tions. the main toxicities of the eGFr inhibitors include rash, diarrhea, hypomagnesemia and hy-persensitivity reactions.

skin toxicities, such as papulopustular rash, have been reported to occur in greater than 80 percent of patients who receive panitumumab or cetuximab. as shown in the skin toxicity evaluation proto-col with panitumumab (stepp) trial, doxycycline or minocycline started a day before a patient starts these agents and continued for six weeks signifi-cantly decreases the incidence of rash and does not compromise efficacy (exhibit 2).13 although not everyone develops rash, pre-emptive therapy will allow patients to continue with therapy so it may impact survival. rash is associated with survival in population analyses, but a grade 2 or 3 rash does not mean “the drug is working”, and vice versa, for an individual patient.

exhibit 2: stepp results13

Prob

abili

ty (%

)

100908070605040302010

0 2 4 6 8Time to first Occurrence of skin Toxicity (weeks)

eventsn (%)

Median (95% Cl)Weeks

Pre-emptive 14 (29) Nrreactive 29 (62) 2.1 (2.1 to 6.3)

Pre-emptive n 48 44 36 27 0Censored 0 1 1 5 27

reactive n 47 36 18 16 0Censored 0 2 1 0 15


conclusionin mCrC, it is important to remember that the goal of therapy is not cure but is palliation. For most pa-tients, the gain of time and maintaining quality of life are more important than response rates. the ad-dition of newer agents to the therapeutic options has increased median survival. the role of genetic test-ing and biologics in managing this disease continues to evolve.

tanios bekaii-saab, Md is section Chief, gastrointestinal Oncology Program and associate Professor of Medicine and Pharmacology at The Ohio state university – James Cancer hospital.

references1. Wilhelm sm, Dumas J, adnane l, et al. regorafenib (bay 73-4506): a new

oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyro-

sine kinases with potent preclinical antitumor activity. Int J Cancer.

2011;129(1):245-55.

2. mross K, Frost a, steinbild s, et al. a phase i dose-escalation study of rego-

rafenib (bay 73-4506), an inhibitor of oncogenic, angiogenic, and stromal

kinases, in patients with advanced solid tumors. Clin Cancer Res.

2012;18(9):2658-67

3. strumberg D, schultheis b. regorafenib for cancer. Expert Opin Investig

Drugs. 2012;21(6):879-89.

4. tol J, Koopman m, Cats a, et al. Chemotherapy, bevacizumab, and cetux-

imab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-72.

5. hecht Jr, mitchell e, Chidiac t, et al. a randomized phase iiib trial of

chemotherapy, bevacizumab, and panitumumab compared with chemotherapy

and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol.

2009;27(5):672-80.

6. bokemeyer C, bondarenko i, makhson a, et al. Fluorouracil, leucovorin,

and oxaliplatin with and without cetuximab in the first-line treatment of meta-

static colorectal cancer. J Clin Oncol. 2009;27(5):663-71.

7. tejpar s. biomarkers to predict response to anti-eGFr antibodies. Clin Adv

Hematol Oncol. 2011;9(6):486-7.

8. evaluation of Genomic applications in practice and prevention (eGapp)

Working Group, Calonge n, Fisher nl, et al. recommendations from the

eGapp Working Group: can testing of tumor tissue for mutations in eGFr

pathway downstream effector genes in patients with metastatic colorectal cancer

improve health outcomes by guiding decisions regarding anti-eGFr therapy?

Genet Med. 2013 Feb 21. [epub ahead of print]

9. Di nicolantonio F, martini m, molinari F, et al. Wild-type braF is re-

quired for response to panitumumab or cetuximab in metastatic colorectal can-

cer. J Clin Oncol. 2008;26(35):5705-12.

10. van Cutsem e, Köhne Ch, láng i, et al. Cetuximab plus irinotecan, fluo-

rouracil, and leucovorin as first-line treatment for metastatic colorectal cancer:

updated analysis of overall survival according to tumor Kras and braF mu-

tation status. J Clin Oncol. 2011;29(15):2011-9.

11. maughan ts, adams ra, smith CG, et al. addition of cetuximab to oxali-

platin-based first-line combination chemotherapy for treatment of advanced

colorectal cancer: results of the randomised phase 3 mrC Coin trial. Lancet.

2011;377(9783):2103-14.

12. tveit Km, Guren t, Glimelius b, et al. phase iii trial of cetuximab with

continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (nordic

FloX) versus FloX alone in first-line treatment of metastatic colorectal can-

cer: the norDiC-vii study. J Clin Oncol. 2012;30(15):1755-62.

13. lacouture me, mitchell ep, piperdi b, et al. skin toxicity evaluation pro-

tocol with panitumumab (stepp), a phase ii, open-label, randomized trial

evaluating the impact of a pre-emptive skin treatment regimen on skin toxici-

ties and quality of life in patients with metastatic colorectal cancer. J Clin Oncol.

2010;28(8):1351-7.


sKin CanCers are the most Common human cancer. less than 2 percent of the 3.5 mil-lion cases of skin cancer are melanoma; however, 70 percent of the skin cancer deaths are from melanoma (exhibit 1).1

melanoma is one of the few cancers with an in-creasing incidence. the areas of the united states with high death rates for melanoma are the sunnier parts of the country. sun exposure is a major factor in the development of melanoma.

While most melanoma is detected early and can be surgically resected, stage iii and stage iv mela-noma carry a poor prognosis.2 unlike other cancers, melanoma can recur after many years. For many other cancers, if a patient is cancer free for five to 10 years they are considered cancer free.

one adjuvant therapy for melanoma to reduce the risk of recurrence is interferon-α. in multiple studies, interferon has been shown to reduce recur-rence rates; however, based on the available data, it is hard to say that interferon prolongs survival.3 although several studies show a survival benefit, the

benefit appears to be small (hazard ratio for death = 0.89, 95% Ci = 0.83 to 0.96; p = .002).3 there are questions how much this modest improvement in survival is worth. if the patient is less than 70 and has no liver dysfunction, interferon will probably provide some survival benefit. in older or sicker pa-tients with multiple comorbidities, it probably does not improve survival. the newest interferon agent is pegylated interferon, but survival data with this agent are similar.

prior to 2002, trials of various agents in treating metastatic melanoma did not find any major benefit. two important breakthroughs in treatment changed the landscape for metastatic disease. one came in 2002 with the discovery that a large number of melanoma tumors have a mutation in the braF gene, which makes b-raf protein. the gene is also referred to as proto-oncogene b-raf and v-raf murine sarcoma viral oncogene homolog b1. the b-raf protein is involved in sending signals inside cells, which are involved in directing cell growth. the second breakthrough was the development of

summaryThe treatment landscape for metastatic melanoma is dramatically changing with the discovery of various genetic mutations and the development of agents that target these mutations. Other significant developments include various ways to stimulate the immune system to attack the cancer. With these advancements, overall survival for this disease is increasing, but improvements still need to be made.

Key points• although a low incidence skin cancer, melanoma accounts for the majority of deaths from skin cancer.• Various genetic mutations occur in melanoma, and the body location of the disease determines the likely mutations.• Braf inhibitors may be the primary choice for Braf mutation-positive patients.• although dramatically effective in reducing disease burden, the efficacy of Braf inhibitors is of short duration.• immunotherapy does not reduce disease burden in many patients; however, in those for whom it works, the benefit can be long lasting.

Optimizing Treatment Strategies in the Management of Metastatic Melanoma

adil daud, MBBsfor a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm,

click on Oncology and then on recent advances in Melanoma Therapy


agents that target the braF mutation, specifically the v600 mutation [vemurafenib (Zelboraf®), dab-rafenib (tafinlar®)].

subsequently to the braF mutation discovery, many more mutations have been discovered and boris bastian and others have shown that the loca-tion of melanoma determines the likely mutations (exhibit 2).4-6 overactivation of the n-ras (rat sar-coma) and mapK (mitogen activation protein ki-nase) pathways are often found in many tumor types (including melanoma) and are believed to play a sig-nificant role in cancer development and progression. accordingly, inhibitors of this pathway are actively investigated. in melanoma, n-ras and b-raf ac-tivating mutations occur in about 15 to 20 percent and 60 percent of cases, respectively. remarkably, they are mutually exclusive.

the most common site for melanoma in the u.s. for men is the trunk and the legs for women. thus, the majority of these tumors have a braF muta-tion; therefore, targeting braF should be an effec-tive avenue of treatment.

the initial published trial of vemurafenib showed dramatic results, with an overall response rate of 81 percent.7 in the past, getting response rates of 10 or 20 percent was difficult. in a study of vemurafenib compared with dacarbazine, 57 percent of patients who received vemurafenib responded to therapy, whereas only 8.5 percent of dacarbazine patients re-sponded.8 the disappointing result from this trial was the overall survival data were not as impressive as the progression-free survival data. the difference in overall survival (os) was only four months. re-gardless of age or disease stage, a braF inhibitor appears to benefit all patients, but resistance will de-velop in six to nine months.

the major adverse effect of braF inhibition is squamous cell carcinoma. squamous cell carcinoma occurs in about 20 percent of patients treated with a braF inhibitor alone. the braF inhibitors are so photosensitising that patients must completely cover their skin and avoid the sun as much as possible.

the next evolution in therapy is to block more than one pathway of tumor cell growth and sur-vival to prevent the development of resistance with braF inhibition alone. there is also some thought that combining blockade therapies might prevent the development of squamous cell carcinoma.

Data from animal models show that combining braF inhibition with a meK inhibitor that is also involved in the mapK pathway improves efficacy results. a human trial, conducted of this combi-nation (vemurafenib and trametinib (mekinist®) in patients with the braF v600 mutation, found that using the combination increased progression-free survival (pFs) from 5.4 months to 9.4 months.9 the combination caused significantly fewer skin adverse effects than vemurafenib alone, including squamous cell carcinoma. the combination does result in one unusual adverse effect - cyclical fevers. the combination also worked in about 50 percent of patients who had previously failed braF inhibi-tion alone. trametinib was approved by the FDa in may of 2013.

another avenue of treatment is harnessing the immune system to attack the cancer. ipilimumab (yervoy®) is one agent that has been approved with better efficacy, easier administration, and fewer ad-verse effects than earlier therapies such as interleu-kin and interferon. ipilimumab augments t-cell ac-tivation and proliferation that essentially takes the brakes off the immune system. it blocks cytotoxic

exhibit 1: annual incidence and deaths from skin cancer in the united states1

Basal Cell

squamous

Melanoma

Merkel Cell

deaths

incidence

8,000

600

2,500

700,000

60,000

2,800,000


t-lymphocyte antigen 4 (Ctla-4), which turns “off” t- cells when they are no longer needed to fight an infection.

this agent does not have a significant effect on pFs but does have a positive benefit on os in metastatic disease. in one trial, at year one 46 percent of people treated with ipilimumab were alive, compared with 25 percent of those who did not receive it.10 simi-lar benefit was seen at two years. ipilimumab has an advantage in that although not a lot of patients respond with tumor shrinkage, if they respond, the response can last for many years. only about 5 to 10 percent of treated patients have tumor shrinkage and another 10 percent have stable disease.

ipilimumab has also been studied in combina-tion with chemotherapy to see if that would im-prove survival. in patients with previously untreated metastatic melanoma, ipilimumab plus dacarbazine was compared to dacarbazine alone. median os was 11.2 months with the combination compared with 9.1 months with chemotherapy alone.11

one of the current controversies in melanoma management is whether a young, healthy person should receive immunotherapy with the hope that the disease will disappear or should they be given a braF inhibitor, knowing that most of the time the disease will come right back but everyone responds. therefore, there are two polar opposite choices – a remotely possible long-term cure or excellent op-

portunity for tumor shrinkage in the majority of people. it would be nice to have both.

immune system t-cells can be stimulated to attack tumor cells but they can become “exhausted”. the t-cell can be reenergized to kill tumors by blocking programmed death 1 (pD-1), an inhibitory receptor expressed by t-cells. a trial published in 2012 with an anti-pD-1 antibody (bms-936558) produced a response in 28 percent of melanoma patients.12 this agent also appears to work in kidney and non-small cell lung cancer. there is some thought that it will work across the board in all types of cancer. this is an exciting development that might be able to push the response threshold higher for immunotherapy.

another area of research is blocking pD-l1 that is on lymphocytes. preliminary data suggest that blocking pD-l1 will produce response in different types of cancer.

targeting interleukin 12 (il-12) is yet another area of melanoma treatment research. il-12 is a key mediator of communication between macrophages, effector-t cells and natural killer (nK) cells. intra-tumoral gene electroporation uses electric charges to facilitate entry of plasmid Dna encoding il-12 into tumor cells (exhibit 3). effective for locally treated disease, electroporation can also induce re-sponses in untreated distant disease, suggesting that adaptive immune responses are being elicited that can target melanoma-associated antigens.13 this is a

exhibit 2: the location of Melanoma determine the likely Mutations4-6

uvealgNaQ 32%g11 45%

acralC-Kit 5-10%Nras 25%Braf 10%

scalp/face Nras 15%Braf 28%

Trunk/legs Nras 18%Braf 57%

MucosalC-Kit 10-20%Nras 15%


promising approach that can trigger systemic anti-tumor immune responses without the systemic tox-icity associated with intravenous interleukin. if the immune system can be stimulated to work against a tumor, lasting responses can occur.

conclusionin the past few years, there have been unprec-edented advances in melanoma therapy. braF inhibitors may be the primary choice for braF mutation-positive patients. Work needs to be done to determine what to do with patients who have braF-resistant tumors. the role of combination therapy of braF inhibitors and meK inhibitors needs to be defined. immunological therapies are another area of significant advancement. one agent has reached the market, and it is hoped more will do so in the next few years. the future holds many other possible combinations or triple therapy to block more pathways to further prolong survival in metastatic melanoma.

adil daud, Mbbs is a Clinical Professor of Medicine and Co-director of the Melanoma Program at the university of California in san francisco.

references1. u.s. Cancer statistics Working Group. united states Cancer statistics: 1999–

2009 incidence and mortality Web-based report. atlanta (Ga): Department of

health and human services, Centers for Disease Control and prevention, and

national Cancer institute; 2013. available at: http://www.cdc.gov/uscs.

2. balch Cm, buzaid aC, soong sJ, et al. Final version of the american Joint

Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol.

2001;19(16):3635-48.

3. mocellin s, pasquali s, rossi Cr, nitti D. interferon alpha adjuvant therapy

in patients with high-risk melanoma: a systematic review and meta-analysis. J

Natl Cancer Inst. 2010;102(7):493-501.

4. van raamsdonk CD, Griewank KG, Crosby mb, et al. mutations in Gna11

in uveal melanoma. N Engl J Med. 2010;363(23):2191-9.

5. Curtin Ja, busam K, pinkel D, bastian bC. somatic activation of Kit in

distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-6.

6. lee Jh, Choi JW, Kim ys. Frequencies of braF and nras mutations are

different in histological types and sites of origin of cutaneous melanoma: a me-

ta-analysis. Br J Dermatol.;164(4):776-84.

7. Flaherty Kt, puzanov i, Kim Kb, et al. inhibition of mutated, activated

braF in metastatic melanoma. N Engl J Med. 2010;363(9):809-19

8. sosman Ja, Kim Kb, schuchter l, et al. survival in braF v600-mutant ad-

vanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-14

9. Flaherty Kt, infante Jr, Daud a, et al. Combined braF and meK inhibi-

tion in melanoma with braF v600 mutations. N Engl J Med.

2012;367(18):1694-703.

10. hodi Fs, o’Day sJ, mcDermott DF, et al. improved survival with ipilim-

umab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-23.

11. 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.

12. topalian sl, hodi Fs, brahmer Jr, et al. safety, activity, and immune cor-

relates of anti-pD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54.

13. Cha e, Daud a. plasmid il-12 electroporation in melanoma. Hum Vaccin

Immunother. 2012;8(11):1734-8.

exhibit 3: in-Vivo electroporation

injection of plasmid electrode insertion electroporation


FeCal inContinenCe (Fi) is the inCa-pacity to defer the urge to pass gas or stool at a so-cially acceptable time and place. estimating preva-lence is difficult because of underreporting primarily caused by lack of awareness, lack of discussion by health care providers, and by patient embarrassment. nearly 15 million noninstitutionalized adults in the united states have Fi, with an overall prevalence of 15 percent in the community for both men and women aged 70 years and over.1,2 it is one of the most common reasons for nursing home admission.1 the overall prevalence among nursing home residents is 45 percent, with a prevalence of 10 to 15 percent reported among more independent residents and up to 70 percent among the most dependent residents.3

the economic and social impact of Fi is enormous. the total cost for evaluation and treatment of patients has been estimated to be $17,166 per year per patient.4 severe Fi is associated with 55 percent higher health care costs compared with continent patients.5 in 2004, approximately $400 million was spent on adult diapers.6 there are also the added costs of treating complications associated with Fi including:

• severe itching, burning, and soreness of the perineum

• incontinence dermatitis• infections

• skin erosion.7

Fi tends to be a silent affliction in the community. an internet-based survey was completed between september and December 2010, by 142 people, all with Fi not caused by irritable bowel syndrome. the survey found that 68 percent of people with Fi had not been diagnosed by a physician.8 the most common reasons for not receiving a diagnosis:

• patients are too embarrassed to discuss their condition,

• patients feel they can manage their symptoms on their own,

• patients discuss their symptoms, but report physicians implied not much could be done or

the condition is a normal part of aging.of those with a diagnosis, 37 percent consulted

three or more physicians before receiving a diagno-sis, and 18 percent say their doctors have not identi-fied a cause. many patients waited some time before consulting a physician about their symptoms, with 7 percent waiting more than 10 years.

Fi symptoms are experienced frequently. in the previous survey, most patients (83 percent of diag-nosed and 70 percent of undiagnosed) experience Fi at least once per week, and many (47 percent of diagnosed, 27 percent of undiagnosed) experience symptoms four or more times weekly.8 symptoms

summaryfecal incontinence is an underdiagnosed and underreported condition affecting millions of americans. it can be embarrassing and results in significant impact on quality of life. Numerous treatments are available that can improve this condition and a patient’s daily life.

Key points• fecal incontinence significantly impacts quality of life.• Treatment includes identifying any reversible causes, conservative treatments, noninvasive treatment with an injectable agent, and surgical options.• a stepped approach to therapy can be used starting with conservative measures and moving forward through noninvasive and then surgical options.• The noninvasive option is less costly and carries less risk than the surgical options.

Advances in the Treatment of Fecal Incontinence

Beth Moore, Md, faCs, fasCrs for a CMe/Ceu version of this article, please go to www.namcp.org/cmeonline.htm,

click on Chronic illness then autoimmune and then on fecal incontinence: New Treatment Options


are more common during the day and frequently in-terfere with daily activities or cause missed work or social activities. nearly 70 percent of diagnosed and approximately 45 percent of undiagnosed patients say Fi often or always interferes with daily activities. similarly, 73 percent of diagnosed and 55 percent of undiagnosed patients indicate Fi causes missed so-cial activities, and 38 percent and 26 percent, respec-tively, report missed work. thus, Fi has a significant impact on quality of life.9

Continence for stools depends on four main fac-tors: rectal sensation, rectal storage capacity, anal sphincter strength, and stool consistency. Fi can re-sult from a defect in any of these mechanisms but is frequently multi-factorial. the different causes of Fi are listed in exhibit 2.10

several nerves are involved in rectal sensation. the pudendal nerve controls both internal and external sphincters.11 the internal anal sphincter is under in-voluntary control and is smooth muscle. it accounts for about 75 percent of continence. the external anal sphincter, under voluntary control and striated muscle, is responsible for 15 percent of continence.

there are two main recognized forms of Fi: pas-sive and urge Fi. passive is leakage without notice and is related to low anal resting pressure and internal sphincter deficiency.12 urge is the inability to with-stand the urge to defecate and is often attributed to an insufficiency in external sphincter tone and activity.

evaluation of the Fi patient will include patient history and physical and diagnostic testing. these tests may include anorectal manometry and sensory testing, anal endosonography, defecography, rectal sensory testing, pelvic scans, and/or neurophysi-ologic testing of anorectal function. the majority of incontinent patients with intact sphincters have normal pudendal nerve terminal motor latency.

management begins with assessment, which should include consideration of severity and im-pact (exhibit 3).13 any potentially reversible causes such as laxative overuse should be considered and corrected. once reversible causes are addressed, it is recommended that treatment start with conser-vative therapy, including diet, fiber, and antimotil-ity agents. other conservative therapies, as listed in exhibit 3, can also be used at any point in therapy.

exhibit 1: impaired Quality of life (fiQl)9

lifestyle Coping depression embarrasment

fi patients gi patients not affected by fi4

3.5

3

2.5

2

1.5

1

*p <0.01

exhibit 2: causes of fecal incontinence10

anal sphincter weakness Traumatic (obstetric, surgical) or nontraumatic (scleroderma, internal sphincter degeneration of unknown etiology, pudendal neuropathy)

disturbances of the pelvic floor

rectal prolapse, descending perineum syndrome, weakening or dropping of pelvic floor due to age

inflammatory conditions radiation proctitus, Crohn’s disease, ulcertive colitis

Central nervous system disorders

dementia, stroke, brain tumor, multiple sclerosis, spinal cord lesions

diarrhea irritable bowel syndrome, postcholecystectomy diarrhea

**

*

*


if conservative therapy fails, patients may be consid-ered for such nonsurgical options as injectable thera-pies. if conservative therapy and nonsurgical options fail, patients may be considered for surgical options such as sphincter repair or sacral nerve stimulation.

Dietary changes, increasing fiber intake, and sphinc-ter exercises can be helpful for some patients. there have been mixed results of studies of biofeedback.14 this option is labor intensive and requires commitment from patient and staff. medications commonly used in Fi are stool softeners and antimotility/antidiarrheals. Docusate is an example of a stool softener that increases water content of the stool. loperamide hydrochloride decreases Gi transit time and increases absorption of water from the Gi tract. Diphenoxylate/atropine is also used, but there can be issues with dependence. unfor-tunately, conservative therapy is inadequate for most patients with moderate to severe Fi.8, 15,16

anal sphincter repair is the most common surgery for Fi. this procedure results in an average hospital

stay of three days. it is appropriate for highly symp-tomatic patients with a defined defect of the exter-nal sphincter.13 the majority of patients initially have subjectively good outcomes, but the results tend to de-teriorate over time. there is a 35 to 80 percent success rate over four to five years with anal sphincter repair.

sacral nerve stimulation involves mild electri-cal stimulation to the sacral nerves (s2, s3, or s4). electrical stimulation of the sacral nerve allows for activation or inhibition of effector organs that the sacral nerves innervate (bladder, urinary and anal sphincters, pelvic floor, and rectosigmoid colon). sacral nerve stimulation is performed with a sur-gically implanted device. the interstim device was FDa approved in 2011 and is indicated for treatment of chronic fecal incontinence in patients who have failed or are not candidates for more conservative treatments. the device consists of a neurostimula-tor that delivers electrical pulses to the sacral nerve, an electrical lead implanted on a sacral nerve, and

exhibit 3: fi current treatment practices13

surgiCal OPTiONs • sphincter repair • dynamic graciloplasty • artificial bowel sphincter • stoma • sacral Nerve stimulation

NONsurgiCal OPTiON • injectable therapy • radiofrequency

CONserVaTiVe TheraPies • diet • fiber therapy • antimotility treatment

*The following can be used atany point in therapy

• antidiarrneal agents • enemas, laxitives, and suppositories • Biofeedback • anal plug

exhibit 4: estimated treatment costs for fi24,25

hospital, Procedure and device Costs

$30,000

$25,000

$20,000

$15,000

$10,000

$5,000

$0injectable bulking

agentartificial bowel

sphinctersacral nervestimulator

$30,000$27,000

$5,000


a programmer that controls the pulses. the neuro-stimulator and the lead are permanent implants.

to determine if a patient will benefit from a stimu-lator, a test stimulation phase is conducted. a tempo-rary lead is percutaneously placed at the sacral nerve for 14 days. if there is less than 50 percent reduc-tion in incontinent episodes, the device is removed. patients who have a greater than 50 percent reduc-tion in episodes move on to the chronic implant phase. the percutaneous lead and test stimulator are removed and replaced with an implanted lead and neurostimulator. the permanent implants are a sur-gical procedure requiring sedation.

the efficacy of sacral nerve stimulation has been assessed in an open label trial.17 one hundred thir-ty-three patients went through the test stimulation and 120 moved forward with chronic implantation. eighty-six percent of the chronic implant patients had a greater than 50 percent reduction in the num-ber of incontinent episodes per week. perfect con-tinence was achieved in 40 percent of the subjects. the device improved the fecal incontinence severity index and positively impacted quality of life.

From the open label trial, 83 patients were avail-able for three-year assessment. eighty- six percent of these 83 still maintained efficacy. they had a mean of 1.7 Fi episodes per week compared with 9.4 at baseline. adverse effects with the sacral stimulator include implant site pain (28 percent), paresthesia (15 percent), change in the sensation of stimulation (12 percent), and infection (10 percent). in this study, this intervention cost up to $30,000 per patient. the amount included the device, plus physician and hos-pital costs, and costs associated with recalibration

(including hospitalization) and device adjustment or alternative treatments in cases of failure.

a radiofrequency procedure (seCCa) is another invasive procedure that is currently rarely performed. it consists of radiofrequency (rF) energy delivered, through four electrodes attached to needles, distal to the dentate line of the anal canal where there is no pain sensation. one-minute treatment sets, with a goal of 20 sets each composed of four needle inser-tions, are conducted. the procedure takes about 60 minutes and is performed in the endoscopy suite or ambulatory surgery unit under conscious sedation or general anesthesia. the rF energy induces colla-gen denaturization, the tissue contracts, and muscle tone is improved. FDa approved indications for this procedure are treatment of Fi in those patients with incontinence at least once per week and who have failed more conservative therapy.

there are limited data on the efficacy of the rF procedure. in three studies that enrolled small num-bers of patients, Fi scores decreased and quality of life improved.18-20 the improvements were main-tained for up to five years. ulcerations and minor bleeding were reported in these small clinical trials.

a noninvasive procedure is the biocompatible tis-sue-bulking agent (solesta®). this is a viscous com-bination of hyaluronic acid and dextranomer-linked beads that is injected into the submucosal layer of the anal canal. it appears to narrow the anal canal, augmenting the sphincter muscle, allowing for bet-ter sphincter control and is indicated for the treat-ment of fecal incontinence in patients 18 years and older who have failed conservative therapy.

the injection of the bulking agent is given in a

ConservativeTherapies

Minimally invasiveTreatments

surgicalTherapies

exhibit 5: fi treatment paradigm

• generally safe• low success rates• Patients may not wish to proceed to surgery• Patients may not be candidates for surgery

• Outpatient• No anesthesia (injectable therapy) or partial (rf)• Patients may resume limited physical activity immediately (injectable therapy) or 7 days (rf)• unlikely to impede future procedures (injectable therapy)• Proven safety and efficacy in clinical trials

• invasive• high cost• Prolonged recovery• general anesthetic• Potential safety issues


physician’s office or outpatient setting without anes-thesia through an anoscope. because the injection site is proximal to the dentate line, it is typically painless.

three studies have been published with this agent.11,21,22 in a double-blind placebo study, 53.2 percent of patients had an initial response compared with 30.7 percent in the placebo group.11 in a long-term, follow-up report from one of the studies, 83 of 115 patients completed a 24-month follow-up assess-ment.23 at 24 months, 62.7 percent of patients were considered responders and experienced a greater than 50 percent reduction in the total number of Fi epi-sodes. the median number of Fi episodes declined by 68.8 percent. the mean number of incontinence-free days increased from 14.6 at baseline to 21.7 at 24 months. Fi-related quality of life scores also showed significant improvements. the most common ad-verse events were proctalgia (13.3 percent) and py-rexia (9.6 percent). the majority of adverse effects were mild to moderate, self-limited, and resolved within one month of the injection.

exhibit 4 compares the cost of bulking agents with the cost of surgical implantation of an artifi-cial sphincter and a neurostimulator. the injectable bulking agent’s estimated costs are based on one treatment administered at the physician’s office. the neurostimlator cost estimates are based on the manu-facturer’s common billing information.24,25 exhibit 5 compares some of the advantages and disadvantages of the major treatments for Fi.

conclusionFecal incontinence has an enormous impact on an affected individual’s quality of life and results in sig-nificant economic costs. treatment can improve this condition. although effective for minor Fi, conser-vative treatments are not usually effective for mod-erate to severe Fi. those patients will require non-surgical or surgical intervention.

beth Moore, Md, facs, fascrs is director of the Colorectal Can-cer Center at Cedars-sinai Medical Center.

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for fecal incontinence in a us community. Am J Gastroenterol. 2010;105(2):412-9.

2. Whitehead We, borrud l, Goode ps, et al, for the pelvic Floor Disorders

network. Fecal incontinence in us adults: epidemiology and risk factors. Gas-

troenterology. 2009;137:512-7.

3. landefeld Cs, bowers bJ, Feld aD, et al. national institutes of health state-

of-the science conference statement: prevention of fecal and urinary inconti-

nence in adults. Ann Intern Med. 2008;148(6):449-58.

4. mellgren a, Jensen ll, Zetterström Jp, et al. long-term cost of fecal incon-

tinence secondary to obstetric injuries. Dis Colon Rectum. 1999;42(7):857-67.

5. Dunivan G, heymen s, palsson os, et al. Fecal incontinence in primary care:

prevalence, diagnosis, and health care utilization. Am J Obstet Gynecol.

2010;202:493.e1-6.

6. rao s, american College of Gastroenterology practice parameters Commit-

tee. Diagnosis and management of Fecal incontinence. Am J Gastroenterol.

2004;99(8):1585-604.

7. Farage ma, miller KW, sherman sn, tesvat J. Cutaneous effects and sensi-

tive skin with incontinence in the aged. Textbook of Aging Skin. 2010:755-769.

8. international Foundation for Functional Gastrointestinal Disorders (iFFGD). man-

aging incontinence. a survey of those who live with it. Incontinence. 2011;319:1-4.

9. rockwood th, Church Jm, Fleshman JW, et al. Fecal incontinence Quality

of life scale: quality of life instrument for patients with fecal incontinence. Dis

Colon Rectum. 2000;43(1):9-16; discussion 16-7.

10. bharucha ae. management of fecal incontinence. Gastroenterol Hepatol.

2008;4(11):807-817.

11. halland m, talley nJ. Fecal incontinence: mechanisms and management.

Curr Opin Gastroenterol. 2012;28(1):57-62.

12. Graf W, mellgren a, matzel K, et al, on behalf of the nasha Dx study

Group. efficacy of dextranomer in stabilized hyaluronic acid for treatment of faecal

incontinence: a randomized, sham-controlled trial. Lancet. 2011;377:997-1003.

13. tjandra J, Dykes sl, Kumar rr, et al, and the standards practice task Force

of the american society of Colon and rectal surgeons. practice parameters for

the treatment of fecal incontinence. Dis Colon Rectum. 2007;10:1497-1507.

14. heymen s, Jones Kr, ringel y, et al. biofeedback treatment of fecal incon-

tinence: a critical review. Dis Colon Rectum. 2001;44(5):728-36.

15. abrams p, andersson Ke, birder l, et al. Fourth international Consultation

on incontinence recommendations of the international scientific Committee:

evaluation and treatment of urinary incontinence, pelvic organ prolapse, and

fecal incontinence. Neurourol Urodyn. 2010;29(1):213-240.

16. norton C, Whitehead We, bliss DZ, et al. management of fecal inconti-

nence in adults. Neurourol Urodyn. 2010;29(1):199-206.

17. mellgren a, Wexner sD, Coller Ja, et al. long-term efficacy and safety of

sacral nerve stimulation for fecal incontinence. Dis Colon Rectum.

2011;54(9):1065-75.

18. ruiz D, pinto ra, hull tl, et al. Does the radiofrequency procedure for

fecal incontinence improve quality of life and incontinence at 1-year follow-up?

Dis Colon Rectum. 2010;53(7):1041-6.

19. lefebure b, tuech JJ, bridoux v, et al. temperature-controlled radio fre-

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21. Dodi G, Jongen J, de la portilla F, et al. an open-label, noncomparative,

multicenter study to evaluate efficacy and safety of nasha/Dx Gel as a

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24. medtronic. interstim therapy for 2012 Common billing Codes, January 2012.

25. acticon neosphincter, ams for life 2011 Common billing and Coding

Flashcard.

© 2013 Bayer HealthCare Pharmaceuticals and Algeta ASA. All rights reserved.BAyer, the Bayer Cross, and Xofigo are registered trademarks of Bayer. AlgetA is a trademark of Algeta ASA. 600-10-0005-13a 07/13 Printed in USA

To learn more, visit www.xofigo-us.com

NOW APPROVEDFor the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. there were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. the incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/l, the platelet count ≥100 × 109/l, and hemoglobin ≥10 g/dl. Prior to subsequent administrations, the ANC should be ≥1 × 109/l and the platelet count ≥50 × 109/l. Discontinue Xofigo if

hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care

• Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. the administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. therefore, radiation protection precautions must be taken in accordance with national and local regulations

• Adverse Reactions: the most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. the most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

Important Safety Information

Please see following pages for brief summary of full Prescribing Information.

Xofigo (radium Ra 223 dichloride) Injection, for intravenous useInitial U.S. Approval: 2013

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1 INDICATIONS AND USAGEXofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.2 DOSAGE AND ADMINISTRATION2.3 Instructions for Use/Handling General warningXofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization.Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.Radiation protectionThe administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handlingFollow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination.For patient careWhenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments.

4 CONTRAINDICATIONSXofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1

study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:

[see Warnings and Precautions (5.1)]6.1 Clinical Trials ExperienceBecause 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.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%).Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301)Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % %Blood and lymphatic system disordersPancytopenia 2 1 0 0Gastrointestinal disordersNausea 36 2 35 2Diarrhea 25 2 15 2Vomiting 19 2 14 2General disorders and administration site conditionsPeripheral edema 13 2 10 1Renal and urinary disordersRenal failure and impairment 3 1 1 1

Laboratory AbnormalitiesTable 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo.Table 4: Hematologic Laboratory Abnormalities Hematologic Xofigo (n=600) Placebo (n=301)Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4Abnormalities % % % %Anemia 93 6 88 6Lymphocytopenia 72 20 53 7Leukopenia 35 3 10 <1Thrombocytopenia 31 3 22 <1Neutropenia 18 2 5 <1

Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.Fluid StatusDehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site ReactionsErythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.Secondary Malignant NeoplasmsXofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic ChemotherapyIn the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONSNo formal clinical drug interaction studies have been performed.

calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Category X [see Contraindications (4)]Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo. 8.3 Nursing MothersXofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and efficacy of Xofigo in pediatric patients have not been established.In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 – 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric UseOf the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.8.6 Patients with Hepatic Impairment

radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal ImpairmentNo dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive PotentialContraceptionBecause of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo. InfertilityThere are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGEThere have been no reports of inadvertent overdosing of Xofigo during clinical studies.There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1

were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityAnimal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATIONAdvise patients:

receiving Xofigo. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections.

output while being treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency.

Xofigo. Follow good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers.

reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in NorwayXofigo is a trademark of Bayer Aktiengesellschaft.© 2013, Bayer HealthCare Pharmaceuticals Inc.All rights reserved.Revised: 05/2013


there is a hiGh rate oF oCCurrenCe of major depressive disorder (mDD) with a 17 per-cent lifetime prevalence.1 this prevalence corre-sponds to a national population projection of 32.69 to 35.1 million u.s. adults with lifetime mDD. in any given year, 19 million american adults, or 9.5 percent of the u.s. population, suffer from depres-sive disorders. the average age of onset of depres-sion has changed significantly over the years. Fifty years ago it was 29 years old; the average age today is 14.5.

mDD is a disease of long duration and chronic-ity. thirty-three percent of patients have episodes of greater than two years’ duration. the rate of re-currence within two to three years of recovery is greater than 50 percent.

mDD has become a major public health concern

and is responsible for significant social impairment, including deterioration of family and interpersonal relationships, lost work productivity, and general suffering. it is the most common psychiatric dis-order in the united states, yet few patients receive adequate treatment. the morbidity of mDD is comparable to angina and advanced coronary artery disease. additionally, depression is the leading cause of disability in america. by 2020, it is projected that depression will be the leading cause of disability worldwide.2 mortality is also an issue with depres-sion. approximately 15 percent of depressed patients who are hospitalized once for depression will com-mit suicide.

in addition to significant personal and social costs, mDD results in significant economic costs. the annual cost of this disease is estimated at over $80

summaryMajor depressive disorder has a significant impact on patients, families, workplaces, and the health care system. Clinicians and managed care plans both need to under-stand the importance of adequate treatment in reducing the long-term impact and burden of this disease. There are numerous strategies for improving care of patients with Mdd such as treatment pathways and stepped care approaches.

Key Points• Major depressive disorder is a costly disease for patients, society, and the health care system.• Patients need to be treated beyond the disappearance of symptoms to have a remission. • it is important to prevent future episodes early on during the course of Mdd because it can become self-sustaining.• lifestyle changes, support systems, and being engaged in one’s own health care are important to successful Mdd management.• follow-up tools and communication strategies can improve the outcome in depression management.• understanding the mind-body connection in depression can inform a variety of treatment methods to provide optimal patient care.

Updated Strategies and Outcomes in the Diagnosis and Treatment of Major

Depressive DisorderKen hopper, Md

for a CMe/Ceu version of this article please go to www.namcp.org/cmeonline.htm, then click on Behavioral health and then the activity title


billion.3 Depression is one of the top 10 conditions driving medical costs, ranking seventh in a national survey of employers.

Depression is frequently associated with, and may negatively impact, other medical disorders. health care use and costs are twice as high in patients with diabetes and heart disease who also have depression compared with those without depression. untreated mental disorders in patients with other chronic ill-nesses are estimated to cost commercial and medi-care purchasers between $130 and $350 billion an-nually. approximately 217 million days of work are lost annually to related mental illness and substance use disorders (costing employers $17 billion/year).

Depression is the greatest cause of productivity loss among workers.

beyond preventing the significant consequences of this disease, treatment of mDD is important for long-term health of the brain. inadequately treated depression may have a progressive course and may be associated with functional and structural changes in the brain.4-6

patients need to be treated beyond the disappear-ance of symptoms to have a remission. many times clinicians who do not understand this will stop ther-apy too early. stopping therapy prematurely sets the patient up for recurrent episodes and possibly future resistance to therapy. Continuing therapy beyond

exhibit 1: depression screening tools

Most Commonly used depression screening Tools in adults

Tool Cost reference sensitivity/ specificity4

Beck depresion inventory fee available for purchase from http://pearsonassess.com/

100% / 75%

Center for epidemiologic study depression scale (Ces-d)

free Tool available for download: http://projects.ipro.org/index/ami_ktools

79% / 77%

Patient health Questionnaire (PhQ-9) free Tool available for download: http://www.depression-primarycare.org/

88% / 88%

general health Questionnnaire-12 free Tool available for download: http://www.workhealth.org/

83% / 76%

Zung self-depression scale free exam available on-line: http://www.psychology.com/

97% / 67%

geriatric depression scale free hartford institute for geriatric Nursing http://www.hartfordign.org/

100% / 63%

exhibit 2: depression chronic care Model

improved Outcomes

The Chronic Care Model

Communityresources and Policies

health systemsOrganization of health Care

self-Management

support

Clinicalinformation

systems

deliverysystemdesign

decisionsupport

Productiveinteraction

informed.activated

Patient

Prepared.Proactive

Practice Team


the remission stage can delay the time to another episode or even delay the development of another episode.

it is important to adequately treat mDD early on during the course in an individual because mDD can become self-sustaining through recurrent epi-sodes and the functional and structural changes dis-cussed above. early in the disease course, triggers such as a job loss or death of a loved one are required to trigger an episode, whereas future episodes occur without a particular trigger in people who are not adequately treated. episodes can also become more frequent.

Diagnosis should be made following the ameri-can psychiatric association diagnostic criteria.7 the majority of cases of depression are treated in pri-mary care, but the diagnosis can be difficult. many patients do not present to a clinician complaining of depressive symptoms. over 70 percent of patients present with physical symptoms only.8 another co-nundrum is clinicians having only a few minutes to see a patient.

numerous screening tools are available to assist clinicians in identifying patients with depression (exhibit 1). For example, the phQ-9 is the nine-

item depression scale on the patient health Ques-tionnaire. this is a powerful tool for assisting pri-mary care physicians in diagnosing depression and in selecting and monitoring treatment. some prac-tices use a two-question screen to initially identify patients for further screening with the phQ-9.

once identified, depression is like most other chronic illnesses; it requires a multidimensional ap-proach to manage (exhibit 2). lifestyle changes, support systems, and being engaged in one’s own health care are important to success. because of our fragmented health care system, there is little integra-tion between primary care and behavioral health. this fragmented and uncoordinated care results in significant unmet behavioral health needs and un-successful chronic disease management.

better integration between primary care and be-havorial health can improve the management of mDD. exhibit 3 outlines an example management pathway using primary care and specialty referral. it is important for all primary care practices to have in place a mechanism for dealing with the severely de-pressed patient who is at immediate risk for suicide. it is the equivalent activity to having a pathway for deal-ing with acute chest pain. a stepped care approach to

exhibit 3: depression assessment pathway

refer to crisis team or on-call psychiatrist

refer to community mental health teamor psychiatrist

Patientwith

possibledepression

• Medication• Case management by telephone• refer for CBT

Clinical assessment• Template• PhQ9• May need more than one assessment

Moderate to severe depression

sTeP 3

Mild depressionsTeP 2

Chronic atypi-cal, refractory, or recurrent severe

depressionsTeP 4

Watchful waiting

• information leaflet with self-help advice• gOal exercise referral• signposting (Cruse, relate, CaB, etc.)

regular follow-up by gP or

mental health worker

subclinical or intervention

declinedsTeP1

severe depression with intermediate

to high risk of harm or severe distress

sTeP 5

reassess in 2 weeks

remission: reviewin 2 months

improved butstill symptomatic:continue step 3

Not improved: re-evaluate treatment from this stepor move to step 4

reassess in 6 - 8 weeks

resolution: no intervention

Not improved: refer for self-help CBT in step 3

resolution: no intervention

Not improvedmove to step 2

reassess in 2 weeks


managing depression that is similar to the pathway approach can also be utilized to match the needs of people with depression to the most appropriate ser-vices depending on the characteristics of their illness and personal/social circumstances (exhibit 4).9

patients need to be engaged and involved in their care to achieve success. if a patient has a voice in choosing treatment, they have a better outcome.10 the patient’s preferred treatment choice may not al-ways be the best choice clinically for the patient but, in general terms, if someone has a positive attitude toward a particular treatment it is probably best to start there, if clinically appropriate. For example, if a patient has a positive attitude about psychothera-py but has fears about medications, psychotherapy

would be the better choice for initial therapy.the various pharmacologic antidepressant classes

include serotonin selective reuptake inhibitors (ss-ris), serotonin norepinephrine reuptake inhibitors (snris), tricyclic antidepressants, and monoamine oxidase inhibitors. psychotherapeutic options in-clude cognitive behavioral therapy, interpersonal therapy, problem-solving therapy, supportive thera-py, and group therapy. Where patients receive their psychotherapy can have an impact. an interesting study found that receiving cognitive behavioral therapy outdoors in a forest led to much better out-comes than receiving the same therapy in a hospital setting.11 setting goes along with the positive atti-tude toward treatment.

exhibit 4: depression treatment stepped care Model9

The recommendations in this guideline are presented within a stepped care framework that aims to match the needs of people with depression to the most appropriate services, depending on the characteristics of their illness and their personal and social circumstanses. each step represents increased complexity intervention with higher steps assuming interventions in previous steps.

step 1: recognition in primary care and general hospital settings

step 2: Treatment of mild depression in primary care

step 3: Treatment of moderate to severe depression in primary care

step 4: Treatment of depression by mental health specialists

step 5: inpatient treatment for depression

Who is responsible for care? What do they do? What is the focus?

step 5: inpatient care, crisis teams risk to life, severe self neglect

Medication, combined treatments, eCT

step 4: Mental health specialists, including crisis teams

Treatment-resistant recurrent, atypical and

psychotic depression, and those at significant risk

Medication, complex psycho-logical interventions, combined treatments

step 3: Primary care team, primary care mental health worker

Moderate or severe depression

Medication, psychological inter-ventions, social support

step 2: Primary care team, primary care mental health worker Mild depression

Watchful waiting, guided self-help, computerized CBT, exercise, brief psychological interventions

step 1: gP, practice nurse recognition assessment


physical fitness also impacts depression. exercise can treat episodes and also ward off recurrence. people who are regular exercisers are less likely to develop depression. in one study, exercise was equal to medication in treating mild to moderate levels of depression.

Diet also has an impact. a more balanced diet re-duces the risk for depressive illness. Consumption of a diet rich in processed foods independently in-creases the risk of developing depressive symptoms over five years, whereas a diet rich in whole foods was found to protect against the development of

exhibit 5: augmentation therapy

lithium

risks Benefits recommendations

• Well documented adverse effects: weight gain, tremor, increased thirst and urination, mild cognitive impairment

• •

documented efficacy with rates as high as 30% to 65% response times can be as fast as 48 hours though some cases reported 4-6 week delays in response

• •

dosage should be adjusted to result in a serum blood level between .4 and .8 meq per l aiming for the lowest level dosage is prudent

thyroid hormone

• • •

few controlled studies have focused on use asaugmentative therapy adverse effects: irritability, sweating, arrhythmias Can interfere with thyroid metabolism if taken chronically

• •

May be used to augment response to tricyclic antidepressants shown to be effective in 50% to 60% of patients

• •

Triiodothyronine has been shown to be more effective than tetraiodothyronine doses should be small and usage should be limited to 2-3 weeks

pindolol

• •

adverse effects including heart rate reduction, nausea, diarrhea (less than 10% of study participants) limited testing regarding long term effect and efficacy

• •

accelerates onset action of antidepressants has been shown to be effective augmentor of ssris

• Pindolol at dosages of 2.5 to 7.5 mg per day for a trial period of up to 6 weeks may prove to be an effective ssri augmentor

buspirone

• •

adverse effects include lightheadedness and nausea Pharmacokinetic interaction with nefazodone can increase adverse effects

• •

encourages serotonin release, although it has no specific or intrinsic antidepressant effects Open studies show improved antidep-pressant response in of patients over three month period

• • •

Caution necessary when prescribing buspirone with nefazo-done standard dosages of 15 to 30 mg per day have shown augmenta-tive antideppressant effects lowest dose should be prescribed initially to rule out interaction (2.5 mg twice daily)


depression.12 there is a definite connection between other

chronic illnesses and depression. the presence of type 2 diabetes nearly doubles an individual’s risk of depression and almost 30 percent of patients with diabetes meet criteria for clinical depression. back/neck and other chronic pain also have a significant depression component. treating depression will im-prove a patient’s other chronic diseases. there is also a connection between substance abuse and depres-sion. both will require treatment in order to have success in treating either disease.

up to 70 percent of depressed patients respond to treatment with a greater than 50 percent decrease in depression scores but fail to achieve remission from their emotional and physical symptoms. thus, mul-tiple treatments or adjustments may be necessary to achieve remission.

if a patient is not responding to therapy, treatment resistance has to be considered. between 10 and 30 percent of depressed patients taking an antidepres-sant are partially or totally resistant to treatment. reasons for resistance may include undiagnosed or misdiagnosed medical conditions (such as anemia), medication-induced depression (e.g., beta blockers, methyldopa), untreated comorbid disorders such as eating disorders or substance abuse, medication ad-verse effects, and poor treatment adherence.

there are five strategies for overcoming resistance – optimization, medication substitution, combina-tion therapy, and augmentation.13 if the dosage pre-scribed is too low, or the length of treatment time is inadequate, therapy should be optimized. When a patient’s history suggests inadequate therapy, the clinician should maximize the dosage or duration of the therapy. an adequate duration for a trial of antidepressant therapy has been defined by some clinicians as four to six weeks. others assert that a minimum of six weeks is necessary,

people who have not responded to traditional antidepressant therapy may benefit from drug sub-stitution. Changing from one antidepressant to an-other in the same class has not produced impres-sive response rates; however, some studies suggest that switching to an antidepressant with a different mechanism of action is often associated with a bet-ter response rate. studies have shown that switching nonresponders from a tricyclic antidepressant to an alternative antidepressant class may result in a 50 to 60 percent positive response rate.

Combination therapy involves the addition of a second antidepressant agent to the therapeutic regi-men. Combination therapy may also include con-current administration of two or more anti-depres-sant agents. some typical examples include adding

trazodone, desipramine, or bupropion to an ssri. therapeutic responses of combination therapy may be different than a response achieved by either drug alone, and may be potentially beneficial during the early stages of mDD.

augmentation therapy consists of adding a sec-ond agent, not routinely prescribed for depression, to the therapeutic regimen when there is a limited response to the antidepressant. Common augmen-tation therapy agents include lithium, thyroid hor-mone, pindolol, or buspirone. exhibit 5 compares the risks and benefits of these options.13 Care must be taken in using pindolol, a beta blocker, because beta blockers can sometimes worsen depression. the atypical antipsychotics are also used for augmenta-tion, have their own unique adverse effects, and are heavily advertised for this purpose.

Combination antidepressants and augumentation therapy have pros and cons. some of the favorable aspects are that these strategies build on therapeu-tic gains already achieved, the addition of a second compound is generally well tolerated, and there can be a more rapid onset of antidepressant effects during the crucial early phase. the response rate is comparable or superior to drug substitution. the negative aspect is that there is increased potential of drug interaction, increased potential of reduced ad-herence when multiple medications are prescribed, and increased risk of adverse effects. additionally, efficacy and long-term effects may not yet be known in some cases.

Follow-up tools and communication strategies can improve the outcome in depression management. it is well known that nonadherence is an important reason for suboptimal treatment outcomes. patients frequently report stopping medications because they read about possible adverse effects on the internet, or they took it for a week and then stopped because they did not feel better. patients also only take the medication when they feel bad, or stop the medica-tion as soon as they feel better. seventy-five percent of antidepressants are stopped by patients by month four of therapy.

there are numerous interventions that can be used to improve adherence. patients and fam-ily members need education regarding the disease and treatment options. Common adverse effects of the prescribed antidepressant medication should be openly discussed with patients. patients should be reassured that other medication options will be explored in case of adverse effects. particularly im-portant is emphasis that these medications need to be taken on a daily basis to be effective. Clinicians should explain to patients that there is strong evi-dence that continued treatment with antidepressant


medication has a neuroprotective effect. they need to understand that depression can get worse if not consistently treated.

understanding the mind-body connection in de-pression can inform a variety of treatment methods to provide optimal patient care. For instance, patients should be encouraged to participate in physical ac-tivity, have a healthy diet and limit processed foods. another aspect of the mind-body connection’s contri-bution to treatment success is allowing patient prefer-ence to inform treatment. patients can participate in support groups and, if possible, support groups can be conducted outdoors or in aesthetically pleasing envi-ronments. patients need to be educated on the impor-tance of structure in daily life, the need to continue with activities of daily living, and the importance of avoiding spending increased time in bed. patients need to adhere to regular sleep and wake times. Family members should get involved early in treatment. they can provide extra support and help implement recom-mendations, monitor medication adherence, and pro-vide better feedback on the patient’s functioning.

conclusionmajor depressive disorder results in significant personal, social, and economic costs. Care of pa-tients with mDD can be improved by allowing patient preference to shape treatment, by imple-menting mind-body treatments, and by integrat-ing primary care and behavioral health services. For patients who do not respond to initial treat-ments, treatment adherence needs to be consid-ered. if patients have treatment resistance or se-vere mDD, they need to be referred to behavioral health specialists for case management and more aggressive pharmacotherapy.

Ken hopper, Md is an executive Consultant with BhM healthcare so-

lutions.

references1. CDC. Current Depression among adults --- united states, 2006 and 2008.

MMWR. 2010;59(38);1229-35.

2. murray CJl, lopez aD. the Global burden of Disease: a Comprehensive

assessment of mortality and Disability from Diseases, injuries and risk Factors

in 1990 and projected to 2020. Geneva, switzerland; World health organiza-

tion, 1996.

3. Greenberg pe, Kessler rC, birnbaum hG, et al. the economic burden of

depression in the united states: how did it change between 1990 and 2000? J

Clin Psychiatry. 2003;64(12):1465-75.

4. murray CJ, lopez aD. evidence-based health policy--lessons from the Glob-

al burden of Disease study. Science. 1996;274(5288):740-3.

5. everson sa, roberts re, Goldberg De, Kaplan Ga. Depressive symptoms

and increased risk of stroke mortality over a 29-year period. Arch Intern Med.

1998;158(10):1133-8.

6. Kessler rC, berglund p, Demler o, et al. the epidemiology of major depres-

sive disorder: results from the national Comorbidity survey replication

(nCs-r). JAMA. 2003;289(23):3095-105.

7. american psychiatric association. Diagnostic and statistical manual of men-

tal Disorders. Fifth edition. may 2013.

8. simon Ge, vonKorff m, piccinelli m, et al. an international study of the relation

between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-35.

9. bower p, Gilbody s. stepped care in psychological therapies: access, effective-

ness and efficiency. narrative literature review. Br J Psychiatry. 2005;186:11-7.

10. Kocsis Jh, leon aC, markowitz JC, et al. patient preference as a moderator

of outcome for chronic forms of major depressive disorder treated with nefazo-

done, cognitive behavioral analysis system of psychotherapy, or their combina-

tion. J Clin Psychiatry. 2009;70(3):354-61.

11. Kim W, lim sK, Chung eJ, Woo Jm. the effect of cognitive behavior

therapy-based psychotherapy applied in a forest environment on physiological

changes and remission of major depressive disorder. Psychiatry Investig.

2009;6(4):245-54.

12. akbaraly tn, brunner eJ, Ferrie Je, et al. Dietary pattern and depressive

symptoms in middle age. Br J Psychiatry. 2009;195(5):408-13.

13. Cadieux, rJ. practical management of treatment-resistant Depression. Am

Fam Physician. 1998;58(9):2059-62


Introduction the u.s. manaGeD Care lanDsCape is rapidly changing and emerging health technolo-gies will play a central role in shaping tomorrow’s health care marketplace. the patient protection and affordable Care act (ppaCa) of 2010 specifies payment reform provisions, including value-based purchasing, accountable care organizations (aCos), bundled payments, and the medical home, target-ing improvements in quality and efficiency at a time when health care costs comprise 23 percent of the federal budget.1 these pending changes in delivery models demand more evidence of value, and in-crease pressure to demonstrate the benefits and risks associated with health technologies and services. although primarily targeted at the federally funded

programs such as medicare, these reforms are not limited to that sector and are reverberating through-out commercial payers as well as they realign their business models to address health reform mandates and/or improve operational efficiencies.

medical devices, which represent one key type of emerging health technology/innovation, span a range of diagnostic and therapeutic technologies, including but not limited to implantable devices (e.g., knee and hip joints, spinal disks, and pacemak-ers), minimally or non-invasive devices (e.g., bone growth stimulators, insulin pumps and monitors, deep brain stimulation, external counterpulsation), and diagnostic devices (e.g., imaging such as mri, signals such as eKG or in vitro diagnostics). other complex devices such as surgery assist robots, in-

summaryas payment restructuring provisions of health care reform are adopted in the Medi-care marketplace and beyond, understanding and implementing value-based reim-bursement will become a necessity for managed care organizations (MCOs). MCO medical directors understand the potential benefits of focusing on value-based decision making to improve quality and cost of care, but the implementation of value-based reimbursement models is in the earliest stages in the u.s. further, per-spectives on what value-based decision making is, how to structure value-based de-cision models, evidence expectations for individual technology types, and means of integrating these concepts into conventional health technology assessment (hTa) and operational models is highly variable among key health stakeholders (e.g., pay-ers, providers, and manufacturers). as this concept is integrated as a component of u.s. health reform, some technologies such as medical devices may involve special considerations given existing reimbursement processes that may challenge our abil-ity to more robustly characterize value in the context of u.s. health delivery and incorporate appropriate value-reward mechanisms.

some of the barriers to evaluating value for medical devices identified by a na-tional survey of medical directors include the lack of rigorous efficacy data, difficul-ties in identifying costs because of bundled coding and the lack of a standard ap-proach for medical device manufacturers to demonstrate the value of an individual product. given the uncertainties and challenges at present, the best approach for implementing this type of reimbursement for medical devices will likely have to begin with pilot projects, potentially facilitated through strategic partnerships with key payer and/or provider stakeholders (e.g., accountable care organizations, inte-grated delivery Networks).

GBEMTI Perspectives: Value-Based Reimbursement for Medical Devices in the

U.S. – Where Do We Stand? eric faulkner, Joshua ransom, Natalie heidrich, Brad lucas, Md and geneva Briggs, Pharmd, BCPs


ternal monitoring devices, or use of targeted ultra-sound or radioactivity for therapeutic applications) are also emerging. medical devices are also increas-ingly being developed as combination products in-volving pharmaceuticals and diagnostics, enabling increasingly sophisticated means to address key health care challenges. in addition, medical devices are being developed to overcome the limitations of patient compliance by automatically delivering drugs through implanted chips.8 With over 100,000 types of marketed medical devices, this grouping of technologies has wide-reaching impact on health outcomes and costs.2

Despite the fundamental role that medical devices play in u.s. patient care, the structure of histori-cal u.s. reimbursement mechanisms and payment systems have made it difficult to recognize the value of medical technology.2 medical devices have been estimated to make up 5 to 6 percent of healthcare spending in the u.s. but reimbursement for medi-cal devices has not kept pace with other healthcare spending, with medical device prices increasing ap-proximately 1 percent per year while the consumer price index for medical care has risen 4.7 percent per year.3 this can partially be explained due to the fact that reimbursement for medical devices is often em-bedded in procedural codes and associated payments and not subject to separate payment as are many pharmaceuticals. this bundling of medical technol-ogy costs into procedural payments improves the predictability and consistency of decision making, but at the same time reduces the ability of payers, end users such as hospitals or clinics, and manufac-turers to track and characterize the value of indi-vidual or alternative medical technologies. Current-ly, reimbursement and other incentives (e.g., rapid regulatory pathway, limited intellectual property protections) do not support development of optimal evidence on the comparative value of medical de-vices, although the pressure for technology manu-facturers to provide an increasing array of evidence to support coverage and uptake is growing.4 at pres-ent, technology manufacturers are caught between expectations to more definitively demonstrate value and the reality that system incentives are not opti-mally engineered to reward differential value.

While emerging medical technologies will play a central role in shaping tomorrow’s managed care environment, ongoing health system changes and reform efforts in the u.s. may challenge the abil-ity of health care innovations to reach patient care. as health decisions makers “tighten” their belts and focus on the balance of quality and cost, emerging technologies must prove added value to the system.

value-based reimbursement (or value-based pur-

chasing if directed at the provider), represents one avenue to both support and reward development of evidence characterizing the value of new medical technologies. the concept of value-based reim-bursement generally is considered to involve differ-entially reimbursing individual products and services based on the value provided to the health system.5,6 in health care, value can be broadly considered to be a function of efficacy, quality, efficiency, safety, and cost. in value-based reimbursement, providers are held accountable for the quality and cost of the health care services they provide by a system of re-wards and consequences, conditional upon achiev-ing pre-specified performance measures. incentives are set to discourage inappropriate, unnecessary, and costly care. the key elements of value-based pur-chasing include but are not limited to: • Contracts spelling out the responsibilities of purchasers and all suppliers of goods and services • information to support the management of purchasing activities • Quality management (including quality measures and other performance metrics) to drive continuous improvements in the process of health care purchasing and in the delivery of health care services • incentives to encourage and reward desired practices by providers and consumers • education to help end user become better health care consumers7

the benefits of value-based reimbursement sys-tems to various stakeholders are numerous and may include: 1. all stakeholders - improved patient care and outcomes 2. payer - supports innovation and related improvements - improved evidence-base to formulate coverage decisions - lower health care costs/total spend - improved cost-effectiveness and quality of care - ability to limit access to technologies of limited value 3. provider - Clearer evidence of the differential value of technology alternatives - better information upon which to base clinical pathways and decision standards increasingly required under quality and performance management initiatives (e.g., aCo models) 4. manufacturer


- Clearer path and possibly reduced time to market - Faster uptake - improved reimbursement/pricing for better outcomes

under a value-based reimbursement model, med-ical technologies would be paid for based on “value” rather than via traditional “one size fits all” proce-dural payments, enabling those technologies that provide marked value over alternatives to be dif-ferentially rewarded for improving health outcomes and resource utilization. With this type of model, some devices that are currently used in the system may be further restricted or no longer covered.

the u.s. is not alone in the move to value-based reimbursement for technology and other services. other nations, especially the united Kingdom, have evolving efforts on value-based pricing.9,10 austra-lia’s pharmaceutical benefits pricing authority (pbpa) is increasingly suggesting alternative pricing agreements in negotiations although this is focused on pharmaceutical therapies.9,11 additionally, Ger-many recently changed its reimbursement system to a value based pricing system that directly compares the value of new entrants to established products.9,12

in order to gain a better understanding of the is-sues surrounding value-based reimbursement for medical devices and potential for this concept to be integrated into u.s. managed care practices, a tar-geted internet-based survey was conducted by the Genomics, biotech, and emerging medical tech-nologies institute (Gbemti) of the national as-sociation of managed Care physicians (namCp) member medical directors.

Methods the Gbemti was established in 2011 as an institute of the namCp. the namCp represents medical directors from payer, purchaser (employers), and provider systems such as ipas, aCos, phos, and medical groups. the goal of Gbemti is to support and characterize the value of genomics, biotechnolo-gy, regenerative medicine, and medical technologies as these new modalities enter and impact the health care system. the Gbemti seeks to support collab-orative stakeholder engagement around emerging health technologies to consider their potential to improve patient outcomes, impact on managed care management practices and value to the health care market place. the institute is guided by an execu-tive leadership Council (elC) composed of over 90 payer and manufacturer members. the Gbemti is unique in that it is a multi-stakeholder group cen-tered on bringing medical director decision makers and manufacturers together to address key trends

and topics that are transforming u.s. health care and explore means to improve managed care deci-sion making and patient access to emerging health technologies.

the Gbemti is divided into four key technology divisions:

• biopharmaceuticals and specialty products• Diagnostics and personalized medicine• emerging medical Devices• regenerative medicineto address the objectives of the institute, each di-

vision is focusing on questions unique to that re-spective division and developing a series of perspec-tives papers focused on key managed care challenges associated with these technology areas. the goal of these papers is to evaluate payer/managed care per-spectives and implications for improving managed care processes, policies, and patient outcomes for each core emerging technology area. value-based reimbursement for medical devices was chosen as the first topic under the emerging medical Devices division. this paper and all subsequent ones pub-lished by the institute have been peer reviewed by the Gmemti elC.

the survey questions addressed key drivers, infor-mation needs, and payer perspectives on opportuni-ties for moving toward value-based reimbursement for medical devices. the survey was randomly dis-seminated to medical director members of nam-Cp and 56 total responses were obtained, with 41 providing complete data. of the total respondents, approximately 70 percent identified themselves as medical directors at commercial mCos and 30 percent identified themselves as medical directors of health system and provider organizations (e.g., academic medical centers, hospital and other health systems, large physician practices). the sample also included payer decision makers from leading u.s. mCos (i.e., aetna, Cigna, humana, Wellpoint, united healthcare), which collectively represent more than 115 million covered lives in the u.s.

evaluating Value of Medical devicesthe current foundation for payer value assessment, coverage, and payment of new devices juxtaposes the availability of evidence against the evidence that payers consider ideal. because much of the device literature has historically centered on relatively small efficacy and safety studies instead of overall health outcomes, payers and health technology agencies of-ten find the evaluation of devices challenging. Fur-ther, broader health outcomes research on individual devices is also difficult given procedural payment that does not enable tracking of outcomes benefits via sources like claims data and/or longitudinal pa-


tient medical records. Despite these challenges, the majority of survey respondents felt that the current process managed care uses to evaluate devices (e.g., evaluation by the medical policy Committee of the health plan) is an adequate vehicle for assessment of medical technologies. however, approximately 80 percent of respondents felt there is not a standard way for manufacturers to demonstrate device value to payers or employer purchasers (exhibit 1). because all the necessary or desired information is not deliv-ered consistently, the lack of a standard significantly decreases the efficacy of the mCo evaluation process and suggests that patient access to technologies may be impacted by variability in assessment approaches, as has been demonstrated in other studies of payer technology assessment approaches in the u.s.19

many different factors complicate evaluation of the value of medical technologies, as evidenced by the variability seen in survey responses. almost half of the respondents (47 percent) thought lack of evi-dence was the main factor (exhibit 2). twenty-nine percent thought the lack of analysis standards and difficulty of conducting the analysis was the major issue. three separate small groups of 12 percent each thought the biggest hindrance was either the lack of internal capabilities and/or expertise in medical technology evaluation and/or evidence gaps that may compromise or distort hta results. interest-ingly, only 12 percent of all respondents, and one-fourth of payers who mentioned the lack of evidence considered market incentives to generate evidence as a factor influencing evidence availability. this last

exhibit 2: What do you think is a factor that currently complicatesevaluation of the value of medical technologies?

n = 41

29%

lack of evidence

inadequate standards of hTa

lack of expertise/Capabilities

Variability in how Manufacturerssubmit evidence for review

47%

12%12%

exhibit 1: is there a standard (protocol) for manufacturers to demonstrate device value to payers or employer purchasers?

80%

yesNo

n = 41

20%


point may be a significant issue with the implemen-tation of value-based reimbursement if device man-ufacturers are unable to recover the costs associated with generating the additional evidence required by payer and provider stakeholders. at present, incen-tives are insufficiently aligned for this to occur “or-ganically.”

the major issue is the lack of evidence and dif-ficulty in conducting the analysis (due to gaps in evidence and lack of standardization). payers sug-gested that they are seeking more robust evidence (e.g., robustly designed controlled studies with suf-ficient statistical power), including ideally com-parative evidence, on devices but have historically found sufficient evidence to address key questions and overcome gaps in the evidence and/or weaker study designs for devices. the need for better evi-dence supports the notion of earlier engagement between manufacturers and payers when research is being designed to help fill that gap to the extent possible. this may include alternative study designs, registries or indirect data comparisons to fill gaps in the evidence. additionally, payers in the survey and through discussions of the elC indicated that they would welcome documents like value dossiers or and economic analysis similar to those produced by pharmaceutical companies. Currently, value dossiers and economic analyses are less commonly available from device manufacturers. this provides an op-portunity for device manufacturers to articulate the value story for the product and helps to mitigate the variability in payer and provider hta processes as-sociated with devices and helps the payers by fram-ing and providing supporting evidence aligned with key value drivers.

being able to collect and analyze data on costs and outcomes is essential for implementing value-based reimbursement. a significant complicating factor in determining the overall cost impact of medical devices is the fact that medical devices are rarely re-imbursed directly. the cost of the device is typically embedded into the reimbursement of the procedure or service that uses the device. this makes it diffi-cult for payers, providers and manufacturers to assess the real world evidence of value after new devices have been introduced into care and to characterize comparative effectiveness. multiple solutions could help to address this limitation in device evaluation, including (1) “tagging” each device with a unique identifier or (2) splitting procedural codes for dis-tinct devices so that associated outcomes and costs could be tracked and monitored in the future. how-ever, the latter may be more challenging to execute given the tendency toward bundling versus splitting associated with procedural code development, the need to significantly alter internal tracking/payment systems, and the challenges of reconciling with cod-ing bodies.

as shown in exhibit 3, only 40 percent of survey respondents felt that it is very important or impor-tant to understand the incremental cost impact of individual devices. another 40 percent felt under-standing incremental cost impacts were only some-what important, of minor importance or unimport-ant. twenty percent of payers gave qualified answers that depended upon the scenario, suggesting that emphasis on factors such as volume and incremental cost varies on a case-by-case basis. payers and pro-viders included in the analysis appear to be equally split on their satisfaction with the existing bundled

exhibit 3: how important is it for you to understand the incremental impact of new medical devices when the device in use is included in a bundled payment

and/or the risk is primarily born by the hospital?

n = 41

13%

Very importantimportantsomewhat importantMinor importanceunimportantdepends/unknown

20%

27%

7% 7%

27%


payment system for procedures and/or the need for incremental information on devices to be a priority compared with other health reform efforts.

implementation of Value-based reimbursement Modelsaccording to this survey, a majority (67 percent) of health plans have not yet considered development of value-based reimbursement models for medical technologies (exhibit 4). importantly, approxi-mately one-third of plans have considered develop-ment of these models, though many of these have not enacted reforms that would address aspects of value-based reimbursement for devices. a paper on the implementation of value-based reimbursement implementation by employer groups noted that like the adoption of any new idea there are pioneers (ear-

ly adopters), dabblers, and do-nothings (those who wait and see).7 the plans that have considered these models already may be the early adopters.

although many plans have not yet considered val-ue-based reimbursement models, almost 80 percent of respondents thought these type of models for de-vices were very important or important for improv-ing care and outcomes (exhibit 5). thus, there is a significant disconnect between perception of im-portance and actual implementation of value-based reimbursement models, perhaps due to the level of system change required to reshape existing device payment models. implementation of such models must consider incentives that support change for the key stakeholders, the degree to which such changes would actually improve cost and quality of care (i.e., demonstration of proof of principle), and the cost of

exhibit 5: to what extent do you think that value-based rimbursement for medical technologies is important to improving patient care and outcomes?

unimportant

somewhat important

important

Very important

100%

80%

60%

40%

20%

0%

5%

18%

55%

23%

exhibit 4: has your health plan considered development of value-basedreimbursement models for medical technologies?

n = 41

yesNo

33%

67%


transitioning business models and systems to support value-based reimbursment.

participants were asked how they saw value-based reimbursement being implemented differently from current models (exhibit 6). nearly half of survey participants saw pilots as a necessary step forward. Creation of pilots in focus areas where outcomes/cost gains are anticipated would be a starting place that would enable payers to qualify that potential-gains/efficiencies are possible (i.e., measure) and determine which changes or management practices are likely to drive the most change (i.e., model/test) before broader rollout (implementation).

there was a disagreement among participants of more than two to one, whether reimbursement pre-miums should focus on current practices of higher reimbursement for generally positive outcomes vs. tying pricing premiums to the incremental value. providing limited or no reimbursement for “inad-equate” outcomes may not be an acceptable risk that some manufacturers are willing to take vs. the exist-ing payment system. however, some payer members of the elC suggested that evidence of improved in-cremental outcomes might enable some manufac-turers to engage in targeted contracting discussions outside of procedural payments in the absence of a full value-based pricing mechanism. only a minor-ity suggested the implementation of a medical de-vice formulary as one potential approach.

another issue with determining the value of new technology is having available resources for engag-ing in discussions with medical technology manu-facturers regarding the value of new technologies. survey participants were asked about such resourc-es within their health plan (on a scale of 1 to 10 with 10 extremely resourced). the responses varied

greatly among the plans with no respondent rating their plan as 10 - extremely resourced. the average response was a 6 and these plans suggested a willing-ness to discuss evidence plans and outcomes with manufacturers, with the caveats that (a) time and staff resourcing for such engagement is limited and (b) they are more likely to engage on technologies that have higher clinical and financial impact po-tential.

For payers and providers, respondents indicated that evidence of comparative device value might also be integrated into guidelines or clinical path-ways if available. this may be particularly true in the case of emerging aCo models, where provid-ers are incented to identify and leverage additional care efficiencies or as a means to refine payer cov-erage policies. ideally, availability of comparative evidence would drive use toward the most efficient devices where alternatives exist, including perhaps use in some patient subpopulations where value is strongly differentiated. this could represent a sig-nificant change in access based on available evidence of value, though system incentives do not explicitly support development of such evidence as a common practice.

the survey identified seven possible methods for accomplishing value-based reimbursement pilots/demonstration projects – (1) coverage with evidence development for promising technologies, (2) nego-tiation of differential payments with device manu-facturers that demonstrate significant incremental value versus alternatives, (3) development of de-vice registries for target technology categories for real-world evidence generation, institution of in-dividual technology tracking codes linked to dis-tinct devices/manufacturers, (4) development of a

exhibit 6: how would value-based-reimbursement be implemented differently from current models?

n = 41

29% Pilots/Progressive auth

higher reimb for positive outcomes; limited/none for inadequate outcomes

higher reimb for incrementalimprovement

device formulary

50%

14%7%


medical technology formulary, (5) reducing patient copayments/deductibles for procedures that involve high-value medical technologies, and (6) tiering case rates to account for differential value of medi-cal technologies. participants identified the method they thought “most feasible”. as shown in exhibit 7, the results were heterogeneous with no clear pref-erence on the most feasible method of accomplish-ing value-based payment, potentially indicating that thinking about value-based reimbursment remains in the early stages in the u.s.

the fact that coverage with evidence develop-ment (CeD) for promising technologies is the biggest pie slice in exhibit 7 indicates that if suf-ficient value-based information is available at the time of launch then promising technologies would have a time period to deepen their evidence-base and some technologies may loose coverage or face tighter restrictions depending upon how they com-pare to alternatives.

in practice however, commercial payers have not adopted coverage with evidence development ap-proaches due to the following factors: (a) concerns that actual coverage changes, including subsequent denials, would be more difficult to execute vs. de-nial of coverage at initial reimbursement assessment, (b) perspectives that it is not the payer’s responsibil-ity to fund a products evidence development, and (c) concerns regarding patient and public perceptions if subsequent evidence suggests that coverage denial of these tentative technologies is warranted.

a lead government organization such as the Cen-ter for medicare and medicaid services that more strongly pushes CeD or a public/private u.s. payer network that co-supports CeD may make imple-

mentation of this concept more feasible for broader u.s. payer groups. incentives and opportunities/risks of CeD would need to be more fully explored to support broader adoption, despite respondent in-terest in this approach to support evidence-develop-ment and value-based reimbursement.

survey findings also suggest that stronger differ-entiating evidence may open additional avenues for manufacturer negotiation with payers and providers. elC discussions suggest that high-impact medical technologies with sufficient evidence may be in a better position to support coverage and uptake and have better opportunities to negotiate higher con-tracted rates versus those lacking evidence. howev-er, definitive criteria regarding the therapeutic areas and scenarios that would support alternative con-tracting approaches were not discussed and should be considered in greater detail in future research.

improving coding with individual technology tracking codes linked to existing procedures was also highlighted as an approach that would help sup-port value-based decision making. however, the extent to which this might be done in practice is unclear. more than 75 percent of respondents were willing to consider enacting a device formulary, though only 14 percent think it is the most feasible option to support value-based reimbursement of devices. reducing copays and tiered payment were viewed as the least likely examples of changes that would facilitate value-based reimbursement.

From this survey, it appears that there may not be a clear best approach for implementing value-based device reimbursement. payer and provider stake-holders had highly variable perspectives on the ap-proaches that might enable value-based reimburse-

exhibit 7: Which of the following options would you view as MOsT feasible to support value-based reimbursement pilots/demonstration projects for medical technologies?

14%Coverage

Negotiation

registry

Codes

formulary

reducing Copay

Tiering

18%

14%

27%

n = 41n = 28

18%

5%5%


ment for medical devices. While payers may consider pilots in this area and acknowledge that the existing system has limitations, minimizing risk overall re-mains a key management goal. For manufacturers, cost and time of additional evidence generation may be prohibitive without a clear incentive to support return on the development investment.

survey limitationslimitations of this analysis may include respondent bias, as it was not possible to determine whether re-spondents held a particular interest in medical de-vices and/or are early adopters. based on the lim-ited number of respondents, survey findings may not be fully representative of u.s. medical direc-tor perspectives, but do point to trends in payer and provider views on value-based reimbursement for medical devices.

next steps and future directions mCo medical directors appear to be interested in and understand the importance of value-based reim-bursement but are in the very early days of adoption. there appears to be a disconnect between perceived importance and willingness to alter existing ap-proaches from the payer side. payers are not aligned on a standard definition of value-based reimburse-ment for medical devices, how to calculate value, or how to implement value-based reimbursement pro-grams. Key findings from the survey follow: • there is no standard for medical device manufacturers to demonstrate value to managed care plans in the u.s.

• plans want more rigorous efficacy data to determine the value of devices, but did not offer clear avenues to reward additional evidence generation activities of manufacturers. there is a willingness from many participating payers to evaluate evidence of differential value, engage in early discussions with manufacturers, and welcome of synthesized evidence of value (e.g., dossiers) from manufacturers at present rewarding differential value would be taken on a case-by-case basis and manufacturers could consider one or more of the reward mechanisms noted in this study.

• payers were most willing to consider pilot approaches as a means to test novel value-based reimbursement approaches for devices, suggesting that payer-manufacturer partnerships may be possible under the proper circumstances.

• payers would need to see clearer demonstration points that value-based reimbursement may effectively enable redistribution of the plan before they would consider broadly disrupting

existing payment paradigms for devices (e.g., bundled payment).

this survey suggests several considerations im-portant to building a foundation for value-based re-imbursement for medical devices in u.s. managed care. these include the following:

1. Develop a standard ‘evidence roadmap’ for medical devices which identifies key decision crite-ria and aligns evidence generation approaches (e.g., study designs) with the most important questions and value drivers.

this would be a useful step toward improving the clarity and consistency of device assessment. evi-dence standards for devices would also help ensure that manufacturers, payers and policy makers are “working from the same playbook” and have de-fined “rules of the road” for evidence development. evidence standards must be robust enough to satisfy payer decision makers and ensure that introduction of new devices does not result in unnecessary access barriers. evaluation of stakeholder incentive struc-tures would also support realignment of incentives in a manner palatable to key stakeholders and may be a necessary parallel step toward supporting more comprehensive evidence generation efforts to char-acterize device value.

2. Develop standard approaches for modeling and calculating medical device value.

this would simplify uncertainties in device as-sessment and should be aligned with standard evi-dence development approaches. this would also require developing a more standard perspective on definitions of value-based reimbursement for medi-cal devices.

3. establish strategic partnerships with data/ana-lytics companies, mCos, aCos, and manufacturers to develop the standards and analysis approaches

since payers seem to willing to entertain pilots and have little agreement over the appropriate methods to implement value-based reimbursement, a stra-tegic partnership with data/analytics companies to develop the standards and analysis approaches may increase payer acceptance of value-based reimburse-ment and improve the evidence base being presented by manufacturers. in some cases, this could involve multiple manufacturers of a particular device type taking a combined approach to payer partnering around new value demonstration models, where de-vice applications are sufficiently similar (e.g., diag-nostic imaging, orthopedics, spinous implantables, topical drug-device delivery systems). by taking an informed, proactive approach to the evolving mar-ket trend regarding value-based reimbursement, medical device manufacturers have the opportunity to help sustain ongoing product innovation and suc-


cess in the marketplace. however, pilot designs must be strategically aligned with incentives and decision drivers and have clear anticipated benefits to have the greatest likelihood for payer acceptance.

We remain at the earliest stages of considering value-based reimbursement models for devices in the u.s., but this paper suggests several avenues that may enable advancement and exploration of the concept. the extent to which value-based-reim-bursement approaches may allow payers to continue to contain costs while incentivizing manufacturers to significantly improve patient outcomes and inno-vation remains to be seen, but is most likely to move forward initially in small and measured steps.

eric faulkner, co-director, NaMCP genomics, Biotech, & emerging Medical Technologies institute, director, global Market access, Quintiles. Joshua ransom, co-director, NaMCP genomics, Biotech, & emerg-ing Medical Technologies institute, Principal Consultant, Quintiles. natalie heidrich, director, National Payers and strategic initia-tives, ethicon. brad lucas, Md, National Medical director, Centene.geneva briggs, pharmd., BCPs, Briggs & associates.

acknowledgements: Our thanks and acknowledgements to the ge-nomics, Biotech, and emerging Medical Technology institute of the National association of Managed Care Physicians, representing over 90 commercial payers, provider executives, and health care technol-ogy manufacturers.

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introductionaDvantaGe health solutions, inC. (ahs), a local health plan that insures many em-ployer groups in indiana, wanted to test the hy-pothesis that provider engagement with aligned incentives could improve outcomes on a specific population with a benefit structure typically not amenable to usual health plan interventions. one of the large employer groups insured by ahs with about 5,000 employees and dependents has a benefit plan that does not discourage over utilization of cer-tain low-value but high-cost medical services and is not amenable to the usual utilization management

strategies. For example in 2011, the copayment for pCp office visits was $25; copayment for emergen-cy room visits was $0; copayment for advanced im-aging services such as computed tomography (Ct), magnetic resonance imaging (mri) and positron emission tomography (pet) scans was $0; and the cost differential between generic and brand name drugs was just $5.

there was overutilization of emergency room services for nonemergent problems that was nei-ther cost effective nor safe for the members. most of these nonemergent conditions like upper respiratory illnesses (uri), urinary tract infections (uti) and

summaryPhysician engagement is critical to the success of any program where physicians are accountable for the quality, cost and overall care of an assigned population of patients like an accountable care organization (aCO). it is well known that physi-cians control the majority of health care cost. however, as overall health care cost is a factor of unit cost and utilization rate of services, physicians could impact utiliza-tion of services but still not be able to control overall health care cost due to lack of control of cost of hospital-based services and outpatient procedures. The aCO could mitigate this problem through price transparency – where providers are given ready access to the unit price of certain high-cost services by the provider and facil-ity so they can direct their patients to lower cost settings/providers assuming the quality of care is comparable. The aCO could also provide the referring physicians a list of preferred specialists or hospitals with not just lower pricing but also better outcomes.

Key points• The level of physician engagement could directly affect the level of achievement of the triple aim – better care for individuals, better health for populations and lower growth in expenditures.• Physicians make decisions that control 87 percent of health care costs.1• alignment of incentives will increase physician engagement.• Overall cost is determined by both utilization of services and unit cost of services.• Physicians, especially primary care physicians (PCPs), have very little control over the cost of hospital- based services and most outpatient procedures.• To improve overall cost, providers should partner with hospitals to reduce both utilization and unit cost of services. although aCOs sponsored by physician groups have seen more growth recently, the majority of aCOs are still sponsored by hospitals5. To remain competitive in the post health care reform environment, these hospital-sponsored aCOs have to reduce overutilization of services and lower their pricing. The lost revenue from reducing unit cost and decreasing over utilization of services could be recouped from the shared savings agreements with payers.

Physician Engagement is Critical to the Success of any Accountable Care Organization

anthony N. akosa, Md, MBa


suture removals could have been easily handled by the members’ primary care physicians.

Creating a medical home for every member would give them access to personalized, coordinated and comprehensive primary care when it is convenient for them. this would improve both the quality of care provided to the members and member satis-faction. ahs also felt that physician engagement would be the key to decreasing the overutilization of some of these low-value but high-cost services as physicians serve as key advisors to patients and make decisions that control 87 percent of personal health spending.1

program goals and objectivesthe goals of the program are similar to achieving the institute for healthcare improvement (ihi) triple aim: improve the health of the population, enhance the patient experience of care (including quality, access, and reliability); and reduce, or at least control, the per capita cost of care.2

the program objectives are: avoidance of unnec-essary utilization, especially emergency room and advanced imaging (Ct, mri and pet scans); uti-

lization of services at the right place and right time; for example, encouraging the members to utilize urgent care centers after hours for nonurgent prob-lems like uri instead of going to the er; part-nering with providers to promote outreach, health prevention and patient engagement; improving ge-neric utilization rate when appropriate by providing generic alternatives at point of care (provider prac-tices); and improving member satisfaction of overall care provided.

there were three provider groups in one of the counties in indiana to whom all the members were assigned and they were named provider Group 1 (Group 1), provider Group 2 (Group 2) and pro-vider Group 3 (Group 3). ahs met with Group 1 and Group 2 to explain the program, the provider incentive and the provider Dashboard for each pro-vider. Group 3 was not engaged in the program and did not meet with ahs. although Group 3 was not engaged, ahs still sent information about the pro-gram to the members assigned to them.

the program was called a shared savings incen-tive program and comprises:

• member engagement activities

exhibit 1: advantage health solutions, inc.sm — Zero Copayment Prescription drug listing for 2011

acyclovir (ZOViraX)albuterol soln neb (aCCuNeB)allopurinolamitriptyline (elaVil)amitriptyline hcl/perphenazine (eTrafONe/fOrTe)amitriptyline hcl/perphenazine (TriaVil)amitriptyline/chlordiazepixide (liMBiTrOl)amoxicillin & k clavulanate (augMeNTiN)amoxicillin & k clavulanate susp (augMeNTiN susP)amoxicillin (aMOXil)antipyrine/benzocaine (auraglaN)atenolol (TeNOrMiN)atropine sulfate (isOPTO aTrOPiNe)baclofen (liOresal)belladonna alkaloids (aNTi-sPas)belladonna alkaloids (dONNaTal)benazepril (lOTeNsiN)benzonatate (TessalON Pearls)benztropine (COgeNTiN)betameth/propylene glycol (diPrOleNe af)betameth/propylene glycol (diPrOleNe)betamethasone dipropionate (diPrOsONe)betamethasone dipropionate (MaXiVaTe)betamethasone valerate (ValisONe)bisoprolol (ZeBeTa)bumetanide (BuMeX)buspirone (BusPar)captopril (CaPOTeN)captopril/hctz (CaPOZide)carbamazepine (TegreTOl)carbamazepine sr (TegreTOl Xr)carvedilol (COreg)cephalexin (KefleX)chlorhexidine (PerideX)cimetidine (TagaMeT)ciprofloxacin (CilOXaN)citalopram (CeleXa)

clonidine (CaTaPres)clonidine hcl/chlorthalidone (COMBiPres)cyclobenzaprine (fleXeril)dexamethasone (deCadrON)dexamethasone (heXadrOl)diclofenac ophth sol (VOlTareN OPhTh sOl)diclofenac potassium (CaTaflaM)diclofenac sodium (VOlTareN/Xr)dicyclomine (BeNTyl)digoxin (laNOXiN)diltiazem (CardiZeM/sr/Cd)diltiazem (dilaCOr Xr)diltiazem (TiZaC)doxazosin (Cardura)doxepin (siNeQuaN)doxycycline hyclate (PeriOsTaT)doxycycline hyclate (ViBraMyCiN)doxycycline hyclate (ViBra-TaBs)enalapril (VasOTeC)enalapril/hctz (VasereTiC)erythromycin base (eMgel)erythromycin base (e-MyCiN)erythromycin base (eryCeTTe)erythromycin base (eryderM)erythromycin base (erygel)erythromycin base (eryMaX)erythromycin base (T-sTaT)erythromycin base/benzoyl peroxide (BeNZaMyCiN)erythromycin ethylsuccinate (e.e.s.)erythromycin ethylsuccinate (ery-Ped)erythromycin stearateerythromycin/sulfisoxazole (PediaZOle)estradiol (esTraCe Tabs)estropipate (OgeN)estropipate (OrThO-esT)famotidine (PePCid)fluconazole (difluCaN)

fluconazole susp (difluCaN susP)fluocinolone acetonide (syNalar)fluocinonide (lideX/e)fluoxetine (PrOZaC)fluphenazine hcl (PerMiTil)fluphenazine hcl (PrOliXiN)furosemide (lasiX)gentamicin (garaMyCiN)gentamicin (geNOPTiC)glimepiride (aMaryl)glipizide & metformin (MeTagliP)glyburide (diaBeTa)glyburide (glyCrON)glyburide (glyNase)glyburide (MiCrONase)glyburide/metformin (gluCOVaNCe)guanfacine (TeNeX)hctz/amiloride (MOdureTiC)hctz/atenolol (TeNOreTiC)hctz/bisoprolol (ZiaC)hctz/propranolol (iNderide)hctz/triamterene (dyaZide)hctz/triamterene (MaXZide)hydralazine (aPresOliNe)hydralazine/hctz (aPresaZide)hydrocortisone (COrTef)hydrocortisone (COrTeNeMa)hydrocortisone (hTyONe)hydrocortisone (laCTiCare-hC)hydrocortisone (NuTraCOrT)hydrocortisone (PeNeCOrT)hydrocortisone (PrOCTOCOrT hC)hydrocortisone acetate (aNusOl hC)hydrocortisone acetate w/pramoxine cr (aNalPraM-hC)hydrocortisone acetate/urea (CarMOl hC)hydrocortisone butyrate cr (lOCid)hydrocortisone valerate (WesTCOrT)ibuprofen (MOTriN)


• provider engagement activities• health navigator activities

Member engagement activitiesmarketing collateral to educate members about the program was completed in the first quarter of 2011. the educational campaign informed the members how the program would benefit them by providing improved access to providers, $0 copayment for spe-cific generic drugs, decreased unnecessary emergen-cy room (er) and advanced imaging utilization to improve patient safety. it is known that unnecessary use of all forms of ionizing radiation, especially Cts in children, could increase cancer risk. Frequent er visits for nonurgent conditions could increase the risk of nosocomial infection and uncoordinated care with poorer outcomes.

ahs developed a zero copayment drug list for 2011 (exhibit 1) and the plan paid 100 percent of the cost of any of the drugs on this list in 2011. if the provider felt the drugs on this list were not ap-propriate for the member or the member requested a brand name drug, then the member would be re-sponsible for the appropriate copayment specified in

the employer’s prescription Drug Coverage benefit. ahs identified members who were on brand name drugs that were available generically. these mem-bers were sent a letter listing all their brand name drugs, generic alternatives and annual cost savings if their providers switched them to generic alternatives (exhibit 2.)

to make it more convenient for the members to obtain their prescription medications, ahs part-nered with a local pharmacy that offers concierge services to members such as the delivery of medica-tions to home and place of work. the pharmacy also has branches at two provider practices. the phar-macy could dispense drugs prescribed by the pro-viders at point of care, thereby increasing adherence and generic utilization. members could still utilize other pharmacies of their choice and do not have to use the pharmacy ahs partnered with.

ahs also embedded a health navigator in one of the provider practices to work directly with the pro-viders and members. her role was to facilitate care management processes to promote awareness and compliance by identifying members with chronic conditions that ahs has Disease management (Dm)

exhibit 1: advantage health solutions, inc.sm — Zero Copayment Prescription drug listing for 2011

indapamide (lOZOl)indomethacin (iNdOCiN/sr)ipratropium (aTrOVeNT Nasal sPray)ipratropium/albuterol neb soln (duONeB)isoniazid & rifampin ( rifaMaTe)isoniazid (isONaZid)isoniazid (NydraZid)isosorbide dinitrate (dilaTraTe-sr)isosorbide dinitrate (isOrdil)isosorbide dinitrate (sOrBiTraTe)isosorbide mononitrate (iMdur)lactulose (CePhulaC)lactulose (ChrONulaC)lactulose (duPhalaC)lactulose (eNulOse)levobunolol (BeTagaN)levothyroxine (leVOThrOid)levothyroxine (syNThrOid)levothyroxine (uNiThrOid)lidocaine cr (lMX 4)lisinopril (PriNiVil)lisinopril (ZesTril)lisinopril/hctz (PriNZide)lisinopril/hctz (ZesTOreTiC)lithium carbonate (esKaliTh/Cr)lithium carbonate (liThOBid)lithium carbonate (liThONaTe)lithium citrateloratadine (ClariTiN) OTClovastatin (MeVaCOr)medroxyprogesterone (PrOVera)medroxyprogesterone iM (dePO-PrOVera)megestrol (MegaCe)meloxicam (MOBiC)metformin (gluCOPhage)metformin Xr (gluCOPhage Xr)methyldopa (aldOMeT)methyldopa/hctz (aldOril)

methylprednisolone (MedrOl)metoclopramide (reglaN)metoprolol succinate er (TOPrOl Xl)metoprolol tartrate (lOPressOr)metronidazole (all forms)nadolol (COrgard)naproxen (eC-NaPrOsyN)naproxen (NaPrOsyN)naproxen sodium (aNaPrOX ds)neomycin suf/polymy/buffers/hc (PediOTiC)neomycin sulfate/hcneomycin sulfate/polymyxin/hc (COrTisPOriN)neomycin/bacitracin/polymyxin (NeOsPOriN)neomycin/polymyxin/dexameth (deXaCidiN)neomycin/polymyxin/dexameth (MaXiTrOl)nortriptyline (aVeNTyl)nortriptyline (PaMelOr) nystatin (MyCOsTaTiN)nystatin (NilsTaT)oxybutynin (diTrOPaN)oxybutynin sr (diTrOPaN Xl)paroxetine (PaXil)paroxetine cr (PaXilCr)paroxetine susp (PaXil susP)penicillinphenazopyridine (PyridiuM)pilocarpine hcl (salageN)pilocarpine hcl (PilOCar)pilocarpine hcl/epinephrine (e-PilO)polymyxin b sulfate/tmp (POlyTriM)pravastatin (PraVaChOl)prazosin (MiNiPress)prednisone (delTasONe)prochlorperazine edisylate (COMPaZiNe)

promethazine (PheNergaN)propranolol (iNderal)ranitidine (ZaNTaC)selenium sulfide (eXsel)selenium sulfide (selsuN)silver sulfadiazine (silVadeNe)sodium citrate/citric acid (CyTra-2)sotalol (BeTaPaCe/af)spironolactone (aldaCTONe)spironolactone/hctz (aldaCTaZide)sulfacetamide sodium (BlePh 10)sulfacetamide sodium lot (seBiZON/KlarON)sulfacetamide/prednis sp (VasOCidiN)sulfacetamide/prednisolone ac (BlePhaMide)sulfacetamide/sulfur, sublimed (NOVaCeT)sulfacetamide/sulfur, sublimed (PleXiON)sulfacetamide/sulfur, sublimed (sulfaCeT-r)terazosin (hyTriN)terbinafine (laMisil)tetracycline (aChrOMyCiN)thioridazine (Mellaril)thioridazine (Mellaril-s)thiothixene (NaVaNe)timolol (BlOCadreN)timolol (TiMOPTiC/Xe)tobramycin (TOBreX)tobramycin/dexamethasone (TOBradeX)trazodone (desyrel)triacinolone acetonide (arisTOCOrT)triacinolone acetonide (KeNalOg)triamcinolone acetonide (KeNalOg W/OraBase)trihexyphenidyl (arTaNe)verapamil (CalaN/sr)verapamil extended-release (isOPTiN/sr)warfarin (COuMadiN)


programs for whom the Disease management edu-cators were unable to contact. the health naviga-tor worked with providers’ offices to find out when members who did not respond to ahs’s Dm cam-paign were scheduled to see their pCp and discussed Dm participation and incentive/benefits with the pCp and/or member. the health navigator also re-ferred members who qualified for case management and behavioral health management programs based on the health plan’s identification process.

all the members received a provider survey at the beginning of the second quarter of 2011 utilizing the Cahps® (Consumer assessment of healthcare providers and systems) Clinician & Group survey, and a follow-up survey with the same tool was sent out to the same members 12 months later.

provider engagement activities before and after the program, ahs tracked four categories of metrics by provider groups that includ-

exhibit 2

June 2011

JOhN dOeaBC driVeCiTy, sTaTe ZiP

RE: Generic Alternatives / Copay Savings

dear adVaNTage Member:

We want you to know that you may be able to save money on some of your prescription drugs. as you may know, many brand name drugs are available as a generic. for those drugs not yet available generically, there may be a different drug like it that has a generic.

you may be able to save money on your copays by talking to your doctor about other choices. The next page shows a list of your drugs with a different drug available as a generic for lower copay.

read the list and see how much money you could save! We know these changes are not right for everyone. Only you and your doctor can decide if a change is right for you. This change could lead to savings on your copay up to the amount you see listed over the course of a year.

if you have questions about your prescription drugs, ask your doctor or phar-macist for more information. also, you could save even more by using the mail order pharmacy. Visit www.advantageplan.com to find out more about your prescriptions, the mail order pharmacy, the Care-ADVANTAGE program, or the special Chrysler Only Zero Copay Medication list.

sincerely,adVaNTage health solutions, inc.

Common Brand Name Medications and alternatives

retail Prescription drugs -up tp 30-day supply

drug Copay alternative Copay annual

siNgulair (montelukast) 12 zafirlukast (aCCOlaTe) 6 $72

CresTOr (rosuvastatin) 12 simvastatin (ZOCOr) 0 $144

Total savings in 12 months $216


ed utilization, member satisfaction, and quality and disease management participation.

the providers were incentivized based on their individual performance on the three utilization metrics compared to the benchmark that was ahs Commercial average rates. the utilization metrics

were: utilization of generic prescription, utilization of er and utilization of advanced imaging (Ct, mri and pet.) two-thirds of the total incentive was allocated to improving generic prescription uti-lization because it was felt that was the metric that would be easiest for the providers to impact, and it

exhibit 3

Benchmarks

generic utilization Percentage

advanced imaging rate /1000

er rate/1000

75% 216 214

Provider Metrics

date Number of Members

generic utilization Percentage

advanced imaging rate/1000

er rate/1000

January 11 187 68.63% 64.17 705.88

february 11 187 64.05% 128.34 192.51

March 11 188 71.51% 255.32 319.15

april 11 189 67.54% 698.41 571.43

May 11 189 66.77% 63.49 444.44

June 11 188 63.00% 63.83 382.98

July 11 197 69.01% 304.57 487.31

august 11 197 67.59% - 1,035.53

september 11 194 65.15% 123.71 123.71

October 11 193 62.55% 186.53 746.11

November 11 197 64.60% 60.91 365.48

december 11 197 66.67% 243.65 487.31

Payout Calculation

date Number of Members

generic 50% level

generic 75% level

generic 100% level

advanced imaging

50% level

advanced imaging

75% level

advanced imaging

100% level

er 50% level

er 75% level

er 100% level

Monthly Total

January 11 187 467.50 467.50

february 11 187 467.50 467.50 935.00

March 11 188 940.00 235.00 1175.00

april 11 189 -

May 11 189 472.50 472.50

June 11 188 470.00 470.00

July 11 197 -

august 11 197 -

september 11 194 485.00 485.00 970.00

October 11 193 482.00 482.50

November 11 197 492.50 192.50

december 11 197 246.25 246.25

grand Totals $940.00 - - $481.25 - $3,337.50 - - $952.50 $5,700.25

(chart cont. next page)


was also the metric that had the highest variance from the ahs benchmark. the other two met-rics combined accounted for a third of the incentive. each provider received a quarterly report of his/her performance on these three metrics and also the incentive payout for that quarter (exhibit 3). the providers also received a report comparing them to their peers - all the other providers in that particular group excluding their names (exhibit 3). Group 3 providers did not get any incentive or quarterly re-port of their performance.

ahs met with Group 1 and 2 providers to explain the program and get buy-in. the series of meetings with the providers were completed in april 2011. Group 1 providers met with ahs initially and their management team subsequently had multiple meet-ings with these providers to explain the program and quarterly results. Group 2 providers met with

ahs only once and there were no subsequent meet-ings with the providers.

the provider Dashboard reports were available to the providers monthly and displayed utilization, financial and quality metrics by providers bench-marked against their peers. the provider Dash-board had over 40 metrics, including the three that the providers were incentivized on. the providers were initially given a hard copy of their individ-ual dashboards and were instructed to inform the health navigator to provide them with monthly updates from the health plan’s web-based report-ing platform. the providers also had access to each of his/her patients’ member Dashboard reports through the health navigator, and it displayed gaps in care, chronic conditions, medications and prospective risk score for each provider’s patient panel. the prospective risk score is used to predict

exhibit 3 (cont.)

Payout distribution schedule

date Method amount

distribution #1 6/30/2011 50% of 1st Quarter 2011 earnings

$1,288.75

distribution #2 9/30/2011 50% of (2011 yTd earn-ings less distribution #1

$471.25

distribution #3 12/31/2011 50% of (2001 yTd earn-ings less distribution #

1 and #2

$485.00

distribution #4 3/31/2012 Total 2011 earnings less distributions #1, #2, #3

$3,466.25

Provider Payout Metrics

utilization of generic Prescriptions

utilization rate amount of Payout $10pmpm/Total $15pmpm

70% - 72.4% 50% = $5.00 pmpm

72.5% - 74.9% 75% = $7.50 pmpm

75% 100% = $10.00 pmpm

utilization of emergncy services

utilization rate amount of Payout $2.5pmpm/Total $15pmpm

239 - 263 50% = $1.25 pm pm

215 - 238 75% = $1.87 pmpm

0 - 214 100% = $2.50 pmpm

utilization of advanced imaging services (CT, Mri, PeT)

utlization rate amount of Payout $2.5pmpm/Total $15pmpm

238 - 262 50% = $1.25 pmpm

217 - 237 75% = $1.87 pmpm

0 - 216 100% = $2.50 pmpm


future health care cost based on the chronic disease burden of the particular member, and it is normal-ized for that particular population. For example, a member with a score of 10 is expected to cost the plan 10 times the average cost of that particular population in 12 months.

health navigator activities as cited previously, ahs also “embedded” a health navigator in one of the provider offices, but she traveled to the other practices to meet with the pCps and their office staffs. the embedded health navigator worked closely to engage the providers to coordinate the care of the assigned plan members, implement up-to-date coordinat-ed care plans and communicate with the whole health care team on behalf of the assigned plan members. she acted as a resource and liaison with providers regarding the programs that make up ahs care management programs and other related health plan initiatives. the health navigator was also available for questions that the providers had about the program and a few of the providers took advantage of this.

she educated provider offices on the use of pro-vider portal (especially for prior authorization re-quests) to improve efficiency and provider satisfac-tion. ahs piloted automated prior authorization (auto auth) system utilizing milliman Care Guide-lines with all the providers to improve efficiency

in their offices and reduce the number of calls they have to make to the health plan to request prior au-thorization. the auto auth system allows the pro-vider or office staff to enter an authorization request and if it meets the milliman evidence-based clinical guidelines, the requester would immediately receive an approval notice, thereby avoiding a phone call or fax to the health plan. the health navigator also informed providers of the partnership with the local pharmacy to provide easy access to generic drugs at point of care for patients.

the health navigator was also responsible for coordinating the member satisfaction surveys, tracking the quality metrics and care coordina-tion activities. member satisfaction was measured with the Cahps® Clinician & Group survey re-sults. Quality metrics include breast cancer screen-ing rates, colorectal cancer screening rates, and comprehensive diabetic care eye exam rates. the disease management participation rate was the per-centage of members with chronic diseases that were enrolled in these programs. the chronic diseases that were targeted include hypertension, diabetes mellitus, coronary artery disease, congestive heart disease, chronic obstructive pulmonary disease, asthma and migraine.

the health navigator worked with the local hos-pitals in the area to set up daily emergency room (er) and inpatient notification processes. this helped ahs contact members who were seen in

exhibit 4

group 1 4th Quarter 2011

Provider Provider address

Provider City

Provider state

Provider Zip

Values sum of 4th

Quarter 2011 Payout

sum of Members

Physician 1 dr. Jane doe 123 river road

indianapolis iN 46240 3,466.25 197

Physician 1 2,880.39 122

Physician 2 3,837.69 224

Physician 3 2,983.75 242

Physician 4 942.22 111

Physician 5 3,296.88 149

Physician 6 3,466.25 193

Physician 7 1,825.46 158

Physician 8 1,283.75 64

Physician 9 3,547.50 200

grand Total 27,530.14 1,660


the er in a timely fashion rather than utilize our current process where we use claims data that takes three months or more. the inpatient census helped improve our discharge coordination outreach and complex case management components of our care management program.

results and discussion the Group 1 providers were considered highly en-gaged. Group 2 providers were considered moder-ately engaged, and Group 3 providers were con-sidered unengaged. Group 3 was considered the control groups as these providers were not engaged

exhibit 5

Measurement

utilization goal group 1 group 2 group 3 all groups

generic utilization rate % Baseline 75% 62% 65% 67% 64%

end of Program 67% 68% 70% 68%

% Change 5% 3% 3% 4%

p-value <0.05 <0.05 <0.05

advanced imaging rate (CT,Mri,PeT)/1000

Baseline 216 284 316 415 314

end of Program 211 173 195 190

% Change -26% -45% -53% -39%

p-value <0.05

<0.05 <0.05

er rate/1000 Baseline 214 232 296 229 264

end of Program 214 283 233 251

% Change -8% -5% 2% -5%

p-value <0.05 <0.05 0.65

satisfaction

Member satisfaction rate (Overall satis-faction for adult patients)

Baseline 88.42%

end of Program 88.25%

% Change 0.17%

p-value 0.97%

Quality

Breast Cancer screening Baseline 70% 63% 60% 66%


% Change -5% -7% -4% -5%

p-value <0.05 <0.05 <0.05

Colorectal Cancer sreening Baseline 40% 38% 37% 39%


% Change 6% 3% 11% 5%

p-value <0.05 <0.05 <0.05

diabetic eye exam Baseline 33% 22% 33% 28%


% Change 6.3% -4.0% -7.6% 1.6%

p-value <0.05 <0.05 <0.05

disease Management Participation

Care-adVaNTage participation rate Baseline 42%

end of Program 41%

% Change -1%

p-value <0.05


in the program but their patients received the same intervention letter that members assigned to Group 1 and 2 did (exhibit 2). ahs compared 2010 (base-line) versus 2011 provider performance despite the fact that the series of meetings with the providers was not completed until april 2011.

the per member per month (pmpm) cost for the population increased by 5 percent from 2010 to 2011. however, most of the affiliated hospitals in-creased their charge master from 2010 to 2011 as ev-idenced by the increased unit cost for most services by 9 percent. the pmpm cost is a factor of utiliza-tion and cost of services. the providers can control utilization of most services but have very little, if any, control over the cost of hospital-based services. the providers did not have access to the unit cost of services and were required to refer patients within their network of providers unless the service was not available in their network.

When the 2011 pmpm was recalculated using 2010 cost of all services, the recalculated pmpm was down by 1.7 percent due to decreased overuti-lization of services. in comparison, the average an-nual growth rate for national health expenditure (nhe) from 2000 to 2010 was 5.6 percent.3 When adjusted for average annual inflation of 2 to 4 per-cent, the recalculated pmpm was still lower than the average nhe annual growth rate.4 We calculat-ed the total cost savings for the three components of the program (generic drug, advanced imaging and er utilization) divided by the total payout to all the providers in 2011, and the return on investment (roi) on the program was 8:1.

the three objectives of the program were met for the employer group – increased generic utilization, decreased emergency room and advanced imaging utilization. however, some of the provider groups did better than the others. the generic utilization from 2010 to 2011 increased by 5 percent, 3 percent and 3 percent for Groups 1, 2 and 3 respectively, and all the increases were statistically significant (exhib-it 4). the overall generic utilization for all groups increased by 4 percent mainly due to provider in-centive and member education. the group that was most engaged (Group 1) had the highest increase in generic drug utilization. the nonengaged group (Group 3) still had an increased generic utilization, most probably due to member education as the let-ter provided in exhibit 2 was sent to all members regardless of whether their providers were engaged or not.

the emergency room utilization decreased by 8 percent and 5 percent for Group 1 and 2 respective-ly, but increased by 2 percent for Group 3. although the Group 3 increase was not statistically significant,

it is worth noting that ahs relied on providers to decrease unnecessary emergency room utilization. ahs will not deny any unnecessary er visit if the member was directed to the er by his/her provider regardless of whether the visit meets prudent layper-son definition of an emergency or not. like most health plans, ahs uses an auto pay list for er ser-vices so that certain diagnosis of er services such as fractures are automatically paid and not pended for medical review. We turned off the auto pay list for this employer on June 1, 2011 and manually re-viewed all the er visits. before applying the pru-dent layperson rule as required by the state law, we contacted the member’s provider to ask the office staff if they referred the member to the er. if they did not, ahs then applied the prudent layperson rule in determining whether the visit would be ap-proved or not.

advanced imaging utilization decreased for all three groups and all were statistically significant. ahs also implemented an automated precertifi-cation tool utilizing milliman Care Guidelines in 2011 and advanced imaging was added to the prior authorization list. although Group 3 had a higher decrease in advanced imaging than the other two groups, this was probably due to the precertification requirement rather than provider engagement.

the quality metrics that were tracked were breast cancer screening, colorectal cancer screening and diabetic eye examination. the breast cancer screen-ing decreased in all three groups in 2011 while the colorectal cancer screening increased. Group 3 had the lowest breast cancer screening decrease and the highest colorectal cancer screening increase of all three groups. only Group 1 had an increase in dia-betic eye examination rate (6.3 percent) and Group 3 had a higher decrease than Group 2 (exhibit 4). the quality measure results were mixed probably because the providers were not incentivized on these measures and the program lasted for less than 12 months due to the longer than anticipated pro-vider engagement process of four months.

the participation in care management (Care-aD-vantaGe program) also decreased from 42 per-cent in 2010 to 41 percent in 2011. the Care-aD-vantaGe program includes these disease states: diabetes mellitus, congestive heart disease, chronic obstructive pulmonary disease, hypertension, mi-graine, asthma and coronary heart disease. this is an opt-out program where members are enrolled auto-matically but have the option to disenroll themselves. the average ahs Commercial line of business par-ticipation rate in 2011 was 38 percent. however, the complex case management (CCm) participation rate for the sickest members (top 0.5 -1 percentile of the


population) increased by 53 percent from 2010 to 2011. this was mainly due to the er and inpatient notification process managed by the health naviga-tor. the CCm program is for members with com-plex medical needs regardless of diagnosis.

the adult Cahps® Clinician & Group survey was administered to all the adult members and a fol-low-up survey was also sent out 12 months later to only those who responded to the initial survey. the overall satisfaction rate before and after the program for all the groups was 88.42 percent and 88.25 per-cent indicating no statistically significant change. the baseline survey results were not shared with the pro-viders and this could have contributed to the results.

conclusionengaged primary care physicians can bend the cost curve by effectively managing overutilization of services, especially for medicare shared savings program (mssp) and pioneer aCos where provid-ers do not have to worry about unit cost variation especially for hospital-based services and outpatient procedures for which they have very little control over. this is because Centers for medicare and medicaid services (Cms) is the sole payer for the mssp and pioneer aCo programs.

however, this strategy might not be as effective for Commercial aCos with multiple payers due to price variations, but this could be mitigated by price transparency and empowering providers to utilize this information in their decision-making process. this relatively short pilot program produced an roi of 8:1.

the providers were incentivized on the three uti-lization metrics (generic prescription, er and ad-vanced imaging rates) only and the engaged provid-ers generally had a better outcome. this study did not show an improved outcome on the “better care for individuals” and “better health for populations” of the triple aim probably because the providers were not incentivized on the related metrics.

anthony n. akosa, Md, Mba is the VP of Medical affairs and infor-matics at adVaNTage health solutions, inc.sM and is an assistant Professor in the department of family Medicine at indiana university school of Medicine.

acknowledgementsThe author would like to extend his gratitude to the ahs employees listed below. The study would not have been possible without their commitment of time and effort. shelly leary, MBa, CCP (health Navi-gator); linda york, Phd., fNP, rN, CMC (director Medical affairs); Phil-ip yadon (Quality analyst); Brian W. Musial, rPh (director of Pharma-cy), Toni Williams, Bs (Care Management analyst) and hunter heniser, Mha (Medical affairs intern).

references1. sager a. and socola D., “health Costs absorb one-Quarter of economic

Growth, 2000–2005,” Data brief no. 8, boston, ma: boston university

school of public health, February 2005. www.ihi.org/offerings/initiatives/

tripleaim/pages/measuresresults.aspx

2. health Care Costs: a primer. Key information on health Care Costs and

their impact. may 2010. www.kff.org/insurance/upload/7670-03.pdf

3. leavitt partners: Growth and Dispersion of accountable Care organizations.

June 2012 update. www.usinflationcalculator.com/inflation/historical-infla-

tion-rates/


barriers to integrationthere are many barriers that have precluded true integration between medical and be-havioral health. in general, primary care physicians lack the training to properly diagnose and treat men-tal illness conditions. a complementary component of this barrier is the lack of physicians. nationwide, there is a shortage of both primary care physicians and psychiatrists; conversely, there is a rising demand for mental health services, causing a gap in health care treatment. For those areas in which physician short-ages are not an issue, payment becomes a primary obstacle. Financial reimbursement for health care is addressed differently for each sector and contributes to a silo effect that maintains separation between be-havioral health and other medical services. logisti-cally, billing is generally completed independently between care providers, and often the distinctions in care, coding, and general practice areas, mean that different systems that may not be compatible are in place. ensuring that all parties are appropriately re-imbursed is an important piece of integration, and there is great opportunity for financial/billing prac-

tice models to be developed to eliminate this bar-rier to integration. Coding additionally needs to be examined to ensure that there is an integration of coding, or complementary coding, in place and that all parties and practice types are knowledgeable as to how to best utilize this coding to accurately reflect services provided, and receive appropriate compen-sation. Finally, barriers to care are further expanded when there is a lack of adoption of communication strategies between the two sectors. Care manage-ment and Case management are offering some im-provements to this area, but for most providers the communication gap is still in place.

potential integration Models

The Chronic Care Modelthe Chronic Care model begins with outpatient and strives to identify behavioral health disorders early in the process. the cost savings, with early detection of mental health issues, and depression in particular, are derived from fewer emergency room admissions/readmissions. (exhibit 2).

summaryhealth care costs are rising in uncontrollable rates. One of the major components of health care expenses is Behavioral health and the lack of integration between behavioral and medical care. Currently, each sector is treated independently, which is sometimes referred to as the silo effect. This silo effect contributes to the rising health care costs and simultaneously provides a disservice to the patient. Many patients who are treated in a primary care setting additionally have mental health issues. The integration of medical and behavioral health can help reduce costs and provide better quality care.

Key points• Top 5 percent of patients using 50 percent of health care resources• 60 to 80 percent have co-morbid mental conditions• 70 to 85 percent receive no mental health treatment• 80 to 90 percent with a mental health condition see no mental health specialist• 5 to 15 percent get mental health treatment and would be expected to improve outcomes

How Behavioral Health Integration Can Reduce Health Care Costs

Mark rosenburg, Md, Phd


The Stepped Care Approachthe stepped Care approach strives to provide care that is the least disruptive for the patient and least extensive, intensive and expensive needed for optimal results.2 the 4 Quadrant model identi-fies which populations are best served in the pri-mary care setting, which are best served in the be-havioral health setting, and which may be served in either. (exhibit 3)

potential solutionsthere are many issues surrounding the integration of behavioral health. Fortunately, there are many proactive solutions that may be implemented sepa-rately or in conjunction with one another.

Training for Primary Care Physiciansone of the biggest hurdles is the lack of training and, therefore, the inability to treat at least the more mild cases of mental health conditions. in-

exhibit 1: statistics1-3

85% of behavioral health patients are seen in the phyiscal health sector

Only 13% of patients treat-ed by PCP’s get evidence-

based care

65% receive no behavioral health treatment

70% of all behavioral health treatment is provided by primary care physicians

(PCP’s)

Only 3% of behavioral health providers work in the

general medical sector

80% of expenses for pa-tients with mental condi-

tions are from medical benefits, half of which are for physical health services

exhibit 2

community

resources and Policies

self-Managementsupport

health systemOrganization of health Care

delivery system designdecision support

Clinical information systems

improvedactivatedpatient

preparedproactivepractive

team

improvedoutcomes+ =


troducing behavioral health screening tools and other evidence-based screening tools into primary care can lead to better outcomes. primary care is already treating mental health conditions to some extent. providing additional education on the latest diagnosis and treatment techniques will improve the quality of care offered to those who have concurrent behavioral and physical conditions.

CollaborationCollaboration between primary care and behav-ioral health is essential. While primary care should be able to diagnose and treat certain mental health conditions, there should be a referral network to reach out to behavioral health professionals. pro-viding a mechanism for primary care to reach out to behavioral health in order to either receive im-mediate answers to questions or to refer the pa-tient if extensive care is needed is critical. Con-versely, should a behavioral health specialist need assistance in the treatment of a medical condition, there should be a network of contacts to provide immediate assistance and/or a referral should the medical condition be complex. Collaboration and the forming of health care networks are initial steps on the road to integration.

Behavioral Health Fellowshipsto take the referral networks and training to the next level, behavioral health can offer fellowships. these fellowships would provide training to pri-mary care physicians who wish to gain additional knowledge on how to diagnose and treat complex

mental health cases. of course not all primary care physicians want to pursue this option nor do they have the time to do so, but it would create a niche for those who crave this knowledge.

Network Psychiatristadding a network psychiatrist would provide col-laboration between behavioral and physical providers. this position would lead the charge for champion-ing integration and advocate the implementation of evidence-based practices for integrated primary care.

Behavioral Health Coordinatora behavioral health Coordinator in each network works closely with the network psychiatrist in set-ting priorities for practice interventions, identifying priority populations, and identifying complex cases for discussion in case management settings. behav-ioral health Coordinators are, in general, licensed behavioral health professionals or registered nurses that have extensive experience in mental health. they serve as a liaison between the network psy-chiatrist and the network Case managers.

Mobile Crisis Unitsrelationships can be formed with mobile crisis units throughout the community. these mechanisms are available 24/7 and can serve as an additional re-source when a patient presents with complex or multiple mental health issues.

Case Managementthe goal of integrated Case management is to break

exhibit 3: the 4 Quadrant Model

Quad iii• Patients with low Bh and low physical needs• served in PC setting• e.g., patients with moderat depression and uncontrolled diabetes

Quad iV• Patients with high Bh and high physical needs• served in PC and specialty Mh setting• e.g., patients with schizophrenia and hepatitis C

Quad i• Patients with low Bh and low physical needs• served in PC setting• e.g., patients with moderate alcohol abuse and fibromyalgia

Quad ii• Patients with high Bh and low physical needs• served in PC and specialty Mh setting• e.g., patients with bipolar disorder and chronic pain

the 4 Quadrant Model


down complexity-based health barriers across multiple domains in order to appropriately address and treat pa-tients in a holistic manner. Case management can be the liaison between behavioral and physical health and can serve as a resource in linking to community resources.

Telemedicinetelemedicine is the ability for physicians, generally psychiatrists, to perform consults and assessments without a physical face-to-face interaction with the patient. it is a collaborative effort between psychia-try and physician leaders in both primary practices and hospitals. telemedicine provides an avenue in which shared decision making can be brought to the forefront. the use of telemedicine through prima-ry practice may help improve accessibility to care, decrease the stigma often associated with mental health, improve patient compliance with specialty referral, and broaden the scope of patients and fami-lies who can be effectively managed.

Electronic Health Records and Health Informa-tion Changesthe sharing of information is essential in order to achieve integration. one of the hurdles involves the use of separate systems for primary care and behavioral health. many times these systems aren’t compatible with one another or access cannot be granted to the ap-propriate party to allow the information to be shared. the sharing of records enables both parties access to be able to treat the whole patient and remove the silo

effect. one of the more recent innovations is the use of health information exchanges. health informa-tion exchanges are designed to provide exchange of information that is secure and confidential, compatible across multiple electronic health record systems, and is accessible to only those who require the information.

Reimbursementreimbursement is one of the largest barriers to overcome when integrating behavioral and medical health. some organizations are devising innovative ways to deal with the financial issues. Colorado has a model in place that is working very well. in fact, other states, such as oregon, are beginning to adopt their model. the global payment model is called shape (sustaining healthcare across integrated primary Care efforts) and is the result of a statewide project to identify and find solutions to the financial barriers of integration. according to the study, there are five steps which organization should follow to help identify and isolate these issues. (exhibit 4).

conclusionthe cost of health care is rising astronomically. there are many measures that have been put in place to help reduce these costs such as healthcare re-form. a high portion of the costs is attributed either directly or indirectly to the inability of integration between behavioral health and physical health treat-ment. When treated separately, health care becomes very costly, and even more importantly, the patient

exhibit 43

• Clarify the current billing regulations and train staff in integrated care sites to optimize existing revenue sources to provide cost-efficient, medically necessary care.recommendation 1:

• Resolve confusion about same-day billing restrictions and pursue efforts to reduce administrative barriers.recommendation 2:

• Examine the viability of paying for Health and Behavior Assessment codes under insurance plans.recommendation 3:

• Test and analyze the viability of global funding strategies to financially sustain inte grated care services.recommendation 4:

• Plan and implement a stadardized statewide data-collection system to document financial, operational and clinical outcomes, and costs of intergrated care services.recommendation 5:


isn’t receiving the optimal treatment. treating sepa-rately can cause a deterioration in the other condi-tions. there are many possible solutions that can be implemented individually or in tandem with one an-other. solving the behavioral health integration can vastly reduce health care spending and improve the health of those with comorbidity issues.

Mark rosenburg, Md, phd, president, bhM healthcare solutions and director, NaMCP Behavioral health institute.

Thank you to the members of the NaMCP/aaMCN Behavioral health institute elC for their discussion and input on this article.

references1.(Kathol) Kathol, roger G., rebecca perez, and Janice s. Cohen. The Inte-

grated Case Management Manual. 2010. manual. www.springerpub.com/sam-

ples/9780826106339_chapter.pdf>.

2. (The British Journal of Psychiatry)

3. (Warhover) Warhover, ann. the Colorado blueprint for promoting inte-

grated Care sustainability. march 2012. Document. 25 June 2013.

THORACIC ONCOLOGY UPDATE:

Molecular Biomarker Testing Is Essential for Non-Small Cell Lung Cancer Patients

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During the past decade the identification of molecular biomarkers for clinically relevant

mutations or other genetic abnormalities in non-small cell lung cancer (NSCLC) has improved

the understanding of lung cancer pathogenesis, and of the proliferation and survival of

cancer cells.1 This significant development is setting the stage for a paradigm shift toward

the adoption of treatments directed to the particular genetic makeup of the tumor.1,2

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These molecular subsets show

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Indeed, biomarkers may give

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At Least 10 Known Molecular Biomarkers in NSCLC3

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What is the most significant development you’ve seen in the treatment of lung cancer today?

DG Knowing what is driving the cancer! We have recently been using histology to treat cancer based on the appearance of the cells. But cells that look identical under the microscope can have dramatically different clinical outcomes because of what is driving them at the molecular level. And that is leading us to molecularly based treatment options.

Can many NSCLC patients benefit from this testing? Who should be tested?

DG When you consider both approved and investigational agents, yes, a considerable proportion of NSCLC patients can receive therapy based on molecular testing. But at present I believe that all patients with NSCLC of the adenocarcinoma subtype should be tested.

That seems like a lot of testing. Wouldn’t that require a re-biopsy for many patients?

DG These tests do require adequate tumor tissue. Some patients will need to be re-biopsied — some for lack of sample tissue, but also to look for changes that have occurred over time and as a result of therapy. Other patients may not have to be re-biopsied. To do the testing that reveals the “molecular fingerprint” of each person’s lung cancer, we have to get sufficient tumor tissue at biopsy.

Visit www.lungcancerprofiles.com for the patient perspective on molecular profiling.

David R. Gandara, MDDirector, Thoracic Oncology Program, UC Davis Comprehensive Cancer Center

Curbside ConsultNew Diagnostic Paradigm: Histology + Molecular Profile

Recently it has been proposed that

lung cancer treatment be based on the

histology of the tumor. But there is a

growing consensus that molecular

profiling — testing the tumor at

biopsy for all appropriate biomarkers

— should be part of the clinician’s

standard approach to pathologic

evaluation.1,2 And this is supported

by the National Comprehensive

Cancer Network (NCCN®) Clinical

Practice Guidelines in Oncology (NCCN

Guidelines®) for all non-squamous

non-small cell lung cancer (NSCLC)

histologies, which state5:

References: 1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180. 2. Gandara DR, Li T, Lara PN Jr, et al. Algorithm for codevelopment of new drug-predictive biomarker combinations: accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer. 2012;13(5):321-325. 3. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. 4. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med. 2008;359(13):1367-1380. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-small Cell Lung Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed August 20, 2012. To view the most recent and complete version of the guideline, go online to http://www.nccn.org/. NATIONAL COMPREHENSIVE CANCER NETWORK,® NCCN,® NCCN GUIDELINES,® and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Carr LL, Finigan JH, Kern JH. Evaluation and treatment of patients with non-small cell lung cancer. Med Clin N Am. 2011;95:1041-1054. 7. Goetsch CM. Genetic tumor profiling and genetically targeted cancer therapy. Semin Oncol Nurs. 2011;27(1):34-44. 8. National Institutes of Health. Lung cancer mutation consortium protocol. http://clinicaltrials.gov/ct2/show/NCT01014286. Accessed January 19, 2012. 9. National Cancer Institute. The cancer genome atlas. http://cancergenome.nih.gov/abouttcga/overview. Accessed January 19, 2012. 10. Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152-1158.

The NCCN® recommends EGFR and

ALK testing for all advanced

non-squamous NSCLC, in order to

guide treatment decisions.5 Multiplex

molecular profiling assays may make

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For patients whose tumors test

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But in the future, molecular profiling

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Molecular Profiling Is Key in NSCLC

The discovery of biomarkers has

demonstrated the molecular complexity

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tumors.1,4 But only if patients are tested is

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As additional mutations are discovered

through efforts such as the National

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the Cancer Genome Atlas — and as

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Dr. David Gandara, Director of Thoracic

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Cancer Center, “Our goal is to learn the

‘molecular fingerprint’ of each person’s

lung cancer, and to personalize their

therapy based on this information.

The discoveries that could make this

possible are being made at a rapid pace.”

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