Page 1

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

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. Difficult 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 scientific 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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Journal of Managed Care Medicine The Official Journal of the

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

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Vol. 16, No. 3, 2013



director of communications

COPD from a Managed Care Lens: Emerging Trends and Treatment Choices in COPD Diagnosis and Treatment Joseph Johnson, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Journal management

Effective Diagnosis, Treatment, and Management of Pulmonary Arterial Hypertension Yon K. Sung, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Katie Eads

Jeremy Williams

Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 387-7580 fax (703) 997-5842

Managing Editor

Barry Barnum

Graphic Design

Douglas Murphy Communications, Inc.

Custom Article Reprints

High quality, custom article reprints of individual articles are available in print and electronic formats. Contact Katie Eads,, 804-527-1905 for reprints.

Effective Treatment Strategies for Inflammatory Bowel Disease Joel R. Rosh, MD, FACG, AGAF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Improving Outcomes with Novel Treatment Strategies in the Management of Type 2 Diabetes Yehuda Handelsman, MD, FACP, FACE, FNLA. . . . . . . . . . . . . . . . . . . . . . . . 22 Individualizing Treatment Strategies in the Management of Metastatic Breast Cancer Michael Naughton, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Metastatic Colorectal Cancer: Updates in Treatment Strategies and What’s in the Works Tanios Bekaii-Saab, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Optimizing Treatment Strategies in the Management of Metastatic Melanoma Adil Daud, MBBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Advances in the Treatment of Fecal Incontinence Beth Moore, MD, FACS, FASCRS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

ISSN: 1094-1525. 1094-1525. The Thev Journal is published of Managed by Association Care Services Corporate and Circulation offices: Medicine Inc. is published by Association Services Inc. 4435 Waterfront Drive, Suite 101, 4435 GlenWaterfront Allen, VA Corporate and Circulation offices: 23060; Tel (804) 527-1905; Fax (804) 747-5316. EditoDrive, Suite 101, Glen Allen, VA 23060; Tel (804) 527rial and Production offices: 2613 N. Parham Rd., 1905; B, FaxRichmond, (804) 747-5316. Editorial Suite VA 23294; Tel and (804)Production 272-9100; offices: Box 71895, Richmond, VA 23255-1895; Fax (804)P.O. 272-1694. Advertising offices: Jack Klose, Tel (804) 387-7580; Fax (703) 997-5842. Advertising 804 Broadway, W. Long Branch, NJ 07764; Tel (732) 229-8845; Fax (856) 582-9596. Subscription Rates: offices: Sloane Reed, 4435 Waterfront Drive Ste one year $95 in the United States; one year $105Fax in 101, Glen Allen, VA 23060 Tel (804) 527-1905, Canada; one year $120 international. Back issues (804) 747-5316. All rights reserved. Copyright 2012. are available for $15 each. All rights reserved. No part of2010. this publication maypublication be reproduced or Copyright No part of this may be transmitted in form or byinany means, reproduced orany transmitted any form electronic or by any or mechanical, including photocopy, recording, or means, electronic or mechanical, including photocopy, recording,storage or any or information storage or reany information retrieval system, without trieval consent from the written system, consentwithout from thewritten publisher. The publisher publisher. The publisher does not guarantee, eidoes not guarantee, either expressly or by implicather expressly or by implication, the factual accution, of thethe factual accuracy of the articles and deracy articles and descriptions herein, nor scriptions herein, norguarantee does the publisher guarantee does the publisher the accuracy of any the accuracy of anyoffered views or offered by the views or opinions byopinions the authors of said articles or of descriptions. authors said articles or descriptions.

Physician Engagement is Critical to the Success of any Accountable Care Organization Anthony N. Akosa, MD, MBA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

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How Behavioral Health Integration Can Reduce Health Care Costs Mark Rosenburg, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

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

BPA Audited Publication | Vol. 16, No. 3 | Journal of Managed Care Medicine 3

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

A good day.

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

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

Number of episodes/14 days

Durable efficacy with Solesta 25



20 15 10


15.0 8.6








0 Baseline



Important Safety Information about SOLESTA SOLESTA® (hyaluronic acid/dextranomer) is contraindicated in patients with active inflammatory bowel disease, immunodeficiency disorders or ongoing immunosuppressive therapy, previous radiation treatment to the pelvic area, significant mucosal or full thickness rectal prolapse, active anorectal conditions (including abscess, fissures, sepsis, bleeding, proctitis, or other infections), anorectal atresia, tumors, or malformation, rectocele, rectal varices, presence of existing implant (other than SOLESTA) in anorectal region, or allergy to hyaluronic acid-based products. SOLESTA must not be injected intravascularly as injection of SOLESTA into blood vessels may cause vascular occlusion. Injection in the midline of the anterior wall of the rectum should be avoided in men with an enlarged prostate. SOLESTA should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program on the SOLESTA injection procedure. The most common adverse reactions with SOLESTA (incidence >4%) in the clinical study were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. Please see brief summary of full Prescribing Information on following page. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is a registered trademark of Q-Med AB. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. MCOSOL 12/12-1

• After injection of Solesta, hold the needle at the injection site for an additional 15-30 seconds to minimize leakage of Solesta. • Injections too close to the dentate line or too deep in the tissue might cause excessive pain. • Injection should be stopped if excessive bleeding or pain occurs. • One sterile needle should be used per syringe and injection. Brief Summary Please consult Package Insert for full prescribing information. Indication for Use Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, fiber therapy, antimotility medications). Contraindications Solesta is contraindicated in patients with the following conditions: • Active inflammatory bowel disease • Immunodeficiency disorders or ongoing immunosuppressive therapy • Previous radiation treatment to the pelvic area • Significant mucosal or full thickness rectal prolapse • Active anorectal conditions including: abscess, fissures, sepsis, bleeding, proctitis, or other infections • Anorectal atresia, tumors, stenosis or malformation • Rectocele • Rectal varices • Presence of existing implant (other than Solesta) in anorectal region • Allergy to hyaluronic acid–based products Warnings • Do not inject Solesta intravascularly. Injection of Solesta into blood vessels may cause vascular occlusion. • Injection in the midline of the anterior wall of the rectum should be avoided in men with enlarged prostate. Precautions General precautions • Solesta should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. • The safety and effectiveness of Solesta have not been investigated in patients with complete external sphincter disruption or significant chronic anorectal pain. • The safety and effectiveness of Solesta have not been investigated in patients with previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with rubber band within 3 months, anorectal implants and previous injection therapy, Stapled Transanal Rectal Resection (STARR) or stapled hemorrhoidectomy. • The safety and effectiveness of Solesta have not been studied in patients under the age of 18 years. • The safety and effectiveness of Solesta have not been studied in pregnant or breastfeeding women. • The durability of Solesta has not been studied past 12 months. • The safety and effectiveness of Solesta have been studied in patients who received one or two treatments. In the Pivotal study, the majority of patients received two treatments, four weeks apart. Patient related precautions • Patients with bleeding diathesis or patients using anticoagulant or antiplatelet agents, as with any injections, may experience increased bleeding at injection sites. • Patients should be counseled that a repeated Solesta injection procedure may be required to achieve a satisfactory level of improvement in incontinence. Procedure related precautions • Adequate bowel preparation of the rectum using enema is required prior to injection. The enema should be given immediately prior to the procedure to ensure evacuation of the anorectum. It is recommended that additional cleansing of the injection area with an antiseptic be performed prior to injection. Use of prophylactic antibiotics is recommended. • Solesta should be injected slowly to avoid undue stress on the Luer-lock connection which could cause leakage of the gel.

Device related precautions • The use of needles other than those supplied may impede injection of Solesta due to the properties of the gel and may cause device malfunction. • Solesta is supplied ready to use in a prefilled syringe with a Luer-lock fitting. Carefully examine the unit to verify that neither the contents nor the package has been damaged in shipment. Do not use if damaged. • Solesta is supplied sterile and is intended for single use only. Do not re-sterilize, as this may damage or alter the product. • In the event of accidental contamination of a needle, discard the needle. • Never mix Solesta with other products. • Solesta is to be stored at up to 25°C (77°F), and used prior to the expiration date printed on the label. Do not expose Solesta to either sunlight or freezing, as this may damage or alter the product. • Care should be taken when handling the glass syringes and disposing of broken glass to avoid laceration or other injury. • After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements. Adverse Events Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal fissure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back pain, constipation, C-reactive protein increased, chills, cold sweat, defecation urgency, dermatitis, diarrhea, device dislocation, dizziness, dyspareunia, escherichia bacteremia, fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal pain, genital discharge, genital prolapse, hematochezia, hematospermia, hemorrhoids, infection, injection site abscess, injection site discomfort, injection site hemorrhage, injection site hematoma, injection site inflammation, injection site irritation, injection site nodule, injection site pain, injection site pustule, injection site swelling, injection site ulcer, intestinal mass, malaise, mucosal inflammation, musculoskeletal pain, perineal abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, proctitis, pyrexia, rectal abscess, rectal discharge, rectal hemorrhage, rectal lesion, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum abscess, urinary retention, vaginal discharge, vulvovaginal pain. The adverse event profile of Solesta beyond 24 months* is not known, but is under investigation in post-market studies. The safety evaluation of Solesta in the treatment of fecal incontinence (FI) is based on the results from the Pivotal Clinical study, and is supported by the Open-Label multicenter clinical study and one single site Proof-of-Concept study. The analysis of safety was based on the safety cohort of all 206 patients treated in the Pivotal Study with either Solesta or Sham. Safety data for Solesta are available from 359 treatments in 197 total patients followed for up to 18 months post treatment (ie, 136 subjects from the blinded phase and 61 subjects from the open phase). Directions for Use Solesta should be administered by qualified physicians with experience in the treatment of anorectal conditions and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. Solesta should only be used after a thorough physical evaluation of the patient to exclude treatable underlying disorders. Please consult Package Insert for full directions for use and method of administration. How Supplied Solesta is supplied in a glass syringe with a standard Luer-lock fitting containing 1 mL gel. Each syringe is terminally moist heat sterilized in a pouch. Four pouches, each containing one syringe are packed in a carton together with five Sterican needles (21G x 4¾ inches, 0.80 mm x 120 mm), patient record labels and a Package Insert. The needles are sterilized by ethylene oxide. Storage Store at a temperature up to 25°C (77°F) and protect from sunlight and freezing. 06/11

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

©2012 Salix Pharmaceuticals, Inc.

All rights reserved.

Printed in the USA.


Alan Adler, MD, MS Medical Director Independence Blue Cross

Editorial Review Board

Devena Alston-Johnson, MD Medical Director CIGNA E. Paul Amundson, MD Chief Medical Officer Dakotacare

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

Philip Painter, MD Chief Medical Officer Humana

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

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Tim Newman, MD Medical Director FirstEnergy Denis Oâ&#x20AC;&#x2122;Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans Gary Owens, MD Principle Gary Owens Associates

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

Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc. Mark R. Rosenburg, MD, PhD President/CEO Behavioral Health Management Joseph Schappert, MD Chief Medical Officer PAML Christine M. Seals, MD Medical Director Umpqua Health Alliance

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

COPD from a Managed Care Lens: Emerging Trends and Treatment Choices in Diagnosis and Treatment Joseph Johnson, MD

Summary Despite advances in therapy, chronic obstructive pulmonary disease (COPD) continues to result in significant morbidity, mortality, and economic costs. A new paradigm 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.

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 developed countries.4 COPD also imposes a significant economic burden 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 diagnostic 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 percent 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- | Vol. 16, No. 3 | Journal of Managed Care Medicine 7

Exhibit 1: Hospital Stays Drive Direct COPD Costs for Payers 6 Adjusted Mean Episode-Level Cost of COPD-Related Visits

Mean Cost (2008 US$, Thousands)



35 30 25 20 15


10 5 0




Outpatient Visit (n=19,641)

Urgent Outpatient Visit (n=13,833)

Emergency Department Visit (n=1,231)

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 inhaled corticosteroids instead of the guideline preferred 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 inhaled corticosteroids compared with bronchodilators.10 The GOLD guidelines for initial pharmacologic management of COPD have bronchodilators as central to COPD management (Exhibit 3).8 All

Standard Hospital Admission (n=1,547)

ICU Stay (n=837)

patients should be on either a long-acting beta agonist 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 readmission 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 Low 9 HEDIS* Measure: Estimates the number of members aged >40 years newly diagnosed with COPD who received spirometry to confirm the diagnosis HEDIS Spirometry Test Rate (HMO Averages, 2010)

Patients Receiving Spirometry, %

50 40

41.7% 33.9%



20 10 0



*Healthcare Effectiveness Data and Information Set

8 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Managed Medicaid

Exhibit 3: Current GOLD Pharmacologic Treatment Guidelinesa8 Patient Group

First Choice

Second Choice

Alternative Choiceb

A. Low Risk Less Symptoms

SA anticholinergic pm or SA beta2-agonist pm

LA anticholinergic or LA beta2-agonist or SA beta2-agonist and SA anticholinergic


B. Low Risk More Symptoms

LA anticholinergic or LA beta2-agonist

LA anticholinergic and LA beta2-agonist

SA beta2-agonist and/or SA anticholinergic

ICS + LA beta2-agonist or LA anticholinergic

LA anticholinergic and LA beta2-agonist

C. High Risk Less Symptoms

Theophylline PDE-4 inhibitor SA beta2-agonist and/or SA anticholinergic Theophylline

D. High Risk More Symptoms

ICS + LA beta2-agonist or LA anticholinergic

ICS and LA anticholinergic or ICS + LA beta2-agonist and LA anticholinergic or ICS + LA beta2-agonist and PDE-4 inhibitor or LA anticholinergic and LA beta2-agonist or LA anticholinergic and PDE-4 inhibitor

Carbocysteine SA beta2-agonist and/or SA anticholinergic Theophylline

Medications in each box are listed in alphabetical order and, therefore, not necessarily in order of preference. 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. a


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 disease progression in which the severity of the disease

Exhibit 4: 2011 GOLD Grading Combines Symptomatic Assessment with Spirometric Classification and/or Exacerbation Risk8 Patient Category


Spirometric Classificationa

Exacerbations per year




Low Risk, Less Symptoms

GOLD 1-2





Low Risk, More Symptoms

GOLD 1-2





High Risk, Less Symptoms

GOLD 3-4





High Risk, More Symptoms

GOLD 3-4




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. | Vol. 16, No. 3 | Journal of Managed Care Medicine 9

Exhibit 5: Paradigm Shift in How We Diagnose, Treat, and Manage COPD Patients




Differential Diagnosis of COPD


Enhance early use of Spirometry in outpatient clinics by PCPs

Right Treatment at the Right Time


Use of various treatments in accordance with revised GOLD guidelines

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 spirometric 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 providers diagnose, treat, and manage COPD patients to address the gaps (Exhibit 5). Managed care can play a role in closing these gaps by educating primary 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. Conclusion

COPD is a costly disease in terms of both patient impact and economic costs. Although easy diagnostic 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.

Manage Readmissions


Get ready for upcoming Medicare COPD quality requirements

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 pulmonary 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 obstructive pulmonary disease among managed care patients. Int J Chron Obstruct Pulmon 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 Accessed May 5, 2013. 9. National Committee for Quality Assurance. The State of Health Care Quality 2011. Available at 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: Promoting Greater Efficiency in Medicare. Washington DC 2007.

Joseph Johnson, MD is the Chief Medical Officer at Arizona Integrated Physicians.

References 1. National Heart, Lung, and Blood Institute. Chronic Obstructive Pulmonary Disease. Available at pdf. Accessed May 5, 2013. 2. Hoyert DL, Xu JQ. Deaths: preliminary data for 2011. Natl Vital Stat Rep. 2012;61(6):1-65.

10 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Effective Diagnosis, Treatment, and Management of Pulmonary Arterial Hypertension Yon K. Sung, MD For a CME/CEU version of this article, please go to, and then click the activity title.

Summary Although rare, pulmonary arterial hypertension (PAH) results in significant management 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 hypertension 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.

The pulmonary vasculature is a lowpressure system with a normal mean pulmonary artery 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 pulmonary 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 progresses 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 exercise 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 affect 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, survival has improved to 78 percent of patients alive at three years, but this is still not optimal.6 Survival with PAH is very dependent on the underlying cause.7 The best survival rate is in those with congenital heart disease as the cause. The worst rates are in those with underlying collagen vascular disease | Vol. 16, No. 3 | Journal of Managed Care Medicine 11

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

or human immunodeficiency virus (HIV) infection. Because the symptoms are nonspecific, PAH diagnosis 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 battery 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 maintained or improved as a result. Patients with positive 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 yearly 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 2: From Early to Symptomatic to Severe PAH Early Symptomatic Severe

CO, cardiac output; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistence; BNP, brain natriuretic peptide; NYHA, New York Heart Association




12 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 3: Key Pathways Implicated in PAH Pathogenesis8

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, anticoagulation has been shown to improve survival. Calcium channel blockers are only indicated for patients who meet criteria for vasoreactivity. Nifedipine, 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 phosphodiesterase (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®). Multiple clinical trials have shown the safety and benefit of PDE inhibitors in PAH. Another area targeted with medication is endothelin, 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. Although 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 severe 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 injection or inhalation. The FDA approved agents include epoprostenol (Veletri®, Flolan® for injection), treprostini (Remodulin® for infusion and Tyvaso® for inhalation), and iloprost (Ventavis® for inhalation). Observational studies with epoprostenol show improved survival compared to historical controls.9,10 There are significant issues with giving prostacyclins 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 inhalation 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- | Vol. 16, No. 3 | Journal of Managed Care Medicine 13

Exhibit 4: Comparing Agents Agent


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, headache, flushing

Oral once a day or twice a day dosing 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

• •

Prostacyclins Inhaled

Trials have suggested survival benefit Improvement in hemodynamics, exercise tolerance, and quality of life

• • •

Complications with IV catheters Site pain with SC catheters Side effects - flushing, headaches, jaw pain, nausea, diarrhea

Non- invasive

• •

Compliance Side effects - headache, flushing, diarrhea, cough

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 bosentan. Combination therapy is frequently done in clinical practice because there are so few options for these patients. Current therapy has some limitations. The available 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 disease. 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 Anticoagulate + Diuretics + Oxygen + Digoxin

Acute Vasoreactivity Testing Positive

Oral CCB


Lower Risk

Higher Risk

1) ERAs or PDE-5 2) Prostacyclins

1) Prostacyclins 2) ERAs or PDE-5

No Sustained Response Yes Continue CCB

Reassess: Consider combination therapy

Investigational protocols

14 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Atrial Septostomy Lung Transplant

ive care for this disease includes pulmonary rehabilitation and management of comorbidities that can worsen the disease. These include anemia and thyroid 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-effectiveness study, treatment with sildenafil and bosentan was determined to be cost effective.13

2. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023-30. 3. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-619. 4. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216-23. 5. Dâ&#x20AC;&#x2122;Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343-9. 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

A complete workup for pulmonary hypertension is needed to properly classify PAH, prescribe appropriate 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.

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 hypertension. N Engl J Med. 2004;351(14):1425-36. 9. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: 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-

Yon K. Sung, MD is a Clinical Instructor in the Division of Pulmonary/

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

Critical Care at the Vera Moulton Wall Center for Pulmonary Vascular

12. Said Q, Martin BC, Joish VN, et al. The cost to managed care of managing

Disease at Stanford University School of Medicine.

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

1. Simonneau G, Robbins I, Beghetti M, et al. Updated clinical classification of

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

pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43-S54.

nomic evaluation. Health Technol Assess. 2009;13(49):1-320. | Vol. 16, No. 3 | Journal of Managed Care Medicine 15

Effective Treatment Strategies for Inflammatory Bowel Disease Joel R. Rosh, MD, FACG, AGAF For a CME/CEU version of this article, please go to, and then click the activity title.

Summary The treatment of inflammatory bowel disease (IBD) has changed significantly since the introduction of immune system altering biologics. Using these agents in combination 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.

Inflammatory bowel disease (IBD) appears to develop as the result of interplay of genetic predisposition, environmental triggers, and immune regulation in the bowel. More than 60 genetic 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 response 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 occur 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 mucosal 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 corticosteroids, 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 diagnosing and treating patients with IBD.1,2 These treatment guidelines should be followed to maintain response and remission in adult patients with IBD. Ulcerative Colitis

UC 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

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

Exhibit 1: Evolving Goals of Therapy for IBD: Sustained Deep Remission


Clinical Parameters



Improved symptoms

Improved quality of life


No symptoms

Decreased hospitalization

Deep remission

Normal endoscopy

Avoidance of surgery


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 activity is defined as more than four bowel movements daily and/or presence of blood or pus with or without systemic symptoms. Twenty percent of patients present with low activity and 10 percent with fulminant disease. In mild to moderate disease, disease remission can be induced with a variety of agents including oral aminosalicylates, topical mesalamine or corticosteroids, or a combination (Exhibit 2). Combination of oral and topical aminosalicylates is more effective 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速), or adilimumab (Humira速). Infliximab and adilimumab 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 going 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 inhibitors, tacrolimus and cyclosporine, or infliximab. Studies have found these second-line agents to have similar efficacy. Higher doses of infliximab are required to manage severe disease compared to lesser disease activity. For patients who develop complications such as toxic megacolon, colectomy is the treatment option. 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 severe disease requiring second- line treatment or colectomy.6-10 Once remission is induced, the patient is converted 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 markers for mucosal healing include serum C-reactive protein (CRP) and fecal markers, calprotectin and lactoferrin. Low CRP values reflect minimal disease activity. Fecal markers can be obtained from a stool sample. Calprotectin levels primarily indicate health of the colon, whereas fecal lactoferrin is better for measuring small bowel health. The use of fecal markers to assess mucosal healing is an area of the field that is emerging. | Vol. 16, No. 3 | Journal of Managed Care Medicine 17

Exhibit 2: Sequential Therapies for UC Disease Severity at Presentation

Colectomy Anti-TNF Anti-TNF Cyclosporine Thiopurine



Moderate Aminosalicylate

Aminosalicylate Thiopurine



Crohnâ&#x20AC;&#x2122;s Disease

Crohnâ&#x20AC;&#x2122;s disease (CD) diagnosis is based on a composite of endoscopic, radiographic, and pathological 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 serologic testing are not recommended at this time; however, in the future, this type of testing will likely be used. Because Crohnâ&#x20AC;&#x2122;s disease patients do require many tests over their lifetime that use radiation, there should be attempts to decrease the amount of radiation exposure in these patients to limit the risk of cancer. Some advances in imaging to define the extent of disease within the gastrointestinal tract and to reduce exposure to radiation include the use of video capsule endoscopy (VCE) and magnetic resonance enterography (MRE). With VCE, a pill-sized video camera is swallowed. The camera has its own light source and takes pictures of the small intestine 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 remission 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 corticosteroids. Mesalamine and sulfasalazine primarily

Induction Maintenance

work on the muscosa and do not treat any transmural disease. Because of this, the majority of patients will require immune modification with corticosteroids 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 dependent. 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 steroids. It requires four to six weeks, but it is difficult for patients to comply with. Once a patient is in remission, maintenance therapy is started. Thiopurines are used for maintenance therapy in CD. Prior to use, patients should be tested for their metabolic ability. The thiopurines are converted to inactive metabolites by the Phase II drugmetabolizing 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 homozygous 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

18 Journal of Managed Care Medicine | Vol. 16, No. 3 |

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

agents are FDA approved -infliximab, adilimumab, and certolizumab (Cimzia®). Natalizumab, an anti-integrin agent, is typically reserved for anti-TNF agent intolerant or unresponsive patients. Patients must be screened for John Cunningham ( JC) virus infection before therapy. The JC virus can cause progressive multifocal leukoencephalopathy (PML), also known as progressive 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. Biologics

Biologic agents have changed the way IBD is treated. These agents aggressively target the inflammation 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 approved 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 failure 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 prognostic 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 severe hospitalized patients.

There are three areas to consider in maximizing benefit from biologics – combination therapy, dose optimization, and immunogenicity. Combining biologics 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 compared with biologic alone.12 Current recommendations are to start with a combination of biologic and azathioprine or 6-mercaptopurine when a biologic 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 adequate 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 patient 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 reaction. Concomitant immunomodulators help reduce antibody production which is the main reason for using 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. | Vol. 16, No. 3 | Journal of Managed Care Medicine 19

Exhibit 4: Sequential Therapies for Crohnâ&#x20AC;&#x2122;s Disease Disease Severity at Presentation

Natalizumab Anti-TNF Anti-TNF +/ Thiopurine/MTX





Aminosalicylate Aminosalicylate Budesonide Budesonide/Thiopurine Mild

Induction Maintenance

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

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 patients with IBD who are treated with thiopurines versus those never treated with one of these agents.15 The contribution of significant exposure to radiation in these patients to the risk of developing lymphoma is not known. Stopping thiopurine therapy as people age decreases the risk of lymphoma to that of the general population. Anti-TNF agents also increase 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 lymphoma that primarily affects men younger than 35 years old. Treatment of patients with inflammatory bowel disease (IBD) using anti-TNF agents in combination with thiopurines has been associated with HSTCL. Thirty-eight cases have been reported and all have been uniformly fatal.17 Although lymphomas occur, it is important to note that these are still rare adverse effects. Nonadherence

Of course, all the IBD medications only work if the patient takes them. As with most chronic disease, 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 maintenance 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 patientprovider relationship. Managed care can have a role in supporting patients to be adherent with therapy. Health Monitoring

In addition to medication specific monitoring, patients 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 immunosuppressed 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. Conclusion

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. Joel R. Rosh, MD, FACG, AGAF is an Associate Professor of Pediatrics at the University of Medicine and Dentistry of New Jersey and is Director of Pediatric Gastroenterology at the Goryeb Childrenâ&#x20AC;&#x2122;s Hospital/ Atlantic Health.

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

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

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

9. Cacheux W, Seksik P, Lemann M, et al. Predictive factors of response to cy-

18. Kane SV, Sumner M, Solomon D, Jenkins M. Twelve-month persistency

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

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


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

10. Ananthakrishnan AN, McGinley EL, Binion DG. Does it matter where you | Vol. 16, No. 3 | Journal of Managed Care Medicine 21

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, and then click the activity title.

Summary Type 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.

More than 60 percent of U.S. adults are overweight or obese. The obesity epidemic in America contributes to the diabetes and cardiovascular disease (CVD) epidemics currently in the United States. Obesity does this through the development of insulin resistance and the metabolic syndrome 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 complications of the disease are well known and include amputation, blindness, renal failure, and cardiovascular disease. Every day in the U.S., 5,205 new cases of diabetes are diagnosed, 230 people have a diabetesrelated amputation, 133 people with diabetes progress 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 accepted 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 enormous socio-economic burden. In the U.S., over $200 billion was spent on diabetes in 2011.6 The American Association of Clinical Endocrinologists (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 reductions 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

22 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 1: Metabolic-Insulin Resistance Syndrome1 Factors Contributing to Insulin Resistance Central obesity

Clinical consequences

Metabolic and Vascular abnormalities Hemostatic abnormalities

Hypertension Stroke

Vascular inflamation Genetic factors Family history Population groups

Insulin Resistance

Sedentary lifestyle Low physical activity Increased age

Abnormal vascular SMC, medical and endothelial function Abnormal FFA, VLDL and HDL metabolism + visceral fat deposition



High TG Low HDL


Impaired glucose tolerance Diabetes

Impaired homeostasis

achieve glycemic control, most patients will require combination therapy. The American Diabetes Association (ADA) published a treatment algorithm in 2008 that emphasized the addition of insulin or sulfonylureas to metformin 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, possible risks of blood glucose fluctuation independent of A1C, and did not consider the impact of medication 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 contraindicated and disregarded cliniciansâ&#x20AC;&#x2122; knowledge and preference. In response to issues with the ADA algorithm, the AACE developed its own algorithm.10 The principles of this management algorithm were to minimize the risk of hypoglycemia, minimize the risk of weight gain and other drug-related adverse events, and to individualize the management plan by considering 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 potential 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 initially 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 therapy, with or without additional orally administered agents. For a patient with an A1C level greater than 9.0% who is asymptomatic, triple therapy is recommended. If, however, the patient is symptomatic, or therapy with similar medications has failed, it is appropriate to initiate insulin therapy, either with or without additional orally administered agents. The algorithm is available at the AACE website www. 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 patients 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 diabetes 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 [ByettaÂŽ] or liraglutide [VictozaÂŽ]) or an oral dipeptidyl peptidase 4 (DPP4) inhibitor (sitagliptin [ Januvia], saxagliptin [Onglyza], and linagliptin [Trajenta]) that prolongs the | Vol. 16, No. 3 | Journal of Managed Care Medicine 23

Exhibit 2: We are far from achieving basic goals in patients with type 2 Diabetes 5 NHANES

Patients Achieving Goal (%)

60 50



57.1 43.1



45.5 39.2


30 20 7.0

10 0

A1C <7.0%


BP <130/80mm Hg LDL-C <100 mg/dL Achieved All 3 Goals

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 agonists and the DPP-4 inhibitors. Liraglutide, seemingly, has better weight loss properties and it results in greater A1C reduction than other GLP-1 agonists. Long-acting exenatide has fewer adverse effects 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 diabetes 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 percent 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 cholesterol (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 3: AACE 2011 Diagnosis of Diabetes and Pre DM7


IFG or IGT High Risk for DM


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 mg Random PG > 200 + Symptoms


505% to 6.4% For screening*

> 6.5% Secondary**

* Requires testing FG or GTT

** Confirm with Glucose when possible

24 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 4: AACE Treatment Goals7 Parameter

Treatment Goal for Non-Pregnant Adults

Glucose A1C (%)

Individualize based on co-morbidities, duration of disease, hypoglycemia 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 â&#x20AC;&#x153;less healthyâ&#x20AC;? - 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


< 100 highest risk; < 130 high risk


> 40 in men; 50 in women


< 150

Blood Pressure (mm Hg) Systolic

< 130


< 80

Anticoagulant Therapy Aspirin

For secondary CVD prevention or primary prevention for very high risk patients

with diabetes will reduce risk of CVD.13,14 Statins are the treatment of choice in the absence of contraindications. Combinations of statins with bile acid sequestrants, niacin, fibrates and/or cholesterol absorption inhibitors should be considered in situations of inadequate goal attainment. The other lipid-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 lowering reduces the risk of micro- and macrovascular complications of diabetes.15,16 Therapeutic recommendations 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 blockers (ARB) with subsequent addition of other agents as needed for control. Thiazide diuretics and beta

blocker use should be limited because of their potentially 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 highrisk patients (10 year risk > 10 percent). The use of low-dose (75 mg to 162 mg daily) aspirin is recommended 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 customized for each individual patient. When combination therapy is prescribed, medications with complementary mechanisms should be used. The effectiveness of therapy needs to be evaluated frequently. 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. | Vol. 16, No. 3 | Journal of Managed Care Medicine 25


The obesity epidemic contributes to the diabetes and CVD epidemics. To begin to manage the diabetes epidemic, providers need to target multiple conditions to reduce risk. It requires utilizing lifestyle 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 without causing hypoglycemia, while producing favorable effects on weight. Patients need comprehensive care of all risk factors, with combination medications, to reduce CVD and other complications of diabetes.

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 mellitus:








2009;373(9677):1765-72. 9. American Diabetes Association. Standards of Medical Care in Diabetesâ&#x20AC;&#x201D;2008. Diabetes Care. 2008;31(S1):S12-S54. 10. Rodbard H, Jellinger P, Davidson JA, et al. Statement by an American Association 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.

Yehuda Handelsman, MD, FACP, FACE, FNLA is Medical Director and Principal Investigator at the Metabolic Institute of America in Tarzana, CA.


11. American Diabetes Association. Standards of Medical Care in Diabetesâ&#x20AC;&#x201D;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.

1. Kendall DM, Harmel AP. The metabolic syndrome, type 2 diabetes, and


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

13. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol

Care. 2002;8(20 Suppl):S635-53.

substantially below currently recommended levels in patients with coronary

2. Garber AJ, Handelsman Y, Einhorn D, et al. Diagnosis and management of

heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes

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

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

begin? A consensus statement from the American College of Endocrinology and

14. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of

the American Association of Clinical Endocrinologists. Endocr Pract.

cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative


Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-con-

3. Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet:

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

Diagnosed and undiagnosed diabetes in the United States, all ages, 2010. Atlanta.

15. UKPDS Group. Tight blood pressure control and risk of macrovascular and

4. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB.Is glycemic control improving

microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective

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

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

5. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic

16. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of inten-

target achievement in the United States, 1999 to 2006. Am J Med.

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



26 Journal of Managed Care Medicine | Vol. 16, No. 3 |

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

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 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®

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 Amarin Pharma Inc. Bedminster, NJ 07921

© 2012 Amarin Pharmaceuticals Ireland Limited.

All rights reserved.

130033 1/2013

Reprint Code: XXXXXX

VASCEPA® (icosapent ethyl) Capsules, for oral use Brief summary of Prescribing Information Please see Full Prescribing Information for additional information about Vascepa. 1 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. 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 ADMINISTRATION Assess 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 CONTRAINDICATIONS VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components. 5 WARNINGS AND PRECAUTIONS 5.1 Monitoring: Laboratory Tests In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA. 5.2 Fish Allergy VASCEPA 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 REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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*

Placebo (N=309) Adverse Reaction Arthralgia



VASCEPA (N=622) n %





*Studies included patients with triglycerides values of 200 to 2000 mg/dL. An additional adverse reaction from clinical studies was oropharyngeal pain. 7 DRUG INTERACTIONS 7.1 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 POPULATIONS 8.1 Pregnancy Pregnancy 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 middose 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 Mothers Studies 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 Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of 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 DEPENDENCE VASCEPA does not have any known drug abuse or withdrawal effects. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 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 INFORMATION 17.1 Information for Patients See VASCEPA Full Package Insert for Patient Counseling Information. Distributed by: Amarin Pharma Inc. Bedminster, NJ, USA Manufactured by: Banner Pharmacaps, Tilburg, The Netherlands or Catalent Pharma Solutions, LLC, St. Petersburg, FL, USA Manufactured for: Amarin Pharmaceuticals Ireland Limited, Dublin, Ireland

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

Individualizing Treatment Strategies in the Management of Metastatic Breast Cancer Michael Naughton, MD For a CME/CEU version of this article, please go to, click on Oncology and then on Metastatic Breast Cancer 2012

Summary The treatment of metastatic breast cancer continues to evolve with better understanding of the underlying biology and genetics and newer medications. Although not yet curable, progress is being made with increases in overall median survival. Several new medications are changing the treatment paradigm for advanced 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.

Breast cancer is the most common solid tumor in women. There are an estimated 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 declining steadily since the early 1990s. Better treatment and early diagnosis are possible reasons for this decline. There are approximately 40,000 deaths annually 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 metastatic 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 sensitive tumors tend to be less aggressive, while HER-2 positive tumors are typically more aggressive. Many effective therapies are available with variable efficacy 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 effective. The risks and benefits of palliative therapy must be weighed. Treatment is selected based on prob- | Vol. 16, No. 3 | Journal of Managed Care Medicine 29

Exhibit 1: Metastatic Setting Metastatic Breast Cancer Diagnosed ER or PR + No Visceral Crisis

ER or PR Visceral Crisis



Tamoxifen +OA




HER2 ÷ Disease

ER, estrogen receptor; PR, progesterone receptor; OA, ovarian ablation; AI, Aromatase Inhibitors

Exhibit 2: Hormone Therapy • Pre-menopausal – Ovarian ablation • Surgery • Radiation • Hormonal - GNRH – Selective Estrogen Receptor Modulator (SERM) • Tamoxifen • Toremifene

ability of tumor response, probability of symptomatic 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 triple negative (Exhibit 1). There are HER-2 positive and estrogen receptor (ER) positive specific therapies. 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-

•Post-menopausal – SERM • Tamoxifen • Toremifene – Aromatase Inhibitors (AI) • Letrozole • Anasrozole • Exemestane – Estrogen • Estradiol – Anti-estrogen • Fulvestrant

ture, the group of patients with triple negative disease 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 common in postmenopausal patients and often responds to endocrine therapies. Therapy is aimed at reducing levels of estrogen in the body and will depend on whether the woman is premenopausal or postmenopausal (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. Another avenue for blocking estrogen is the use of selective estrogen receptor modulators (SERMs) such

30 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 3: BOLERO-2 (12 mo f/up): Response and Clinical Benefit2 60



Everolimus + Exemestane Placebo + Exemestane



P <0.0001



20 10 0


P <0.0001 1.3%


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 inhibitors 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 patient 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 manage hormone responsive metastatic breast cancer. One novel agent that has been approved for treating metastatic disease is everolimus, an mTOR (mammalian target of rapamycin) inhibitor. mTOR is a downstream signal for cancer cell growth and survival. Research has indicated that aberrant signaling through the mTOR pathway is associated with resistance 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 progressed on an aromatase inhibitor. The combination of everolimus with exemestane led to an improvement 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 moving on to chemotherapy, everolimus is a better tolerated therapy. The addition of this agent has opened up a whole new area of treating the metastatic postmenopausal population. HER-2 positivity occurs in about 20 percent of

Clinical Benefit

breast cancers. With the development of targeted therapies, median survival in these patients is now about four years. For patients with HER-2 positive 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®), lapatinib (Tykerb®), pertuzumab (Perjeta®), and adotrastuzumab 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 improving survival. There are data supporting targeting the HER-2 mechanism throughout the disease course. The tumor 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 extracellular 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 complementary 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 chemotherapy 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 combination molecule of trastuzumab and a chemotherapy agent (emtansine) that delivers the chemotherapy | Vol. 16, No. 3 | Journal of Managed Care Medicine 31

Exhibit 4: Dual Targeting of HER-2 Receptor May Have Enhanced Efficacy



Downstream signaling pathways Cell proliferation Cell Survival

into the tumor cell thus minimizing damage to normal cells. Emtansine is an old agent that was never marketed because it was too toxic. Ado-trastuzumab emtansine is indicated, as a single agent, for the treatment of patients with HER-2 positive, metastatic breast cancer who previously received trastuzumab 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 chemotherapy 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 higher response rates. Combination therapy has not been shown to improve survival but is appropriate to use when a patient has a high disease burden.

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.

References 1. 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 advanced 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, CortĂŠs J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461-71.


As the understanding of the underlying biology of breast cancer has improved, so has therapy improved. Agents are now selected based on the receptors found on the tumor. For patients with metastatic breast cancer who are estrogen receptor-positive, treatment will be sequential endocrine therapy possibility with the addition of everolimus. There are several agents available now that target HER-2 positive tumors and these remain effective throughout multiple lines of therapy because of the tumorâ&#x20AC;&#x2122;s continued reliance on the HER-2 pathway. The next 32 Journal of Managed Care Medicine | Vol. 16, No. 3 |

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, and then click the activity title.

Summary Metastatic colorectal cancer (MCRC) management has improved significantly in the past decade. Several medications have been approved since the late 1990s, resulting 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.

The management of metastatic colorectal cancer (MCRC) has improved significantly since the late 1990s. Until 1996, 5-fluorouracil (5FU) 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 median 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 inhibitor, was approved initially as a second-line treatment for patients with MCRC in 1996. In 2002, capecitabine (Xeloda®), an oral fluoropyrimidine prodrug converted into 5-FU by thymidine phosphorylase, 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 approved 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 vascular 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 treatment 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 (Stivarga®). Ziv-aflibercept is a recombinant fusion protein | Vol. 16, No. 3 | Journal of Managed Care Medicine 33

Exhibit 1: Regorafenib Targets Multiple Tumor Pathways1-3 Regorafenib

Inhibition of proliferation


Inhibition of tumor microenvironment signaling

Inhibition of neoangiogenesis



consisting of VEGF-binding portions from the extracellular 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 combined 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 homolog) gene. The protein product of the normal KRAS gene performs an essential function in normal 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 outcomes in patients with KRAS mutations, patients

should be tested for KRAS mutations before treatment.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 prognosis. Two mutations are typically reported on testing â&#x20AC;&#x201C; 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 studies showed no difference between codon 13 and codon 12 KRAS mutation response.8 Based on current evidence, any patient with KRAS mutations is unlikely to receive significant benefit from cetuximab or panitumumab and has a very poor prognosis. 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 response. BRAF is a primary effector of KRAS signaling. 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 mutations.9 The addition of cetuximab to chemotherapy regimens in patients with BRAF mutations has been shown to be beneficial in improving median progression-free survival and overall survival.10 The findings from recent studies are allowing clinicians to better tailor therapy. For example, dual

34 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Probability (%)

Exhibit 2: STEPP Results13

100 90 80 70 60 50 40 30 20 10

Pre-emptive Reactive

Events n (%)

Median (95% Cl) Weeks

14 (29) 29 (62)

NR 2.1 (2.1 to 6.3)

0 2 4 6 Time to First Occurrence of Skin Toxicity (weeks)


Pre-emptive n Censored

48 0

44 1

36 1

27 5

0 27

Reactive n Censored

47 0

36 2

18 1

16 0

0 15

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 survival might be impacted, quality of life needs to be considered. Sequential use of all active agents in rational 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 chemotherapy 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 molecular 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 typically be agents they have not been exposed to previously. 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 palliative setting because of its favorable toxicity profile. Bevacizumab can be continued beyond progression. If the patient progressed quickly (i.e., in less than three months), the bevacizumab should be discontinued. If they progressed later, it can be contin-

ued. When continued, there is a modest improvement in overall survival (1.4 months). Because the agents used to treat MCRC cause significant 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, antidiarrheals, and dose adjustments. For example, several trials have demonstrated that scheduled oxaliplatin interruptions decrease neurotoxicity without impacting efficacy. The biologic agents have different adverse effect profiles than chemotherapy. The main toxicities for bevacizumab include hypertension and, less commonly, thromboembolic events, primarily in elderly patients with risk factors, and GI perforations. The main toxicities of the EGFR inhibitors include rash, diarrhea, hypomagnesemia and hypersensitivity 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 Protocol with Panitumumab (STEPP) trial, doxycycline or minocycline started a day before a patient starts these agents and continued for six weeks significantly 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 â&#x20AC;&#x153;the drug is workingâ&#x20AC;?, and vice versa, for an individual patient. | Vol. 16, No. 3 | Journal of Managed Care Medicine 35


In MCRC, it is important to remember that the goal of therapy is not cure but is palliation. For most patients, the gain of time and maintaining quality of life are more important than response rates. The addition of newer agents to the therapeutic options has increased median survival. The role of genetic testing and biologics in managing this disease continues to evolve.

6. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic 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?

Tanios Bekaii-Saab, MD is Section Chief, Gastrointestinal Oncology

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

Program and Associate Professor of Medicine and Pharmacology at

9. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is re-

The Ohio State University – James Cancer Hospital.

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

References 1. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new

cer. J Clin Oncol. 2008;26(35):5705-12. 10. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer:

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

updated analysis of overall survival according to tumor KRAS and BRAF mu-

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

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


11. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxali-

2. Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation study of rego-

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

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

colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet.

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



12. Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with

3. Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Investig

continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic

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

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

4. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetux-

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

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

13. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation pro-

5. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of

tocol with panitumumab (STEPP), a phase II, open-label, randomized trial

chemotherapy, bevacizumab, and panitumumab compared with chemotherapy

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

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

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



36 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Optimizing Treatment Strategies in the Management of Metastatic Melanoma Adil Daud, MBBS For a CME/CEU version of this article, please go to, click on Oncology and then on Recent Advances in Melanoma Therapy

Summary The 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.

Skin cancers are the most common human cancer. Less than 2 percent of the 3.5 million 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 increasing 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 melanoma 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 recurrence 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 patients 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 | Vol. 16, No. 3 | Journal of Managed Care Medicine 37

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


600 8,000



Basal Cell


Squamous Melanoma


Merkel Cell


agents that target the BRAF mutation, specifically the V600 mutation [vemurafenib (Zelboraf 速), dabrafenib (Tafinlar 速)]. Subsequently to the BRAF mutation discovery, many more mutations have been discovered and Boris Bastian and others have shown that the location of melanoma determines the likely mutations (Exhibit 2).4-6 Overactivation of the N-Ras (rat sarcoma) and MAPK (mitogen activation protein kinase) pathways are often found in many tumor types (including melanoma) and are believed to play a significant role in cancer development and progression. Accordingly, inhibitors of this pathway are actively investigated. In melanoma, N-Ras and B-Raf activating 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 mutation; therefore, targeting BRAF should be an effective 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 responded.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. Regardless of age or disease stage, a BRAF inhibitor appears to benefit all patients, but resistance will develop 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 survival 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 combination (vemurafenib and trametinib (Mekinist 速) in patients with the BRAF V600 mutation, found that using the combination increased progressionfree 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 inhibition 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 速) is one agent that has been approved with better efficacy, easier administration, and fewer adverse effects than earlier therapies such as interleukin and interferon. Ipilimumab augments T-cell activation and proliferation that essentially takes the brakes off the immune system. It blocks cytotoxic

38 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 2: The Location of Melanoma Determine the Likely Mutations 4-6 GNAQ 32% G11 45%

Uveal Scalp/Face

Trunk/Legs C-Kit 5-10% NRAS 25% BRAF 10%

NRAS 15% BRAF 28%

NRAS 18% BRAF 57%




s al C-Kit 10-20% NRAS 15%

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 Similar 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 combination with chemotherapy to see if that would improve 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. Intratumoral 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 responses in untreated distant disease, suggesting that adaptive immune responses are being elicited that can target melanoma-associated antigens.13 This is a | Vol. 16, No. 3 | Journal of Managed Care Medicine 39

Exhibit 3: In-Vivo Electroporation

Injection of plasmid Electrode insertion Electroporation

promising approach that can trigger systemic antitumor immune responses without the systemic toxicity associated with intravenous interleukin. If the immune system can be stimulated to work against a tumor, lasting responses can occur. Conclusion

In the past few years, there have been unprecedented 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.

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 meta-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 advanced 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 inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694-703. 10. Hodi FS, Oâ&#x20AC;&#x2122;Day SJ, McDermott DF, et al. Improved survival with ipilimumab 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 correlates 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.

Adil Daud, MBBS is a Clinical Professor of Medicine and Co-Director of the Melanoma Program at the University of California in San Francisco.

References 1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999â&#x20AC;&#x201C; 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: 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.

40 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Advances in the Treatment of Fecal Incontinence Beth Moore, MD, FACS, FASCRS For a CME/CEU version of this article, please go to, click on Chronic Illness then AutoImmune and then on Fecal Incontinence: New Treatment Options

Summary Fecal 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.

Fecal incontinence (FI) is the incapacity to defer the urge to pass gas or stool at a socially acceptable time and place. Estimating prevalence 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 diagnosis, and 18 percent say their doctors have not identified 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 diagnosed 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 | Vol. 16, No. 3 | Journal of Managed Care Medicine 41

Exhibit 1: Impaired Quality of Life (FIQL)9 FI patients 4



GI patients not affected by FI *


*p <0.01 *

3 2.5 2 1.5 1


Coping Depression Embarrasment

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, Crohnâ&#x20AC;&#x2122;s disease, ulcertive colitis

Central nervous system disorders

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


Irritable bowel syndrome, postcholecystectomy diarrhea

are more common during the day and frequently interfere 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 social activities, and 38 percent and 26 percent, respectively, report missed work. Thus, FI has a significant impact on quality of life.9 Continence for stools depends on four main factors: rectal sensation, rectal storage capacity, anal sphincter strength, and stool consistency. FI can result 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 involuntary 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: passive 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 withstand 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 neurophysiologic 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 impact (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 conservative therapy, including diet, fiber, and antimotility agents. Other conservative therapies, as listed in Exhibit 3, can also be used at any point in therapy.

42 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 3: FI Current Treatment Practices13

CONSERVATIVE THERAPIES • Diet • Fiber therapy • Antimotility treatment

NONSURGICAL OPTION • Injectable therapy • Radiofrequency

*The following can be used at any point in therapy • Antidiarrneal agents • Enemas, laxitives, and suppositories • Biofeedback • Anal plug

SURGICAL OPTIONS • Sphincter repair • Dynamic graciloplasty • Artificial bowel sphincter • Stoma • Sacral Nerve Stimulation

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 $0

$5,000 Injectable bulking agent

If conservative therapy fails, patients may be considered for such nonsurgical options as injectable therapies. 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 sphincter 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. Unfortunately, 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

Artificial bowel sphincter

Sacral nerve stimulator

stay of three days. It is appropriate for highly symptomatic patients with a defined defect of the external sphincter.13 The majority of patients initially have subjectively good outcomes, but the results tend to deteriorate 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 electrical 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 surgically 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 neurostimulator that delivers electrical pulses to the sacral nerve, an electrical lead implanted on a sacral nerve, and | Vol. 16, No. 3 | Journal of Managed Care Medicine 43

Exhibit 5: FI Treatment Paradigm Conservative Therapies

• Generally safe • Low success rates • Patients may not wish to proceed to surgery • Patients may not be candidates for surgery

Minimally Invasive Treatments

Surgical Therapies

• 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

a programmer that controls the pulses. The neurostimulator and the lead are permanent implants. To determine if a patient will benefit from a stimulator, a test stimulation phase is conducted. A temporary lead is percutaneously placed at the sacral nerve for 14 days. If there is less than 50 percent reduction in incontinent episodes, the device is removed. Patients who have a greater than 50 percent reduction 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 surgical procedure requiring sedation. The efficacy of sacral nerve stimulation has been assessed in an open label trial.17 One hundred thirty-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 number of incontinent episodes per week. Perfect continence 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 available 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 hospital 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 insertions, 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 collagen 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 numbers of patients, FI scores decreased and quality of life improved.18-20 The improvements were maintained for up to five years. Ulcerations and minor bleeding were reported in these small clinical trials. A noninvasive procedure is the biocompatible tissue-bulking agent (Solesta®). This is a viscous combination 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 better sphincter control and is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy. The injection of the bulking agent is given in a

44 Journal of Managed Care Medicine | Vol. 16, No. 3 |

physician’s office or outpatient setting without anesthesia 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 longterm, follow-up report from one of the studies, 83 of 115 patients completed a 24-month follow-up assessment.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 episodes. The median number of FI episodes declined by 68.8 percent. The mean number of incontinencefree 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 adverse events were proctalgia (13.3 percent) and pyrexia (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 artificial 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 manufacturer’s common billing information.24,25 Exhibit 5 compares some of the advantages and disadvantages of the major treatments for FI.

prevalence, diagnosis, and health care utilization. Am J Obstet Gynecol. 2010;202:493.e1-6. 6. Rao S, American College of Gastroenterology Practice Parameters Committee. 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 sensitive skin with incontinence in the aged. Textbook of Aging Skin. 2010:755-769. 8. International Foundation for Functional Gastrointestinal Disorders (IFFGD). Managing 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 incontinence: 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 incontinence 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

Fecal incontinence has an enormous impact on an affected individual’s quality of life and results in significant economic costs. Treatment can improve this condition. Although effective for minor FI, conservative treatments are not usually effective for moderate to severe FI. Those patients will require nonsurgical or surgical intervention.



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 frequency energy delivery (Secca procedure) for the treatment of fecal incontinence: results of a prospective study. Int J Colorectal Dis. 2008;23(10):993-7. 20. Takahashi-Monroy T, Morales M, Garcia-Osogobio S, et al. SECCA pro-

Beth Moore, MD, FACS, FASCRS is Director of the Colorectal Can-

cedure for the treatment of fecal incontinence: results of five-year follow-up.

cer Center at Cedars-Sinai Medical Center.

Dis Colon Rectum. 2008;51(3):355-9.


Multicenter Study to Evaluate Efficacy and Safety of NASHA/Dx Gel as a

1. Rey E, Choung RS, Schleck CD, Zinmeister AR, et al. Onset and risk factors

Bulking Agent for the Treatment of Fecal Incontinence. Gastroenterol Res Pract.

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


21. Dodi G, Jongen J, de la Portilla F, et al. An Open-Label, Noncomparative,

2. Whitehead WE, Borrud L, Goode PS, et al, for the Pelvic Floor Disorders

22. Danielson J, Karlbom U, Sonesson AC, et al. Submucosal injection of stabi-

Network. Fecal incontinence in US adults: epidemiology and risk factors. Gas-

lized nonanimal hyaluronic acid with dextranomer: a new treatment option for

troenterology. 2009;137:512-7.

fecal incontinence. Dis Colon Rectum. 2009;52(6):1101-6.

3. Landefeld CS, Bowers BJ, Feld AD, et al. National Institutes of Health state-

23. La Torre F, de la Portilla F. Long-term efficacy of dextranomer in stabilized

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

hyaluronic acid (NASHA/Dx) for treatment of faecal incontinence. Colorectal

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

Dis. 2013;15(5):569-74.

4. Mellgren A, Jensen LL, Zetterström JP, et al. Long-term cost of fecal incon-

24. Medtronic. InterStim Therapy for 2012 Common Billing Codes, January 2012.

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

25. Acticon Neosphincter, AMS for Life 2011 Common Billing and Coding

5. Dunivan G, Heymen S, Palsson OS, et al. Fecal incontinence in primary care:

Flashcard. | Vol. 16, No. 3 | Journal of Managed Care Medicine 45


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

To learn more, visit Important Safety Information

• 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 Xofigotreated 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%)

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

© 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.



Printed in USA

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. 2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (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 protection The 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 handling Follow 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 care Whenever 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 CONTRAINDICATIONS Xofigo 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 PRECAUTIONS 5.1 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 lifethreatening 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 REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬ ¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 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 3-4 Abnormalities % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 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 XoďŹ go and in 2% of patients on placebo. Among patients who received XoďŹ go, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naĂŻve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naĂŻve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on XoďŹ go and 1% of patients on placebo. XoďŹ go increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patientsâ&#x20AC;&#x2122; oral intake and ďŹ&#x201A;uid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on XoďŹ go. Secondary Malignant Neoplasms XoďŹ go contributes to a patientâ&#x20AC;&#x2122;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, XoďŹ go 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 XoďŹ go 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 Chemotherapy In the randomized clinical trial, 16% patients in the XoďŹ go 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 XoďŹ go will tolerate subsequent cytotoxic chemotherapy. 7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ calcium channel blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go 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 XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go 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 XoďŹ go. 8.3 Nursing Mothers XoďŹ go 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 XoďŹ go, 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 Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/ disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go 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 identiďŹ ed 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 .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTEDÂŹ 3INCEÂŹ 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 Impairment No dedicated renal impairment trial for XoďŹ go 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 Potential Contraception Because 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 XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, 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 3INGLEÂŹ 8OlGOÂŹ DOSESÂŹ UPÂŹ TOÂŹ ÂŹ K"QÂŹ ÂŹ MICROCURIE ÂŹ PERÂŹ KGÂŹ BODYÂŹ WEIGHTÂŹ were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal 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. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹ BEÂŹ COMPLIANTÂŹ WITHÂŹ BLOODÂŹ CELLÂŹ COUNTÂŹ MONITORINGÂŹ APPOINTMENTSÂŹ WHILEÂŹ receiving XoďŹ go. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹ STAYÂŹ WELLÂŹ HYDRATEDÂŹ ANDÂŹ TOÂŹ MONITORÂŹ ORALÂŹ INTAKE ÂŹ mUIDÂŹ STATUS ÂŹ ANDÂŹ URINEÂŹ output while being treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹAREÂŹNOÂŹRESTRICTIONSÂŹREGARDINGÂŹCONTACTÂŹWITHÂŹOTHERÂŹPEOPLEÂŹAFTERÂŹRECEIVINGÂŹ XoďŹ go. Follow good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed 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 ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹ AREÂŹ SEXUALLYÂŹ ACTIVEÂŹ TOÂŹ USEÂŹ CONDOMSÂŹ ANDÂŹ THEIRÂŹ FEMALEÂŹ PARTNERSÂŹ OFÂŹ reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment. Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. Š 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

Updated Strategies and Outcomes in the Diagnosis and Treatment of Major Depressive Disorder Ken Hopper, MD For a CME/CEU version of this article please go to, then click on Behavioral Health and then the activity title

Summary Major depressive disorder has a significant impact on patients, families, workplaces, and the health care system. Clinicians and managed care plans both need to understand 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.

There is a high rate of occurrence of major depressive disorder (MDD) with a 17 percent lifetime prevalence.1 This prevalence corresponds 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 depressive disorders. The average age of onset of depression 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 chronicity. Thirty-three percent of patients have episodes of greater than two years’ duration. The rate of recurrence 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 disorder 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 depression. Approximately 15 percent of depressed patients who are hospitalized once for depression will commit 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 | Vol. 16, No. 3 | Journal of Managed Care Medicine 49

Exhibit 1: Depression Screening Tools Most Commonly Used Depression Screening Tools in Adults Tool



Sensitivity/ Specificity4

Beck Depresion Inventory


Available for purchase from

100% / 75%

Center for Epidemiologic Study Depression Scale (CES-D)


Tool available for download:

79% / 77%

Patient Health Questionnaire (PHQ-9)


Tool available for download:

88% / 88%

General Health Questionnnaire-12


Tool available for download:

83% / 76%

Zung Self-Depression Scale


Exam available on-line:

97% / 67%

Geriatric Depression Scale


Hartford Institute for Geriatric Nursing

100% / 63%

Exhibit 2: Depression Chronic Care Model The Chronic Care Model

Community Resources and Policies SelfManagement Support

Informed. Activated Patient

Health Systems Organization of Health Care Delivery System Design

Decision Support

Productive Interaction

Clinical Information Systems

Prepared. Proactive Practice Team

Improved Outcomes

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 illnesses are estimated to cost commercial and Medicare purchasers between $130 and $350 billion annually. 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 disappearance of symptoms to have a remission. Many times clinicians who do not understand this will stop therapy too early. Stopping therapy prematurely sets the patient up for recurrent episodes and possibly future resistance to therapy. Continuing therapy beyond

50 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 3: Depression Assessment Pathway Severe depression with intermediate to high risk of harm or severe distress STEP 5

Patient with possible depression

Clinical assessment • Template • PHQ9 • May need more than one assess- ment

Refer to crisis team or on-call psychiatrist

Chronic atypical, refractory, or recurrent severe depression STEP 4

Refer to community mental health team or psychiatrist

Moderate to severe depression STEP 3

• Medication • Case management by telephone • Refer for CBT

Mild depression STEP 2

Subclinical or intervention declined STEP1

• Information leaflet with self-help advice • GOAL exercise referral • Signposting (Cruse, Relate, CAB, etc.)

Watchful waiting

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 episodes and the functional and structural changes discussed 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 American Psychiatric Association diagnostic criteria.7 The majority of cases of depression are treated in primary 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 conundrum 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-

Remission: review in 2 months

Reassess in 6 8 weeks

Regular followup by GP or mental health worker

Improved but still symptomatic: continue step 3 Not improved: re-evaluate treatment from this step or move to step 4

Resolution: no intervention Reassess in 2 weeks

Reassess in 2 weeks

Not improved: refer for self-help CBT in step 3 Resolution: no intervention Not improved move to step 2

item depression scale on the Patient Health Questionnaire. This is a powerful tool for assisting primary care physicians in diagnosing depression and in selecting and monitoring treatment. Some practices 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 approach 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 integration between primary care and behavioral health. This fragmented and uncoordinated care results in significant unmet behavioral health needs and unsuccessful chronic disease management. Better integration between primary care and behavorial 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 depressed patient who is at immediate risk for suicide. It is the equivalent activity to having a pathway for dealing with acute chest pain. A stepped care approach to | Vol. 16, No. 3 | Journal of Managed Care Medicine 51

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?

Step 5: Inpatient care, crisis teams

What is the focus?

Risk to life, severe self neglect

What do they do?

Medication, combined treatments, ECT

Treatment-resistant recurrent, atypical and psychotic depression, and those at significant risk

Medication, complex psychological interventions, combined treatments

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

Moderate or severe depression

Medication, psychological interventions, social support

Step 2: Primary care team, primary care mental health worker

Mild depression

Step 4: Mental health specialists, including crisis teams

Step 1: GP, practice nurse


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 services 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 patientâ&#x20AC;&#x2122;s preferred treatment choice may not always 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 psychotherapy but has fears about medications, psychotherapy

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

would be the better choice for initial therapy. The various pharmacologic antidepressant classes include serotonin selective reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Psychotherapeutic options include cognitive behavioral therapy, interpersonal therapy, problem-solving therapy, supportive therapy, 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 outcomes than receiving the same therapy in a hospital setting.11 Setting goes along with the positive attitude toward treatment.

52 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 5: Augmentation Therapy Lithium Risks •

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

Benefits •

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

Recommendations •

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

Caution necessary when prescribing buspirone with nefazodone Standard dosages of 15 to 30 mg per day have shown augmentative antideppressant effects Lowest dose should be prescribed initially to rule out interaction (2.5 mg twice daily)

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 antideppressant response in of patients over three month period

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 reduces the risk for depressive illness. Consumption of a diet rich in processed foods independently increases the risk of developing depressive symptoms over five years, whereas a diet rich in whole foods was found to protect against the development of | Vol. 16, No. 3 | Journal of Managed Care Medicine 53

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 improve a patient’s other chronic diseases. There is also a connection between substance abuse and depression. 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, multiple 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 antidepressant 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 adverse effects, and poor treatment adherence. There are five strategies for overcoming resistance – optimization, medication substitution, combination therapy, and augmentation.13 If the dosage prescribed 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 substitution. Changing from one antidepressant to another in the same class has not produced impressive response rates; however, some studies suggest that switching to an antidepressant with a different mechanism of action is often associated with a better 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 regimen. Combination therapy may also include concurrent administration of two or more anti-depressant 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 second agent, not routinely prescribed for depression, to the therapeutic regimen when there is a limited response to the antidepressant. Common augmentation therapy agents include lithium, thyroid hormone, 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 augmentation, 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 therapeutic 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 adherence 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 medication 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 family 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 important 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 evidence that continued treatment with antidepressant

54 Journal of Managed Care Medicine | Vol. 16, No. 3 |

medication has a neuroprotective effect. They need to understand that depression can get worse if not consistently treated. Understanding the mind-body connection in depression can inform a variety of treatment methods to provide optimal patient care. For instance, patients should be encouraged to participate in physical activity, have a healthy diet and limit processed foods. Another aspect of the mind-body connectionâ&#x20AC;&#x2122;s contribution to treatment success is allowing patient preference to inform treatment. Patients can participate in support groups and, if possible, support groups can be conducted outdoors or in aesthetically pleasing environments. Patients need to be educated on the importance 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 recommendations, monitor medication adherence, and provide better feedback on the patientâ&#x20AC;&#x2122;s functioning.


References 1. 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 Organization, 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 Global 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 depressive 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 Mental 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.

Major depressive disorder results in significant personal, social, and economic costs. Care of patients with MDD can be improved by allowing patient preference to shape treatment, by implementing mind-body treatments, and by integrating primary care and behavioral health services. For patients who do not respond to initial treatments, treatment adherence needs to be considered. If patients have treatment resistance or severe MDD, they need to be referred to behavioral health specialists for case management and more aggressive pharmacotherapy.

9. Bower P, Gilbody S. Stepped care in psychological therapies: access, effectiveness 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 nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination. 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

Ken Hopper, MD is an Executive Consultant with BHM Healthcare So-

Fam Physician. 1998;58(9):2059-62 | Vol. 16, No. 3 | Journal of Managed Care Medicine 55

GBEMTI Perspectives: Value-Based Reimbursement for Medical Devices in the U.S. â&#x20AC;&#x201C; Where Do We Stand? Eric Faulkner, Joshua Ransom, Natalie Heidrich, Brad Lucas, MD and Geneva Briggs, PharmD, BCPS

Summary As payment restructuring provisions of health care reform are adopted in the Medicare marketplace and beyond, understanding and implementing value-based reimbursement 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, perspectives on what value-based decision making is, how to structure value-based decision 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., payers, 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 ability 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 national survey of medical directors include the lack of rigorous efficacy data, difficulties in identifying costs because of bundled coding and the lack of a standard approach 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, Integrated Delivery Networks).

Introduction The U.S. managed care landscape is rapidly changing and emerging health technologies will play a central role in shaping tomorrowâ&#x20AC;&#x2122;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, targeting 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 increase 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 throughout 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 pacemakers), 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- | Vol. 16, No. 3 | Journal of Managed Care Medicine 57

ternal monitoring devices, or use of targeted ultrasound or radioactivity for therapeutic applications) are also emerging. Medical devices are also increasingly being developed as combination products involving 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 historical 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 medical devices has not kept pace with other healthcare spending, with medical device prices increasing approximately 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 embedded in procedural codes and associated payments and not subject to separate payment as are many pharmaceuticals. This bundling of medical technology 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 manufacturers to track and characterize the value of individual or alternative medical technologies. Currently, 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 devices, although the pressure for technology manufacturers to provide an increasing array of evidence to support coverage and uptake is growing.4 At present, technology manufacturers are caught between expectations to more definitively demonstrate value and the reality that system incentives are not optimally 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 ability 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 reimbursement generally is considered to involve differentially 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 rewards and consequences, conditional upon achieving pre-specified performance measures. Incentives are set to discourage inappropriate, unnecessary, and costly care. The key elements of value-based purchasing 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 systems 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

58 Journal of Managed Care Medicine | Vol. 16, No. 3 |

- Clearer path and possibly reduced time to market - Faster uptake - Improved reimbursement/pricing for better outcomes Under a value-based reimbursement model, medical technologies would be paid for based on “value” rather than via traditional “one size fits all” procedural payments, enabling those technologies that provide marked value over alternatives to be differentially 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 Australia’s Pharmaceutical Benefits Pricing Authority (PBPA) is increasingly suggesting alternative pricing agreements in negotiations although this is focused on pharmaceutical therapies.9,11 Additionally, Germany 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 issues surrounding value-based reimbursement for medical devices and potential for this concept to be integrated into U.S. managed care practices, a targeted Internet-based survey was conducted by the Genomics, Biotech, and Emerging Medical Technologies Institute (GBEMTI) of the National Association of Managed Care Physicians (NAMCP) member medical directors. Methods

The GBEMTI was established in 2011 as an institute of the NAMCP. The NAMCP represents medical directors from payer, purchaser (employers), and provider systems such as IPAs, ACOs, PHOs, and medical groups. The goal of GBEMTI is to support and characterize the value of genomics, biotechnology, regenerative medicine, and medical technologies as these new modalities enter and impact the health care system. The GBEMTI seeks to support collaborative stakeholder engagement around emerging health technologies to consider their potential to improve patient outcomes, impact on managed care management practices and value to the health care market place. The Institute is guided by an Executive Leadership Council (ELC) composed of over 90 payer and manufacturer members. The GBEMTI is unique in that it is a multi-stakeholder group centered on bringing medical director decision makers and manufacturers together to address key trends

and topics that are transforming U.S. health care and explore means to improve managed care decision making and patient access to emerging health technologies. The GBEMTI is divided into four key technology divisions: • Biopharmaceuticals and Specialty Products • Diagnostics and Personalized Medicine • Emerging Medical Devices • Regenerative Medicine To address the objectives of the Institute, each division is focusing on questions unique to that respective division and developing a series of perspectives papers focused on key managed care challenges associated with these technology areas. The goal of these papers is to evaluate payer/managed care perspectives and implications for improving managed care processes, policies, and patient outcomes for each core emerging technology area. Value-based reimbursement for medical devices was chosen as the first topic under the Emerging Medical Devices division. This paper and all subsequent ones published by the Institute have been peer reviewed by the GMEMTI ELC. The survey questions addressed key drivers, information needs, and payer perspectives on opportunities for moving toward value-based reimbursement for medical devices. The survey was randomly disseminated to medical director members of NAMCP 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 Devices

The 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 often find the evaluation of devices challenging. Further, 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- | Vol. 16, No. 3 | Journal of Managed Care Medicine 59

Exhibit 1: Is there a standard (protocol) for manufacturers to demonstrate device value to payers or employer purchasers? 20%

Yes No 80%

n = 41

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 delivered 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 evidence 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. Interestingly, only 12 percent of all respondents, and onefourth 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 complicates evaluation of the value of medical technologies? 12%


29% Lack of Evidence Inadequate Standards of HTA Lack of Expertise/Capabilities Variability in How Manufacturers Submit Evidence for Review

n = 41

60 Journal of Managed Care Medicine | Vol. 16, No. 3 |


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? 20%


Very Important Important Somewhat Important Minor Importance Unimportant




n = 41



point may be a significant issue with the implementation of value-based reimbursement if device manufacturers are unable to recover the costs associated with generating the additional evidence required by payer and provider stakeholders. At present, incentives are insufficiently aligned for this to occur “organically.” The major issue is the lack of evidence and difficulty in conducting the analysis (due to gaps in evidence and lack of standardization). Payers suggested that they are seeking more robust evidence (e.g., robustly designed controlled studies with sufficient statistical power), including ideally comparative 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 evidence 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 opportunity for device manufacturers to articulate the value story for the product and helps to mitigate the variability in payer and provider HTA processes associated with devices and helps the payers by framing 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 reimbursed directly. The cost of the device is typically embedded into the reimbursement of the procedure or service that uses the device. This makes it difficult 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 distinct devices so that associated outcomes and costs could be tracked and monitored in the future. However, 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 coding bodies. As shown in Exhibit 3, only 40 percent of survey respondents felt that it is very important or important to understand the incremental cost impact of individual devices. Another 40 percent felt understanding incremental cost impacts were only somewhat important, of minor importance or unimportant. 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 providers included in the analysis appear to be equally split on their satisfaction with the existing bundled | Vol. 16, No. 3 | Journal of Managed Care Medicine 61

Exhibit 4: Has your health plan considered development of value-based reimbursement models for medical technologies? 33%

Yes No


n = 41

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 Models

According 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, approximately one-third of plans have considered development 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 value-based reimbursement models, almost 80 percent of respondents thought these type of models for devices were very important or important for improving care and outcomes (Exhibit 5). Thus, there is a significant disconnect between perception of importance 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?

100% 80%

5% 18%


60% 55% 40%

Somewhat Important Important Very Important

20% 23% 0%

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Exhibit 6: How would value-based-reimbursement be implemented differently from current models? 14%



Pilots/Progressive Auth Higher reimb for positive outcomes; limited/none for inadequate outcomes Higher reimb for incremental improvement Device formulary


n = 41

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 potentialgains/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 premiums 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 â&#x20AC;&#x153;inadequateâ&#x20AC;? outcomes may not be an acceptable risk that some manufacturers are willing to take vs. the existing payment system. However, some payer members of the ELC suggested that evidence of improved incremental outcomes might enable some manufacturers to engage in targeted contracting discussions outside of procedural payments in the absence of a full value-based pricing mechanism. Only a minority suggested the implementation of a medical device formulary as one potential approach. Another issue with determining the value of new technology is having available resources for engaging in discussions with medical technology manufacturers regarding the value of new technologies. Survey participants were asked about such resources 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 willingness 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 potential. For payers and providers, respondents indicated that evidence of comparative device value might also be integrated into guidelines or clinical pathways if available. This may be particularly true in the case of emerging ACO models, where providers are incented to identify and leverage additional care efficiencies or as a means to refine payer coverage 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 significant 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 â&#x20AC;&#x201C; (1) coverage with evidence development for promising technologies, (2) negotiation of differential payments with device manufacturers that demonstrate significant incremental value versus alternatives, (3) development of device registries for target technology categories for real-world evidence generation, institution of individual technology tracking codes linked to distinct devices/manufacturers, (4) development of a | Vol. 16, No. 3 | Journal of Managed Care Medicine 63

Exhibit 7: Which of the following options would you view as MOST feasible to support value-based reimbursement pilots/demonstration projects for medical technologies?



5% 27%


Coverage Negotiation Registry Codes Formulary Reducing Copay Tiering

n = 41 n = 28


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 medical technologies. Participants identified the method they thought â&#x20AC;&#x153;most feasibleâ&#x20AC;?. As shown in Exhibit 7, the results were heterogeneous with no clear preference on the most feasible method of accomplishing 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 development (CED) for promising technologies is the biggest pie slice in Exhibit 7 indicates that if sufficient 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 compare to alternatives. In practice however, commercial payers have not adopted coverage with evidence development approaches due to the following factors: (a) concerns that actual coverage changes, including subsequent denials, would be more difficult to execute vs. denial of coverage at initial reimbursement assessment, (b) perspectives that it is not the payerâ&#x20AC;&#x2122;s responsibility 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 Center 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 interest in this approach to support evidence-development and value-based reimbursement. Survey findings also suggest that stronger differentiating 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 contracted rates versus those lacking evidence. However, definitive criteria regarding the therapeutic areas and scenarios that would support alternative contracting 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 support 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 stakeholders had highly variable perspectives on the approaches that might enable value-based reimburse-

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ment for medical devices. While payers may consider pilots in this area and acknowledge that the existing system has limitations, minimizing risk overall remains 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 Limitations

Limitations of this analysis may include respondent bias, as it was not possible to determine whether respondents held a particular interest in medical devices and/or are early adopters. Based on the limited number of respondents, survey findings may not be fully representative of U.S. medical director 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 reimbursement but are in the very early days of adoption. There appears to be a disconnect between perceived importance and willingness to alter existing approaches from the payer side. Payers are not aligned on a standard definition of value-based reimbursement for medical devices, how to calculate value, or how to implement value-based reimbursement programs. 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 important to building a foundation for value-based reimbursement 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 criteria 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. Evidence standards for devices would also help ensure that manufacturers, payers and policy makers are “working from the same playbook” and have defined “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 structures 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 characterize device value. 2. Develop standard approaches for modeling and calculating medical device value. This would simplify uncertainties in device assessment and should be aligned with standard evidence development approaches. This would also require developing a more standard perspective on definitions of value-based reimbursement for medical devices. 3. Establish strategic partnerships with data/analytics 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 strategic partnership with data/analytics companies to develop the standards and analysis approaches may increase payer acceptance of value-based reimbursement 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 device applications are sufficiently similar (e.g., diagnostic imaging, orthopedics, spinous implantables, topical drug-device delivery systems). By taking an informed, proactive approach to the evolving market trend regarding value-based reimbursement, medical device manufacturers have the opportunity to help sustain ongoing product innovation and suc- | Vol. 16, No. 3 | Journal of Managed Care Medicine 65

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-reimbursement approaches may allow payers to continue to contain costs while incentivizing manufacturers to significantly improve patient outcomes and innovation remains to be seen, but is most likely to move forward initially in small and measured steps.

shift from volume to value. Deloitte Center for health care solutions. 2012. 10. Faden RR, Chalkidou K. “Determining the Value of Medications – The Evolving British Experience.” New England Journal of Medicine. 2011; 364(14):1289-91 11. Annual Report For the year ended 30 June 2010. Pharmaceutical Benefits Pricing Authority. Available at: publishing.nsf/Content/74C7CDABFFEFC8A0CA256F180046E152/$File/ PBPA%20Annual%20Report%20final.pdf. 12. “Reinventing biopharma: Strategies for an evolving marketplace. The value challenge.” Economist Intelligence Unit. 2012 Jan. 13. Obremskey WT, Dail T, and Jahangir AA. Value based purchasing of medical devices. Clin Orthop Relat Res 2012. 470(4): 1054-64. (http://www.ncbi. 14. Chernew ME, et al. Evidence that value based insurance can be effective. Health Aff. 2010. 29(3): 530-6. (

Eric Faulkner, Co-Director, NAMCP Genomics, Biotech, & Emerging

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Medical Technologies Institute, Director, Global Market Access, Quintiles.

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ing Medical Technologies Institute, Principal Consultant, Quintiles.

16. Smith HE, et al. Spine Care: evaluation of the efficacy and cost of emerging

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technology. Am J Med Qual. 2009. 24 (6 Supp): 25S-31S.

tives, Ethicon.

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Brad Lucas, MD, National Medical Director, Centene.

dure and CO2 laser vaporization for the treatment of cervical intraepithelial

Geneva Briggs, PharmD., BCPS, Briggs & Associates.

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Acknowledgements: Our thanks and acknowledgements to the Ge-

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References 1. The Patient Protection and Affordable Care Act of 2010 (Public Law 111148), as amended by the Health Care and Education Reconciliation Act of 2010. 2. Faulkner E, Richner R, Brown M, Burken M, Kelley L. Market access challenges for device and diagnostic companies: adaptive approaches for value characterization. Advanced Medical Technology Industry Association, Washington, DC. October 2010. 3. Donahue G, King G. Estimates of Medical Device Spending in the U.S.AdvaMed. 2011. 4. Ackerman S, Dix Smith M, Ehreth J, Eldessouki R, Sullivan E. Therapeutic and diagnostic device outcomes research. International Society for Pharmacoeconomics and Outcomes Research. 2011. 5. Deloitte Center for Health Solutions. Issue Brief: Value-based purchasing: A strategic overview for industry stakeholders. July 2011. Accessed


center-for-health-solutions/82e4b2de53ebe210VgnVCM1000001a56f00aRC RD.htm. 6. Robinson J. Value-based purchasing for medical devices. Health Affairs. 2008;27(6):1523–1531. 7. Meyer J, Rybowski L, Eichler R. Theory and Reality of Value-Based Purchasing: Lessons from the Pioneers. AHCPR Publication No. 98-0004 Available at 8. Farra et al. First in Human Testing of Wirelessly Controlled Drug Delivery Microchip. Sci Transl Med. 2012. 4(122): 122ra21 9. Keckley, PH. Value based pricing for pharmaceuticals: Implications of the

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Physician Engagement is Critical to the Success of any Accountable Care Organization Anthony N. Akosa, MD, MBA

Summary Physician 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 physicians 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 utilization 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 facility 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. Introduction

ADVANTAGE Health Solutions, Inc. (AHS), a local health plan that insures many employer groups in Indiana, wanted to test the hypothesis 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 certain 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 emergency room visits was $0; copayment for advanced imaging 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 neither cost effective nor safe for the members. Most of these nonemergent conditions like upper respiratory illnesses (URI), urinary tract infections (UTI) and | Vol. 16, No. 3 | Journal of Managed Care Medicine 67

acyclovir (ZOVIRAX) albuterol soln neb (ACCUNEB) Allopurinol amitriptyline (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 stearate erythromycin/sulfisoxazole (PEDIAZOLE) estradiol (ESTRACE Tabs) estropipate (OGEN) estropipate (ORTHO-EST) famotidine (PEPCID) fluconazole (DIFLUCAN)

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 satisfaction. 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 Objectives

Exhibit 1: Advantage Health Solutions, —

The 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 unnecessary utilization, especially emergency room and advanced Imaging (CT, MRI and PET scans); uti-

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)

lization of services at the right place and right time; for example, encouraging the members to utilize urgent care centers after hours for nonurgent problems like URI instead of going to the ER; partnering with providers to promote outreach, health prevention and patient engagement; improving generic utilization rate when appropriate by providing generic alternatives at point of care (provider practices); 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 Provider 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 provider. 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 program to the members assigned to them. The program was called a Shared Savings Incentive Program and comprises: • Member engagement activities

68 Journal of Managed Care Medicine | Vol. 16, No. 3 |

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 citrate loratadine (CLARITIN) OTC lovastatin (MEVACOR) medroxyprogesterone (PROVERA) medroxyprogesterone IM (DEPOPROVERA) 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/hc neomycin 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) penicillin phenazopyridine (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)

• Provider engagement activities • Health Navigator activities Member Engagement Activities

Marketing 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 specific generic drugs, decreased unnecessary emergency 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 appropriate for the member or the member requested a brand name drug, then the member would be responsible for the appropriate copayment specified in

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)

the employer’s Prescription Drug Coverage Benefit. AHS identified members who were on brand name drugs that were available generically. These members 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 partnered with a local pharmacy that offers concierge services to members such as the delivery of medications to home and place of work. The pharmacy also has branches at two provider practices. The pharmacy could dispense drugs prescribed by the providers 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 providers 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) | Vol. 16, No. 3 | Journal of Managed Care Medicine 69

Exhibit 2

June 2011 JOHN DOE ABC DRIVE CITY, 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 pharmacist for more information. Also, you could save even more by using the mail order pharmacy. Visit 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





SINGULAIR (montelukast)


zafirlukast (ACCOLATE)



CRESTOR (rosuvastatin)


simvastatin (ZOCOR)



Total savings in 12 months $216

programs for whom the Disease Management Educators were unable to contact. The Health Navigator worked with providers’ offices to find out when members who did not respond to AHS’s DM campaign were scheduled to see their PCP and discussed DM participation and incentive/benefits with the PCP and/or member. The Health Navigator also referred 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-

70 Journal of Managed Care Medicine | Vol. 16, No. 3 |

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 utilization 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




Provider Metrics Date

Number of Members

Generic Utilization Percentage

Advanced Imaging Rate/1000

ER Rate/1000

January 11


February 11








March 11 April 11









May 11





June 11





July 11





August 11





September 11





October 11





November 11





December 11





Payout Calculation Date

January 11

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


February 11


March 11



April 11


May 11




June 11




July 11


August 11


September 11






935.00 1175.00 -



October 11




November 11




December 11


Grand Totals

246.25 $940.00




246.25 -






(chart cont. next page) | Vol. 16, No. 3 | Journal of Managed Care Medicine 71

Exhibit 3 (cont.) Payout Distribution Schedule Date



Distribution #1


50% of 1st Quarter 2011 Earnings


Distribution #2


50% of (2011 YTD Earnings LESS Distribution #1


Distribution #3


50% of (2001 YTD Earnings LESS Distribution # 1 and #2


Distribution #4


Total 2011 Earnings LESS Distributions #1, #2, #3


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


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

was also the metric that had the highest variance from the AHS benchmark. The other two metrics 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 report 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 meetings with these providers to explain the program and quarterly results. Group 2 providers met with

AHS only once and there were no subsequent meetings with the providers. The Provider Dashboard reports were available to the providers monthly and displayed utilization, financial and quality metrics by providers benchmarked against their peers. The Provider Dashboard had over 40 metrics, including the three that the providers were incentivized on. The providers were initially given a hard copy of their individual dashboards and were instructed to inform the Health Navigator to provide them with monthly updates from the health plan’s web-based reporting 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

72 Journal of Managed Care Medicine | Vol. 16, No. 3 |

Exhibit 4 Group 1 4th Quarter 2011

Physician 1


Provider Address

Provider City

Provider State

Provider Zip

Values Sum of 4th Quarter 2011 Payout

Sum of Members

Dr. Jane Doe

123 River Road






Physician 1



Physician 2



Physician 3



Physician 4



Physician 5



Physician 6



Physician 7



Physician 8



Physician 9



Grand Total



future health care cost based on the chronic disease burden of the particular member, and it is normalized 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 â&#x20AC;&#x153;embeddedâ&#x20AC;? 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 coordinated 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 Provider Portal (especially for prior authorization requests) to improve efficiency and provider satisfaction. AHS piloted Automated Prior Authorization (Auto Auth) system utilizing Milliman Care Guidelines 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 authorization. The Auto Auth system allows the provider 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 coordination activities. Member satisfaction was measured with the CAHPSÂŽ Clinician & Group Survey results. Quality metrics include breast cancer screening rates, colorectal cancer screening rates, and comprehensive diabetic care eye exam rates. The disease management participation rate was the percentage 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 hospitals in the area to set up daily emergency room (ER) and inpatient notification processes. This helped AHS contact members who were seen in | Vol. 16, No. 3 | Journal of Managed Care Medicine 73

Exhibit 5 Measurement Utilization Generic utilization rate %



Group 1









68% 4%

End of Program

Advanced Imaging Rate (CT,MRI,PET)/1000

Group 3

% Change










All Groups





End of Program





% Change



p-value ER rate/1000

Group 2













251 -5%

<0.05 214

End of Program % Change













End of Program




60% -5%

Satisfaction Member Satisfaction Rate (Overall satisfaction for adult patients)



End of Program


% Change




Quality Breast Cancer Screening

Colorectal Cancer Sreening

Diabetic Eye Exam

% Change













End of Program




45% 5%

% Change













End of Program




29% 1.6%

% Change








Disease Management Participation Care-ADVANTAGE participation rate



End of Program


% Change




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 engaged. Group 2 providers were considered moderately engaged, and Group 3 providers were considered unengaged. Group 3 was considered the control groups as these providers were not engaged

74 Journal of Managed Care Medicine | Vol. 16, No. 3 |

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 (baseline) 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 increased their charge master from 2010 to 2011 as evidenced by the increased unit cost for most services by 9 percent. The PMPM cost is a factor of utilization 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 overutilization of services. In comparison, the average annual 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 percent, the recalculated PMPM was still lower than the average NHE annual growth rate.4 We calculated 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 â&#x20AC;&#x201C; 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 (Exhibit 4). The overall generic utilization for all groups increased by 4 percent mainly due to provider incentive 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 letter 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 respectively, 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 layperson definition of an emergency or not. Like most health plans, AHS uses an auto pay list for ER services 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 reviewed all the ER visits. Before applying the prudent layperson rule as required by the state law, we contacted the memberâ&#x20AC;&#x2122;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 approved or not. Advanced imaging utilization decreased for all three groups and all were statistically significant. AHS also implemented an automated precertification 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 screening 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 diabetic 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 provider engagement process of four months. The participation in care management (Care-ADVANTAGE program) also decreased from 42 percent in 2010 to 41 percent in 2011. The Care-ADVANTAGE program includes these disease states: diabetes mellitus, congestive heart disease, chronic obstructive pulmonary disease, hypertension, migraine, asthma and coronary heart disease. This is an opt-out program where members are enrolled automatically but have the option to disenroll themselves. The average AHS Commercial line of business participation 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 | Vol. 16, No. 3 | Journal of Managed Care Medicine 75

population) increased by 53 percent from 2010 to 2011. This was mainly due to the ER and inpatient notification process managed by the Health Navigator. The CCM program is for members with complex medical needs regardless of diagnosis. The Adult CAHPS® Clinician & Group Survey was administered to all the adult members and a follow-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 percent indicating no statistically significant change. The baseline survey results were not shared with the providers and this could have contributed to the results. Conclusion

Engaged 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 providers 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 utilization metrics (generic prescription, ER and advanced imaging rates) only and the engaged providers 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 Informatics at ADVANTAGE

Health Solutions, Inc. SM and is an Assistant

Professor in the Department of Family Medicine at Indiana University School of Medicine.


The 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 Navigator); Linda York, PhD., FNP, RN, CMC (Director Medical Affairs); Philip Yadon (Quality Analyst); Brian W. Musial, RPh (Director of Pharmacy), Toni Williams, BS (Care Management Analyst) and Hunter Heniser, MHA (Medical Affairs Intern).

References 1. 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. TripleAim/Pages/MeasuresResults.aspx 2. Health Care Costs: A Primer. Key Information on Health Care Costs and their Impact. May 2010. 3. Leavitt Partners: Growth and Dispersion of Accountable Care Organizations. June 2012 Update.

76 Journal of Managed Care Medicine | Vol. 16, No. 3 |

How Behavioral Health Integration Can Reduce Health Care Costs Mark Rosenburg, MD, PhD

Summary Health 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

Barriers to Integration

There are many barriers that have precluded true integration between medical and behavioral health. In general, primary care physicians lack the training to properly diagnose and treat mental 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 shortages 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 behavioral health and other medical services. Logistically, 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 reimbursed is an important piece of integration, and there is great opportunity for financial/billing prac-

tice models to be developed to eliminate this barrier 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 compensation. Finally, barriers to care are further expanded when there is a lack of adoption of communication strategies between the two sectors. Care Management and Case Management are offering some improvements to this area, but for most providers the communication gap is still in place. Potential Integration Models The Chronic Care Model

The 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). | Vol. 16, No. 3 | Journal of Managed Care Medicine 77

Exhibit 1: Statistics1-3

85% of behavioral health patients are seen in the phyiscal health sector

65% receive no behavioral health treatment

70% of all behavioral health treatment is provided by primary care physicians (PCPâ&#x20AC;&#x2122;s)

Only 13% of patients treated by PCPâ&#x20AC;&#x2122;s get evidencebased care

Only 3% of behavioral health providers work in the general medical sector

80% of expenses for patients with mental conditions are from medical benefits, half of which are for physical health services

The Stepped Care Approach

The 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 identifies which populations are best served in the primary care setting, which are best served in the behavioral health setting, and which may be served in either. (Exhibit 3)

Potential Solutions

There are many issues surrounding the integration of behavioral health. Fortunately, there are many proactive solutions that may be implemented separately or in conjunction with one another. Training for Primary Care Physicians

One 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 2

Community Resources and Policies Self-Management Support

Improved activated patient


Health System Organization of Health Care Delivery System Design Decision Support Clinical Information Systems

prepared proactive practive team

78 Journal of Managed Care Medicine | Vol. 16, No. 3 |


Improved outcomes

Exhibit 3: The 4 Quadrant Model

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

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

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. Collaboration

Collaboration between primary care and behavioral 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. Providing a mechanism for primary care to reach out to behavioral health in order to either receive immediate answers to questions or to refer the patient if extensive care is needed is critical. Conversely, 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 Fellowships

To take the referral networks and training to the next level, behavioral health can offer fellowships. These fellowships would provide training to primary 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 Psychiatrist

Adding a Network Psychiatrist would provide collaboration between behavioral and physical providers. This position would lead the charge for championing integration and advocate the implementation of evidence-based practices for integrated primary care. Behavioral Health Coordinator

A Behavioral Health Coordinator in each network works closely with the Network Psychiatrist in setting priorities for practice interventions, identifying priority populations, and identifying complex cases for discussion in case management settings. Behavioral 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 Psychiatrist and the Network Case Managers. Mobile Crisis Units

Relationships can be formed with mobile crisis units throughout the community. These mechanisms are available 24/7 and can serve as an additional resource when a patient presents with complex or multiple mental health issues. Case Management

The goal of integrated Case Management is to break | Vol. 16, No. 3 | Journal of Managed Care Medicine 79

Exhibit 43

Recommendation 1:

• 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 2:

• Resolve confusion about same-day billing restrictions and pursue efforts to reduce administrative barriers.

Recommendation 3:

• Examine the viability of paying for Health and Behavior Assessment codes under insurance plans.

Recommendation 4:

• Test and analyze the viability of global funding strategies to financially sustain inte grated care services.

Recommendation 5:

• Plan and implement a stadardized statewide data-collection system to document financial, operational and clinical outcomes, and costs of intergrated care services.

down complexity-based health barriers across multiple domains in order to appropriately address and treat patients 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.

effect. One of the more recent innovations is the use of Health Information Exchanges. Health Information 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.


Telemedicine 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 psychiatry 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 primary 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 families who can be effectively managed. Electronic Health Records and Health Information Changes

The 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 appropriate 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


Reimbursement 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). Conclusion

The cost of health care is rising astronomically. There are many measures that have been put in place to help reduce these costs such as Healthcare Reform. A high portion of the costs is attributed either directly or indirectly to the inability of integration between behavioral health and physical health treatment. When treated separately, health care becomes very costly, and even more importantly, the patient

80 Journal of Managed Care Medicine | Vol. 16, No. 3 |

isnâ&#x20AC;&#x2122;t receiving the optimal treatment. Treating separately can cause a deterioration in the other conditions. There are many possible solutions that can be implemented individually or in tandem with one another. Solving the behavioral health integration can vastly reduce health care spending and improve the health of those with comorbidity issues.

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

References 1.(Kathol) Kathol, Roger G., Rebecca Perez, and Janice S. Cohen. The Integrated Case Management Manual. 2010. Manual.>. 2. (The British Journal of Psychiatry)

Mark Rosenburg, MD, PhD, President, BHM Healthcare Solutions

3. (Warhover) Warhover, Ann. The Colorado Blueprint for Promoting Inte-

and Director, NAMCP Behavioral Health Institute.

grated Care Sustainability. March 2012. Document. 25 June 2013. | Vol. 16, No. 3 | Journal of Managed Care Medicine 81



Molecular Biomarker Testing Is Essential for Non-Small Cell Lung Cancer Patients 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

Over 50% of NSCLC Cases Are Linked to Known Molecular Biomarkers

At Least 10 Known Molecular Biomarkers in NSCLC3

According to recent studies, more than 50% of NSCLC cases are linked to one of at least 10 currently known biomarkers for NSCLC — and many of these patients may test positive for mutations or other genetic abnormalities that are “drivers” for their cancers and are treatable with approved biomarker-driven therapies or investigational agents in clinical trials.2,3


Unknown EGFR






Now that more than half of NSCLC cases can be linked to one or more of these biomarkers, it is possible to subdivide the histological subtypes of NSCLC — adenocarcinoma, squamous cell carcinoma, and large cell carcinoma — into clinically relevant molecular subsets.1 Sponsored by:

In partnership with:

These molecular subsets show the considerable heterogeneity of non-small cell tumors and suggest why patients with similar clinical stage and tumor histology can have dramatically different clinical outcomes.4 Indeed, biomarkers may give clinicians an indication of the patient’s prognosis (outcome independent of treatment), as well as the treatment sensitivity/resistance of the tumor to specific agents.4,5 Moreover, as genomic and mutational research continues, more biomarkers will inevitably be discovered, so that the proportion of NSCLC cases with unknown drivers will continue its decline. The ultimate goal of this approach to treatment is to identify every driver mutation for non-small cell lung cancer, and design a corresponding treatment for each of these oncogenes.1,2,4

ADVERTISEMENT New 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:

For patients whose tumors test positive for a biomarker that is treatable with approved or investigational agents, the benefits of testing are self-evident.1,5,6 But in the future, molecular profiling will help an increasing proportion of patients with NSCLC because the additional information it reveals about their tumor has the potential to guide clinical management.2,7

Molecular Profiling Is Key in NSCLC The discovery of biomarkers has demonstrated the molecular complexity of NSCLC, and it highlights the need to move toward molecularly based classification and treatment of these tumors.1,4 But only if patients are tested is it possible for them to potentially benefit from these developments.

of “ Determination the specific molecular abnormalities of the tumor is critical for predicting sensitivity or resistance to a growing number of targeted therapies.

– NCCN Guidelines® Version 3.2012, for Non-Small Cell Lung Cancer 5

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 the prospective genotyping of tumors possible, to aid clinical decision making and management.1

Curbside Consult

As additional mutations are discovered through efforts such as the National Cancer Institute’s Lung Cancer Mutation Consortium (LCMC) and the Cancer Genome Atlas — and as new agents are developed to address these abnormalities — the hope for the over 215,000 people diagnosed with lung cancer each year is that these advances will lead to more treatment options.1,8-10 In the words of Dr. David Gandara, Director of Thoracic Oncology at UC Davis Comprehensive 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.”

David R. Gandara, MD Director, Thoracic Oncology Program, UC Davis Comprehensive Cancer Center

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 for the patient perspective on molecular profiling.

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 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. Accessed January 19, 2012. 9. National Cancer Institute. The cancer genome atlas. 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. © 2012 Pfizer Inc.

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