Journal of Managed Care Medicine Volume 17, Number 4 by Jeremy Williams

Vol. 17, No. 4, 2014

Educating Medical Directors of Employers, Health Plans and Provider Systems

FEATURED ARTICLES INCLUDE: Overcoming Current Challenges in the Management of Relapsed/Refractory Multiple Myeloma Updated Strategies for the Management and Treatment of Chronic Pain Updated Therapeutic Strategies for Partial or Nonresponse to Treatment in Major Depressive Disorder PLUS: Fall Managed Care Forum Guide

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

A good day.

It’s no accident. Solesta: a unique treatment for FI • • • •

An injectable, biocompatible gel Nonsurgical, in-office procedure No anesthesia required May preclude need for more invasive surgical procedures

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

Number of episodes/14 days

Durable efficacy with Solesta 25

P=0.001

n=136

20 15

53%

15.0

8.6

6.2

7.0

Baseline

Months

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

T:6.875”

Safety Data

Brief Summary

Please consult Package Insert for full prescribing information.

Indication for Use

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

Contraindications

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

Warnings

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

Precautions

SLTA13CDNY0608_Solesta_BS_6.875x9.875_r3.indd 1

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

Patient Counseling Information

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

Directions for Use

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

Post-treatment care

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

Re-treatment procedure

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

How Supplied

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

Storage

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

11/19/13 12:14 PM

T:9.875”

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

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

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director of communications Jeremy Williams

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Journal of Managed Care Medicine The Official Journal of the National Association of Managed Care Physicians Medical Directors Institute A Peer-Reviewed Publication Vol. 17, No. 4, 2014

TABLE OF CONTENTS Overcoming Current Challenges in the Management of Relapsed/Refractory Multiple Myeloma George Somlo, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Improving Outcomes in the Prevention and Management of CINV Rudolph Navari, MD, PhD, FACP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 New and Emerging Strategies in the Effective Management of Hepatitis C David H. Winston, MD, FACP, AGAF.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Optimizing Outcomes in the Management of Obesity: The Role of Novel Therapeutic Agents Doina Kulick, MD, MS, FACP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 GOLDen Strategies for Prevention, Assessment and Management of COPD Robert Sussman, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Practical Antiplatelet Strategies for Improving ACS Outcomes R. Scott Wright, MD, FACC, FESC, FAHA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Recent Advances and Emerging Data in the Treatment of Hypertriglyceridemia Michael Miller, MD, FACC, FAHA, FNLA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Therapeutic Updates in the Prevention and Treatment of Osteoporosis Steven T. Harris MD, FACP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Undertreated Stroke Prevention in Atrial Fibrillation: The Risk of Bleeding versus the Risk of Stroke Michael Miller, MD, FACC, FAHA, FNLA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Updated Strategies for the Management and Treatment of Chronic Pain Eric S. Hsu, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Updated Therapeutic Strategies for Partial or Nonresponse to Treatment in Major Depressive Disorder Mark Rosenberg, MD, PHD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Private Companies Providing Health Care Price Data: Who Are They and What Information Do They Provide? Kathryn A. Phillips, PhD and Anna Labno, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . 75 PLUS: Fall Managed Care Forum Guide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 5

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

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

Gary Owens, MD Principal Gary Owens Associates

Devena Alston-Johnson, MD Medical Director CIGNA

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

Philip Painter, MD Chief Medical Officer Humana

E. Paul Amundson, MD Chief Medical Officer Dakotacare

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

Linda Ash-Jackson, MD Medical Director Hometown Health

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

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

Paul Bluestein, MD Chief Medical Officer Connecticare

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

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

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

Anthony Bonagura, MD Chief Medical Officer Aetna, Inc.

Karen Knowles, MD Internal Medicine Physician HCA/Emcare

Salil V. Deshpande, MD Market Medical Officer United Healthcare

Catherine Marino, MD Chief Medical Officer MagnaCare

Michael Fine, MD Medical Director Health Net

Jeff Martin, PharmD Clinical Account Director Innoviant, Inc.

John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina

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

Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint

Wesley Mizutani, MD Director Clinical Research & Chairman Department of Rheumatology Healthcare Partners

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

Thomas Morrow, MD Next IT

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

Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare 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

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

Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions, Inc. Carlos Ramirez, MD Chief Medical Officer Valley Baptist Health Plans Paul Rein, DO Medical Director Port Warwick Ambulatory Surgery Center Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc. Joseph Schappert, MD Chief Medical Officer PAML Christine M. Seals, MD Medical Director Umpqua Health Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPE, ACOI Vice President Medical Affairs/Chief Medical Officer Group Health Plan William D. Strampel, DO, FACOI Dean, College of Osteopathic Medicine Michigan State University Prentiss Taylor, MD Corporate Medical Director Advocate At Work at Advocate Health Care Pamella Thomas, MD,MPH, FACOEM Consulting Medical Director Wellness Health & Productivity Strategies Robert A. Ziff, MD, MBA, FACS, CPE East Central Region Medical Director, Senior Products Humana

Overcoming Current Challenges in the Management of Relapsed/Refractory Multiple Myeloma George Somlo, MD For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although considered incurable, multiple myeloma (MM) can be treated for several years with novel therapies. Once a patient relapses or fails to respond to initial therapy, subsequent lines of therapy depend on previous therapies received and duration of response, but there are now many different choices, including some which are oral therapies. Key Points • MM is considered incurable. • Relapsed/refractory MM can be treated with multiple lines of treatment, but the response declines with each subsequent treatment. • Two new agents were recently FDA approved for relapsed/refractory MM. • Additional agents are on the horizon

Multiple myeloma (MM) is a cancer of the plasma cell characterized by excessive numbers of abnormal plasma cells in the bone marrow. There is overproduction of intact monoclonal immunoglobulins (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free antibody light chains). The most common presenting symptom is new bone pain. The clinical features of this disease include bone pain, often with loss of height; constitutional weakness, fatigue, and weight loss; anemia; renal disease; infections; neutropenia; hypogammaglobulinemia; hypercalcemia; hyperviscosity; and neurologic dysfunction from spinal cord or nerve root compression. It is the second most frequent hematologic malignancy after non-Hodgkin’s lymphoma with MM accounting for 10 to 15 percent of hematologic cancers. There are approximately 23,500 new cases annually in the United States. MM is considered incurable with a median sur-

vival after diagnosis of four to six years. However, with newer agents, this disease can many times be converted into a chronic disease. This cancer is more common in men than women and the incidence in African Americans is about twice that of Caucasians. The median age at diagnosis is 70 years. Most cases of MM initially start as monoclonal gammopathy of unknown significance (MGUS). MGUS is found in over 3 percent of those over age 50. Over 70 percent of patients diagnosed with MM had a detectable myeloid (M) protein previously. Molecular diagnostic tools, such as gene expression profiling and fluorescence in situ hybridization (FISH) analysis, can identify accurate prognostic factors that can aid in the development of personalized treatment for patients with MM (Exhibit 1). Routine clinical use of molecular diagnostic tools provides information to guide therapeutic decision

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 7

Exhibit 1: Prognostic Factors for MM

Expected OS > 6 - 7yrs t(11;14); t(6:14) Hyperdiploidy Normal cytogenetics/FISH

Expected OS 2 - 3 yrs t(4;14); t(14;16); t(14;20) Del(17p) Del(1p-) and/or amp 1p by FISH Del(13) by cytogenetics Hyperdiploidy GEP-high-risk signature

Elevated LDH and B2 microglobulin > 5.5 are also markers of high risk OS = overall survival; t = translocation; Del = deletion; amp = amplification FISH = fluorescence in situ hybridization; GEP = gene expression profile LDH = lactate dehydrogenase

Exhibit 2: Suggested Treatment Approach for Newly Diagnosed Patients3

Patients with newly diagnosed multiple myeloma

Transplant-eligible patient

Three-drug primary treatment

Transplant-ineligible patient

Three-drug primary treatment

Autologous stem cell transplantation

Maintenance until progression or intolerance

Three-drug primary treatment

Consolidation therapy and/or maintenance until progression or intolerance

making. The NCCN guidelines provide a framework for diagnosis, staging, and management of MM.1 Once diagnosed, patients are staged using one of two classifications systems. Staging is important because it predicts median survival. The aim for initial treatment is complete response (CR) or very good partial response (VGPR). The NCCN guidelines define a VGPR as a 90 percent reduction in myeloid (M) protein levels.1 The International Myeloma Working Group (IMWG) has

also published response criteria which are being used more frequently.2 These criteria add a stringent complete response (sCR) category that is defined as a normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Trying to achieve a sCR is the goal of therapy under these criteria. A sCR predicts a better prognosis than a CR or a VGPR. For initial therapy, the old treatment paradigm was chemotherapy followed by a stem cell transplant (SCT). The new paradigm includes novel agents [le-

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

Exhibit 3: Suggested Treatment Approach for Patients with Relapsed or Progressive Disease1,3 Patients with Relapse or Progressive Disease

Transplant-eligible patient

Transplant-ineligible patient

Autologous stem cell transplantation

Salvage therapy on or off clinical trial

Progressive disease Palliative care

Salvage therapy on or off clinical trial

Allogenic stem cell transplant on clinical trial

Additional autologous stem cell transplant

nalidomide (Revlimid速), bortezomib (Velcade速)]. Novel agents are used in induction followed by a SCT, consolidation, and maintenance because regimens that include novel agents have been shown to be more efficacious than the previously standard chemotherapy regimens. For example, almost two-thirds of those treated have a VGPR or better response with the combination of bortezomib/ dexamethasone versus 40 percent with vincristine/ doxorubicin/dexamethasone (VAD). This higher response rate does translate into a better progression-free survival. The algorithm shown in Exhibit 2 is a suggested treatment approach for patients newly diagnosed with MM.3 In general, patients will first be assessed for stem cell transplant eligibility. Patients up to age 70 with no additional comorbidities are considered transplant eligible. Ideally, initial therapy for MM would meet the goal of allowing rapid disease control and reversal of disease-related complications (such as hypercalcemia, renal dysfunction, and anemia), decrease the risk of early death, and allow successful collection of stem cells when a stem cell transplant is considered as a therapeutic option. Combination therapies with two or three agents are used for both transplant-eligible and transplant-ineligible patients. Based on best efficacy, the ideal regimen would be bortezomib, lenalidomide, and dexamethasone. Other possible regimens include cyclophosphamide/bortezomib/dexamethasone, lenalidomide/

dexamethasone, or bortezomib/dexamethasone. In patients who are eligible for transplant, the use of primary treatments followed by maintenance therapy combines maximal tumor reduction with continuous treatment, which is important in delaying the regrowth of tumors. In patients who are ineligible for transplant, consolidation therapy (2 to 4 cycles of combination therapies after primary treatment) and maintenance therapy (continuous therapy with single agents until the time of disease progression) are used. For patients who are not eligible for transplants, the old regimen was melphalan and prednisone (MP). Melphalan is an alkylating agent which damages the bone marrow so a stem cell transplant is not a treatment option. With the advent of novel therapies, the standard regimen has changed to include these agents and have been shown to improve progression-free survival (PFS). The combination of bortezomib/melphalan/prednisone (VMP) results in an eight month PFS advantage over MP.4 Thus, VMP is now a standard regimen. Lenalidomide is also an option with MP. Lenalidomide, used as maintenance in this setting, results in an improvement in PFS. Overall, maintenance therapy with lenalidomide or bortezomib is important in maintaining a response. The management of relapsed or refractory MM is shown in Exhibit 3.1,3 Relapse is defined as a new plasmacytoma or new bone metastatic site, increase

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 9

Exhibit 4: Anticoagulation Prophylaxis Recommendations7

Risk Factors • Myeloma

• Diabetes

• Hyperviscosity

• Acute infection

• Obesity

• Immobilization

• Previous VTE

• General surgery

• Central venous catheter

• Any anesthesia

or pacemaker

Risk Assessment

Prophylaxis

0 or 1 risk factor

Aspirin

2 or more risk factors

LMWH or warfarin†

• Trauma

• Cardiac Disease

• Use of erythropoietin

• Chronic renal disease

• Clotting disorders

• Myeloma therapy: - High-dose dexamethasone* - Doxorubicin - Multiagent chemotherapy LMWH = low-molecular-weight heparin Obesity: body mass index ≥ 30 kg/m2 * ≥ 480 mg per month. † Full-dose warfarin (target INR 2-3).

in bone/plasmacytoma site of greater than one centimeter, hyperkalemia, progressive anemia, new or recurrent renal dysfunction, or reappearance/ rise in M protein level or doubling of M protein at two consecutive time points. In treating patients with relapsed or progressive myeloma, the quality and duration of response to previous therapy are the most important prognostic factors. Novel agent combination therapy is the treatment of choice for patients with relapsed or refractory myeloma. Retrospective analyses indicate that these novel agent combinations are associated with a superior outcome when given at first relapse than when given later. Autologous SCT is an option for patients who did not undergo transplantation at diagnosis, as well as for those who underwent transplantation and had a prolonged duration of remission (1 year or more). If progression occurs after six months of therapy, the patient can still receive a regimen containing a novel agent even if they received it in the past. A third agent can be added if the patient has progressed on two agents. Relapsed/refractory MM can be treated with multiple lines of treatment, but the response declines with each subsequent treatment. Choosing to use lenalidomide and/or bortezomib requires careful consideration of patient factors. Appropriate patient selection will aid safe administration and avoid unnecessary dose reduction and dis-

continuation, thus ensuring best efficacy. Efficacy of these two agents is enhanced by concomitant dexamethasone. Fragile patients greater than 75 years may need to receive a reduced dexamethasone dose to avoid toxicity. Patients who get lenalidomide need to receive an anticoagulant to prevent thromboembolism. This need may not allow lenalidomide to be used in people with history of bleeding. In patients with renal failure, a bortezomib containing regimen would likely be the better choice than lenalidomide. Patients who get a bortezomib regimen need varicella (shingles) prophylaxis. Peripheral neuropathy (PN) is a relatively common adverse effect of bortezomib therapy. It occurs in about 35 percent of those with relapsed/refractory MM who receive this agent.5,6 PN can be a dose limiting adverse effect. There are many other reasons for PN, including B12 deficiency or type 2 diabetes, which should be considered before altering the bortezomib regimen. The frequency of administration can be adjusted or it can be given subcutaneously instead of intravenously. Lenalidomide causes cytopenias, including neutropenia, thrombocytopenia, and anemia. These can also be therapy limiting. Erythropoietin, transfusions, and granulocyte-colony stimulating factor (G-CSF) prophylaxis are options to treat or minimize cytopenias.

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

The International Myeloma Working Group (IMWG) has developed thromboprophylaxis guidelines specifically for patients with MM receiving immunomodulation treatment. These guidelines determine prophylaxis by the number of risk factors present (Exhibit 4).7 Low-molecular-weight heparin (LMWH) or full-dose warfarin is recommended for patients with two or more risk factors, or for those receiving high-dose dexamethasone, doxorubicin, or multi-agent chemotherapies. Two new novel agents were recently approved by the FDA. Carfilzomib, a selective irreversible proteasome inhibitor, has been studied in relapsed/refractory MM with good safety and efficacy profile. Given intravenously, it results in an overall response rate of 34 percent in a heavily pretreated population.8 The response lasts a median of 7.8 months with overall survival of 15.6 months. The major distinction from bortezomib, a reversible proteasome inhibitor, is a lower rate of PN. It is under evaluation in combination in the front line and salvage setting. It does work in patients who have progressed on bortezomib. Pomalidomide (Pomalyst 速), an immunomodulatory lenalidomide analogue, was FDA approved for relapsed/refractory MM in early 2013. When studied in a heavily pretreated population, 58 percent of patients achieved an overall response rate with pomalidomide/dexamethasone; one patient achieved a CR.9 Responses were seen in 29 percent of 13 lenalidomide-refractory patients. Like lenalidomide, cytopenias are the most frequent adverse effects of this agent. Pomalidomide is indicated for patients with MM who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Other novel agents under study include ixazomib, an oral proteasome inhibitor; CNTO 328, an anti-interleukin 6 antibody; vorinostat, a histone deacetylase inhibitor already approved for T-cell lymphoma; and elotuzumab, an antibody against a cell surface protein (CS1). There are also agents under study targeting specific genetic alterations in MM. It is hoped that more novel agents will

reach the market and will advance the treatment of this disease. Conclusion

Regimens containing lenalidomide or bortezomib have shown efficacy in relapsed/refractory myeloma and have become the standard of care for both initial and relapsed/refractory treatment. The selection of regimens should be a rational process, based upon patient characteristics. The new novel agents (carfilzomib and pomalidomide) are useful additions, especially for patients who have progressed or relapsed on other novel agents or who have issues with neuropathy. Other agents need further testing in ongoing and planned clinical trials. George Somlo, MD is a Professor in the Department of Medical Oncology and Research at the City of Hope Comprehensive Cancer Center in Duarte, CA.

References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. 2.2014. Available at nccn.org. 2. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-73. 3. Palumbo A, Anderson Kl. Multiple myeloma. N Engl J Med. 2011;364(11):1046-60. 4. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-17. 5. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24(19):3113-20. 6. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-40. 7. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-23. 8. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-25. 9. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus lowdose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008-14.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 11

The S-ICD™ System

Protection Without Touching the Heart

The World’s First and Only Subcutaneous ICD The S-ICD System is a new innovative solution that provides protection from sudden cardiac arrest without touching the heart. Data from the IDE Study and the EFFORTLESS Registry demonstrate excellent real-world results, including low rates of complications and high conversion efficacy.

>92.1%

of patients complication-free @ 180 days1,2

>96%

Conversion efficacy of spontaneous episodes1,2

To learn more, visit www.bostonscientific.com/sicd-clinicalstudies S-ICD™ System from Boston Scientific CRM Indications for Use The S-ICD™ System is intended to provide defibrillation therapy for the treatment of life-threatening ventricular tachyarrhythmias in patients who do not have symptomatic bradycardia, incessant ventricular tachycardia, or spontaneous, frequently recurring ventricular tachycardia that is reliably terminated with anti-tachycardia pacing. Contraindications Unipolar pacemakers are contraindicated for use with the S-ICD System. Warnings and Cautions The S-ICD System contains sterile products for single use only. Do not resterilize. Handle the components of the SICD System with care at all times and maintain proper sterile technique. All Cameron Health implantable components are designed for use with the Cameron Health S-ICD System only. Connection of any S-ICD System components to any other ICD system will result in failure to deliver lifesaving defibrillation therapy. General • External defibrillation equipment should be available for immediate use during the implantation procedure and follow-up. • Placing a magnet over the SQ-RX Pulse Generator suspends arrhythmia detection and therapy response. Removing the magnet resumes arrhythmia detection and therapy response. • Battery depletion will eventually cause the SQ-RX Pulse Generator to stop functioning. Defibrillation and excessive numbers of charging cycles shorten the battery longevity. • The S-ICD System has not been evaluated for pediatric use. • The S-ICD System does not provide long-term bradycardia pacing, Cardiac Resynchronization Therapy (CRT) or Anti-Tachycardia Pacing (ATP). Potential Adverse Events related to implantation of the S-ICD System may include, but are not limited to, the following Acceleration/induction of atrial or ventricular arrhythmia; Adverse reaction to induction testing; Allergic/adverse reaction to system or medication; Bleeding; Conductor fracture; Cyst formation; Death; Delayed therapy delivery; Discomfort or prolonged healing of incision; Electrode deformation and/or breakage; Electrode insulation failure; Erosion/extrusion; Failure to deliver therapy; Fever; Hematoma; Hemothorax; Improper electrode connection to the device; Inability to communicate with the device; Inability to defibrillate or pace; Inappropriate post-shock pacing; Inappropriate shock delivery; Infection; Keloid formation; Migration or dislodgement; Muscle stimulation; Nerve damage; Pneumothorax; Post-shock/post-pace discomfort; Premature battery depletion; Random component failures; Stroke; Subcutaneous emphysema; Surgical revision or replacement of the system; Syncope; Tissue redness, irritation, numbness or necrosis. Refer to the product labeling for specific indications, contraindications, warnings/precautions and adverse events. Rx only. (Rev. D) All trademarks are the property of their respective owners. 1 Weiss, et al. The safety and efficacy of a totally subcutaneous implantable defibrillator. Circulation 2013. 2 Lambiase, et al. Worldwide experience with a totally subcutaneous ICD; Preliminary results of the EFFORTLESS S-ICD Registry. European Heart Journal 2014.

Improving Outcomes in the Prevention and Management of CINV Rudolph Navari, MD, PhD, FACP For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Preventing chemotherapy-induced nausea and vomiting (CINV), especially from the very beginning of treatment, is important for reducing health care costs related to uncontrolled CINV and maintaining patient quality of life. The most effective evidence-based regimen should be used. Regimens are guided by published guidelines and selected based on the emetogenicity of the given chemotherapy and patient factors. • • • •

Key Points Prevention is the goal. The most effective antiemetic regimens should be used with the very first round of chemotherapy. The regimen is selected based on emetogenicity of the chemotherapy being given and patient risk factors. Current medications excel at reducing incidence of vomiting, but nausea continues to be an issue.

Chemotherapy-induced nausea and vomiting (CINV) is incredibly important in terms of quality of life (QOL) and cost-effective management. Historically, nausea and vomiting are some of the most feared adverse effects of chemotherapy.1,2 With the development of newer antiemetics, vomiting rates are much improved; however, nausea is still an issue. CINV comes in various forms. Acute CINV starts within one to two hours after chemotherapy administration. The peak intensity is within five to six hours with resolution within 12 to 24 hours. Effective regimens exist to prevent acute CINV. Delayed CINV has a peak onset 48 to 72 hours after chemotherapy and diminishes after one to three days. The delayed form occurs in 50 to 90 percent of patients treated with highly emetogenic regimens and 35 to 70 percent with moderately emetogenic therapy. The newer agents have reduced the rates of delayed emesis, but therapy can still be improved. Delayed emesis is more common with platinum containing regimens. Breakthrough CINV is

defined as nausea and vomiting occurring despite adequate preventive therapy. Refractory CINV can occur during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in previous cycles. Anticipatory emesis is associated with uncontrolled emesis during prior chemotherapy. This can be prevented by preventing CINV during the first round of chemotherapy. Anticipatory emesis needs to be prevented because it is difficult to treat. The most effective regimens should be used with the very first round of chemotherapy. Avoidance of CINV is important because it can lead to dehydration, electrolyte imbalances, impaired health-related quality of life, negative impact on activities of daily living, and hospitalization. Patient and treatment-related factors need to be considered in designing an antiemetic regimen. Patient-related risk factors for CINV include younger age (<50), female gender, no or minimal prior alcohol use, prior CINV, and anxiety. Treatment-related risk factors include moderate to high emeto-

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 13

Exhibit 1: Antiemetics for CINV Drug

Pathway

Target

Adverse Effects

Ondansetron Granisetron Palonosetron

Serotonin

Acute

Headache, constipation, asthenia, diarrhea, sedation

Substance P

Delayed

Prolonged INR, slows dexamethasone and benzodiazepine metabolism

Dexamethasone

Prostaglandins?

Delayed Breakthrough

HTN, glucose, psych.

Prochlorperazine

Dopamine

Breakthrough

Akathisias, sedation, dizziness

Metoclopramide

Gut motility, Dopamine

Delayed

Akathisias, dystonia

Haloperidol

Dopamine

Delayed Breakthrough

Akathisias, dystonia, prolonged QT, urinary retention

Olanzapine

Dopamine, Serotonin

Acute, Delayed

Sedation

Dronabinol

Cannabinoid

Breakthrough, Refractory

Sedation, dizziness, dysphoria, euphoria, hallucinations

Histamine

Breakthrough

Sedation

Aprepitant, Netrupitant* Rolapitant*

Diphenhydramine *Investigational

genicity of chemotherapy agents or regimens and moderate to high drug dose. For example, highly emetogenic regimens include the combination of anthracycline and cyclophosphamide and platinumbased regimens. CINV appears to occur via two different mechanismsâ&#x20AC;&#x201D;one is located in the central nervous system (CNS) and the other is mediated in the gastrointestinal (GI) tract (peripheral). The central mechanism is thought to be activation of the chemotherapy trigger zone (CTZ) by a chemotherapeutic agent. Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center. The peripheral mechanism is thought to be local irritation and damage to the GI mucosa by the chemotherapeutic agent resulting in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers. In both instances, the neurotransmitters may act independently or in combination to induce vomiting. The predominate neurotransmitter in the peripheral mechanism is serotonin with substance P predominating in the central mechanism. Thus, the available antiemetics target serotonin, substance P, and other neurotransmitters. Exhibit 1 lists the available antiemetics. Dexamethasone, an inexpensive agent, is most effective in combination antiemetic regimens. Because it is short-term therapy, no significant ad-

verse effects typically occur when used at recommended doses and schedules. It can cause insomnia and hyperglycemia in those with diabetes. The most effective dose of dexamethasone appears to be 20 mg daily. Older agents of low therapeutic index including dopamine receptor antagonists (metoclopramide, haloperidol, prochlorperazine) and cannabinoids are not very effective and cause significant adverse effects. These agents are typically reserved for refractory or breakthrough CINV. Serotonin (5-HT3) receptor antagonists bind to 5-HT3 receptors in the periphery and CNS. The two first generation agents, ondansetron and granisetron, have equal efficacy. Additionally, oral and intravenous formulations of these agents have been shown to be equally effective. Palonosetron, only available as an injectable, is a second generation agent with greater efficacy in prevention of acute and delayed CINV. Its higher binding affinity and longer half-life partially account for the improved efficacy. Palonosetron has a unique binding site on the 5-HT3 receptor, which increases its affinity at other sites.3 Palonosetron is indicated for the prevention of acute CINV associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy and the prevention of delayed CINV associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. It is the first and only 5-HT3 receptor antagonist specifically indicated for delayed CINV. Response rates

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

Exhibit 2: Antiemetic Guidelines: High Emetic Risk5,6 Emetogenic Risk Category High

NCCN*

ASCO

Acute (day 1): 5-HT3 antagonist/ dexamethasone/ NK1 antagonist or olanzapine

Acute (day 1): 5-HT3 antagonist/ dexamethasone/ NK1 antagonist

Delayed (days 2 - 4): dexamethasone/ NK1 antagonist AC Regimens Moderate

Delayed (days 2 - 4): dexamethasone/ NK1 antagonist

Acute and Delayed: As above

Acute: As above Delayed: NK1 Antagonist

Acute (day 1): 5-HT3 antagonist/ dexamethasone Optional: NK1 antagonist or 5-HT3 antagonist/ dexamethasone/olanzapine

Acute (day 1): Palonestron plus Corticosteroid Delayed (days 2-3): Corticosteriod

Delayed (days 2-3): Corticosteroid * NCCN lists palonosetron as preferred May also add Lorazepam and H2 blocker or proton pump inhibitor 5-HT 3, serotonin; NK1, neurokinin 1; AC, anthracycline

are higher if it is given with dexamethasone. In combination with dexamethasone, similar response rates for acute nausea are seen with palonosetron and intravenous granisetron. Palonosetron/dexamethasone combination is more effective for delayed CINV.4 The choice between the first and second generation 5-HT3 agents has to be a balance between the higher efficacy but also higher cost with palonosetron. The palonosetron is most likely cost effective despite the higher cost because of the greater efficacy. The current guidelines recommend palonosetron as the preferred agent when highly and moderately emetogenic chemotherapy are given (Exhibit 2).5,6 Aprepitant is the only neurokinin-1 (NK-1) antagonist currently available. Fosaprepitant is the intravenous form of aprepitant. Three additional agents (netupitant, rolapitant, maropitant) are in active development. These agents prevent binding of substance P to NK-1 receptors. The substance P/NK1 complex is primarily associated with delayed emesis. Aprepitant is indicated in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly and moderately emetogenic cancer chemotherapy, including high-dose cisplatin. The addition of aprepitant to a standard regimen of 5-HT3 antagonist and dexamethasone increases both acute and delayed CINV response rates when

highly emetogenic chemotherapy is used. Aprepitant does not significantly improve response rates when moderately emetogenic therapy is given.7 Although aprepitant significantly reduces emesis, it does not significantly reduce nausea. Olanzapine, an antipsychotic that blocks 5-HT3, 5-HT2C, dopamine, and histamine receptors, has been studied in CINV.8,9 The addition of olanzapine, an inexpensive generic, to palonosetron and dexamethasone significantly reduces the rate of nausea.8 Additionally, it has been compared to aprepitant. Complete response was not statistically different, but olanzapine was more effective in reducing nausea (Exhibit 3).10 The NCCN guidelines now include olanzapine as a first-line regimen. Long-term use of olanzapine can lead to significant adverse effects but short-term use of it as an antiemetic primarily only causes sedation. Conclusion

Prevention is the goal of CINV management; therefore, the best combination of therapy must be given the first time. The development of serotonin antagonists and the neurokinin-1 antagonist, aprepitant, have resulted in a significant improvement in the prevention of CINV. Corticosteroids are useful antiemetics; they provide synergy with 5-HT3 antagonists and play an important role in the treat-

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 15

Exhibit 3: Comparison of Olanzapine and Aprepitant10

Percent of Patients with No Nausea

OLN + PAL + DEX vs APR + PAL + DEX No Nausea 87

No Nausea OPD (n = 121)

No Nausea (APD (n = 120)

Acute (0 - 24 h)

Delayed (24 - 120 h)

Overall ( 0 - 120 h)

OLN = olanzapine PAL = palonosetron DEX = dexamethasone APR = aprepitant

ment of delayed emesis. Drug combinations should be prescribed for the entire time of risk. Prevention of nausea associated with emetogenic chemotherapy is still a problem. Olanzapine appears to be an effective agent. Research must continue until all episodes of nausea and vomiting associated with cancer treatment are prevented. The goal of therapy is no CINV for at least five days following chemotherapy. Guidelines have been established to help manage populations of patients; however, outliers do exist.

Eur J Cancer Care (Engl). 2013;22(1):41-50. 4. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10(2):115-24. 5. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2014. Available at www.nccn.org. 6. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetic Use in Oncology: Updated Guideline Recommendations from ASCO. Am Soc Clin Oncol Educ Book. 2012:532-40 7. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant

Rudolph Navari, MD, PhD, FACP is a Professor of Medicine and Associ-

for the prevention of chemotherapy-induced nausea and vomiting in patients

ate Dean and Clinical Director at Harper Cancer Research Institute at the

with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol.

Indiana University School of Medicine â&#x20AC;&#x201C; South Bend in South Bend, IN.

2005;23(12):2822-30.

References

8. Navari RM, Einhorn LH, Loehrer PJ Sr, et al. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced

1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the

nausea and vomiting: a Hoosier oncology group study. Support Care Cancer.

side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer.

2007;15(11):1285-91.

1997;76(8):1055-61.

9. Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention of

2. Lindley C, McCune JS, Thomason TE, et al. Perception of chemotherapy

chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res.

side effects cancer versus noncancer patients. Cancer Pract. 1999;7(2):59-65.

2009;28:131.

3. Jin Y, Sun W, Gu D, et al. Comparative efficacy and safety of palonosetron

10. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the pre-

with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea

vention of chemotherapy-induced nausea and vomiting: a randomized phase III

and vomiting: a meta-analysis.

trial. J Support Oncol. 2011;9(5):188-95.

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

Redefining treatment for various clinical indications with a personalized, non-invasive MR-guided focused ultrasound therapeutic platform

Meet InSightec at NAMCP Booth #512 US.insightec.ocm | 1-214630-2000

New and Emerging Strategies in the Effective Management of Hepatitis C David H. Winston, MD, FACP, AGAF  For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although a curable infection, hepatitis C virus (HCV) infection can only be cured if infected patients are identified and treated appropriately. The primary care provider is the most important link in identifying these patients. The treatment guidelines have recently dramatically changed with the approval of newer agents with fewer adverse effects and greater efficacy. Key Points • HCV is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. • A significant increase in the cases of cirrhosis and hepatocellular carcinoma is predicted if currently infected patients are not identified and treated. • Primary care providers need to screen, diagnose, and refer for treatment these mostly asymptomatic patients. • Screening for HCV should be done based on risk factors, not symptoms or lab tests. • All baby boomers should be screened. • First-generation, direct-acting antivirals are no longer recommended.

All oral regimens are on the horizon. Hepatitis C virus (HCV) is a single-stranded RNA virus. It is the only member of genus Hepacivirus in the Flaviviridae family and humans are the only known natural host. Unlike the DNA viruses human immunodeficiency virus (HIV) and hepatitis B virus (HBV), HCV infection can be cured. This is possible because the virus resides in the cytoplasma of the cell rather the nucleus or incorporated into DNA like HBV and HIV, respectively.1,2 HCV infection is a global health issue. The highest rates of infection are seen in Far East Asia, Africa, and South East Asia. Worldwide, 200 million persons have been infected with HCV (anti-HCV positive).3,4 One hundred seventy million have chronic disease worldwide (HCV RNA positive). Over four million Americans have been infected with HCV and 3.2 million have been identified with chronic disease.5 The true prevalence of chronic disease is probably at least three times higher.6 There are six different HCV genotypes that differ from each other by 31 to 34 percent in their nucleo-

tide sequences. The most common genotypes seen in the United States are 1, 2, and 3. Exhibit 1 shows how the various genotypes and viral loads are divided in the U.S.7,8 In the U.S., males and African Americans have higher rates.9 Baby boomers (>50) are the most common age group to be affected.9 As shown in Exhibit 2, underdiagnosis and undertreatment are significant issues.10,11 The majority of people who get infected with acute HCV will develop chronic HCV (Exhibit 3). About 20 percent of those will develop cirrhosis. Some will develop hepatocellular carcinoma and decompensated cirrhosis. In the U.S., acute HCV infections peaked between 1970 and 1990 during an era of peak intravenous drug use. The peak of chronic HCV prevalence was in 2001. But the true epidemic from HCV infections is yet to come. Because of the time delay in developing cirrhosis, the highest prevalence of cirrhosis is projected to be between 2010 and 2030.13 Using a model to project future HCV infection prevalence, disease severity, and burden on the health care

18 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org

Exhibit 1: Genotype and Viral Load in U.S. Patients7,8

Genotype 2,3 LVL 7.3%

Genotype 4,5,6 HVL 2.7% Genotype 4,5,6 LVL 1.3%

Genotype 2,3 HVL 14.7%

Genotype 1 HVL 49.5%

Genotype 1 LVL 24.5%

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

Exhibit 2: Chronic HCV in U.S. (3.2M)10,11

Undiagnosed ~2.4M (75%)

Diagnosed .8M (25%)

59% of diagnosed HCV patients UNTREATED ~590K (18% of all HCV)

41% of diagnosed HCV patients TREATED ~410K (13% of all HCV)

system, the continued maturation of current cases will result in a 61 percent increase in cirrhosis, a 279 percent increase in decompensated patients, a 68 percent increase in HCC, a 528 percent increase in the need for liver transplantation, and a 223 percent increase in liver-related deaths. Thus, despite the decreasing incidence of HCV infection, the future health care burden attributable to HCV-related liver disease will be significant (Exhibit 4).13 There are several factors associated with progression from chronic HCV infection to cirrhosis including alcohol consumption (>30 g/day in males,

>20 g/day in females), disease acquisition at greater than 40 years, male gender, HIV or HBV co-infection, concomitant hepatic steatosis, and daily cannabis use. Patients who are initially exposed to HCV when they are older than 40 years of age generally have a higher degree of fibrosis regardless of how long they have had the disease, compared with individuals who are infected at a younger age. Hepatic steatosis is relatively common in the U.S. because of our rates of obesity. Other factors have been shown to not affect progression. These include transaminase level (ALT), viral load, mode of transmission,

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 19

Exhibit 3: Hepatitis C: Natural History12 Acute HCV Infection 75 - 85%

15 - 25% Recovery

Anti-HCV + HCV-RNA +

Chronic HCV Infection

Anti-HCV + HCV-RNA -

80%

20%

Stable

75%

Cirrhosis 25%

Decompensation

Stable

4% Hepatocellular CA

Death or Liver Transplant

Exhibit 4: The Tsunami of HCV Cirrhosis Complications: Decompensation and HCC13 160,000

Hepatocellular Cancer Decompensated Cirrhosis

Number of Cases

140,000 120,000 100,000 80,000 60,000 40,000

and genotype. HCV infection is the reason for 60 percent of all cases of hepatocellular carcinoma in the U.S. hepatic decompensation includes ascites, variceal bleeding, and encephalopathy. The primary care provider (PCP) has a unique window of opportunity to make a diagnosis of HCV and refer for treatment prior to the development of cirrhosis and its complications. Early diagnosis and treatment can improve survival, improve quality of life, and will reduce the economic burden of HCV and result in cost savings. Thus, HCV infection screening is the first step to a cure. There are both patient and provider barriers to

2030

2020

2010

2000

1990

1970

1960

1950

1980

20,000

screening. Persons infected with HCV are usually asymptomatic, unaware of their infection, and are unaware of the risk factors for HCV.14 Fifty-six percent of infected people are asymptomatic. For those that are symptomatic, the most common symptom is nonspecific fatigue. In general, PCPs do not include routine HCV risk factor assessment in their practice. Elevated LFTs, not risk factors, is the current marker for PCPs to order a liver panel. Because of the incidence of fatty liver in the U.S., the normal ALT values have risen (men, up to 30, women up to 19). HCV is spread through contact with infected blood. Intravenous drug use now accounts for two-

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

Exhibit 5: Recommendations for Patients Who are Initiating Therapy for HCV Infection or Who Experienced Relapse after Prior PEG/RBV Therapy, by HCV Genotype15 Genotype

Recommended

Alternative

IFN eligible: SOF + PEG/RBV x 12 weeks IFN ineligible: SOF + SMV + RBV x 12 weeks

IFN eligible: SMV x 12 weeks + PEG/RBV x 24 weeks IFN ineligible: SOF + RBV x 24 weeks

SOF + RBV x 12 weeks

None

SOF + RBV x 24 weeks

SOF + PEG/RBV x 12 weeks

IFN eligible: SOF + PEG/RBV x 12 weeks IFN ineligible: SOF + PEG/RBV x 24 weeks

SMV x 12 weeks + PEG/RBV x 24 - 48 weeks

SOF + PEG/RBV x 12 weeks

PEG/RBV x 48 weeks

5 or 6

thirds of HCV cases in the U.S. Anyone who received blood or blood products or a solid organ transplant before 1992 or was a hemodialysis patient before 1992 is also at risk. Other risk factors for infection include needle sticks, intranasal cocaine with shared implements, body piercing with contaminated needles, tattooing with contaminated needles or ink, and incarceration. Less common risk factors include sharing of household items that could carry infected blood (razors, toothbrushes, manicure implements), traumatic contact with blood from cuts or nose- bleeds, and perinatal transmission. Sexual transmission accounts for less than 5 percent of all cases. It is seen in high-risk sexual behavior (multiple sex partners, prostitutes, man to man sex) where there is trauma to the mucosa. The risk in monogamous partners is extremely low. It’s been up to the PCP to identify and screen all their patients for risk factors for HCV. Ask about risk factors when asking about alcohol and tobacco. Unfortunately, risk-based screening is not working. The CDC and the U.S. Preventive Services Task Force (USPSTF) now recommend a one-time screening for all persons born between 1945 and 1965 because of their high prevalence of HCV.15, 16 Under new health care regulations, all screening tests recommended by the USPSTF are covered for those with insurance. Cost is no longer a patient factor for not being screened. Thus, PCPs should screen all baby boomers and all patients with risk factors regardless of age and all patients with increased liver function tests. The primary goal of HCV treatment is permanent eradication of virus from serum. This is defined as a sustained viral response (SVR), which is an undetectable HCV RNA six months after completion of treatment. A SVR is synonymous with “cure”. Cure rates have significantly improved since the early 1990s, from 5 percent of patients to greater than

80 percent with improved regimens utilizing direct acting antivirals (DAAs). SVR leads to improved outcomes of reduced morbidity and mortality.17-19 Interferon and ribavirin were the first two therapies approved for HCV management and are still part of the backbone of therapy. Because it is injectable, has multiple contraindications and causes adverse effect, interferon is difficult to adhere with. Peg-interferon and ribavirin both cause significant adverse effects. Psychiatric adverse effects with peg-interferon, particularly depression, can be significant. Peg-interferon also causes hematologic side effects (anemia, neutropenia, thrombocytopenia), flu-like symptoms, nausea, diarrhea, dyspepsia, retinopathy, and thyroid toxicity. Ribavirin causes hemolytic anemia, cough, dyspnea, anorexia, rash, pruritis, and is teratogenic. The unsatisfactory response rate in genotype 1 (54 to 56%) led to the development of the DAAs that directly inhibit viral replication. The first approved DAAs were two protease inhibitors, telaprevir and boceprevir. Because of significant adverse effects, drug interactions, multiple daily dosing, and lower efficacy, the first-generation DAAs are no longer recommended for use.20 Two second- generation protease inhibitors [Simeprevir (Olysio®) and sofosbuvir (Sovaldi®)] were approved in late 2013. These agents are improvements over the first-generation agents in terms of pill burden, drug interactions, and adverse effects. Simeprevir, a NS3/4A protease inhibitor given once a day, is effective in genotypes 1, 2, 4, 5, 6. It is given as a 150mg daily dose with interferon and ribavirin for 12 weeks with 24 or 48 weeks total treatment based on response-guided therapy (RGT). Not all patients with the same genotype respond to treatment in the same way; therefore, treatment duration is tailored based on individual response. RGT permits a shorter duration of treatment without reducing the

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 21

SVR rate in patients who achieve benchmarks. With simeprevir, SVR rates between 70 and 91 percent are seen based on relapse status, presence of cirrhosis, genotype and use of RGT. About the same SVR results were seen with 1a and 1b genotypes; 1a has historically been harder to treat. This agent has a favorable safety profile with no increased rates of anemia or rash which both were problems with the first-generation DAAs. It does have multiple drug interactions. Sofosbuvir is a NS5B polymerase nucleoside inhibitor with potent antiviral activity against genotypes one through six with a high barrier to resistance. Treatment is for 12 weeks with no RGT needed. It is given as a once-a-day tablet in combination with interferon and ribavirin. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. It is generally safe and well-tolerated in clinical studies to date (> 3,000 patients). In combination with interferon and ribavirin, SVR rates vary from 80 to 100 percent. Sofosbuvir is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for coadministration of interferon. The standard of care for HCV infection as of July 2014 is the use of sofosbuvir in various combinations, depending on genotype (Exhibit 5).20 Simeprevir is an alternative agent. Because therapy for HCV is changing rapidly, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society–USA (IAS– USA) has developed a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations for hepatitis C management. These most up-to-date guidelines can be found at hcvguidelines.org. Numerous therapies are under development for HCV infection. Hopefully, as treatment advances there will be shorter treatment duration with SVR rates of 95 percent or more with fewer adverse events. The holy grail for hepatologists is to develop an all oral medication regimen for all genotypes. Interferon free regimens will likely be approved in the near future. A once-daily fixed-dose combination of the NS5A inhibitor ledipasvir and sofosbuvir for the treatment of chronic hepatitis C genotype 1 infection in adults will likely be the first. Conclusion

HCV is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. All patients with risk factors and all baby boomers need to be screened for HCV. The new DAAs have produced a dramatic par-

adigm shift in HCV treatment with high cure rates, shorter duration of treatment, and fewer side effects. David H. Winston, MD, FACP, AGAF is Section Head, Gastroenterology and Hepatology, at CIGNA HealthCare of Arizona in Sun City, AZ.

References 1. Pawlotsky JM. Virology of hepatitis B and C viruses and antiviral targets. J Hepatol. 2006;44(1 Suppl):S10-3. 2. Siliciano JD, Siliciano RF. A long-term latent reservoir for HIV-1: discovery and clinical implications. J Antimicrob Chemother. 2004;54(1):6-9. 3. WHO. Hepatitis C. 2014. Available at www.who.int/mediacentre/factsheets/fs164/en/. 4. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333-42. 5. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;367:1859-61. 6. Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090-101. 7. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341(8):556-62. 8. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States. J Viral Hepat. 2000;7(3):196-202. 9. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-14. 10. IOM. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC. 2010 . 11. CDC. Hepatitis C fact sheet. Available at www.cdc.gov. 12. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002:36(Suppl. 1):S21-S29. 13. Davis G, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-21. 14. Smith BD, Jorgensen C, Zibbell JE, Beckett GA. Centers for Disease Control and Prevention initiatives to prevent hepatitis C virus infection: a selective update. Clin Infect Dis. 2012;55 Suppl 1:S49-53. 15. AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. Available at /www.hcvguidelines.org. 16. US Preventive Health Services Task Force. Screening for Hepatitis C Virus Infection in Adults. Available at www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm. 17. Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology. 2008;135(3):821-9. 18. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122(5):1303-13. 19. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147(10):677-84.

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

Optimizing Outcomes in the Management of Obesity: The Role of Novel Therapeutic Agents Doina Kulick, MD, MS, FACP For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Excess weight continues to occur in epidemic proportions in the United States. Two new treatments were recently approved for long-term management of this disease. As providers become more familiar with the long-term use of medication for managing weight, hopefully more of those affected will be treated and reach goal weights. • • • •

Key Points Overweight and obesity are epidemic in the United States. All adults should be screened for excess weight and offered treatment if appropriate. Lorcaserin and phentermine/topiramate are new agents approved for long-term use in managing weight. Treatment guidelines for overweight and obesity were updated in 2013.

In June 2013, the American Medical Association recognized obesity as a disease but, of course, it has been understood as such since the days of Hippocrates. Our understanding of how and why obesity develops is incomplete, but involves the integration of social, behavioral, cultural, physiological, metabolic, and genetic factors.1 Obesity is the fastest growing public health issue in America. If current trends continue, 103 million American adults will be considered obese by 2018. In 2008, medical spending attributable to obesity was estimated at $147 billion (9.1% of annual medical spending). Obesity-related direct expenditures are expected to account for more than 21 percent of the nation’s direct health care spending in 2018.2 The aging population and the ascending trend of the obesity epidemic are placing an unprecedented burden on Medicare. The average annual U.S. Medicare costs per person increases steadily as weight during young adulthood and middle age increases.3 Obesity is a serious risk factor for other diseases.

Excess body weight accounts for up to 90 percent of type 2 diabetes cases, 26 to 28 percent of hypertension cases, and 23 percent of cases of coronary heart disease in men and 15 percent in women.4-6 Data from the Cancer Prevention Study II, a prospective study of mortality among more than a million men and women in the United States, show that risk of death from all causes, cardiovascular disease and cancer increases throughout the range of moderate and severe overweight for both men and women in all age groups.7 A high body mass index was especially predictive of death from cardiovascular disease. The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults.8 A high-intensity intervention is more than one person-to-person (individual or group) session per month for at least the first three months of the intervention.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 23

Exhibit 1: Body Mass Index Adult Categories BMI (Kg/m2) = weight in kilograms divided by the square of height in meters Underweight

< 18.5

Normal weight

18.5 - 24.9

Overweight

25 - 29.9

Obese I

30 - 34.9

Obese II

35 - 39.9

Obese III

> 40

The diagnosis of overweight and obesity is made by calculating body mass index (BMI). Based on BMI, patients can be classified (Exhibit 1). This classification is designed to relate BMI to risk of disease. However, since BMI and disease risk vary among individuals and among different populations, the classification must be viewed as a broad generalization. Individuals who are very muscular may have a BMI placing them in an overweight category when they are not overly fat. Very short persons (under 5 feet) may have high BMIs that may not reflect overweight or fatness. Older persons often have lost muscle mass and have more fat for a given BMI than younger persons, women may have more fat for a given BMI than men, and persons with clinical edema may have less fat for a given BMI. Since disease risk increases with increasing BMI, there are three classes to define obesity. However, susceptibility to develop obesity-related conditions (Exhibit 2) at a given weight varies among individuals. Some individuals may have multiple risk factors and mild obesity, whereas others may have fewer risk factors with more severe obesity. In addition to BMI, waist circumference should be measured. This is a better measure of central adiposity which correlates with visceral adiposity, a risk factor for metabolic syndrome, cardiovascular disease, type 2 diabetes, and others. Elevated waist circumference (> 40 inches in men, > 35 inches in women) is an independent predictor of mortality. It does not add predictive value if BMI is greater than 35. Physicians diagnose only one in five obese patients as having the disease. In a study of 9,827 patients seen at Mayo Clinic for an annual exam, 2,543 were obese (based upon a calculated BMI â&#x2030;Ľ30), but only 505 (19.9%) had a diagnosis of obesity documented somewhere in their chart.9 Many barriers to addressing overweight and obesity by primary care providers (PCPs) have been

identified. These include lack of physician training, lack of confidence in patientsâ&#x20AC;&#x2122; ability to change their eating and exercise behavior, inadequate reimbursement, inadequate treatment resources and lack of time.10 PCPs have an average of four minutes to address each clinical item during a visit.11 The 5As (Ask, Assess, Advise, Assist, Arrange) have been used widely for smoking cessation, and some evidence suggests that they can also be successful for weight loss.12 As a first step, the PCP can ask the patient if it is alright to talk about their weight; this demonstrates respect and helps to reduce stigma. Next, the PCP determines the patientâ&#x20AC;&#x2122;s preparedness to work on weight control and, if the patient is ready, delivers clear, strong advice about the importance of weight loss. Strategies for weight loss are then given with follow-up appointment(s) or referral(s) to other resources. The cornerstone of obesity treatment is lifestyle management that incorporates three essential components: dietary therapy, physical activity, and behavior therapy. Research indicates that the combination of these modalities results in an average of 8 percent weight loss after six months of treatment. However, for many patients, lifestyle therapy alone is not sufficient to achieve or/and to maintain weight loss. Others have difficulty adopting and maintaining new lifestyle patterns. This eventually thwarts their weight-loss efforts, resulting in weight regain and feelings of failure. For these patients, the adjunctive use of antiobesity medications to augment their treatment may be useful. Prescribing pharmacological treatment for patients assessed at high risk and for whom dietary and physical activity therapy has not been successful is commonly applied to many other chronic disease states treated by the PCP, including hyperlipidemia, hypertension, and diabetes. However, many physicians remain wary of prescribing antiobesity medications due to limited experience using these agents, concern over lack of safety data regarding long-term therapy, a general lack of knowledge about obesity in general, and concern about weight regain once the medications are discontinued. Despite this uncertainty, antiobesity medications are more widely used today than in the early 1990s. The treatment selection based on BMI from the 2013 guidelines for managing overweight and obesity are given in Exhibit 3.13 Obesity medications are FDA approved for patients with a BMI of 30 or above or a BMI of 27 or above with concomitant dyslipidemia, hypertension, type 2 diabetes, coronary heart disease, or sleep apnea. Additionally, the patient has not lost the recommended one pound per week on lifestyle therapy alone.

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

Exhibit 2: Comorbid Conditions Pulmonary Disease Abnormal Function Obstructive Sleep Apnea Hypoventilation Syndrome

Idiopathic Intracranial hypertension Stroke Cataracts

Nonalcoholic Fatty Liver Disease NASH Cirrhosis

Coronary Heart Disease Diabetes Dyslipidemia Hypertension

GERD Gall Bladder Disease

Pancreatitis

Gynecoloic Anormalities Abnormal Menses Infertility Polycystic Ovarian Syndrome

Increased Risk for Cancer Breast, Uterus, Cervix, Colon, Esophagus, Pancreas, Kidney, Prostate

Osteoarthritis Skin

Phelebitis Venous statis

Gout

Older agents approved only for short-term use (< 3 months) include phentermine (Adipex ®, CIV), diethylpropion (Tenuate®, CIV), phendimetrazine tartrate (CIII), and benzphetamine (Didrex ®, CIII). Three agents are approved for longer term use (> 6 months) - orlistat (Xenical®), lorcaserin (Belviq®, CIV), and phentermine/topiramate (Qsymia®, CIV). The short-term agents, with the exception of phentermine, are not extensively used because of issues with adverse effects. Phentermine leads to a 4.4 to 22 pound weight loss over the course of three months. Orlistat is not extensively used because of the adverse effects related to its mechanism of action of preventing fat absorption. Average weight loss with orlistat is 6.6 pounds over six to 12 months.

Lorcaserin and the combination of phentermine with topiramate are both newer to the market. Lorcaserin is a selective agonist of the brain serotonin 2C receptor. The selectivity for central serotonin 2C receptors is approximately 15 and 100 times over that for serotonin receptors 2A and 2B respectively. The mechanism of action is similar to fenfluramine and dexfenfluramine except it is specific for the 2C serotonin receptor that is not found on the heart or heart valves. The result is a compound with a desirable satiety effect and no heart valve damage. Echo studies showed no increased incidence of FDAdefined cardiac valvulopathy. Fenfluramine and dexfenfluramine were withdrawn from the market because of valvulopathy concerns.

Exhibit 3: 2013 AHA/ACC/TOS Guidelines for the Overweight and Obesity Management13

Treatment Lifestyle Therapy* Medication

BMI Category 25 - 26.9

27 - 29.9

30 - 34.9

36 - 39.9

> 40

with comorbid

Surgery * Dietary therapy, physical activity and behaviour therapy

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 25

Exhibit 4: Weight Loss with Various Medications and Lifestyle Counceling14-18 Length of Trial

Total Weight Loss

13 wks

4 - 14 lbs

2-6

3 - 10

Orlistat

> 1 year

12 lbs

Lorcaserin

> 1 year

13 lbs

CR-Phen/Topiramate

> 1 year

22 lbs

Drug Phentermine

NNT* 5%WL

ยง

10%WLยง

* NNT = number needed to treat, ยงWL = weight loss percentage

Lorcaserin is given 10 mg twice daily and costs approximately $220/month. In one of the trials used to approve this agent, at one year, 47.5 percent of patients in the lorcaserin group and 20.3 percent in the placebo group had lost 5 percent or more of their body weight (P<0.001), corresponding to an average loss of 12.76 pounds with lorcaserin and 4.84 pounds with placebo (P<0.001).14 Among the patients who had lost 5 percent or more of their baseline weight at one year, the loss was maintained in more patients who continued to receive lorcaserin during year two(67.9%) than in patients who received placebo during year two (50.3%, P<0.001). Lorcaserin should be discontinued if patients do not lose 5 percent of their starting body weight in three months. The controlled release combination of phentermine and topiramate combines two agents with different mechanisms of action. Phentermine induces central norepinephrine release, which decreases appetite. Topiramate has effects on sodium and GABA channels and inhibits carbonic anhydrase isoenzymes, but the specific mechanism promoting weight loss is unclear. Topiramate was approved in 1996 for the treatment of seizures and in 2004 for migraine prophylaxis. Costs for this combination are approximately $200/month. In combination, phentermine and topiramate cause greater weight reduction than either agent alone. In a two-year study, the combination was associated with significant, sustained weight loss (-1.8%, -9.3%, and -10.5% for placebo, 7.5/46, and 15/92; P<0.0001 compared with placebo). Significantly more combination-treated subjects at each dose achieved 5, 10, 15 and 20 percent weight loss compared with placebo (P<0.001). Cardiovascular and metabolic variables and rates of incident diabetes decreased in comparison with placebo.15 This combination is given once a day in an escalating dose to reduce risk of adverse effects. The most significant side effects include dry mouth, tingling,

constipation, altered taste, insomnia, dizziness, nausea and blurred vision. Because of the potential for teratogenicity with topiramate, this combination has a Risk Evaluation and Mitigation Strategy (REMS). Women of child-bearing age should have a pregnancy test before starting this drug and monthly thereafter. It is also contraindicated in patients with hyperthyroidism, glaucoma, and in patients who have taken monoamine oxidase inhibitors within 14 days. Because topiramate can produce renal stones, this combination preparation should be used cautiously in patients with a history of renal stones. The initial dose of phentermine/topiramate is 3.75/23 mg for 14 days, followed by 7.5/46 mg thereafter. If after 12 weeks a 3 percent loss in baseline bodyweight is not achieved, the dose can be increased to 11.25/69 mg for 14 days, and then to 15/92 mg daily. If an individual does not lose 5 percent of body weight after 12 weeks on the highest dose, phentermine/topiramate should be discontinued gradually, as abrupt withdrawal of topiramate can cause seizures. Exhibit 4 compares the average weight loss seen with the various agents.14-18 The weight loss is greatest with the phentermine/topiramate combination, but lorcaserin may be better tolerated. The number needed to treat to achieve a 5 and 10 percent weight loss are also lowest with phentermine/topiramate. Conclusion

Lorcaserin and phentermine/topiramate are two new weight loss agents that help obese and overweight patients with concomitant weight-related conditions lose a significant amount of their excess weight. These agents combined with lifestyle and behavioral changes can help a number of patients begin to control their weight. Doina Kulick, MD, MS, FACP is an Associate Professor of Medicine at the University of Nevada Reno School of Medicine.

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

References

10. Ma J, Xiao L, Stafford RS. Adult obesity and office-based quality of care in

1. National Heart, Lung and Blood Institute. Clinical Guidelines on the Identi-

the United States. Obesity (Silver Spring). 2009;17(5):1077-85.

fication, Evaluation, and Treatment of Overweight and Obesity in Adults. 98-

11. Abbo ED, Zhang Q, Zelder M, Huang ES. The increasing number of clini-

4083. 1998.

cal items addressed during the time of adult primary care visits. J Gen Intern Med.

2. United Health Foundation, the American Public Health Association and

2008;23(12):2058-65.

Partnership for Prevention. The Future Costs of Obesity: National and State

12. Rao G. Office-based strategies for the management of obesity. Am Fam

Estimates of the Impact of Obesity on Direct Health Care Expenses. 2009.

Physician. 2010;81(12):1449-56.

3. Daviglus ML, Liu L, Yan L, et al. Relation of body mass index in young adult-

13. Jensen, MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guide-

hood and middle age to Medicare expenditures in older age. JAMA.

line for the Management of Overweight and Obesity in Adults. A Report of the

2004;292(22):2743-9.

American College of Cardiology/American Heart Association Task Force on

4. Bray GA. Medical consequences of obesity. J Clin Endocrinol Metab.

Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25_

2004;89(6):2583-9.

PA):

5. Wilson PW, Dâ&#x20AC;&#x2122;Agostino RB, Sullivan L. Overweight and obesity as determi-

14. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-con-

nants of cardiovascular risk: the Framingham experience. Arch Intern Med.

trolled trial of lorcaserin for weight management. N Engl J Med. 2010; 363:245-56.

2002;162(16):1867-72.

15. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and

6. Field AE, Coakley EH, Must A, et al. Impact of overweight on the risk of

metabolic benefits with controlled-release phentermine/topiramate in obese

developing common chronic diseases during a 10-year period. Arch Intern Med.

and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3

2001;161(13):1581-6.

extension study. Am J Clin Nutr. 2012;95(2):297-308.

7. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a

16. Yanovski S, Yanovski JA. Long-term drug treatment for obesity: a system-

prospective cohort of U.S. adults. N Engl J Med. 1999;341(15):1097-105.

atic and clinical review. JAMA. 2014;311(1):74-86.

8. U.S. Preventive Services Task Force. Screening for and Management of Obe-

17. Leblanc ES, Oâ&#x20AC;&#x2122;Connor E, Whitlock EP, et al. Effectiveness of primary care-

sity in Adults. Available at www.uspreventiveservicestaskforce.org/uspstf/usp-

relevant treatments for obesity in adults: a systematic evidence review for the

sobes.htm.

U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(7):434-47.

9. Bardia A, Holtan SG, Slezak JM, Thompson WG. Diagnosis of obesity by

18. Kang JG, Park CY, Kang JH, et al. Randomized controlled trial to investi-

primary care physicians and impact on obesity management. Mayo Clin Proc.

gate the effects of a newly developed formulation of phentermine diffuse-con-

2007;82(8):927-32.

trolled release for obesity. Diabetes Obes Metab. 2010;12(10):876-82.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 27

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GOLDen Strategies for Prevention, Assessment and Management of COPD Robert Sussman, MD For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary COPD is an expensive, underdiagnosed disease that significantly impacts patients. Updated guidelines provide recommendations on selecting the most effective therapy. Because these guidelines use a very different approach, providers may require education on their use. Managed care can use the guidelines to ensure patients are receiving appropriate therapy. • • • •

Key Points COPD is preventable and treatable but not always diagnosed. Women account for 65 percent of cases. COPD is the third leading cause of death in the United States. Updated treatment guidelines use a matrix approach to selecting therapy based on symptoms, disease stage, and history of exacerbations.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible and is progressive. There is an abnormal inflammatory response in the lung to particles or gases, but there are also significant extrapulmonary effects. The mechanisms underlying the airflow limitation are small airways disease with airway inflammation, airway fibrosis, luminal plugs, and increased airway resistance and parenchymal destruction with loss of alveolar attachments and decreased of elastic recoil. About 24 million people are estimated to have COPD in the United States. The challenge with this disease is that about half of those remain undiagnosed. The demographics of COPD are changing. It was traditionally perceived as a disease of elderly men. Currently, 70 percent of patients are younger than age 65 and 65 percent are women. The reason for the increase in women is that it became socially acceptable for them to smoke in the 1970s as a result of women’s liberation.

Unfortunately for women, they are more susceptible to the effects of tobacco smoke. They get lung cancer at younger ages and lesser smoking history. The mortality from COPD in women is now higher than that of men. COPD is the third leading cause of U.S. deaths. One person dies of COPD every four minutes. Whereas the death rates from other major diseases such as stroke and heart disease have declined, the death rates for COPD have risen significantly. This is primarily due to the increase in the number of people with COPD as a result of women entering the world of smokers. COPD is an expensive disease. Over 1.5 million emergency room visits and 726,000 hospital admissions every year are the result of COPD. The annual cost of this disease is estimated at $42 billion. More than half of those costs come from exacerbations. In the U.S., smoking is the cause of 90 percent of COPD cases. Lung function normally declines with aging, but smoking accelerates the decline. About 50 percent of lifelong smokers will get COPD. Other

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 31

Exhibit 1: GOLD Guidelines Severity Staging1

• Stage 1

FEV1 > 80%

MILD

• Stage 2

FEV1 50 - 79%

MODERATE

• Stage 3

FEV1 30 - 49%

MODERATE

• Stage 4

FEV1 < 79%

MODERATE

causes include work exposures, genetics (alpha-1 antitrypsin [AAT] deficiency accounts for 1% of cases), second-hand smoke, indoor and outdoor pollution, and recurrent childhood infections. The symptoms of COPD are dyspnea on exertion, cough, and sputum production, particularly in someone with exposure to risk factors such as smoking. This disease cannot be diagnosed purely on clinical grounds. Spirometry has to be done to document airflow limitation and irreversibility. The values which define COPD are a forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio of less than 70 percent and FEV1 is less than predicted. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines provide a framework for diagnosis and managing COPD.1 The goals of treatment are to relieve symptoms, improve exercise tolerance, improve health status, prevent and treat complications, prevent and treat exacerbations, prevent disease progression, and reduce mortality. It has been difficult to show that medications actually prevent disease progression and reduce mortality. Smoking cessation has been shown to reduce progression and mortality. The use of oxygen in severe disease also reduces mortality. The components of COPD management include assess and monitor disease, reduce risk factors, manage stable COPD with education, pharmacologic therapy, and nonpharmacologic therapy, and lastly, manage exacerbations. Assessment and monitoring includes tracking symptoms, severity of the airflow limitation (Exhibit 1), frequency of exacerbations, and comorbidities.1 Symptoms are more important than spirometric staging but both have to be considered. For example, two patients with the same degree of airflow limitation can have very different degrees of symptoms. Symptoms (dyspnea, cough, sputum, and activity limitations) have to be assessed at every visit. Reducing risk factors requires reducing occupational exposures and environmental exposures, and smoking cessation. Reducing occupational exposures may require someone changing jobs. Patients need to be educated how to reduce their exposure to

outdoor and indoor pollutants. Smoking cessation is vitally important for prevention of COPD and to slow progression in those who already have COPD. If patients stop smoking, even with severe disease, the progression is slowed significantly. Smoking history needs to be the fifth vital sign at every health care visit. The single most important motivator for patients to quit is a health care provider advising quitting. Providers can use the 5A approach when working with smokers. First the provider asks about tobacco use and advises those who smoke to quit. Next the patient’s willingness to make a quit attempt is assessed. Providers should assist the patient in their quit attempt and arrange for follow-up. People need both counseling and smoking cessation medications to be successful. Patients do need to be educated about the disease process. Many think that the diagnosis is a death sentence so treatment does not matter. The educational components include disease awareness, risk factor reduction, how and when to use medications, recognizing early symptoms of exacerbation, and need for a healthy lifestyle including nutrition and exercise. Medications for COPD are either bronchodilators, corticosteroids, or phosphodiesterase 4 inhibitors. Bronchodilator medications are central to the symptomatic management of COPD. These are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms. Short-acting bronchodilators for as-needed use include short-acting beta agonists (SABAs), short- acting antimuscarinics (SAMAs), and combination products (SABAs/ SAMAs). Long-acting agents include long-acting beta agonists (LABAs), long-acting antimuscarinics (LAMAs), and combinations of LABAs and inhaled corticosteroids. There is no role for inhaled corticosteroids alone in COPD. Oral corticosteroids are only indicated for treating an exacerbation and not for chronic therapy if at all possible. Theophylline is a mild bronchodilator but infrequently used in the U.S. because of adverse effects. Roflumilast (Daliresp®) is a newer oral agent indicated for maintenance treatment of severe COPD in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment. It is a selective phosphodiesterase 4 inhibitor useful for preventing exacerbations. While the specific mechanism is not well defined, the therapeutic effect is thought to be related to the effects of increased intracellular cAMP in lung cells. The GOLD guidelines outline appropriate medical therapy for patients at various levels of severity and symptomatology. The guidelines have changed from stepped care therapy to a matrix (Exhibit 2).1

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

4 (C)

(D)

(A)

(B)

Risk (Exacerbation History)

Risk (GOLD Classification of Airflow Limitation)

Exhibit 2: Combined Assessment of COPD1

1 mMRC 0-1 CAT < 10

mMRC > 2 CAT > 10

Symptoms (mMRC or CAT score) mMRC = modified medical research council CAT = COPD assessment test

In this process, symptoms are assessed first. Exhibit 3 shows the modified medical research council (mMRC) symptom questionnaire which can be used to assess symptamotology.1 Next, degree of airflow limitation using spirometry and history of exacerbations are determined. Two exacerbations or more within the last year or an FEV1 less than 50 percent of predicted value are considered high risk. One or more hospitalizations for COPD exacerbations should also be considered high risk. Patients would be classified in one of four categories: A is fewer symptoms, low risk; B is more symptoms, low risk; C is fewer symptoms, high risk; and D is more symptoms, high risk. Initial therapy is selected based on category (Exhibit 2).1 Thus, someone with mMRC grade 2 symptoms, one exacerbation in the last year, and GOLD 2 airflow limitation should receive a LAMA or LABA. For category D, most clinicians use triple therapy. The guidelines also detail alternative therapies in the case initial therapy is not sufficient or does not work. Oxygen is another component of nonpharmacologic therapy. Oxygen saturations should be checked in all patients. Blood gases should be checked if FEV1 is less than 50 percent predicted and especially if oxygen saturation is less than 94 percent. Many patients are fine oxygen wise the majority of the time but desaturate when exercising or during sleep.

Indications for oxygen therapy include an oxygen pressure less than 55 or pressure between 55 and 59 with cor pulmonale, polycythemia, or cardiac disease. Patients should use oxygen at least 16 hours per day, which is the duration shown to reduce mortality. Pulmonary rehabilitation is important but not widely available because of the lack of reimbursement. It significantly improves dyspnea, health-related quality of life, and walking distance and may decrease health care utilization and cost. Pulmonary rehabilitation is probably more important than pharmacotherapy. All patients need a nutritional assessment. Underweight patients with COPD have higher mortality than normal weight patients. Overweight patients have the additional comorbidities that come from excess weight. Although AAT deficiency only accounts for 1 percent of COPD cases, the new GOLD guidelines recommend screening all COPD patients for the deficiency because specific treatment is available and it is not always easy to predict which patients have this genetic abnormality.1 High-risk patients include those with early onset (<45) disease, emphysema without risk factors, lower lobe bullous disease, and strong positive family history. In addition to nutritional challenges, other extra-

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 33

Exhibit 3: Modified MRC (mMRC) AQuestionnaire1 PLEASE TICK IN THE BOX THAT APPLIES TO YOU (ONE BOX ONLY)

□ □

mMRC Grade 0: I only get breathless with strenuous exercise. mMRC Grade 1: I get short of breath when hurrying on the level or walking up a slight hill. mMRC Grade 2: I walk slower than people of the same age on the level because of breathlessness or I have to stop for breath when walking at my own pace on the level.

□

mMRC Grade 3: I am too breathless to leave the house or I am breathless when dressing or undressing.

□

Exhibit 4: Manage Stable COPD: Pharmacologic Therapy RECOMMENDED FIRST CHOICE

ICS + LABA or LAMA

GOLD 3

GOLD 2

C ICS + LABA and/or LAMA

B SAMA pm or SABA pm

LABA or LAMA

GOLD 1 mMRC 0-1 CAT < 10

pulmonary effects of COPD include osteoporosis, depression, coronary artery disease, and cancer. The disease itself and the co-sharing of smoking each contribute to all of these except depression. Screening for each of these should be done in every COPD patient. Exacerbations are common in COPD. An exacerbation is an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication. Infection and air pollution are two common causes. The cause is unknown in one-third of cases. Treatment is intensification of pharmacologic

Exacerbrations per year

GOLD 4

mMRC > 2 CAT > 10

therapy with inhaled bronchodilators, oral corticosteroids, and antibiotics if there are signs of infection. Not every exacerbation requires antibiotics or oral corticosteroids. If patients have at least two symptoms of infection (increased sputum production, increased dyspnea, and sputum purulence), antibiotics are likely effective. Preventing exacerbations can go a long way toward reducing the overall costs of COPD management. Seventy-seven percent of patients have at least one exacerbation per year. Fifty to 75 percent of all COPD costs are for exacerbations. Prevention is also important because frequent COPD exacerbations are associated with higher rate of lung function decline

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and lower quality of life. Influenza and pneumonia can lead to exacerbations; therefore, every patient needs an annual influenza vaccine and pneumonia vaccine at appropriate intervals. Other therapies that have been shown to reduce exacerbation rates include an ICS, a LABA/ICS combination, tiotropium (Spiriva. LAMA), and roflumilast. In one study, the ICS/LABA combination reduced the rate of exacerbations requiring hospitalization by 36 percent compared with a LABA alone. The number needed to treat for this combination is very favorable. Only two patients need to be treated with a LABA/ICS combination to prevent one exacerbation. Tiotropium reduces risk of exacerbations and hospitalizations by 14 percent. Roflumilast reduces risk by 17 percent. These exacerbation prevention trials all included different types of patients so comparative efficacy for the medications cannot be determined. Future therapies under investigation are numerous. Pharmacotherapy innovations being studied include LABA/LAMA and ICS/LABA/LAMA combination products. There are studies examining reversal of damage and slowing progression. En-

dobronchial valve therapy for severe disease is under study. The value redirects airflow to the lower lungs; this is essentially a lung reduction procedure without lung tissue removal. Conclusion

In terms of both patient impact and economic costs, COPD is a costly disease. Although easy diagnostic tests and effective therapies are available, patients do not always get an appropriate diagnosis or treatment. The most recent GOLD guidelines use a matrix based on risk for determining appropriate therapy. Providers need to be educated on this revised approach. Robert Sussman, MD is the President and Managing Partner of Pulmonary and Allergy Associates in New Jersey. He is Co-Director of the Pulmonary and Allergy Associates Clinical Research Center.

References 1. Global Initiative for Chronic Obstructive Lung Disease, Inc. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. 2014. Available at www.goldcopd.org.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 35

the handbook

for people with pain

a resource guide 4th edition

The “Handbook for People with Pain” has been revised and refreshed to better help those dealing with chronic pain as well as their caregivers! In The Handbook you will find: • Pain Assessment Tools • Healthy Lifestyle Tips • Resources for Caregivers • Information about Clinical Trials …and much more! Check out our website at http:/www.itfop.com/namcp/ to download your FREE handbook or to order additional free copies. Also available in Spanish.

IN the FACE of PAIN® To Inform and Empower

A service of Purdue Pharma L.P., Stamford, CT 06901

A8961 8/14

Practical Antiplatelet Strategies for Improving ACS Outcomes R. Scott Wright, MD, FACC, FESC, FAHA For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Platelet activation is one culprit in the development of acute coronary syndrome (ACS). To prevent future ACS events, everyone with an event should be considered for dual antiplatelet therapy with aspirin and a P2Y12 inhibitor for at least one year. The selection of which P2Y12 inhibitor will depend on whether the patient is managed medically or surgically and individual factors such as bleeding risk, genetic metabolic capacity, and other factors. • • • •

Key Points ACS is driven by platelet thrombosis. Dual antiplatelet therapy is the standard of care. The choice of the P2Y12 inhibitor varies based on the clinical situation and patient factors. Triple antiplatelet therapy should be reserved for use during percutaneous coronary intervention and perhaps for certain high risk subsets prior to PCI.

Acute coronary syndrome (ACS) is an umbrella term for situations where the blood supplied to the heart muscle is suddenly blocked and includes myocardial infarction (MI) and unstable angina. Platelets are the culprit that triggers the syndrome and obstructs coronary blood flow, producing clinical symptoms in ACS. In addition to platelet aggregation leading to blood clot formation, platelet activation triggers a cascade that likely promotes vasospasm and further platelet thrombosis. Platelet activation results in a vicious cycle; once it starts, the ultimate end is to stop blood flow completely. Preventing ACS requires inactivating platelets. The platelets have multiple receptors that activate with exposure to tissue factor or thrombus. Clinicians have multiple pathways to target the receptors with pharmacotherapy. Based on vast clinical evidence, use of aspirin is strongly associated with risk reduction for having an MI and improvement in ACS survival. Aspirin re-

mains the single most cost-effective therapy in preventing and treating ACS, but risk still remains with monotherapy. Thus, monotherapy with aspirin is no longer the standard of care; every patient with ACS needs to receive at least two oral antiplatelet agents. The benefit of dual antiplatelet therapy (DAPT) is significant. Triple antiplatelet therapy should be used in some patients, but it should be reserved for use during percutaneous coronary intervention (PCI) and perhaps for certain high-risk subsets prior to PCI. Selection of which agents to use for DAPT and triple therapy remains a challenge. Exhibit 1 outlines the guidelines for managing ACS with antiplatelet therapy.1 In addition to aspirin, a P2Y12 inhibitor [clopidogrel (Plavix ®), prasugrel (Effient®), ticagrelor (Brilinta®)] is the second component of DAPT. These agents result in an absolute risk reduction (ARR) of approximately 2 percent but with a higher rate of bleeding compared with placebo. When combined

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Exhibit 1: Class I and Class IIa Recommendations for Initial Management of Unstable Angina/Non ST Segment Elevation MI1 Diagnosis of UA/NSTEMI is Likely or Definite

ASA (Class I, LOE: A)*

Select Management Strategy

Initial Conservative Strategy or Unknown

Invasive Strategy‡

Initiate anticoagulant therapy (Class I, LOE:A) Acceptable options include; • Enoxaparin or UFH (Class I, LOE: A) • Fondaparinux (Class I, LOE: B) • Enoxaparin or Fondaparinux preferred over UFH (Class IIa, LOE: B)

Initiate anticoagulant therapy (Class I, LOE:A)† Acceptable options include; • Enoxaparin or UFH (Class I, LOE: A) • Bivalirudin (Class I, LOE: B) • Fondaparinux (Class I, LOE: B)† Precatheterization: Add second antiplatelet (Class I, LOE: A)§ • Clopidogrel or ticagrelor (Class I, LOE: B) or • GP IIb/IIIa inhibitor (Class I, LOE: A) • (IV eptifibatide or tirofiban preferred)

Initiate clopidogrel or ticagrelor (Class I, LOE: B)

Next step per triage decision at angiography CABG: Maintenance ASA (Class I, LOE: A)

PCI: Class I: • Clopidogrel (LOE: A) or ticagrelor (LOE: B) (if not begun precatheterization) or • Prasugrel (LOE: B) or • Selectively, a GP IIb/ IIIa inhibitor (if not begun precatheterization) (LOE: A)

with aspirin, these agents result in about a 1 percent ARR in risk when the additional risk of bleeding is considered. This is a clinically important reduction in risk. One trial compared prasugrel and clopidogrel in combination with aspirin for efficacy and safety in patients with ACS undergoing PCI. Prasugrel use resulted in an 18 to 20 percent relative risk reduction (2.2 to 2.4% ARR) for a primary event compared with clopidogrel.2 When examining the net clinical benefit, which accounts for the major bleeding events, the benefit was 1.7 percent for prasugrel over clopidogrel. The Trilogy trial examined these same two agents head-to-head in patients with non-STEMI not undergoing PCI (medical management). The

Medical Therapy: D/C IIb/IIIa inhibitors if begun and give clopidogrel or ticagrelor per conservative strategy

primary endpoint was no different between these two agents.3 When the Trilogy data are examined by those who did or did not get angiography, those who had proven platelet-based ACS had a benefit with prasugrel. Overall, prasugrel is effective and superior to clopidogrel in patients undergoing PCI. The data do not support extending its label to the medically managed ACS patient. Prasugrel may have superior efficacy in diabetic patients, but this is yet to be determined. The PLATO trial compared ticagrelor with clopidogrel in combination with aspirin in those with both non-STEMI and STEMI undergoing medical management or PCI. Ticagrelor reduced the primary endpoint more than clopidogrel (8.95 vs. 10.65%).4 This was a 1.7 percent ARR. Ticagrelor

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therapy also reduced risk of MI, death, and stent thrombosis. The risk of major bleeding is higher with this more potent agent. When used in the right situations, even when factoring in the higher bleeding risk, ticagrelor and prasugrel are more efficacious than clopidogrel (1 to 2% ARR). There are some other issues that come into play in selecting a P2Y12 agent. These issues fall into four categories - CYP2C19 issue, bleeding risks, concurrent aspirin dosing concerns, and onset of antiplatelet action. In 2010, the FDA issued a boxed warning about the diminished effectiveness of clopidogrel in patients with impaired ability to convert the drug into its active form (impaired CYP2C19 metabolism). Clopidogrel is a prodrug, which must be activated by several CYP450 liver isoenzymes. Of these isoenzymes, CYP2C19 is responsible for 45 percent of the first step of activation. Genetic variants of CYP2C19 are responsible for the variability in clopidogrel active metabolite bioavailability. One variant, CYP2C19*2, encodes for a nonfunctional protein. Distribution of the CYP2C19*2 variant varies by ethnicity. Fifty percent of people of Chinese decent are found to have this variant. It is found in 34 percent of African Americans, 25 percent of Caucasians, and 19 percent of those of Hispanic origin. Multiple studies support an association between this allele variant and increased risk of cardiovascular events. The increase in risk ranges from 53 to 500 percent (OR 1.5 to 5.0). Neither prasugrel nor ticagrelor are significantly impacted by CYP2C19 variants. The guidelines suggest platelet response testing and genetic variability testing in those with a one in three or one in four chance of having the variant if the results will change management.1 The onset of action of P2Y12 inhibitors varies. Clopidogrel is given as a loading dose to speed up onset. A 600 mg loading dose leads to an onset of activity in two to four hours. The other two agents have onset within 30 minutes, which is probably why they are superior in acute ACS. Because of duration of effect, P2Y12 inhibitors have to be stopped five to seven days before an elective surgery. Aspirin dosing is important with ticagrelor. The aspirin dose should be less than 100 mg daily to prevent adverse effects. Doses between 81 and 325 mg daily can be used with the other two agents. Bleeding risk also is considered. Those over 75, weighing less than 60 kg, or with a previous stroke or

TIA have a significant risk of bleeding with prasugrel and thus it should not be used in those populations. Overall, DAPT with aspirin and clopidogrel is proven therapy in non-STEMI for those being managed conservatively or invasively. DAPT with aspirin and prasugrel is reserved only for those undergoing PCI. Prasugrel results in a higher rate of bleeding after CABG and should be avoided in that setting. DAPT with ticagrelor is effective for patients undergoing PCI, but its role in those who are conservatively managed is still controversial. The duration of DAPT should be at least a year after an ACS event. Continuation of clopidogrel or prasugrel beyond 15 months can be considered in those with a drug-eluting stent. Discontinuation of DAPT at one year can trigger a recurrent ACS event. Use of aspirin after year one is usually adequate and is the guideline-based expectation.1 Patient adherence to DAPT for the first year after ACS is critical. More efforts must be given to promote adherence. Conclusion

Dual antiplatelet therapy for one year in post-ACS patients is the gold standard for preventing future events. Evidence suggests that clopidogrel works well and that the others are slightly more efficacious but with higher bleeding risks. Adherence with DAPT is important during that year of therapy and requires clinician attention. R. Scott Wright, MD, FACC, FESC, FAHA is a Professor of Medicine at the Mayo Clinic in Rochester, MN.

References 1. 2012 Writing Committee Members, Jneid H, Anderson JL, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126(7):875-910. 2. De Servi S, Goedicke J, Schirmer A, Widimsky P. Clinical outcomes for prasugrel versus clopidogrel in patients with unstable angina or non-ST-elevation myocardial infarction: an analysis from the TRITON-TIMI 38 trial. Eur Heart J Acute Cardiovasc Care. 2014 May 12. 3. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297-309. 4. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-57.

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

www.PROVENGEHCP.com

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011. 2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

Recent Advances and Emerging Data in the Treatment of Hypertriglyceridemia Michael Miller, MD, FACC, FAHA, FNLA For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although still controversial, triglyceride levels are important in predicting risk for developing cardiovascular disease. Once identified, hypertriglyceridemia is managed through intensive lifestyle interventions, reducing secondary causes, and, in certain cases, pharmacotherapy. Additional data are needed to determine which patient populations benefit, if at all, from triglyceride-lowering therapy in combination with statins. Key Points • Triglyceride level is an important biomarker of downstream lipid particles which are atherogenic. • Patients should be screened for hypertriglyceridemia with nonfasting levels. • Hypertriglyceridemia is managed with lifestyle changes and reducing secondary causes. • Pharmacotherapy to prevent pancreatitis should be considered in those with very high levels (>500 mg/dl) despite lifestyle changes. • Patients with elevated triglycerides and low HDL, despite statin therapy, may benefit from the addition of omega-3 fatty acids (EPA alone), niacin, or fibrates.

For many years, there has been controversy over the importance of triglycerides as a risk factor for heart disease. Triglycerides (TGs) are water-insoluble lipids consisting of three fatty acids linked to one glycerol molecule. They represent a concentrated source of metabolic energy contributing nine kilocalories per gram. Triglycerides are obtained from dietary sources. Fats are broken down by pancreatic and gastric lipases after intake. The fatty acids are re-esterified in the intestine, taken up in lymphatics, and packaged in chylomicrons which enter the circulation. The chylomicrons are rapidly broken down by lipoprotein lipase. This happens unless you have an inability to catabolize fat particles because of genetics, diabetes, or other metabolic disorders.1 Normally TGs ultimately get broken down into free fatty acids, which are stored as an energy source. TGs themselves are not atherogenic; however, TG-rich lipoproteins are broken down into

cholesterol-rich byproducts, which are atherogenic. TGs are an important biomarker of downstream lipid particles, which are atherogenic. A high TG level indicates that atherogenic lipid particles are increased. Hypertriglyceridemia that results from either increased production or decreased catabolism of triglyceride-related lipoproteins directly influences low-density lipoprotein (LDL) and high-density lipoprotein (HDL) composition and metabolism.1 LDL is atherogenic because it can be taken up into the blood vessel walls but must be modified for this to occur. Modification occurs with cigarette smoking or diabetes. When patients have excess abdominal fat, which is more metabolically active than other fat, they will have elevated TGs, which leads to the metabolic consequences shown in Exhibit 1.1 TG-rich very low-density lipoprotein (VLDL) produced by the liver in this setting will exchange TG for cholesterol esters, resulting in TG-rich LDL and HDL.

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

Exhibit 1: Metabolic Consequences of Hypertriglyceridemia1

Insulin Resistance

FFA

HTGL

CETP

Small, dense HDL

CE HTGL

Liver

Small, dense LDL

CE = cholesteryl ester CETP = cholesteryl ester transfer protein DGAT = diacylglycerol acyltransferase FFA = fat free fatty acid HDL = high-density lipoprotein HTGL = hepatic triglyceride lipase LDL = low-density lipoprotein TG = triglyceride VLDL = very low-density lipoprotein

TG-rich HDL is a problem because the TG competes with cholesterol. This makes HDL inefficient in removing cholesterol from the blood vessel walls (reverse cholesterol transport). HDL is also cleared from the circulation faster so HDL levels tend to be low in this setting. TG-rich LDL particles end up being broken down into small dense LDL, which are more susceptible to being oxidized and taken up into vessel wall.2 Small, dense LDL has enhanced atherogenicity for several other reasons including decreased affinity for liver LDL receptors, longer residence time in the plasma, and more binding to glycosaminoglycans in the blood vessel walls. Higher levels of oxidized LDL also lead to increased endothelial dysfunction, which contributes to the atherosclerosis process. Because elevations in TGs lead to production of small, dense LDL particles, the higher the TG level, the higher the small dense LDL level. 3 Thus, just knowing an LDL level is insufficient to adequately predict an individualâ&#x20AC;&#x2122;s risk of CVD. The

relationship of TG levels and CHD risk has been shown in multiple studies.4 At each quartile value of LDL, elevated TGs increases risk greater than either one alone.5 An optimal TG level is less than 100 mg/dl.1,6 A desirable level is less than 150 mg/dl. Approximately 30 percent of U.S. adults have levels greater than 150 mg/dl. Mexican Americans have the highest predisposition for elevated levels. There are secondary causes of hypertriglyceridemia, which should be identified and treated or eliminated. They include medications, alcohol, coffee, hypothyroidism, diabetes, liver disease, nephrotic syndrome, obesity, lipodystrophy, Gaucherâ&#x20AC;&#x2122;s disease, and Glycogen storage disease type I. Medications implicated include estrogen, tamoxifen, thiazides, beta blockers, corticosteroids, retinoids, protease inhibitors, long-term interferon, and antipsychotics. In addition to atherosclerosis, there are other consequences of hypertriglyceridemia. Patients with levels over 500, and particularly over 1,000 mg/dl,

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 45

Exhibit 2: Effects of Lifestyle Changes on Triglyceride Lowering1

TG-Lowering

Weight loss (5% to 10% of body weight)

20%

Implement a Mediterranean-style diet vs a low-fat diet

10 - 15%

Add marine-derived PUFA (EPA/DHA) (per gram)

5 - 10%

Decrease carbohydrates

1% Energy repacement with MUFA/PUFA

1 - 2%

Eliminate trans fats

1% Energy repacement with MUFA/PUFA

Aerobic activity (2 x per week or more)

are at risk for developing pancreatitis. When levels are well over 1,000, patients also may have eruptive xanthomas and lipemia retinalis. The current lipid guidelines focus heavily on statin use because that is where the majority of evidence for impact on morbidity and mortality lie. Statins are well known to reduce risk, but there is still residual cardiovascular disease risk in patients treated with statins. Part of this residual risk may be from low HDL levels. The TNT study found that despite very low LDL levels (goal of 70 mg/dl) patients with hypertriglyceridemia-related low HDL had higher rates of recurrent events compared to those without.7 An analysis of the PROVE IT-TIMI 22 trial found that each 10 mg/dL reduction in TG reduced coronary heart disease (CHD) risk by 1.8 percent; this was in addition to statin therapy.8 Based on the PROVE IT-TIMI 22 trial, achieving both low LDL-C and low TG (<150 mg/dL) may be important therapeutic strategies in patients after an acute coronary syndrome episode. This is hypothesis generating; a trial studying this needs to be conducted. Contrary to past recommendations, patients should be screened for hypertriglyceridemia with nonfasting levels, provided that patients eat a small amount of fat (~15 gm) for breakfast before screening.1 A fasting level identifies the most optimal state, but that is not where most people stay the majority of time. TG levels at all times should never exceed 500 mg/dl. If a patient has a nonfasting TG greater than 200 mg/dl, a fasting lipid panel should be obtained to further classify the degree of elevation and need for treatment. Lifestyle is important in reducing TG and is recommended for all levels of TG elevations. Paying close attention to lifestyle changes can reduce levels

1% 10 - 15%

50 percent or more (Exhibit 2).1 For TG lowering, medication is only recommended if a patient has levels greater than 500 mg/dl despite lifestyle changes. Fibrates (gemfibrozil, fenofibrate), niacin, omega-3 fatty acids (fish oils), and ezetimibe can all be used to lower TG levels, but there is still controversy as to whether these medications, alone or in combination with statins, reduce risk of CHD. The AIM-HIGH study found that a statin combined with extended-release niacin did not provide additional CHD benefit over a statin alone.9 In this study, the median LDL level on statins was 74 mg/ dl, TG were 163 mg/dl, and HDL was 34.9 mg/ dl. The THRIVE study found similar results of no benefit of extended-release niacin in addition to statins in patients with median LDL of 63 mg/dl, TG 125 mg/dl, and HDL of 44 mg/dl.10 In the trials of fibrates, they also do not provide a significant benefit unless someone has high TG and low HDL despite statin therapy.11 The issue with the fibrate trials and many of the niacin trials is none of them focused on patients with hypertriglyceridemia. Subgroup analyses of the fibrate and niacin studies raise the potential that add-on therapy to statins may provide a benefit in select subpopulations but randomized trials are needed to answer the question. Omega-3 fatty acids are another option for lowering TGs. In one Japanese trial, a low dose of statin plus 1.8 grams per day of eicosapentaenoic acid (EPA) lowered CHD risk 19 percent.12 Omega-3 fatty acids are not without issues. In patients with TG greater than 500 mg/dl, omega-3 fatty acid ethyl esters [combination of EPA and docosahexaenoic acid (DHA)] can increase LDL in addition to lowering TG.13,14 Pure EPA (icosapent

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ethyl, Vascepa®) does not appear to increase LDL in those with TG greater than 500 mg/dl.15,16 Although this is an interesting finding, a clinical trial is needed to prove morbidity and mortality benefit. A trial examining the effects of icosapent ethyl 4 grams per day in combination with statin on prevention of first CV event is ongoing. The patient population is men and women 45 years or older with CHD or type 2 diabetes with one other risk factor. The subjects also have an atherogenic dyslipidemia with elevated triglycerides (150 to 500 mg/dL) despite being at LDL goal on statin.

tion. 1990;82(2):495-506. 4. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115(4):450-8. 5. Assmann G, Schulte H, Funke H, von Eckardstein A. The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J. 1998;19 Suppl M:M8-14. 6. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2889-934 7. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL

Conclusion

cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301-10.

Residual cardiovascular disease risk is high in many patients with CHD or diabetes despite treatment with statins, likely due to elevated triglycerides and triglyceride-induced low HDL. Current guidelines recommend that combination therapy may be necessary to achieve primary targets. Combination therapy with statins and niacin, fenofibrate, or EPA corrects atherogenic lipid abnormalities, with the latter two therapies associated with reduced CV risk in subgroup analyses. Ongoing clinical trials will assess whether combination therapy is clinically superior to statin monotherapy in patients with hypertriglyceridemia.

8. Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51(7):724-30. 9. Guyton JR, Slee AE, Anderson T, Fleg JL, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1580-4. 10. The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014; 371:203-12. 11. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med. 2010;363(7):692-4. 12. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients ( JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090-8.

Michael Miller, MD, FACC, FAHA, FNLA is a Professor of Medicine,

13. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor

Epidemiology and Public Health at the University of Maryland School

in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4(5-6):385-91.

of Medicine in Baltimore, MD.

14. Pownall HJ, Brauchi D, Kilinç C, et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the

References

neutral lipid compositions of high-density and low-density lipoproteins. Athero-

1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular

sclerosis. 1999;143(2):285-97.

disease: a scientific statement from the American Heart Association. Circulation.

15. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester

2011;123(20):2292-333.

(AMR101) therapy in patients with very high triglyceride levels (from the multi-

2. Mudd JO, Borlaug BA, Johnston PV, et al. Beyond low-density lipoprotein

center, placebo-controlled, Randomized, double-blind, 12-week study with an

cholesterol: defining the role of low-density lipoprotein heterogeneity in coro-

open-label extension [MARINE] trial). Am J Cardiol. 2011;108(5):682-90.

nary artery disease. J Am Coll Cardiol. 2007;50(18):1735-41.

16. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapen-

3. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein

taenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent

phenotype. A proposed genetic marker for coronary heart disease risk. Circula-

high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984-92.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 47

STOOL DNA BASED COLON CANCER SCREENING TEST

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Therapeutic Updates in the Prevention and Treatment of Osteoporosis Steven T. Harris MD, FACP For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Loss of bone mass leading to increased risk for fracture occurs in both men and women. Once the risk of fracture is significant, pharmacologic treatment should be initiated. Current medications significantly reduce the risk of fracture but also cause some rare but worrisome adverse effects. Balancing the risk of fracture with medication adverse effects is required for the successful management of osteoporosis. Key Points • Fracture is the key outcome with osteoporosis. • Risk of fracture is determined by the complex interactions among bone mineral density, bone quality and trauma. • There are tools to identify patients at risk of fracture. • Current pharmacologic treatments typically reduce vertebral fracture risk by 30 to 70 percent, with smaller reductions in nonvertebral fracture risk. • No pharmacologic treatment can reduce fracture risk to zero, in part because of the inability to eliminate trauma. • BMD change with medication doesn’t fully predict the reduction in fracture risk. • Long-term treatment with bisphosphonates may be indicated but should be re evaluated after five years of therapy.

Throughout our lifetime, bone remodeling to repair microdamage occurs all the time. Over a decade, the entire skeleton is remodeled. Past midlife, an imbalance between bone resorption and formation develops; thus, a little more bone is resorbed than formed during each remodeling cycle. The newly formed bone is also not as structurally sound as bone formed when one is younger. This age-related bone loss occurs in everyone. Women experience additional bone low due to loss of estrogen at menopause. Accumulated bone loss leads to osteopenia and osteoporosis. Osteoporosis results in increased fracture risk due to low bone density and microarchitectural deterioration. Thus, reduction in fracture risk is the key clinical outcome of interest in this disease. Fracture risk is a combination of quantity of bone, the quality of the bone, and trauma. Bone mineral density (BMD) gives a crude estimate of the quantity of bone in a given anatomic area, but it does not tell anything about bone structure. At present there is no clinically useful measure of bone quality. Treat-

ment with medication treats the bone quantity issue. BMD is related to risk of fracture (Exhibit 1).1 Bone density is measured in terms of a T- score; the T-score indicates the number of standard deviations above or below the average peak bone mass in young adults. A T-score between -1 and -2.5 indicates osteopenia, whereas osteoporosis is a T-score -2.5 or lower.2 The terms osteoporosis and osteopenia were developed for use in older, postmenopausal women and were then extended to older men. Osteopenia describes a BMD range that is essentially low-normal for a young adult. These terms were never intended for application to young men or women and certainly never to children. All women age 65 and older and men 70 and older, regardless of additional risk factors, should be screened for osteoporosis. Postmenopausal women and men age 50 to 69, based on their risk factor profile, can also be screened. In addition to having a personal history of prior fracture, parental history of hip fracture, current smoking, systemic corticoste-

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

Exhibit 1: Bone Mineral Density Continuum of Risk1

Relative Risk of Fracture

Low Bone Mass

Osteoporosis

30 25

Normal

20 15 10 5 0 -5

-4

-3

-2

-1

BMD T-Score

Exhibit 2: Effect of Additional Risk Factors in a 52-Year-Old Woman with T-score -2.0 Risk of Major Fractures

Risk of Hip Fracture

40 30 10-Year Fracture Risk (%)

20 10 0

11 5.8

6.1 1.4

0.8 Age & BMD

Age & BMD Smoking

roids, alcohol intake greater than or equal to three units daily, and rheumatoid arthritis are other risk factors for fracture. Fracture risk can be estimated using the FRAX® tool.3 With FRAX, patients with high enough fracture risk to warrant treatment can be identified. The use of the FRAX tool guides the treatment decisions in osteopenic patients because the decisions are based on the risk of fracture, not the T- score alone. It identifies patients at high risk for fracture to ensure that they are offered treatment to lower risk. Lastly, it helps avoid giving medication to those who are at low risk and have little to gain from treatment. Exhibit 2 illustrates how having more risk factors increases risk. There are some caveats with this tool. The model is not intended for application in those already on

1.5 Age & BMD Smoking Parental Hip Fx

3.0 Age & BMD Smoking Parental Hip Fx Wrist Fx

osteoporosis pharmacologic treatment and is based on femoral neck BMD only. Additionally, it is not clear what margin of error is present in the fracture risk estimates. Lastly, it is not known if all risk factors carry equal weight in predicting the response to pharmacologic treatment. In some cases, FRAX® may underestimate fracture risk. Some risk factors (glucocorticoids, smoking, alcohol) are dose-dependent, but FRAX® doesn’t incorporate dose response. Some factors that increase the risk of fracture independently of their effect on BMD are not included in the tool’s model, including falls, immobilization, diabetes, and certain medications (anticonvulsants, selective serotonin reuptake inhibitors, proton pump inhibitors, and thiazolidinediones). Exhibit 3 provides the recommendations for treatment initiation for postmenopausal women and men

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 51

Exhibit 3: 2008/2013 NOF Guidelines: Treatment Initiation Postmenopausal Women and Men >502 Assess Risk Factors and Measure BMD if Patient Has Risk Factors

T-score between -1.0 and -2.5

Hip or Vertebral Fractures or T-score < -2.5 (Spine, Femoral Neck or Total Hip)

10-year Probability of Hip Fracture >3% or Probability of All Major Fractures >20%

Other Fractures after Age 50 (Excluding Fingers, Toes and Face)

Secondary Causes with High Fracture Risk*

*such as glucocorticoid use or total immobilization

Exhibit 4: 10-Year Probabilities of Adverse Outcomes12-24 65-year-old woman with femoral neck T-score -2.8 and risk factors including personal history of fracture and a parent with a hip fracture

50% 40% 30% 20% 10% 0%

39% 19% 0.11% Major Osteoporic Fx (Untreated)

Major Osteoporic Fx (Treated)*

Fatal Auto Accident

0.50%

0.01%

Atypical Fracture

ONJ

*Fracture risk typical of patient with osteoporosis ONJ = osteonecrosis of jaw FX = fracture

greater than or equal to 50 years.2 Both nonpharmacologic and pharmacologic interventions are indicated for treatment. Taken as a whole, nonpharmacological options are relatively inexpensive and modestly effective. Exercise in particular has other health benefits, although the same is likely to be true for diet optimization. Optimization of the diet, exercise, and fall prevention should be viewed as important adjuncts to the treatment of osteoporotic patients. Pharmacologic treatment significantly decreases fracture risk. Most treatment agents (bisphosphonates, selective estrogen receptor modulators, calcitonin, estrogen, denosumab) act to decrease bone

resorption and are called antiremodeling agents. Denosumab (Prolia速) is a relatively new therapy for osteoporosis. It is a monoclonal antibody to RANKL that is an anti-remodeling agent given as a subcutaneous injection every six months. With these agents, a decrease in resorption is followed by a decrease in formation and BMD improvement tends to plateau after several years. All the antiremodeling agents prevent bone loss and preserve architecture, improve quality of bone, and reduce the risk of vertebral fractures. Alendronate, risedronate, zoledronic acid and denosumab are proven to reduce the risk of nonvertebral and hip fractures. Antiremodeling treatment decreases fracture risk

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

more rapidly and to a larger extent than one would predict from the relatively small changes in BMD.4 Fracture protection can be observed even in the absence of a significant change in BMD. Additionally, fracture protection persists even when the BMD reaches a plateau.5 Thus, BMD stability does not mean nonresponse. Fracture reduction is most conspicuous in older patients with prevalent vertebral fractures. Teriparatide is the only treatment agent that is anabolic; it stimulates bone formation rather than inhibits bone resorption. It increases bone density and size, improves quality of bone, and reduces the risk of vertebral and nonvertebral fractures. There are no hip fracture data for teriparatide. Although bone activating therapy with teriparatide increases BMD more than antiremodeling treatment, it is not yet obvious that fracture protection is greater. The benefits of treatment include reduction in the risk of fracture, reduction in pain and disability, preservation of independence, reduction in height loss, possible positive effect on mortality, and positive effect on a surrogate such as BMD. There are risks or disadvantages of treatment, including the economic cost of treatment. Other costs of treatment are the nuisance value of taking another medication, reminder of illness, and worry about consequences of therapy. Adverse effects of treatment are also an issue. Patient concerns about safety have become the major challenge with the bisphosphonates. Two major safety concerns, osteonecrosis of the jaw and atypical fractures, are rare but still concerning, especially to patients. Bisphosphonates and denosumab, which have both been implicated in causing these safety concerns, work primarily by inhibiting bone breakdown. Thus, the skeleton loses no bone, but if there is no resorption there is no bone repair. With no bone repair, microdamage accumulates and leads to fractures. This is possibly the mechanism of these safety issues that occur with these agents. Osteonecrosis of the jaw (ONJ) is an area of exposed alveolar or palatal bone that typically shows poor healing over several months. Ninety-five percent of reported cases occur in cancer patients receiving large doses of intravenous bisphosphonates and often after an invasive procedure (tooth extraction or implants).6 Risk factors include periodontitis, poor oral hygiene, diabetes, and corticosteroids.7 ONJ is rare in osteoporosis patients (1:10,000 to 1:100,000). It usually heals with conservative treatment in osteoporosis patients on bisphosphonates. All patients on bisphosphonates should be encouraged to comply with regular good oral care. If possible, invasive dental procedures should be complet-

ed prior to bisphosphonate therapy. Routine dental care (cleaning, fillings, etc.) requires no change in therapy. No data indicate if temporary discontinuation of bisphosphonates reduces the risk of ONJ after dental surgery. Short-term discontinuation until healing is reasonable. Atypical fractures that occur in people on bisphosphonates or denosumab are transverse fractures of the femoral diaphysis or in the subtrochanteric region. They may begin with a stress reaction or stress fracture of the lateral femoral cortex and are often bilateral. Prodromal pain in the thigh or groin occurs in about 70 percent of those affected. These atypical fractures can occur in untreated patients, but there is an increased incidence in patients on bisphosphonates greater than five years, often in combination with other medications, especially steroids or estrogen.8-10 The FDA issued a safety warning for bisphosphonates regarding atypical fractures. Any patient who presents with new groin or thigh pain must be evaluated to rule out a femoral shaft fracture. Antiresorptive medication should be discontinued in those who have an atypical fracture. The FDA safety warning suggested periodically reevaluating the need to continue bisphosphonate therapy, particularly in patients treated for five years or more. If 1,000 women with a femoral neck T-score ≤ -1.5, with or without prevalent vertebral fractures, are treated with bisphosphonates for five years, 35 to 50 nonvertebral and 50 to 115 vertebral fractures would be prevented.11 As many as five atypical femur fractures would likely occur. Overall, the risk of an atypical fracture or ONJ is low compared to the risk of common osteoporotic fractures (Exhibit 4).12-14 In addition to the challenges of adverse effects, there are challenges with adherence, defining success, and the optimal duration of therapy. Persistence is an issue with a silent disease like osteoporosis. About 50 percent of patients will stop taking bisphosphonate therapy within one year of starting.15 Success in osteoporosis treatment has been defined as the absence of fracture, which from a patient perspective is not very exciting. The most important clinical objective is the prevention of fractures— both vertebral and nonvertebral fractures. Changes in surrogate markers--bone mineral density (BMD) and biochemical markers of bone turnover--are “necessary” but are not “sufficient” to say treatment was successful. Optimal duration of therapy is another area of controversy. Duration of treatment should be based on risk of fracture, response to therapy, pharmacokinetics of the agent used, and patient preferences.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 53

The benefits and risks of both continuation and discontinuation have to be considered. One might consider stopping therapy for a period of time, a drug holiday, if continued therapy is not associated with any greater benefit. Drug holiday in the management of osteoporosis is a notion that applies only to the bisphosphonates. One might also consider a drug holiday if continued therapy is associated with an increased risk of adverse events. At the five-year treatment point with bisphosphonates, the need for continuing treatment should be reassessed based on fracture history, BMD, and clinical risk factors. For those at low or moderate risk, stopping therapy is a possibility. For those at higher risk, continuing therapy, a drug holiday, or alternative medication during a bisphosphonate holiday are all treatment options. BMD and biochemical markers of bone breakdown, FRAX score, and fractures are considered in determining when and if treatment is restarted.9,16 There is benefit to continuing bisphosphonate therapy beyond five years. Two trials examined long-term use compared with discontinuation. In one trial comparing five years versus 10 years of therapy, switching to a placebo for five years resulted in declines in BMD and increases in biochemical markers of bone turnover, but not to pretreatment levels.17 The incidence of all clinical fractures and nonvertebral fractures was similar in both groups, but there was a lower risk of clinical vertebral fractures in those who continued therapy. Post hoc analyses suggested that continuation was associated with lower risk of nonvertebral fractures in women with a femoral neck T-score â&#x2030;¤ -2.5. In another trial, after treatment with risedronate for three years and discontinuation for one year, spine and hip BMDs decreased significantly and biochemical markers of bone turnover increased to placebo levels.18 The risk of new vertebral fractures was reduced by 46 percent in the former risedronate users compared with the former placebo patients in the year off of treatment. Another trial compared the effects of discontinuing zoledronic acid treatment after three years versus continuing for an additional three years. Femoral neck BMD remained constant in the continuation group and showed a small decrease in the discontinuation group. Significantly fewer morphometric vertebral fractures occurred in the continuation group than in the discontinuation group; there was no difference in nonvertebral, clinical vertebral, or hip fractures.19 Based on these three trials in about 2,000 patients, a definitive decision about drug holiday cannot yet be made. Long-term treatment has not clearly been associated with loss of efficacy. Cessation of treatment after two to five years is as-

sociated with some persisting effect on biochemical markers, as well as BMD; this has been best characterized for alendronate and zoledronic acid. A clinical consensus on bisphosphonate therapy long term is, for patients at high risk for fractures, continued treatment seems reasonable. A drug holiday of one to two years after 10 years of treatment can be considered.20 For lower risk patients, consider a drug holiday after four to five years of BMD stability. BMD and/or bone turnover markers should be followed during a drug holiday period, and therapy reinitiated if bone density declines or markers increase. There are numerous agents under study for managing osteoporosis. Some include selective estrogen receptor modulators (lasofoxifene, bazedoxifene), two forms of strontium, anti-sclerostin antibodies (romosozumab, blosozumab), cathepsin K inhibitor (odanacatib), cyclic analog of parathyroid hormone, and a calcium receptor antagonist. The anti-sclerostin antibodies look most promising as new anabolic bone forming agents. Because the majority of bisphosphonates have or will be going generic soon, the cost of a generic bisphosphonate is very low for reasonably efficacious fracture protection. What this means for any new agents coming along, which will be much more expensive, is unknown. Conclusion

Safe and effective therapies are available to prevent and treat osteoporosis. The choice of therapy will depend on patient factors. Contemporary pharmacologic treatments typically reduce vertebral fracture risk by 30 to 70 percent, with smaller reductions in nonvertebral fracture risk. No pharmacologic treatment is likely to reduce fracture risk to zero, in part because of the inability to eliminate trauma. There are a number of promising pharmacologic agents with most of the emphasis to be placed on the development of novel anabolic agents. Steven T. Harris, MD, FACP is a Clinical Professor of Medicine at the University of California in San Francisco.

References 1. Meunier PJ, Delmas PD, Eastell R, et al. Diagnosis and management of osteoporosis in postmenopausal women: clinical guidelines. International Committee for Osteoporosis Clinical Guidelines. Clin Ther. 1999;21(6):1025-44. 2. National Osteoporosis Foundation. NOF Clinicianâ&#x20AC;&#x2122;s Guide to Prevention and Treatment of Osteoporosis 2013. Available at www.nof.org. 3. WHO Fracture Risk Assessment Tool. Available at www.shef.ac.uk/FRAX/ tool.jsp. 4. Harrington JT, Ste-Marie LG, Brandi ML, et al. Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;74(2):129-35. 5. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are

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related to changes in bone density. J Clin Endocrinol Metab. 2000;85(1):231-6.

fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728-37.

6. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphos-

14. Edwards BJ, Hellstein JW, Jacobsen PL, et al. Updated recommendations for

phonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144(10):753-61.

managing the care of patients receiving oral bisphosphonate therapy: an advi-

7. Khosla S, Burr D, Cauley J, Dempster DW, et al. Bisphosphonate-associated

sory statement from the American Dental Association Council on Scientific

osteonecrosis of the jaw: report of a task force of the American Society for Bone

Affairs. J Am Dent Assoc. 2008;139(12):1674-7.

and Mineral Research. J Bone Miner Res. 2007;22(10):1479-91.

15. Weycker D, Macarios D, Edelsberg J, Oster G. Compliance with drug ther-

8. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphy-

apy for postmenopausal osteoporosis. Osteoporos Int. 2006;17 (11):1645-52.

seal femoral fractures: second report of a task force of the American Society for

16. Compston JE, Bilezikian JP. Bisphosphonate therapy for osteoporosis: the

Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1-23.

long and short of it. J Bone Miner Res. 2012;27(2):240-2.

9. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin

17. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping

Endocrinol Metab. 2010;95(4):1555-65.

alendronate after 5 years of treatment: the Fracture Intervention Trial Long-

10. Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and

term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927-38.

the risk of subtrochanteric or femoral shaft fractures in older women. JAMA.

18. Watts NB, Chines A, Olszynski WP, et al. Fracture risk remains reduced one

2011;305(8):783-9.

year after discontinuation of risedronate. Osteoporos Int. 2008;19(3):365-72.

11. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphy-

19. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zole-

seal femoral fractures: report of a task force of the American Society for Bone

dronic acid treatment of osteoporosis: a randomized extension to the HORI-

and Mineral Research. J Bone Miner Res. 2010;25(11):2267-94.

ZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(2):243-54.

12. Centers for Disease Control. National Vital Statistics Report 2008. Avail-

20. Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clini-

able at www.cdc.gov.

cal Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis

13. Schilcher J, MichaĂŤlsson K, Aspenberg P. Bisphosphonate use and atypical

and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16 Suppl 3:1-37.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 55

MAKE THEIR PRESCRIPTION COUNT.

20%

74%

of patients who visited the Emergency Department (ED) with acute asthma had an empty rescue inhaler1

of patients did not know how many doses were left in their Metered Dose Inhalers (MDIs)2

40%

of patients believed they were taking medication but were actually using an empty or near-empty MDI3

MDls With Dose Counters Provide Helpful Information

25%

of adults found their MDls empty during an asthma exacerbation4

• Refilling prescriptions on time may – help reduce healthcare costs by decreasing asthma-related morbidity and attendant medical costs2,4 – help patients avoid costly ED visits1,4

INDICATION ProAir® HFA (albuterol sulfate) Inhalation Aerosol is indicated in patients 4 years of age and older for the treatment or prevention of bronchospasm with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm.

IMPORTANT SAFETY INFORMATION • Inhaled albuterol sulfate can produce paradoxical bronchospasm that may be life-threatening. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister • Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma

• ProAir® HFA, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), convulsive disorders, hyperthyroidism, and diabetes • Potential drug interactions can occur with betablockers, diuretics, digoxin, or monoamine oxidase inhibitors, and tricyclic antidepressants • Do not exceed the recommended dose • Adverse events, which occurred at an incidence rate of at least 3% with ProAir®HFA, include headache, tachycardia, pain, dizziness, pharyngitis, and rhinitis Please see Brief Summary of full Prescribing Information on the following pages.

REFERENCES: 1. Brenner BE, Leber M, Kohn MS, Camargo C. ED visits for acute asthma by patients who recently ran out of the β-agonist inhaler. Annals of Emergency Medicine. 1997;30:427. 2. Rubin BK, Durotoye L. How do patients determine that their metered-dose inhaler is empty? Chest. 2004;126:1134–1137. 3. Conner JB, Buck PO. Improving asthma management: The case for mandatory inclusion of dose counters on all rescue bronchodilators. J Asthma 50:658–663, 2013. 4. Sander N, Fusco-Walkert SJ, Harder JM, Chipps BE. Dose counting and the use of pressurized metered-dose inhalers: Running on empty. Ann Allergy Asthma Immunol. 2006;97:34–38. ProAir® is a registered trademark of Teva Respiratory, LLC. ©2014 Teva Respiratory, LLC PRA-40697

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR PROAIR® HFA (ALBUTEROL SULFATE) INHALATION AEROSOL For Oral Inhalation Only SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Bronchospasm PROAIR HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. 1.2 Exercise-Induced Bronchospasm PROAIR HFA Inhalation Aerosol is indicated for the prevention of exerciseinduced bronchospasm in patients 4 years of age and older. 4 CONTRAINDICATIONS PROAIR HFA Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol and any other PROAIR HFA Inhalation Aerosol components. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate [see Warnings and Precautions (5.6)]. 5 WARNINGS & PRECAUTIONS 5.1 Paradoxical Bronchospasm PROAIR HFA Inhalation Aerosol can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROAIR HFA Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister. 5.2 Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of PROAIR HFA Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. 5.3 Use of Anti-inflammatory Agents The use of beta-adrenergic-agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen. 5.4 Cardiovascular Effects PROAIR HFA Inhalation Aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of PROAIR HFA Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, PROAIR HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.5 Do Not Exceed Recommended Dose Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. 5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving PROAIR HFA Inhalation Aerosol. 5.7 Coexisting Conditions PROAIR HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.8 Hypokalemia As with other beta-agonists, PROAIR HFA Inhalation Aerosol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. 6 ADVERSE REACTIONS Use of PROAIR HFA may be associated with the following: • Paradoxical bronchospasm [see Warnings and Precautions (5.1)]

• Cardiovascular Effects [see Warnings and Precautions (5.4)] • Immediate hypersensitivity reactions [see Warnings and Precautions (5.6)] • Hypokalemia [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience A total of 1090 subjects were treated with PROAIR HFA Inhalation Aerosol, or with the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol, during the worldwide clinical development program. 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. Adult and Adolescents 12 Years of Age and Older: The adverse reaction information presented in the table below concerning PROAIR HFA Inhalation Aerosol is derived from a 6-week, blinded study which compared PROAIR HFA Inhalation Aerosol (180 mcg four times daily) with a double-blinded matched placebo HFA-Inhalation Aerosol and an evaluator-blinded marketed active comparator HFA-134a albuterol inhaler in 172 asthmatic patients 12 to 76 years of age. The table lists the incidence of all adverse events (whether considered by the investigator drug related or unrelated to drug) from this study which occurred at a rate of 3% or greater in the PROAIR HFA Inhalation Aerosol treatment group and more frequently in the PROAIR HFA Inhalation Aerosol treatment group than in the matched placebo group. Overall, the incidence and nature of the adverse events reported for PROAIR HFA Inhalation Aerosol and the marketed active comparator HFA-134a albuterol inhaler were comparable. Adverse Experience Incidences (% of Patients) in a Six-Week Clinical Trial*

Body System/Adverse Event (as Preferred Term)

Marketed active Matched comparator Placebo PROAIR HFA HFA-134a HFA-134a Inhalation albuterol Inhalation Aerosol inhaler Aerosol (N = 58) (N = 56) (N = 58)

Body as a Whole

Headache

Cardiovascular

Tachycardia

Musculoskeletal

Pain

Nervous System

Dizziness

14 5

7 4

9 2

Respiratory System Pharyngitis Rhinitis

* This table includes all adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of at least 3.0% in the PROAIR HFA Inhalation Aerosol group and more frequently in the PROAIR HFA Inhalation Aerosol group than in the placebo HFA Inhalation Aerosol group. Adverse events reported by less than 3% of the patients receiving PROAIR HFA Inhalation Aerosol but by a greater proportion of PROAIR HFA Inhalation Aerosol patients than the matched placebo patients, which have the potential to be related to PROAIR HFA Inhalation Aerosol, included chest pain, infection, diarrhea, glossitis, accidental injury (nervous system), anxiety, dyspnea, ear disorder, ear pain, and urinary tract infection. In small cumulative dose studies, tremor, nervousness, and headache were the most frequently occurring adverse events. Pediatric Patients 4 to 11 Years of Age: Adverse events reported in a 3-week pediatric clinical trial comparing the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol (180 mcg albuterol four times daily) to a matching placebo HFA inhalation aerosol occurred at a low incidence rate (no greater than 2% in the active treatment group) and were similar to those seen in adult and adolescent trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of PROAIR HFA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reports have included rare cases of aggravated bronchospasm, lack of efficacy, asthma exacerbation (reported fatal in one case), muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste, glossitis, tongue ulceration, and gagging. The following adverse events have been observed in postapproval use of inhaled albuterol: urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles). In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as: angina, hypertension or hypotension, palpitations, central nervous system stimulation, insomnia, headache, nervousness, tremor, muscle cramps, drying or irritation of the oropharynx, hypokalemia, hyperglycemia, and metabolic acidosis.

7 DRUG INTERACTIONS Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with PROAIR HFA Inhalation Aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. 7.1 Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROAIR HFA Inhalation Aerosol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic-blocking agents in patients with asthma. In this setting, consider cardioselective betablockers, although they should be administered with caution. 7.2 Diuretics The ECG changes and/or hypokalemia which may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics. Consider monitoring potassium levels. 7.3 Digoxin Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and PROAIR HFA Inhalation Aerosol. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants PROAIR HFA Inhalation Aerosol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the cardiovascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of PROAIR HFA Inhalation Aerosol or albuterol sulfate in pregnant women. During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established. Animal reproduction studies in mice and rabbits revealed evidence of teratogenicity. PROAIR HFA Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately eight-tenths of the maximum recommended human dose (MRHD) for adults on a mg/m2 basis and in 10 of 108 (9.3%) fetuses at approximately 8 times the MRHD. Similar effects were not observed at approximately onethirteenth of the MRHD. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 630 times the MRHD. In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 65 times the MRHD [see Nonclinical Toxicology (13.2)]. 8.2 Labor and Delivery Because of the potential for beta-agonist interference with uterine contractility, use of PROAIR HFA Inhalation Aerosol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. PROAIR HFA Inhalation Aerosol has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol. 8.3 Nursing Mothers Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of PROAIR HFA Inhalation Aerosol are excreted in human milk. Caution should be exercised when PROAIR HFA Inhalation Aerosol is administered to a nursing woman. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of PROAIR HFA Inhalation Aerosol by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of PROAIR HFA Inhalation Aerosol for the treatment or prevention of bronchospasm in children 12 years of age and older with reversible obstructive airway disease is based on one 6-week clinical trial in 116 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, and one single-dose crossover study comparing doses of 90, 180, and 270 mcg with placebo in 58 patients [see Clinical Studies (14.1)]. The safety and effectiveness of PROAIR HFA Inhalation Aerosol for treatment of exercise-induced bronchospasm in children 12 years of age and older is based on one single-dose crossover study in 24 adults and adolescents with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies (14.2)]. The safety of PROAIR HFA Inhalation Aerosol in children 4 to 11 years of age is based on one 3-week clinical trial in 50 patients 4 to 11 years of age with asthma using the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol comparing doses of 180 mcg four times daily with placebo. The effectiveness of PROAIR HFA Inhalation Aerosol in children 4 to 11 years of age is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of PROAIR HFA 90 mcg and 180 mcg with placebo in 55 patients with asthma and a 3-week clinical trial using the same formulation of albuterol as in PROAIR HFA Inhalation Aerosol in 95 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol four times daily with placebo [see Clinical Studies (14.1)]. The safety and effectiveness of PROAIR HFA Inhalation Aerosol in pediatric patients below the age of 4 years have not been established. 8.5 Geriatric Use Clinical studies of PROAIR HFA Inhalation Aerosol did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5.4, 5.7)]. All beta2-adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 10 OVERDOSAGE The expected symptoms with overdosage are those of excessive betaadrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of PROAIR HFA Inhalation Aerosol. Treatment consists of discontinuation of PROAIR HFA Inhalation Aerosol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of PROAIR HFA Inhalation Aerosol. The oral median lethal dose of albuterol sulfate in mice is greater than 2,000 mg/kg (approximately 6,800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In young rats, the subcutaneous median lethal dose is approximately 2,000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals. Mktd by: Teva Respiratory, LLC Horsham, PA 19044 Mfd by: IVAX Pharmaceuticals Ireland Waterford, Ireland Copyright ÂŠ2014, Teva Respiratory, LLC All rights reserved. PROAIRÂŽ is a registered trademark of Teva Respiratory, LLC

Manufactured In Ireland PA0512PBS-E

Rev 05/12 PRA-40580

Undertreated Stroke Prevention in Atrial Fibrillation: The Risk of Bleeding versus the Risk of Stroke Michael Miller, MD, FACC, FAHA, FNLA For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Atrial fibrillation is an independent risk factor for stroke. To reduce the incidence of stroke, everyone with AF should be evaluated for stroke prevention therapies. Aspirin and warfarin have been the mainstays of therapy but are being replaced by newer anticoagulants for some patient populations. These newer agents have greater efficacy and safety, and are easier to manage than warfarin therapy. Key Points • Atrial fibrillation (AF) is a major risk factor for stroke. • All patients with AF need to be evaluated for stroke risk and bleeding risk related to antithrombotic therapy. • Antiplatelet agents or anticoagulation should be initiated in those who meet national guideline criteria. • The newer anticoagulants are more effective than warfarin and result in reduced risk of intracranial hemorrhage. • Certain patients should still receive warfarin because of lack of data with the new agents.

Atrial fibrillation, abnormal conduction in the atrium, is the most common sustained cardiac arrhythmia affecting more than 2.3 million Americans, or 1 percent of the population.1, 2 It preferentially affects men and the elderly. The lifetime risk of developing AF is one in four for men and women over 40 years of age. Because of our aging population and unhealthy lifestyles, the prevalence is expected to increase by more than 2.5-fold by 2050. There are numerous reasons for a person to develop AF (Exhibit 1). Alcohol ingestion, obesity, and pulmonary embolism are the most common noncardiac triggers for AF. Dilation of the atria from cardiac hypertrophy related to HTN and valvular heart disease can lead to AF. AF occurs on a spectrum. AF can be intermittent (paroxysmal atrial fibrillation- PAF). Those with PAF tend to be symptomatic; they can tell you when an episode is coming on. They have normal heart and atria size. PAF can progress over time to persistent AF. Those with persistent AF tend to have heart disease and mild to moderate enlargement of the left

atria. Ultimately, permanent AF can develop. This stage has significant left atrial enlargement. Stroke is the most common and devastating complication of AF.3 All-cause stroke rate with AF is 5 percent per year. AF is an independent risk factor for stroke leading to a fivefold increase in stroke risk. Approximately 15 percent of all strokes are caused by AF. Stroke risk increases with age and persists even in asymptomatic AF. Risk for stroke in AF can be estimated using the CHADS2 scoring system (Exhibit 2).5 Patients without any additional risk factors beyond AF have an annual risk of 1.8 percent (CHADS2 score = 0). Higher scores indicate a higher annual risk of stroke. A CHADS2 score of 2 or greater is the cutpoint where the benefits of treatment outweigh the risk, which is bleeding. CHA 2DS2-VASc is an additional risk scoring method used by some clinicians (Exhibit 3).6 This score identifies more individuals at high risk for stroke than the CHADS2 score. One of the major goals of treating AF is to pre-

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 59

Exhibit 1: Causes of AF3,4 • Noncardiovascular Causes • Acute/chronic alcohol ingestion

• Cardiovascular Causes • CAD

• Autonomic

• Iatrogenic Causes • Beta-agonists

eg., post MI

• Cardiac and noncardiac surgery

• DM

• HF

• Intracardiac catheters

• Genetic

• HTN

• Obesity

• Primary electrical disorders

• Local anesthetics, caffeinated beverages, other stimulants

• Pulmonary embolism

• Valvular heart disorders

• Severe lung diseases

• Others

• OTC cold remedies

• Sleep apnea • Thyroid disorders • Others CAD = coronary artery disease

Exhibit 2: CHADS2 Score5 Risk Factor

Points

Congestive HF

Hypertension

Age > 75

Diabetes

Prior Stroke/TIA

vent stroke.7 For many years, warfarin and aspirin have been the primary choices for pharmacologic therapy. Warfarin reduces incidence of stroke by about 64 percent compared with placebo.8 Not considering the problems using warfarin, it is one of the most effective interventions in medicine. Antiplatelet therapy with aspirin reduces incidence of stroke by about 22 percent.8 Warfarin is more effective than antiplatelet therapy, but it does have to be managed carefully to avoid adverse effects and to ensure adequate anticoagulation.9 The patient needs to be in the therapeutic range (INR 2 to 3) 65 percent or more of the time to achieve optimal efficacy. The problem is that patients typically spend about 55 percent of the time in the therapeutic range.10 There are also issues with intracranial hemorrhage, gastrointestinal bleeding and other types of bleeding with warfarin.11. To minimize risk of bleeding and maximize stroke risk reduction, an INR of 2 to 3

is the optimal therapeutic range.12-13 Patients with artificial heart valves require more intense anticoagulation. Like estimating stroke risk, there are several scoring systems for estimating the risk of bleeding. The one that appears to be best for predicting risk is the HAS-BLED score.14 A HAS-BLED score is based on one point for each of the following risk factors: hypertension, abnormal renal or hepatic function, history of stroke, history of bleeding, labile INR on warfarin, age greater than 65, and use of medications that cause bleeding or alcohol. A score of less than 3 is considered low risk for bleeding, whereas a score of 3 or higher is high risk. Minimizing the risk of central nervous system (CNS) bleeding during warfarin therapy can be accomplished by achieving and maintaining blood pressure control, using the lowest efficacious INR, and not adding antiplatelet agents to warfarin unless clearly indicated. Older patients with cerebrovascular disease are at special risk for CNS bleeding. Overall, warfarin has a narrow therapeutic window that makes management difficult. Time in therapeutic range is an important metric for assessing efficacy and is influenced by many factors. INR monitoring is important for safety and efficacy, but it is labor intensive, complex, and inefficient. The high rate of adverse events and management difficulties leads to underutilization. An ideal anticoagulant would have a rapid onset of action to avoid the need for overlap with heparin, a wide therapeutic index for increased safety, minimal adverse effect to improve compliance, oral formulation for convenient administration, a predictable an-

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

Exhibit 3: CHA 2DS2-VASc Score6 Risk Factor

Score

Congestive heart failure/LV dysfunction

Hypertension

Age > 75 yrs

Diabetes mellitus

Stroke/TIA/TE

Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque)

Age 65 - 74 yrs

Sex category (i.e female gender)

LLV = left ventricular TE = thromboembolism

Exhibit 4: 2011 ACCF/AHA/HRS Guidelines17,18 Antithrombotic Therapy for Patients with Atrial Fibrillation Risk Category1

Recommended Therapy

No risk factors

Aspirin, 81 to 325 mg daily

One moderate risk factor

Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5)

Any high risk factor or > 1 moderate risk factor

Warfarin (INR 2.0 to 3.0, target 2.5)*

Less Validated/ Weaker Risk Factors1

Moderate Risk Factors

High Risk Factors

Female gender

Age > 75 years

Previous stroke, TIA or embolism

Age 65 to 74 years

Hypertension

Mitral stenosis

Coronary artery disease

Heart failure

Prosthetic heart valve*

Thyrotoxicosis

LV ejection fraction < 35% Diabetes mellitus

*If mechanical valve, target international normalized ratio (INR) > 2.5

Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/min) or advanced liver disease (impaired baseline clotting function). (Level of Evidence: B)

ticoagulant response with fixed-dose unmonitored treatment, no food or drug interactions, availability of an antidote to reverse effect in case of bleeding or urgent surgery, and cost effectiveness to increase accessibility. Newer anticoagulants have been developed in an attempt to achieve an ideal agent. Newer anticoagulants that have been FDA approved since 2011 include dabigatran (Pradaxa速),

a direct thrombin (Factor II) inhibitor, rivaroxaban (Xarelto速), a Factor X inhibitor, and apixaban (Eliquis速), a direct factor Xa inhibitor. The cost of these new agents ranges from $6.75 to $10 per day, which is substantially greater than generic warfarin. With the additional costs of the new agents comes improved efficacy. A meta-analysis of trials with these agents compared with warfarin found they

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Exhibit 5: ACCP Guidelines19

For patients with Nonrheumatic AF, including those with Paroxysmal AF Level of Risk

ACCP Recommendation

Alternative*

Not Recommended

Low Risl CHADS2 = 0

No Therapy

Aspirin

Oral anticoagulation or combination therapy with aspirin and clopidogrel

Intermediate Risk (CHADS2 = 1)

Oral anticoagulation (dabigatran preferred)

Aspirin with clopidogrel

Aspirin

High Risk (CHADS2 = 2)

Oral anticoagulation (dabigatran preferred)

Aspirin with clopidogrel

Aspirin

*For patients with AF unsuitable for, or who refuse, oral anticoagulant (for reasons other than concerns about major bleeding)

were more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF.15 They appear to have a favorable safety profile, with a decreased risk for intracranial bleeding, making them promising alternatives to warfarin. The rate of gastrointestinal bleeding is higher with dabigatran and rivaroxaban compared with warfarin. The new agents have a quick onset of action, which is an advantage over warfarin. A problem with the new agents is there are no inexpensive, readily available laboratory measures to show how adherent patients are or to determine efficacy. INR monitoring is not useful. Reversal of the anticoagulant effect is the other big issue. Warfarin is rapidly reversed with vitamin K. Such an antidote is not readily available for the new agents. A few interventions such as activated charcoal and dialysis have been tried in a few individuals, but an evidence-based antidote is not yet known.16 The overall clinical challenges with the new agents include no validated tests to measure anticoagulation effect, no established therapeutic range, and no antidote for most agents. Assessment of compliance is more difficult than with vitamin K antagonists. There is also the potential for unknown long-term adverse events. Balancing cost against efficacy and lack of head-to-head studies comparing new agents are two other issues. The American College of Cardiology Foundation/American Heart Association guidelines for selecting stroke prevention therapy in patients with AF are given in Exhibit 4.17,18 Patients with prosthetic heart valves and rheumatic valvular heart disease should receive warfarin because the new agents have not been studied in these patient populations. Exhibit 5 shows the American College of Chest Physician guidelines.19 These guidelines do differ in their

recommendations. For example, the recommended therapy for a patient with AF who has a CHADS2 score of 1 from hypertension and no other issues, would be aspirin, warfarin, or dabigatran according to the ACCF/AHA guidelines and dabigatran according to the ACCP guidelines. A cost analysis comparing dabigatran and warfarin found that the cost of AF is largely driven by the drug price for dabigatran and the quality of INR control for warfarin. The cost of dabigatran to prevent one stroke per year is about four to five times that of warfarin, but that has to be weighed against the risk of bleeding and other issues with warfarin.20 The ideal candidates for a new anticoagulant agent are patients who find INR testing burdensome or have low â&#x20AC;&#x2DC;time-in-rangeâ&#x20AC;&#x2122; despite adherence to provider recommendations. They need to be able to afford the new agents or have insurance coverage and have normal renal function. Patients who have renal insufficiency, are taking a stable dose of warfarin and do not find INR testing burdensome, have access to a self-testing machine, or are concerned about the lack of an evidence-based reversal strategy can receive warfarin. In one trial, high-risk patients with atrial fibrillation admitted with a stroke, and who were candidates for anticoagulation, the majority were either not taking warfarin or were subtherapeutic at the time of their stroke.21 Many were on no antithrombotic therapy. Strategies to reduce practice gaps in anticoagulation management for patients with AF can be system or individual based. System-level strategies include increasing the number of anticoagulant clinics, increasing physician reimbursement for anticoagulant monitoring, reminders about stroke risk with AF, and pharmacist flagging of nonanticoagulated patients with AF. Patient strategies include ongoing patient education to reinforce long-term

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adherence with therapy, and patient self-monitoring or self-management of anticoagulation.

8. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-67.

Conclusion

9. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over

AF is projected to affect greater than five million Americans by 2050. AF increases the risk of stroke by approximately fivefold. Anticoagulation therapy reduces the risk of stroke by 64 percent and death by 25 percent; antiplatelet therapy reduces the risk of stroke by 22 percent. Because of the narrow therapeutic window of effectiveness and safety with warfarin, more patients are being put on the new anticoagulants. These new therapies for stroke prevention in AF are effective, reduce intracranial hemorrhage and, depending on the circumstances, may be cost effective. For many patients, the new agents would be the therapy of choice.

antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118(20):2029-37. 10. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm. 2009;15(3):244-52. 11. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2689-96. 12. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120(11):897-902. 13. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med. 1996;335(8):540-6.

Michael Miller, MD, FACC, FAHA, FNLA is a Professor of Medicine,

14. Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORR(2)

Epidemiology and Public Health at the University of Maryland School

HAGES, ATRIA, and HAS-BLED Bleeding Risk-Prediction Scores in Patients

of Medicine in Baltimore, MD.

With Atrial Fibrillation Undergoing Anticoagulation: The AMADEUS (Evalu-

References

With Atrial Fibrillation) Study. J Am Coll Cardiol. 2012;60(9):861-7

1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of

15.. Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and

atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110(9):1042-6.

safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus

2. Go AS, Hylek EM, Phillips KA. Prevalence of diagnosed atrial fibrillation in

warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110(3):453-60.

ating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients

adults: national implications for rhythm management and stroke prevention: the

16. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of

Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA.

oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87 Suppl 1:S141-5.

2001;285(18):2370-5.

17. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused

3. European Heart Rhythm Association; Heart Rhythm Society, Fuster V, Ry-

updates incorporated into the ACC/AHA/ESC 2006 guidelines for the man-

dén LE, et al. ACC/AHA/ESC 2006 guidelines for the management of patients

agement of patients with atrial fibrillation: a report of the American College of

with atrial fibrillation--executive summary: a report of the American College

Cardiology Foundation/American Heart Association Task Force on practice

of Cardiology/American Heart Association Task Force on Practice Guidelines

guidelines. Circulation. 2011;123(10):e269-367.

and the European Society of Cardiology Committee for Practice Guidelines

18. Wann LS, Curtis AB, Ellenbogen KA, et al.. 2011 ACCF/AHA/HRS focused

(Writing Committee to Revise the 2001 Guidelines for the Management of

update on the management of patients with atrial fibrillation (update on dabigatran):

Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006;48(4):854-906.

a report of the American College of Cardiology Foundation/American Heart As-

4. Bajpai A. Epidemiology and economic burden of atrial fibrillation. US Car-

sociation Task Force on practice guidelines. J Am Coll Cardiol. 2011;57(11):1330-7.

diovascular Disease. 2007;14-17.

19. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fi-

5. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classifica-

brillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:

tion schemes for predicting stroke: results from the National Registry of Atrial

American College of Chest Physicians Evidence-Based Clinical Practice

Fibrillation. JAMA. 2001;285(22):2864-70.

Guidelines. Chest. 2012;141(2 Suppl):e531S-75S.

6. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for

20. Ali A, Bailey C, Abdelhafiz AH. Stroke prophylaxis with warfarin or dabi-

predicting stroke and thromboembolism in atrial fibrillation using a novel risk

gatran for patients with non-valvular atrial fibrillation-cost analysis. Age Ageing.

factor-based approach: the euro heart survey on atrial fibrillation.

2012;41(5):681-4.

Chest. 2010;137(2):263-72.

21. Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in high-

7. Prystowsky EN. Management of atrial fibrillation: therapeutic options and

risk patients with atrial fibrillation who are not adequately anticoagulated.

clinical decisions. Am J Cardiol. 2000;85(10A):3D-11D.

Stroke. 2009;40(1):235-40.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 63

Updated Strategies for the Management and Treatment of Chronic Pain Eric S. Hsu, MD For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Chronic pain is a significant issue for patients, society, and health care. Because of the complexity, successful management of chronic pain many times requires a multimodality and interdisciplinary approach. Although pharmacologic therapy tends to be the first treatment chosen, various nonpharmacologic options should be considered and used in combination with or in place of pharmacologic agents. • • • • •

Key Points Psychosocial issues such as anxiety or depression need to be identified because these must be treated in order to have successful pain management. A multimodality approach that uses pharmacologic and nonpharmacologic therapies, including cognitive behavioral therapy, is the best approach for chronic pain. Nonpharmacologic and psychological therapies are underused. Chronic pain management should also be multidisciplinary. Good pain management includes all four of the “A’s” of pain treatment out comes - analgesia, activities of daily living, adverse effects, and aberrant drug taking.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. On physical examination, patients with pain may have allodynia, a painful response to a nonpainful stimulus, and hyperalgesia, a heightened response to painful stimulus. Pain can be categorized as acute or chronic (sometimes labeled persistent). In contrast to chronic pain, relatively high levels of pathology usually accompany acute pain and the pain resolves with healing of the underlying injury. Common sources of acute pain include trauma, surgery, labor, medical procedures, and acute disease states. Acute pain serves an important biological function, as it warns of the potential for or extent of injury. Pain becomes chronic when it persists three or six months beyond onset or beyond the expected period of healing. Chronic pain is associated with low levels of identified underlying pathology that do not explain the presence or the extent of the pain. Chronic pain has also been defined as pain that ceases to serve a protective func-

tion, and instead degrades health and functional capability. Pain can also be classified by origin as nociceptive, neuropathic, or mixed. Nociceptive, or inflammatory, pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli. Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries. Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems. Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia, and diabetic neuropathy. Examples of central neuropathic pain include central post-stroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain. Chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics. Examples of mixed etiology syndromes include post-trauma pain, postoperative pain, cancer pain, chronic back pain and sciatica. Although most pain disorders begin with injury

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

Exhibit 1: Interrelationship of Chronic Pain, Sleep Disturbances, Depression and Anxiety

Chronic Pain

Sleep Disturbances

Depression/ Anxiety

Exhibit 2: Universal Precautions • Diagnosis with Appropriate Differential • Psychological Assessment, Including Risk of Addictive Disorders • Informed Consent and Treatment Agreement • Pre- and Post-Intervention Assessment of Pain Level and Function • Appropriate Trial of Opioid Therapy With/Without Adjunctive Medication • Regularly Assess the “4 A’s” of Pain Medicine • Periodically Review Pain Diagnosis and Comorbid Conditions Including Addictive Disorders • Documentation

or disease, their course and outcome are affected by emotional, behavioral and social factors. An individual’s emotional reaction to, and capacity to cope with, the fluctuating course of pain disorders and their complications such as physical impairment, disability, and loss of role functioning will also affect outcome. Chronic pain significantly interferes with sleep, with most studies showing a positive correlation between pain intensity and degree of sleep disturbance (Exhibit 1). Many chronic pain patients have signs and symptoms of depression and anxiety; sleep deprivation can lead to anxiety, and depression can be both the cause and result of sleep deprivation. Chronic pain, sleep disturbances, and depression/anxiety must be addressed if patients are to be restored to optimal functionality. Because of the complicated factors involved in pain, the management of pain depends on a comprehensive assessment. Psychosocial and psychiatric evaluations should be a fundamental part of any pain

assessment, and are especially important in the management of chronic pain. The process of assessment can be straightforward and brief in the setting of acute pain. It increases in complexity and time required as the pain becomes persistent. All history and physical examination regarding pain and treatment should incorporate the cultural diversity and linguistic competency of the patients. Patients belonging to some racial, ethnic, and socioeconomic groups may be at risk of receiving suboptimal pain management. Surveys reveal a lack of health care provider knowledge that undertreatment of pain is more common in minority patients than others. Language barriers, miscommunication, fear of medication diversion, and financial barriers are major obstacles to optimal pain management for minority populations. Understanding clinician factors that underlie suboptimal pain management is necessary to develop effective strategies to overcome disparities and improve quality of care for patients

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 65

Exhibit 3: Pain Medication Treatment Agreement • Medication is responsibility of the patient. • No illicit substances are allowed. • Only one healthcare provider prescribes pain medications. • Unannounced drug screens can be enforced in follow-up.

with chronic pain.1 Over time, improvements in pain and functional capacity should be measured. Assessment of pain both before and during therapy is important in managing patients with chronic pain. Patients may give a very vague description of their pain. Validated pain scales should be used to document pain levels. This will allow monitoring of pain over time. Universal precautions is a concept in pain management adapted from infectious disease that can be used to reduce clinician barriers. The term universal precautions as it applies to infectious disease came out of the realization that it was impossible for a health care professional to reliably assess risk of infectivity during an initial assessment of a patient. Clinicians realized that the safest and most reasonable approach to take was to apply an appropriate minimum level of precaution to all patients to reduce the risk of transmission of potentially lifethreatening infectious disease to health care professionals. The “universal precautions in pain medicine” paradigm refers to a standardized approach to the assessment and ongoing management of all chronic pain patients (Exhibit 2). A pain management agreement that includes the items in Exhibit 3 is part of the overall safe use of pain medications. Providing a comprehensive standardized approach to chronic pain management requires input from various disciplines. Approaching patient assessment and management within chronic pain treatment in a thorough and respectful manner can help to lessen the stigma, optimize patient care, and contain overall risk from pain medications. Good pain management considers and manages all four of the “A’s” of pain treatment outcomes - analgesia, activities of daily living, adverse effects, and aberrant drug taking. Ideally, patients should have good pain control with improvements in their ability to function, without major adverse effects and without addiction-related behaviors. Therapies used in the treatment of pain can be pharmacologic, nonpharmacologic, and psycho-

logical. Complementary and alternative medicine (CAM) may be treatment options as well. With pharmacologic therapy, the risk and benefits of nonopioid, adjuvant, and opioid analgesics and age-associated changes in pharmacokinetics and pharmacodynamics have to be considered. Nonpharmacologic therapy includes physiotherapy and rehabilitation. Patients may benefit from an exercise program, stretch and strengthening in the musculoskeletal system, massage, manipulation, electrical stimulation, and/or topical application of heat and cold. Interventional pain procedures such as epidural steroid injections and nerve blocks are also options. Psychological management includes cognitive-behavioral therapy, relaxation techniques, biofeedback training, and hypnosis. Nonpharmacologic and psychological treatments tend to be underused because of lack of reimbursement. In choosing pharmacologic therapy, clinicians can use the World Health Organization three-step analgesic ladder from the WHO Cancer Pain Management Guidelines.2 Because there are few chronic pain treatment guidelines, most clinicians use the cancer pain guidelines. Step one is nonopioid analgesics and adjuvant meds. Step two is to move to weak opioid analgesics plus first-step agents. Step three is strong opioid analgesics plus first- and second-step agents. This includes transdermal delivery, subcutaneous injections, intravenous patient controlled anesthesia, neuraxial drug delivery system, neuromodulation, nerve block, and neurolysis (chemical or radiofrequency nerve ablation). Certain adjunctive agents are effective for treating neuropathic pain. Controlled clinical trials and clinical experience document that the lidocaine transdermal patch, because of its nonsystemic mechanism of action, has the least potential for adverse effects or drug interactions. Among systemic agents, gabapentin, which has no significant adverse effects, has demonstrated favorable safety and tolerability. Based upon these factors, as well as being FDA-approved for the treatment of postherpetic neuralgia, the lidocaine patch and gabapentin are often selected as initial treatments for neuropathic pain. Nortriptyline, desipramine, tramadol, and controlled- release oxycodone have also demonstrated safety and tolerability profiles which are more favorable than other adjunctive agents such as amitriptyline, phenytoin, and carbamazepine. Agents with consistent efficacy demonstrated in multiple, randomized, controlled trials for postherpetic neuralagia include lidocaine transdermal patch, capsaicin transdermal patch, gabapentin, and pregabalin (Lyrica®). Agents with consistent efficacy demonstrated in painful diabetic polyneuropathy

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

are duloxetine, pregabalin, and tapentadol extended-release (Nucynta速). There are issues with adverse effects and contraindications with each of the pharmacologic options. Only using pharmacologic therapy is not optimal chronic pain management. Chronic pain management will be more successful when combinations of treatment modalities are used. The American College of Physicians and American Pain Society have published a guideline on the diagnosis and treatment of low back pain (LBP).3 First-line medications for LBP are acetaminophen and nonsteroidal anti-inflammatories. Nonpharmacological therapy with proven benefits for LBP includes spinal manipulation for acute LBP. For subacute or chronic LBP, intensive interdisciplinary rehabilitation, exercise therapy, acupuncture, massage therapy, spinal manipulation, yoga, cognitivebehavioral therapy (CBT), relaxation and biofeedback have shown efficacy. CAM has a place in managing chronic pain. Acupuncture is one example. In addition to frequent use for postoperative pain, chemotherapy-induced nausea and vomiting, and postoperative dental pain, acupuncture has been evaluated in several other chronic pain conditions with promising results.4 As mentioned previously, comorbid conditions such as depression, anxiety, and sleep disturbances also need to be treated to optimally treat chronic pain. The inter-relationship between these three factors (Exhibit 1) is complex, but must be considered carefully if treatment for chronic pain is to be satisfactory. Management and treatment should address both the pain and the comorbidities in order to improve daily functioning and enhance quality of life. The use of multidisciplinary teams for managing chronic pain has been evaluated and found to be effective. One example is the Integrative Health Clinic for Chronic Nonmalignant Pain at a Veterans Administration facility.5 This is an innovative outpatient clinical service that provides nonpharmacological, biopsychosocial interventions using

research-based mind-body skills and complementary and alternative therapies. The study assessed improvement in chronic nonmalignant pain and related depression, anxiety, and health-related quality of life. For the chronic nonspinal-related pain (CNSP) group, depression, anxiety, and bodily pain significantly improved with moderate-to-large effect sizes at six months and these benefits persisted across all follow-up visits. The chronic spinal-related pain (CSP) group showed an improvement trend in bodily pain. The greatest improvement after participation in this program was seen in the CNSP group, with benefits persisting to 24 months in mood and in some health-related quality of life subcategories. Conclusion

Gender and cultural differences, addressing comorbid conditions, and improving daily activity function should all be incorporated into chronic pain management to result in better quality of life for affected patients. Universal precautions for analgesics, nonpharmacologic therapies, psychological treatments, and incorporating complementary and alternative treatments are other considerations in chronic pain management. Eric S. Hsu, MD is a Clinical Professor in the Department of Anesthesiology, Pain Management Center at the David Geffen School of Medicine at UCLA.

References 1. Bekanich SJ, Wanner N, Junkins S, et al. A multifaceted initiative to improve clinician awareness of pain management disparities. Am J Med Qual. 2013 Sep 23. 2. Auret K, Schug SA. Pain management for the cancer patient - current practice and future developments. Best Pract Res Clin Anaesthesiol. 2013;27(4):545-61 3. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147(7):478-91. 4. NIH Consensus Conference. Acupuncture. JAMA. 1998;280(17):1518-24. 5. Smeeding SJ, Bradshaw DH, Kumpfer KL, et al. Outcome evaluation of the Veterans Affairs Salt Lake City Integrative Health Clinic for Chronic Nonmalignant Pain. Clin J Pain. 2011;27(2):146-55.

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 67

We’Re

ALL IN

Weâ&#x20AC;&#x2122;re all striving for healthier outcomes. Still, there is much more we can do to get there. Being vigilant about controlling soaring drug costs. Advocating to make drugs accessible to many instead of the few. And clamping down aggressively on fraud, waste and abuse.

Come see what express Scripts is bringing to the table. Visit Booth #518 at the 2014 Fall Managed Care Forum, November 13-14 at the Bellagio.

Updated Therapeutic Strategies for Partial or Nonresponse to Treatment in Major Depressive Disorder Mark Rosenberg, MD, PhD. For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Major depressive disorder is a common and disabling illness that leads to significant reductions in quality of life and considerable cost to society. For patients who do not benefit from first-line treatment, clinicians need to determine the most appropriate and effective interventions. Treating the nonresponder may require changing antidepressants, adding augmenting medications, adding psychiatric therapy, or somatic treatments. Key Points • MDD is the most common psychiatric disorder in the U.S., but few patients receive adequate treatment. • Depression is frequently associated with other medical disorders and may negatively impact them. • Inadequately treated depression may have a progressive course and may be associated with functional and structural changes in the brain. • Ten to 30 percent of depressed patients who take an antidepressant are partially or totally resistant to treatment. • Patient input into their depression treatment choice may have an impact on the outcome. • Strategies to overcome treatment resistance include optimization, substitution, combination therapy, and augmentation.

Major depressive disorder (MDD) has a high rate of occurrence with a 17 percent lifetime prevalence. This prevalence corresponds to a national population projection of 32.69 to 35.1 million U.S. adults with lifetime MDD and 13.1 to 14.2 million U.S. adults with a 12-month prevalence of MDD. The average age of onset 50 years ago was 29, whereas the average age of onset today is 14.5. For many patients, MDD can become a chronic disorder. Thirty-three percent of patients have depressive episodes lasting more than two years. More than 50 percent of patients will have a recurrent episodes within two to three years of recovery from an episode.1 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. Depression is frequently associated with,

and may negatively impact, other medical disorders. The morbidity related to MDD is comparable to angina and advanced coronary artery disease.2 This disorder also has a high mortality from suicide. The suicide rate is 15 percent in depressed patients hospitalized once for depression. MDD is the most common psychiatric disorder in the United States, yet few patients receive adequate treatment.3 In one study of 12-month use of mental health services in the U.S., only 19.6 percent of those with depression were receiving minimally adequate treatment.4 Inadequately treated depression may have a progressive course and may be associated with functional and structural changes in the brain.5 The changes probably perpetuate the disease. MDD is a costly disorder that results in significant health care resource utilization.6 Depression is the leading cause of disability in the U.S. and by 2020 it is projected that depression will be the lead-

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

Exhibit 1: DSM-V Depression Criteria7 * Five or more of these symptoms must be present in order for a diagnosis of depression to be made. One of these symptoms must be either #1 or #2 Criteria 1.

Depressed mood*

Loss of interest or pleasure

Weight loss or weight gain

Sleep disturbance

Fatigue

Mood swings

Loss of concentration

Low self esteem or guilt

Suicidal ideation or thoughts of death

ing cause of disability worldwide. Depression is one of the top ten conditions driving medical costs, ranking seventh in a national survey of employers. It is the greatest cause of productivity loss among workers. Costs are especially an issue in those with both MDD and a chronic medical condition. Annual medical expenses for those with both chronic medical and behavioral health conditions cost 46 percent more than those with only a chronic medical condition. Untreated behavioral health disorders in chronic illness cost commercial and Medicare purchasers between $130 and $350 billion annually. Because it is a costly disorder, MDD needs to be found and treated. The DSM-V criteria for diagnosis of depression are listed in Exhibit 1.7 Physical symptoms are often the chief complaint in depressed patients. In one study, 69 percent of diagnosed depressed patients reported unexplained physical symptoms as their chief compliant.8 Once diagnosed, MDD needs to be adequately treated. For acute treatment, an initial treatment modality aimed at inducing remission of major depressive episodes and achieving a full return to baseline functions should be selected. Choices include pharmacotherapy, depression-focused psychotherapy, a combination of medications and psychotherapy, or somatic therapies such as electroconvulsive therapy (ECT). The initial treatment selected is influenced by clinical features and patient treatment preferences and should also take into account treatments being provided for other diagnoses. The acute phase of treatment lasts a minimum of six to 12 weeks. Patient input into their depression treatment choice may have an impact its outcome. One study found

that patients did better when they were randomly assigned to the treatment they would have preferred if given a choice. In 429 patients with MDD who participated in a large multisite study comparing nefazodone, cognitive behavioral therapy (CBT), and a combination of these two, patient preference strongly predicted outcomes over 12 weeks of treatment (Exhibit 2).9 The setting of care may also impact outcome. Receiving CBT in a setting other than a hospital, such as outdoors in the forest, may also result in better outcomes.10 Antidepressant medication is recommended as an initial treatment for patients with mild to moderate depression, and should definitely be provided to those with severe depression. Medication efficacy is generally comparable between classes, so selection will largely depend on factors such as side effects, costs, and patient preference. If side effects occur, initial steps should be a dosage decrease or change to a medication not linked to that side effect. Approximately 30 percent of patients treated with an antidepressant will achieve remission (< 7 score on the Hamilton Depression scale). In antidepressant medication trials, up to 70 percent of depressed patients respond to treatment but fail to achieve complete remission from all their emotional and physical symptoms.11 Response is defined as a 50 percent or greater decrease in a patientâ&#x20AC;&#x2122;s depression scale score. At least four to eight weeks of therapy with an antidepressant at an adequate dose is required before an assessment of responsiveness can be made. If minimal or no improvement is apparent, the provider should conduct an additional thorough review of contributory factors and make changes in

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 71

Exhibit 2: Patient Treatment Preference Predicts Outcome9

Percent Remission

Medication 60 40 20 0

Combination 52.2

50.0

45.5

Psychotherapy

39.1

39.8 27.6 28.0

22.2

39.3 17.6

7.7 Medication (n = 33)

Psychotherapy (n = 53)

Combination (n = 255)

None (n = 88)

Preferred Treatment

the treatment plan. Between 10 and 30 percent of depressed patients taking an antidepressant are partially or totally resistant to treatment. Reasons for treatment resistance may include undiagnosed or misdiagnosed medical conditions (such as anemia), nonpsychiatric medications that can negatively impact depression, untreated comorbid conditions including eating disorders or substance abuse, and nonadherence. Nonadherence is an important reason for suboptimal treatment outcomes. Patients frequently report stopping antidepressant medication because of what they read on the Internet about it, it did not work quick enough, and it made them feel bad. Patients also frequently stop therapy once they start feeling better. Seventy-five percent of antidepressants are discontinued by month four of therapy. Interventions to reduce nonadherence include education regarding the disease and how medications and other treatments work. Common adverse effects of the antidepressant medication should be discussed openly with patients. Patients also need to know other medication options will be explored in case of adverse effects. It is especially important to teach patients that these medications need to be taken on a daily basis to be effective and have to be taken for a period of time before they begin to work. It can be helpful to reassure a patient that antidepressant medications are not addictive and that continued treatment has a neuroprotective effect. Pharmacists can be used to help monitor medication adherence. Once all fixable causes of treatment resistance are resolved, a strategy for overcoming resistance will need to be implemented. Four strategies can be used to overcome resistance including optimization, substitution, combination therapy, and augmentation.12

Optimization is maximizing 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 eight 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; 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 nonresponders who are switched 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. 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, atypical antipsychotics, thyroid hormone, pindolol, or buspirone. Add-on therapies should be chosen based on the level of evidence.13,14 The addition of atypical antipsychiatric agents (aripiprazole, olanzapine, and risperidone) and lithium have the most evidence to support their use. Second-line add-on agents include bupropion, mirtazapine, quetiapine, and triiodothyronine. Combination and augmentation strategies have both pros and cons. Adding additional agents can build on therapeutic gains, and the addition of a sec-

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ond compound is generally well tolerated. There also appears to be a more rapid onset of antidepressant effects during the crucial early phase. The response rate of combination or augmentation is comparable or superior to drug substitution. The cons include increased potential of drug interaction, reduced adherence, and increased adverse effects. The efficacy and long-term effects may not yet be known for some medication combinations. For depression resistant to medication, ECT remains an effective therapy for consideration. In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective monoamine oxidase inhibitor (MAOI) antidepressant after allowing sufficient time between medications to avoid interactions. Another option for medication-resistant depression is transcranial magnetic stimulation. For patients who have not responded to four antidepressant trials or ECT, vagus nerve stimulation may be another treatment option. For patients who are not achieving remission with psychotherapy as their primary treatment plan, the intensity, frequency, and duration of their treatment should be considered. A change of treatment type should also be considered. For patients utilizing psychotherapy alone, medications should be considered. Patients who have a history of poor adherence or incomplete response to single modalities may benefit from combined treatment (medication and psychotherapy). Continuation phase pharmacotherapy is strongly recommended following successful acute phase antidepressant therapy, with a recommended duration of continuation therapy of approximately four to nine months.14 The goal of continuation treatment is to prevent relapse in the vulnerable period immediately following remission. During the continuation phase of treatment, patients should be monitored with periodic symptom assessments. Patients treated successfully in the acute phase should continue whichever treatment that worked. In order to reduce the risk of a recurrent depressive episode, patients, who have had three or more prior episodes or who have chronic major depressive disorder, should proceed to the maintenance phase of treatment after continuation therapy. During maintenance, antidepressant medication that produced symptom remission during the acute phase and maintained remission during continuation should be continued at full dose. If therapy was the method of treatment, maintenance treatment should be considered with reduced frequency of sessions. For patients whose depressive episodes have not responded to acute or continuation treatment, but have responded to ECT, ECT maintenance should

be considered. Maintenance treatment with vagus nerve stimulation is also appropriate for individuals whose symptoms have responded to that particular treatment modality. If treatment is going to be discontinued at any time, antidepressant medications have to be tapered over several weeks. A slow taper or temporary change to a longer half-life antidepressant may reduce risk of discontinuation syndrome. The patient should be informed of the potential for a depressive relapse and a plan should be established for seeking treatment in this event. After discontinuation of medication, patients should be monitored for several months, and receive another course of acute treatment if symptoms recur. A variety of lifestyle modifications can improve on outcomes achieved with the previously discussed treatments. Physical activity and a healthy diet should be encouraged. Providers should educate patients 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. It is important to involve family members early in treatment and to educate them regarding the disease process. They can provide extra support and help implement recommendations, monitor medication adherence, and provide better feedback on patient functioning. Support groups can supplement other treatments. Conclusion

Major depressive disorder is significant due to its overall economic and societal costs. For patients who are not responding to treatment, consider allowing patient preference to shape treatment. Patients with treatment-resistant depression should be referred to a psychiatrist for management. Treatment will usually require a combination of therapies including both medication and psychotherapy. Mark Rosenberg, MD, PhD is President of BHM Healthcare Solutions in St Louis, MO.

References 1. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry. 1999;156(7):1000-6. 2. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA. 1989;262(7):914-9. 3. 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. 4. Wang PS, Lane M, Olfson M, et al. Twelve month use of mental health ser-

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12. Cadieux RJ. Practical management of treatment-resistant depression. Am

8. Simon GE, VonKorff M, Piccinelli M, et al.An international study of the

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

relation between somatic symptoms and depression. N Engl J Med.

13. Papakostas GI. Managing partial response or nonresponse: switching, aug-

1999;341(18):1329-35.

mentation, and combination strategies for major depressive disorder. J Clin Psy-

9. Kocsis JH, Leon AC, Markowitz JC, et al.Patient preference as a moderator of

chiatry. 2009;70 Suppl 6:16-25.

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

14. American Psychiatric Association. Practice Guideline for the Treatment of

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Patients With Major Depressive Disorder, Third Edition. 2010. Available at

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

http://www.psych.org/practice/clinical-practice-guidelines.

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

Private Companies Providing Health Care Price Data: Who Are They and What Information do They Provide? Kathryn A. Phillips, PhD and Anna Labno, PhD For a CME/CEU version of this article please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary There is interest in making health care price information more transparent given the increase in enrollment in high-deductible and consumer-directed health plans, and as policy efforts intensify to engage consumers to obtain high value care. We examine the role of private companies that market price transparency tools, primarily to self-insured employers – an important yet understudied topic. What companies exist? How did they emerge? What information do they provide? Where do they get that information? How does the price and quality information provided compare across companies? Key Points • The emergence of price transparency companies is a key trend and these companies fill a gap in health plan and government initiatives. • The leading companies have many similarities but also differences in how they define, obtain, and present price and quality information. • The type of price information provided varies, with differences in whether total costs are included and how they are defined, what is included as a “service” (e.g., whether an office visit is included), what terms are used (e.g., “price”, “cost”, “in-network allowed price”, “what doctors charge”), and what price measures are used (e.g., average, median, “high” and “low” cost providers). • Quality information, when available, comes from a variety of sources, with a range of quality metrics. • Challenges to be addressed include greater transparency and consistency in how price and quality information is defined and used and the role of these companies within the context of other initiatives.

Introduction and Background

There are increasing efforts to make health care price information more transparent, with calls for action from the front page of the New York Times1, the longest Time magazine article ever published,2 and a U.S. Senate Finance Committee hearing.3 There are multiple efforts underway to improve price transparency including pricing tools created by government, insurers, and consumer groups – as well as private companies, which are the focus of this study. We examined the characteristics of private companies that market price transparency tools (“price transparency companies”), which despite rapid growth have been relatively unstudied.

Price transparency companies contract with self-insured employers to provide pricing tools to the company’s employees, using aggregated claims data to estimate prices for health care services. They are often called “third-party vendors” because they serve as intermediaries between employers and insurers Despite the rapid growth of price transparency companies, to our knowledge there have not been any published, peer-reviewed analyses of these companies. Because these companies are privately owned, they are relatively less studied than public price transparency efforts. Yet, they have implications for health care consumers, employers, health plans, and society. Some believe that pricing tools

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 75

Exhibit 1: Timeline of Key Price Transparency Related Initiatives Including When Key Third-party Companies Were Founded

ClearCost Health founded Truven & Compass Healthcare founded Castlight Health founded ChangeHealthcare founded Growth of price disclosure websites by insurers

2003

2005

2007

2009

2011

2013

State legislation on price transparency (New Hampshire; Colorado) Medicare Prescription Drug, Improvement & Modernization Act

Affordable Care Act

CRS report on price transparency and market efficiency

GAO report on difficulty in obtaining price information US Senate Finance Committee Hearing on Health Care Prices

used by self-insured employers may have more impact than public efforts.4,5 Self-insured employers are a key component of U.S. health care, currently covering 60 percent of insured workers and growing, and almost half of companies have/plan to use price transparency tools to provide price information directly to their employees.6 The growth of price transparency companies has been rapid and investor interest is high, e.g., one company garnered one of the largest venture rounds for a health care IT company on record,7 and has been identified as one of the most likely digital health companies to have an IPO in the near future.8 Methods

We conducted a structured, descriptive review by assessing the available evidence on characteristics of five price transparency companies (as of July 2013). Both authors reviewed searches and independently

coded information. We included companies noted as industry leaders in Internet and published reports and that met our definition (a private company focused on providing price information to self-insured employers). We excluded companies focused on individual consumers. Unlike consumer or government websites, private companies do not provide public access to their pricing tools or data sources. We thus conducted extensive internet searches including company websites, business reports, and news articles in addition to PubMed searches. Results

Price transparency companies have rapidly developed to fill a gap between the need for price information and the ability of patients to obtain it (Exhibit 1). Consumer-directed health plans, which created additional incentives for price transparency, started in the 1990s and were further expanded with

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

Exhibit 2: Comparison of Price Transparency Company Characteristics Company

Castlight Health

TruvenHealth Analytics

ChangeHealthCare

ClearCostHealtha

Compass Healthcare

Description and URL

“Castlight Health delivers the solution to enable employers and health plans to lower the cost of health care and provide individuals unbiased pricing and quality information to make smart health care purchase decisions.” www.castlighthealth.com

“The Treatment Cost Calculator gives individuals a clear picture of their financial responsibility before they decide to undergo a treatment or procedure. The online tool provides accurate, real-time estimates of out-of-pocket costs that are personalized to a consumer using their benefits, deductible, provider, and location”. http://healthcare.thom sonreuters.com

Change Healthcare is on a mission to … transform the way Americans purchase and utilize healthcare services, engage members in making educated, cost-effective decisions for themselves and their families on pharmacy, medical and dental purchases. www.changehealthcare. com

ClearCost Health delivers both cost and quality information to health plan participants before they seek care so that they can factor price and quality into their health care decisions. www.clearcosthealth. com

“Compass Professional Health Services provides the pricetransparency, quality checks, and patient advocacy that unlock the power of healthcare consumerism.” www.compassphs.com

Target Customer(s)

- Self-insured employers - Health plans

- Self-insured employers - Health plans - Health Insurance exchanges

- Self-insured employers - Health plans

- Self-insured employers - Union health and welfare trusts

- Self-insured employers - Brokers - Direct-to-consumerb

Date Founded

2008

2008 c

2007

2010

2009

Funding Source

Private equity/venture capital

Private equity/venture capitald

Private equity/venture capitale

Privately held

Services Included

- Healthcare - Prescriptions

- Healthcare

- Healthcare - Prescriptions

What Information provided on Price and Quality

- Personalized to what consumer pays. - Funding status of deductible/HRA. - Total costs. - Price by provider. - In or out of network. - Provider quality rating.

- Personalized to what consumer pays. - Total costs (primary procedure, other procedures, facility). - In or out of network. - Provider and facility quality rating.

- Personalized to what consumer pays. - “Delivers personalized and actionable Ways to Save Alerts™”. - Education programs. - No quality information noted.

- Personalized to what consumer pays. - Total cost. - “Fair Price” practice checkmark. - Provider quality rating.

- Personalized to what consumer pays. - “High” and “low” cost providers. - In-network allowed amount by location. - No quality information noted.

Price Information Sources

- Employer Claims. - “Explanation-ofbenefits forms patients receive after doctor’s visits”g. - “Fee schedules from providers”h.

- Employer/Health Plan Claims and accumulators. - Truven Health MarketScan databases with commercial, Medicare supplemental, and Medicaid population claims”

- Employer Claims (“Proprietary database of client claims data”)i.

- Employer Claimsj (history and ongoing monthly data feeds).

- Employer Claims k

Quality Information Sources

- “Leapfrog Group for Patient Safety, the U.S. DHHS…consumer rating resources”l and “facility scores based on outcomes data collected”m

- Health Plan Provider Directories - NCQA - CMS Core Measures - Consumer Checkbook

Not applicable

- Health Grades “Recognized Physician”n - LeapFrog Group Hospital Safety Score (eff. 10/1/13)

Not applicable

Exhibit 2 Footnotes: All information is from the company website or other readily available public sources unless otherwise noted. Information in quotes is directly from company websites. We invited companies to confirm the accuracy of their information; we made minor revisions based on input from the three companies that responded. Note that there are two companies with similar names ClearCostHealth and ClearHealthCosts, with the latter company focusing on consumers and thus not included Compass SmartShopper program is the exclusive brand name for the Compass program offered to employers through various Anthem Blue Cross and Blue Shield plans across the country. Source: Compass, https://www.compasssmartshopper.com/about.aspx, date accessed: 7/9/2013 c Truven Healthcare was a division of the Thomson Corporation until 2008. Following the merger of Thomson with Reuters (Thomson Reuters, 2008), it became the healthcare business unit. In 2012 Thomson Healthcare was sold to Veritas Capital and the new company was named Truven Health Analytics. Sources: Krauskopf L., Veritas completes purchase of Thomson health unit, http://www.reuters.com/article/2012/06/06/us-veritas-thomsonreuters-healthcare-idUSBRE8551H020120606, date accessed: 7/9/2013 d Veritas completes purchase of Thomson health unit, http://in.reuters.com/article/2012/06/06/veritas-thomsonreuters-healthcare-idINL1E8H62CN20120606, date accessed: 7/9/2013 e Duncan W., Change Healthcare closes $9M series C round Major insurer leads funding for cost transparency play, January 16, 2012, http://nashvillepost.com/news/2012/1/16/change_healthcare_closes_9_million_series_c_round, date accessed: 7/9/2013. Investors include Blue Cross Blue shield investment arm. Source:Pogorelc D, Report: B2B, B2B2C models win as healthcare moves toward a “fully retail experience”, February 21, 2013 , http://medcitynews.com/2013/02/report-b2b-b2b2c-models-win-as-healthcare-moves-toward-a-fully-retail-experience/, date accessed: 7/9/2013 f Note that there are two companies with similar names ClearCostHealth and ClearHealthCosts, with the latter company focusing on consumers and thus not included g Perlroth N., Forbes, Name You Need To Know in 2011: Castlight, November 19, 2010, http://www.forbes.com/sites/nicoleperlroth/2010/11/19/name-you-need-to-know-in-2011-castlight/, date accessed: 7/9/2013 h Meeting Videos, The Health Data Initiative Forum, http://www.iom.edu/Activities/PublicHealth/HealthData/2011-JUN-09/Apps%20Demonstrations/Balcony-A/Castlight.aspx, date accessed: 7/9/2013 i Change:Healthcare, Healthcare Transparency Index, http://www.changehealthcare.com/hcti/ date accessed: 7/9/2013 j ClearCostHealth, https://www.clearcosthealth.com/Expertise.aspx, date accessed: 7/9/2013 k Diamond F., Managed Care, Anthem Offers Money to Educated Consumers, January 2013 http://www.managedcaremag.com/archives/1301/1301.planwatch.html, date accessed: 7/9/2013 l Castlight Frequently Asked Questions, http://www.purdue.edu/hr/Benefits/castlightfaq.html, date accessed: 7/9/2013 m Wall J. K, Indianapolis Business Journal, New tool could drive down employers’ health care costs, January 21-27 2013, Vol. 33 No. 48, http://www.castlighthealth.com/wp-content/uploads/2013/02/ibj_castlight.pdf, date accessed: 7/9/2013 n Shop for medical services based on cost and quality ratings, https://www.clearcosthealth.com/Avaya/Landing.aspx, date accessed: 7/9/2013 a

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 77

Medicare legislation in 2003.9 States also started developing price transparency legislation around this time and insurers increasingly began to develop their own price disclosure websites.10 In 2007, a Congressional Research Service report concluded that it is “reasonable to believe that greater transparency would improve outcomes”,11 and additional reports by the General Accounting Office12 have followed along with federal legislation.10 Against this backdrop, price transparency companies began to be established in 2007, with several founded in rapid succession. The companies are similar in terms of their organizational characteristics, but there are significant differences in what price and quality information is provided, how it is presented, and where the information is obtained (Exhibit 2). The type of price information provided varies, with differences in whether total costs are included and how they are defined (e.g., one company uses a “Fair Price checkmark”), what is included as a “service” (e.g., whether an office visit is included), what terms are used (e.g., “price”, “cost”, “in-network allowed price”, “what doctors charge”), and what price measures are used (e.g., average, median, “high” and “low” cost providers). Although all companies use employer claims for price information, some companies augment claims data with proprietary claims databases. Two companies provide quality information on both providers and facilities, one provides quality information only on providers, and two do not provide quality information. Quality information comes from a variety of sources, with a range of quality metrics. For example, one company uses Healthgrades Recognized Doctor designations, which review state or federal sanctions, malpractice, and board certification but do not include quality metrics such as patient satisfaction or outcomes. Discussion

We found that price transparency companies fill a gap by increasing access to price information, but that the companies themselves could be more “transparent” in how they obtain and provide information, even taking into account that they are private companies and thus need to protect proprietary interests. Given that we could not gain access to actual pricing tools, it was challenging for us to even describe these companies and thus our study should be considered a first step toward greater understanding of the role of these companies. The Catalyst for Payment Reform group developed a comprehensive set of specifications for price transparency that could be used as a model.13 An important goal is to create a consistent typology of price terms that can be used

for both private and public initiatives so that pricing tools and health care prices can be compared. Price transparency companies face several challenges including difficulty in working with small employers because of a lack of sufficient amount of claims data, the need to aggregate claims across multiple sources, and less access to real-time data than insurers. The technical issues in parsing and aggregating claims data, especially for rare procedures and episodes of care vs. single procedures, and in creating pricing tools that are comprehensive yet user-friendly are major challenges for these companies and any price transparency initiative.4 An evolving challenge for these companies is their relationship with insurers, who often have their own pricing tools. Lastly, it is important from a policy perspective to recognize that these companies, which are for-profit and privately owned, may focus on marketing messages that are not critically evaluated, e.g., company’s claims to have significantly lowered the cost of health care for an employer need to be compared against the overall trend of a slowdown in health care price increases. One role for price transparency companies could be to facilitate building evidence on how to best define and present price information. Because these companies are independent from insurers and employers, their tools may generate fewer concerns about privacy and the use of enrollee claims information.6 Positive impacts of price information have not yet been demonstrated and price information can have unintended consequences, so such research is urgently needed.11,12,14,15 Conclusion

As noted by one industry observer, “the shift from the ‘do more, bill more’ reimbursement model to a value and outcome-based reimbursement model will turn health care on its head. Price transparency is just one of the first examples of many.” 7 Given that price transparency companies are likely to continue to fill gaps left by other efforts, it will be important for decision makers to better understand the role of these companies and how they fit into the broader policy context. Kathryn A. Phillips, PhD, Professor of Health Economics and Health Services Research, UCSF and Director, UCSF Center for Translational and Policy Research on Personalized Medicine (TRANSPERS). Dr. Phillips conducts cross-disciplinary, cross-sector research on adoption of new technologies. She has had continuous funding from NIH as Principal Investigator for 25 years and has published > 100 peer-reviewed articles in leading journals. Anna Labno, PhD, Health Care Consultant, Boston Consulting Group.

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

Dr. Labno holds degrees in Biophysics and Physics/Biology from UC-

chasing-Health-Care. Accessed June 27, 2013.

Berkeley and MIT and was at UCSF working on health care issues when

7. Empson R. Castlight Lands A Whopping $100M D Round To Bring Trans-

this work was conducted.

parency

Healthcare

Costs.

Techcrunch

2012;

http://techcrunch.

com/2012/05/01/castlight-100m/. Accessed June 20, 2013.

Acknowledgements

8. Moukheiber Z. What Does It Take To Build A Health IT Company Worth

Dr. Phillips and Dr. Labno have no financial disclosures to report. This

$1 billion? Forbes February 01, 2013.

study was funded by NIH grants to Dr. Phillips (R01HG007063 and P01

9. State Legislation and Actions on Health Savings Accounts (HSAs)and Con-

CA130818) and a UCSF-CTSI Grant Number UL1 RR024131 research

sumer-Directed Health Plans, 2004-2013. 2013; http://www.ncsl.org/issues-

award to Dr. Labno. We gratefully acknowledge comments from Ad-

research/health/hsas-health-savings-accounts.aspx. Accessed June 20, 2013.

ams Dudley UCSF, Clay Johnston UCSF, and Thomas Rice University of

10. State and Federal Actions Related to Transparency and Disclosure of Health

California, Los Angeles.

Charges and Provider Payments. Washington, D.C. : National Conference of

References

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U.S. Leads the World in Health Expenditures. The New York Times June 1, 2013.

Empirical Evidence in Other Markets for the Health Sector. Washington, D.C.

2. Brill S. Why Medical Bills Are Killing Us. Time March 04, 2013.

: Congressional Research Service;2007.

3. Hearing on “High Prices, Low Transparency: The Bitter Pill of Health Care

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lenges and potential effects. N. Engl. J. Med. . 2011;364(10):891-894.

14. Cutler D, Dafny L. Designing transparency systems for medical care prices.

6. Towers Watson/NBGH Employer Survey on Purchasing Value in Health

N. Engl. J. Med. 2011;364:894-895.

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t o w e r s w a t s o n . c o m /e n / I n s i g h t s / IC -Ty p e s / S u r v e y - R e s e a r c h - R e -

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Ac-

www.namcp.org | Vol. 17, No. 4 | Journal of Managed Care Medicine 79

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Eisai

Booth 403

As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we are a fully integrated pharmaceutical business with discovery, clinical, manufacturing and marketing capabilities. Our key areas of commercial focus include oncology and specialty care (Alzheimer’s disease, epilepsy and metabolic disorders). To learn more about Eisai Inc., please visit us at www.eisai/com/US.

Evolution Health Booth 511

Evolution Health provides an all-encompassing mobile integrated health care practice specializing in the care and management of complex patient populations in the home and non-traditional settings. At Evolution Health, our objective is to improve our patients’ experiences. Our mobile integrated health care practice specializes in the care and management of complex patient populations while they are in their homes, in non-traditional settings and as they transition between different levels of care. Our comprehensive team is available 24/7 to care for the patient when and where required. To learn more about Evolution Health, visit www.evhealth. net or call 855.476.4352.

Exact Sciences Corporation Booth 508

prehensive range of integrated pharmacy benefit management services to improve care for patients and reduce waste for plan sponsors. Visit our booth to learn how the application of behavioral sciences, a specialized clinical approach, and actionable data enable better decisions which yield healthier outcomes.

First Call Pharmacy Booth 323

First Call Pharmacy provides national home infusion services from our ACHC accredited, <797> compliant facility, staffed by professionals possessing combined home care experience rivalling anyone. Offering true national coverage and customer service second to none, we will service your patients anywhere in the country, at rates cheaper than most in-network pricing. We also offer the benefit of an extensive national network of over 3,000 full-service home health agencies. Call 800-877-5705 to start your next infusion case.

First Report Managed Care Sponsor

First Report®Managed Care (firstreportnow. com) is a managed markets print and online brand that circulates to more than 21,000 health plan CEOs, hospital formulary committee members, HMO pharmacists, health plan medical directors and pharmacy directors, large employer decision-makers, and state prison facility managers. The editorial mission is focused on delivering news that affects managed market providers. First Report Managed Care reports on dozens of scientific and managed care conferences throughout the world.

Exact Sciences Corp. is committed to playing a role in the eradication of colorectal cancer. As part of this mission we are proud to introduce Cologuard. Cologuard is the first noninvasive screening test for colorectal cancer that analyzes stool DNA and blood biomarkers. Cologuard, which is available through health care providers, offers people at average risk for colorectal cancer an easy-to-use screening test they can do in the privacy of their own home.

Genentech

Express Scripts

Genomic Health

Express Scripts offers the industry’s most com-

Genomic Health, Inc. is the world’s leading

Booth 518

Booth 302

Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California.

Booth 325

provider of genomic-based diagnostic tests that address both the overtreatment and optimal treatment of early stage cancer, one of the greatest issues in health care today. The company is applying its world-class scientific and commercial expertise and infrastructure to lead the translation of massive amounts of genomic data into clinically-actionable results for treatment planning throughout the cancer patient’s journey, from screening and surveillance, through diagnosis, treatment selection and monitoring.

Gilead Sciences Booth 502 and Sponsor

Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. With each new discovery and experimental drug candidate, we seek to improve the care of patients suffering from life-threatening diseases around the world. Gilead’s therapeutic areas of focus include HIV/AIDS, hepatitis, serious respiratory, cardiovascular, and metabolic conditions, cancer and inflammation.

Halt Medical Booth 528

Halt Medical Inc., is the manufacturer of the Acessa procedure – a minimally invasive, same-day (outpatient) therapy for symptomatic uterine fibroids. It uses a technology called radiofrequency ablation. Each fibroid is destroyed by applying energy through a small needle array. The surrounding normal uterine tissue is not affected. The destroyed tissue may then be completely resorbed.

Health Dialog Services Corporation Booth 608

Health Dialog, a subsidiary of Rite Aid Corporation, is a leading provider of health care analytics and decision support, helping to improve health care quality while reducing overall costs. Offerings include health coaching for medical decisions, chronic conditions, and behavior change; population analytic solutions; and consulting services. Health Dialog helps individuals live longer, healthier, and happier lives.

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FACT:

On Average, only 25% of cancer patients receive the right chemo the first time.

Treatment Shouldn’t Be About Averages. Treatment Should Be About Patients.

CorrectChemo is the test that determines the most effective chemo, the first time. And the good news—the report is delivered in just 3 days! CorrectChemo personalizes chemotherapy and reduces the cost of cancer for providers, payers and patients.

CorrectChemo: Significantly reduce treatment cost Dramatically improve the quality of chemo care delivery Enhance the satisfaction of patients and their families

CorrectChemo works and we’re willing to go at risk with IPAs and ACOs to prove it.

Come See Us in Vegas! NAMCP Fall Managed Care Forum 2014 November 13-14, 2014 Dr. Cary Presant, M.D., F.A.C.P. Chief Medical Officer, DiaTech Oncology

www.correctchemo.com or CALL 877.434.2832

LEARN MORE at

Fall Managed Care Forum: Guide to Conference Supporters HeartWare Booth 612

HeartWare is a global medical device company dedicated to delivering safe, highperforming and transformative therapies that enable patients with heart failure to get back to life. The company’s innovative technologies are creating advances in the miniaturization of Ventricular Assist Devices (VADs) leading to less invasive surgical procedures and increasing the patient population who may be suitable for VAD therapy.

Hill-Rom Booth 329

Hill-Rom is a leading global medical technology company. The Vest ® Airway Clearance System treats airway clearance dysfunction and retained secretions with high-frequency chest wall oscillation (HFCWO) in the acute care and homecare setting. The MetaNeb® System, a unique 3-in-1 therapy system, treats atelectasis by providing lung expansion, secretion mobilization and aerosol

delivery of medication. The VitalCough™ System provides a noninvasive therapy that simulates a cough to remove secretions in patients with compromised peak cough flow.

Home Instead Senior Care Booth 614

Home Instead Senior Care® is the world’s largest provider of home care services for seniors. Our services are designed for practically any living arrangement where older adults simply need help to “age in place” with independence, security, and dignity. From basic home care needs to Activities of Daily Living, Alzheimer’s and dementia care, respite, and transitional care services, the Home Instead Senior Care network of nearly 1,000 offices are ready to serve.

Humana Booth 423

Humana Inc., headquartered in Louisville, Kentucky, is one of the nation’s largest publicly traded health benefits companies. Hu-

A World of Opportunity at L.A. Care

mana offers a diversified portfolio of health insurance products and related services - through traditional and consumer-choice plans - to employer groups, governmentsponsored plans, and individuals.  Today, Humana is a leader in consumer engagement. Throughout its diversified customer portfolio, the company provides guidance that can both help lower costs and lead to a better health plan experience.

Impax Pharmaceuticals Booth 523

Impax Pharmaceuticals™ is a branded product division of Impax Laboratories™, Inc. Impax Pharmaceuticals is focused on targeting significant unmet needs, with a primary focus on developing treatments for neurological disorders.

InSightec Booth 512

InSightec, the pioneer and global leader in MRgFUS technology was founded in 1999.

L.A. Care is on a mission to help low-income and vulnerable individuals have access to health care. We seek high-achieving, like-minded professionals to join our team. As America’s largest publicly-operated health plan, we already serve 1.5 million members and will be adding more due to health care reforms. To accommodate this growth, we are expanding our workforce and offer many excellent and new opportunities in the following areas:

Appeals and Grievances Care Management Medical Management Utilization Management L.A. Care Health Plan (Local Initiative Health Authority of Los Angeles County) is a public entity and community-accountable health plan serving residents of Los Angeles County through a variety of health coverage programs including L.A. Care Covered™, Medi-Cal, L.A. Care Cal MediConnect Plan, L.A. Care’s Healthy Kids, L.A. Care Health Plan Medicare Advantage HMO and PASC-SEIU Homecare Workers Health Care Plan. L.A. Care is a leader in developing new programs through innovative partnerships designed to provide health coverage to vulnerable populations and to support the safety net. Located in downtown Los Angeles, L.A. Care offers a great working environment, competitive salaries and excellent benefits.

To apply, and for complete job descriptions, requirements/ qualifications, please visit our website:

http://lacare.force.com/openings

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Fall Managed Care Forum: Guide to Conference Supporters MR guided Focused Ultrasound combines two well-known technologies to create a breakthrough therapy. High intensity focused ultrasound waves precisely heat and destroy targeted tissue non-invasively combined with MRI provides precision anatomical visualization, and real time thermal feedback for treatment monitoring and guidance. ExAblate ® is FDA approved for the treatment of symptomatic uterine fibroids and pain palliation of bone metastases. Learn more at www.us.insightec.com.

Insulet Corporation Booth 604

Come learn how pump therapy can be easier with the OmniPod ® Insulin Management System, the world’s first tubing-free insulin pump. With just two parts, the small, wearable Pod, and the handheld wireless Personal Diabetes Manager, the OmniPod can make diabetes an even smaller part of patients’ everyday lives. (Call Insulet Corporation at 800.591.3455 or visit MyOmniPod.com.

IntelliRide Booth 210

IntelliRide can lead your managed care transportation program to new heights featuring: • Web-based scheduling for real-time communication with members • Stop arrival notifications for members • Web-based reporting and instant report creation for transparent operations • Mobile Data Terminals in vehicles for constant communication and accountability • Self-service web-requests for members to book their own trips (subject to your policies and procedures).

Iroko Pharmaceuticals Booth 321

Iroko Pharmaceuticals, LLC is a global specialty pharmaceutical company, based in Philadelphia, dedicated to advancing the science of analgesia. Iroko is at the forefront of the development of SoluMatrix ® NSAIDs – new low dose drug products based on existing NSAIDs – using iCeutica Inc.’s proprietary SoluMatrix Fine Particle Technology™ exclusively licensed to Iroko for NSAIDs. For more information, visit www.iroko.com.

Johnson & Johnson Health Care Systems Booth 307

Johnson & Johnson Health Care Systems Inc. (JJHCS) provides contracting, supply chain and business services to customers of the Janssen Pharmaceutical Companies of Johnson & Johnson including hospital systems and group purchasing organizations, health plans, physicians, specialty pharmacy providers, distributors and wholesalers, pharmacy benefits managers, long-term care providers, employers, government payer programs and government health care institutions.

KCI/Acelity Booth 310

Acelity is a global wound care and regenerative medicine company, created by uniting the strengths of KCI, LifeCell and Systagenix. We are committed to advancing the science of healing and restoring people’s lives. Headquartered in San Antonio, Texas, Acelity delivers value through our portfolio of innovative and complementary solutions that speed healing, reduce complications and lead the industry in quality, safety and customer experience. We believe in enabling better futures for everyone. Please visit Acelity.com

L.A. Care Health Plan Booth 208

L.A. Care Health Plan (Local Initiative Health Authority of Los Angeles County) is a public entity and community-accountable health plan serving residents of L.A. County through a variety of programs including L.A. Care Covered™, Medi-Cal, Healthy Families, L.A. Care’s Healthy Kids, and L.A. Care Health Plan Medicare Advantage HMO. L.A. Care is a leader in developing new programs through innovative partnerships designed to provide health coverage to vulnerable populations and to support the safety net.

LDR Spine Booth 421

LDR Holding Corporation is a global medical device company focused on designing and commercializing novel and proprietary surgical technologies for the treatment of patients suffering from spine disorders. LDR’s primary products are based on its exclusive VerteBRIDGE® fusion and Mobi® non-fusion

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technology platforms and are designed for applications in the cervical and lumbar spine. These technologies enable products that are less invasive, provide greater intra- operative flexibility, offer simplified surgical techniques and promote improved clinical outcomes for patients as compared to existing alternatives.

Medela Booth 522

Medela’s primary focus is breastfeeding -helping moms to successfully breastfeed their babies for as long as they choose. Meeting this goal responsibly is at the heart of everything we do. The number one choice of hospitals and mothers, Medela is the only researchbased breastfeeding company and manufacturer providing a comprehensive solution of products, services and education. Medela’s full range of breastpumps and breastfeeding products are consistently recommended by caregivers for quality and reliability.

Medical Review Institute of America Booth 315

Medical Review Institute of America (MRIoA) has been an innovative leader in physician peer review for over 30 years. MRIoA offers high quality reviews meeting rapid turn-around times through our national network of active practicing, board certified physicians and other allied specialist. URAC accredited and NCQA certified. Visit us at www.mrioa.com for more information.

Medtronic

Booth 525-527

Medtronic is the global leader in medical technology, offering an unprecedented breadth and depth of innovative products, therapies, and services to fulfill our mission of alleviating pain, restoring health, and extending life. In the past year, more than 9 million people worldwide relied on our therapies, which treat many conditions including cardiac and vascular diseases, diabetes, and neurological and spinal conditions. With a global reach that extends to more than 140 countries, we have a deep understanding of many universal health care challenges. We are using our experience, extensive partnerships, and the passion of more than 46,000 employees to help transform health care

Fall Managed Care Forum: Guide to Conference Supporters worldwide by improving outcomes, expanding access, and enhancing value.

MHC Medical Products Booth 214

EasyTouch is the first and only premium line of disposable diabetic products that offer both significant savings to diabetics and greater profits to retailers. For decades, diabetic patients and retailers were the victim of high priced brand diabetic products. Even today, mid-line or value brands struggle with quality issues that lead to poor consumer acceptance and non-compliance. EasyTouch Diabetic Products has solved the problem by raising the bar on quality while lowering the cost of managing diabetes.

Mission Pharmacal Booth 304

Mission Pharmacal Company is a privately held pharmaceutical company based in San Antonio, Texas. For sixty-five years, the company has been dedicated to identifying unmet health needs in the marketplace and developing innovative prescription and overthe-counter products to meet them.

Myriad Genetic Laboratories Booth 520

Myriad Genetics is a leading molecular and companion diagnostics company dedicated to making a difference in patients’ lives through the discovery and commercialization of transformative products that assess a person’s risk of developing disease, aid in a timely and accurate diagnosis, determine the risk of disease progression and recurrence and guide personalized treatment decisions.

Natera

Booth 309

From conception to delivery, Natera is pioneering next generation accuracy and reliability with tests ranging from preimplantation genetic diagnosis for IVF to breakthrough advances in the field of non-invasive prenatal testing (NIPT). Using advances from the human genome project and powered by sophisticated proprietary bioinformatic algorithms, Natera’s comprehensive portfolio of tests, proven science, and experienced genetic counseling services deliver the most accurate results in the industry.

NovaSom Booth 529

NovaSom, Inc. is a leader in sleep apnea diagnostic testing, with the AccuSom. The clinically validated AccuSom is the only home sleep test that provides 24/7 patient support with the wireless transmission of test results, reducing the time between diagnosis and therapy initiation. OSA diagnosis and treatment is key in addressing co-morbidities such as diabetes, hypertension, heart disease, obesity, stroke, and overall mortality risk.

Novartis Pharmaceuticals Booth 311-313

Novartis Pharmaceuticals Corporation is dedicated to discovering, developing, manufacturing and marketing prescription drugs that help meet our customers’ medical needs and improve their quality of life. For more information please visit our exhibit.

Novo Nordisk Booth 306

We are the world’s leading diabetes care company, built on a legacy of scientific innovation and patient-centered care. We also hold leading positions in hemophilia care, growth hormone therapy, and hormone replacement therapy.

Perkin Elmer

Prometheus Laboratories Booth 409

Prometheus is committed to improving lives through the development and commercialization of novel pharmaceutical and diagnostic products that enable physicians to provide greater individualized patient care. We are primarily focused on the detection, diagnosis and treatment of disorders within the fields of gastroenterology and oncology. We became a part of Nestlé Health Science in July 2011.

Purdue Pharma Booth 504

RCM Health Care Services Booth 531

Booth 319

PerkinElmer is a global company committed to healthier pregnancies, healthier babies and healthier families. PerkinElmer Labs/ NTD, along with our partner lab Good Start Genetics, offers a variety of prenatal and carrier screening test options to suit every patient case. We provide one source to support your genetic testing needs.

Pfizer

Booth 308

across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. To learn more, please visit us at www.pfizer.com.

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work

For more than 35 years, RCM Healthcare Services has provided search and recruitment solutions to the finest health care organizations nationwide. The team at RCM specializes in Executive Placement, as well as, long-term and short-term medical professional staffing in Medical Management, Case Management, Quality Assurance, Utilization Review, Clinical Education, and other Executive Leadership positions. RCM is dedicated to helping companies locate and retain top-tier talent through innovative custom solutions and advanced search techniques.

Rapid Pathogen Screening Booth 419

Rapid Pathogen Screening (RPS) is an emerging developer, manufacturer and marketer of rapid, easy to use, point-of-care diagnostic tests. AdenoPlus® is the first and only point-of-care, CLIA-waived, test for the detection of Adenoviral conjunctivitis with results in 10 minutes.

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Fall Managed Care Forum: Guide to Conference Supporters ResMed Booth 514

ResMed changes lives by developing, manufacturing and distributing medical equipment for treating, diagnosing, and managing sleep-disordered breathing, COPD, and other chronic diseases. We develop innovative products and solutions to improve the health and quality of life of those who suffer from these conditions, and we work to raise awareness of the potentially serious health consequences of untreated sleep-disordered breathing. For more information on ResMed, visit www.resmed.com.

SI-BONE Booth 322

SI-BONE, Inc. is the leading sacroiliac (SI) joint medical device company dedicated to the development of tools for diagnosing and treating patients with low back issues related to SI joint disorders. The company is manufacturing and marketing a minimally invasive surgical (MIS) technique for the treatment of SI joint pathology.

Salix Pharmaceuticals Booth 413-415

Salix Pharmaceuticals is a specialty pharmaceutical company dedicated to acquiring, developing and commercializing brand name, prescription pharmaceutical products used in the treatment of a variety of gastrointestinal diseases. Salix’s strategy is to identify and acquire late-stage proprietary pharmaceutical products having an existing base of safety and efficacy data in humans for the treatment of gastrointestinal disease, and to apply the Company’s regulatory, product development, and sales and marketing expertise to commercialize these products.

Sequenom Laboratories Booth 429

Teva Pharmaceuticals Booth 303

Teva Pharmaceuticals’ North America Brand Pharmaceuticals group is built on the expertise of multiple innovative business units, including respiratory, neurology, women’s health and biologics/specialty products. This brand division leverages the competencies of each therapeutic area, and coordinates and

aligns efforts for a more efficient and effective delivery of health care solutions.

Uroplasty Booth 526

Uroplasty provides transformative treatment options for voiding dysfunctions. Urgent® PC Neuromodulation System is an office-based, clinically proven and cost-effective treatment for overactive bladder and associated symptoms of urgency, frequency and urge incontinence. Urgent PC is not associated with the side-effects or compliance issues of drugs, nor the risks of more invasive treatments. Macroplastique® is a urethral bulking agent for the treatment of adult female Stress Urinary Incontinence.

VITAS Healthcare Corp. Booth 318

Vitas is the nation’s leading hospice provider, giving end of life care for more than 80,000 patients nationally. One of the founders of the hospice movement, Vitas offers palliative care, hospice and data sharing programs to health plans to assist them in to improve member satisfaction, achieve quality goals and manage resources.

VIVUS

Booth 510

VIVUS is a biopharmaceutical company developing innovative, next-generation therapies to address unmet needs in obesity, diabetes, sleep apnea and sexual health for US, European and other world markets.

Valeritas Booth 425

Valeritas develops and commercializes innovative treatment solutions with an initial focus on Type 2 diabetes. Headlining Valeritas’ portfolio is the V-Go®, a disposable insulin delivery device that is simple, convenient, easy to use and provides a continuous preset basal rate of insulin for 24 hours plus ondemand bolus dosing.

Viracor-IBT Laboratories Booth 212

With over 30 years of specialized expertise in infectious disease, immunology and allergy testing for immunocompromised and critical patients, Viracor-IBT is committed

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to helping medical professionals, transplant teams, reference labs and biopharmaceutical companies get results faster, when it matters most. Viracor-IBT is passionate about delivering value to its clients by providing timely, actionable information, never losing sight of the connection between the testing it performs and the patients it ultimately serves. For more information, please visit www.viacoribt.com.

Vistar Technologies Booth 602

Vistar Technologies offers powerful Provider Data Management solutions with comprehensive end-to-end functionality for all aspects of provider and network management. The eVIPs™ system offers robust workflow solutions that will streamline recruiting, enrollment, provider relations, contracting, contract fulfillment, credentialing, ongoing monitoring, quality management and communication management to provide a central provider data repository. Vistar’s solution will serve as a core source system for integration, quality analysis, data access and reporting.

WellDyneRx Booth 204

WellDyneRx maximizes the value of pharmacy benefits through custom solutions and personalized service. With innovative and integrated health strategies, clinical expertise and proactive consultation, WellDyneRx provides clients with the tools and resources they need to optimize their benefit plans, ensuring the highest levels of customer service and member satisfaction.

Wound Care Education Institute Booth 427

Wound Care Education Institute® provides comprehensive online and nationwide onsite courses in the fields of Skin, Wound, Diabetic and Ostomy Management. Health care professionals who meet the eligibility requirements may sit for the prestigious WCC®, DWC® and OMS™ national board certification examinations through the National Alliance of Wound Care and Ostomy ® (NAWCO®), the largest and fastest growing multidisciplinary group of wound care certified professionals in the United States.

BT.

Because their world

is bigger

than their asthma.

exhale ex-couch potato It’s not a medication. It’s clinically proven, long-lasting relief for severe asthma. If asthma is limiting your patients’ options, perhaps it’s time to look beyond medication alone. Bronchial Thermoplasty (BT) delivered by the Alair™ System, a safe and minimally invasive outpatient procedure for patients with severe asthma, now has 5 years of clinical trial follow-up data establishing long-term effectiveness and safety.1,2 Fewer exacerbations, with effectiveness maintained out to 5 years BT is clinically proven to provide a long-term reduction in asthma exacerbations. The decrease in severe exacerbations over 5 years included a substantial reduction in the use of systemic corticosteroids associated with those exacerbations. 2 Long-term reduction in respiratory-related emergency room visits Patients treated with BT showed an 84% reduction in emergency room visits for respiratory symptoms at 1 year compared with sham-controlled patients, with that reduction maintained out to 5 years.1,2 In addition, 79% of patients who were treated with BT reported significant improvements in their asthma-related quality of life within the first year of treatment.1 Discover how BT can benefit your patients and view NEW 5-year trial results at BT5years.com Brief Statement of Relevant Indications for Use, Contraindications, Warnings, and Adverse Events: The Alair Bronchial Thermoplasty System is indicated for the treatment of severe persistent asthma in patients 18 years and older whose asthma is not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Alair System is not for use in patients with an active implantable electronic device or known sensitivity to medications used in bronchoscopy. Previously treated airways of the lung should not be retreated with the Alair System. Patients should be stable and suitable to undergo bronchoscopy. The most common adverse event of BT is an expected transient increase in the frequency and worsening of respiratory-related symptoms. Rx only.

For the treatment of severe asthma in adults

CAUTION: Law restricts this device to sale by or on the order of a physician. Indications, contraindications, precautions, and warnings can be found with product labeling. References: 1. Castro M, et al, for the AIR2 Trial Study Group. Am J Respir Crit Care Med. 2010;181:116-124. 2. Wechsler M, et al; for the AIR2 Trial Study Group [published ahead of print September, 2013]. J Allergy Clin Immunol. doi: 10.1016 /j.jaci.2013.08.009.

Alair and