FEATURED ARTICLES INCLUDE: Advances in the Management of Multiple Sclerosis: A Closer Look at Novel Therapies

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1 Vol. 19, No. 3, 2016 Educating Medical Directors of Employers, Health Plans and Provider Systems FEATURED ARTICLES INCLUDE: Advances in the Management of Multiple Sclerosis: A Closer Look at Novel Therapies Emerging Pharmacologic Treatments and Strategies in the Management of Obesity Best Practices in the Treatment and Management of Relapsed/Refractory Multiple Myeloma

2 Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross Devena Alston-Johnson, MD Medical Director CIGNA E. Paul Amundson, MD Chief Medical Officer Dakotacare Linda Ash-Jackson, MD Medical Director Hometown Health Paul Bluestein, MD Chief Medical Officer Connecticare Richard Bock, MD, MBA Chief Medical Officer Molina Health Care of California Anthony Bonagura, MD Chief Medical Officer Aetna, Inc. Salil V. Deshpande, MD Market Medical Officer United Healthcare Michael Fine, MD Medical Director Health Net John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint Ronald Y. Fujimoto, DO, FAAFP Chief Medical Officer United Healthcare 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 Sarath Gunatilake, MD, DrPH Professor, Health Science Department California State University, Long Beach John W. Heryer, MD, FACS Medical Director Blue Cross Blue Shield of Kansas City Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University Larry L. Hsu, MD Medical Director Blue Cross Blue Shield of Hawaii (HMSA) Stephen Keir, DrPH Co-Director, Center for Quality of Life Support Care Research Robert Preston Tisch Brain Tumor Center John Knispel, MD, CPE, FACOG Regional Medical Officer Humana Karen Knowles, MD Internal Medicine Physician HCA/Emcare Catherine Marino, MD Chief Medical Officer MagnaCare Jeff Martin, PharmD Clinical Account Director Innoviant, Inc. Monte Masten, MD, MBA, MPH Senior Consultant Health & Group Benefits, Tower Watson Wesley Mizutani, MD Director Clinical Research & Chairman Department of Rheumatology Healthcare Partners Thomas Morrow, MD Chief Medical Officer Next IT Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare Tim Newman, MD Medical Director FirstEnergy Denis O Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans Gary Owens, MD Principal Gary Owens Associates Philip Painter, MD Chief Medical Officer Humana Mary H. Pak, MD Medical Director Unity Health Plans Insurance Corporation 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 President Medical Management Consulting, 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 Senior Corporate Medical Director, Medicare Humana 2 Journal of Managed Care Medicine Vol. 19, No. 3

3 JMCM JOURNAL OF MANAGED CARE MEDICINE 4435 Waterfront Drive, Suite 101 Glen Allen, VA (804) fax (804) EDITOR-IN-CHIEF J. Ronald Hunt, MD PUBLISHER Jeremy Williams ADVERTISING REPRESENTATIVE Grant Menard American Medical Communications JOURNAL MANAGEMENT Douglas Murphy Communications Inc. P.O. Box Richmond, VA (804) fax (703) MANAGING EDITOR Barry Barnum GRAPHIC DESIGN Douglas Murphy Communications, Inc. Custom Article Reprints High quality reprints of individual articles are available in print and electronic formats. Contact Jeremy Williams, for reprints. ISSN: The v is Journal published of Managed by Association Care Services Medicine Inc. is published Corporate by NAMCP and Circulation Medical Directors offices: 4435 Institute. Waterfront Corporate Drive, and Suite Circulation 101, Glen offices: Allen, 4435 VA 23060; Tel (804) ; Fax (804) Editorial and Production offices: 2613 N. Parham Rd., Waterfront Drive, Suite 101, Glen Allen, VA 23060; Suite Tel (804) B, Richmond, ; Fax VA (804) 23294; Tel (804) Editorial ; and Fax Production (804) offices: Advertising P.O. Box 71895, offices: Richmond, Jack Klose, VA ; Broadway, Tel W. (804) Long ; Branch, Fax NJ 07764; (703) Tel (732) ; Advertising Fax offices: (856) Sloane Reed, Subscription 4435 Waterfront Rates: one Drive year Ste $95 101, in Glen the United Allen, VA States; one Tel year (804) $ in Canada; one year $120 international. Back issues 1905, Fax (804) All rights reserved. Copy- are available for $15 each. All rights reserved. Copyright No part No of part this of publication this publication may be may repro- be reproduced or transmitted or transmitted in any in form any or form by any or means, by any means, electronic electronic or mechanical, or mechanical, including including photocopy, photocopycording, recording, any information any information storage or storage retrieval or sys- re- retrievatem, without system, written without consent written from consent the publisher. from the publisher. The publisher does not guarantee, either expressly or by implication, the factual accu- The publisher does not guarantee, either expressly racy or by of implication, the articles the and factual descriptions accuracy of herein, the articles nor does and descriptions the publisher herein, guarantee nor does the accuracy the publisher of any views guarantee or opinions the accuracy offered by any the views authors opinions of said offered or by descriptions. the authors of said articles or descriptions. articles POSTMASTER: Send address changes to The POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 Waterfront Journal Drive, of Managed Suite 101, Care Glen Medicine, Allen, VA Waterfront Drive, Suite 101, Glen Allen, VA Journal of Managed Care Medicine The Official Journal of the NAMCP MEDICAL DIRECTORS INSTITUTE A Peer-Reviewed Publication Vol. 19, No. 3, 2016 TABLE OF CONTENTS Treatment Strategies for the Management of Metastatic Melanoma Kim Margolin, MD... 8 Advances in the Management of Multiple Sclerosis: A Closer Look at Novel Therapies Lily Jung Henson, MD, MMM, FAAN Overcoming Challenges to Successful Asthma Adherence and Control Charles Vega, MD, FAAFP Emerging Pharmacologic Treatments and Strategies in the Management of Obesity W. Timothy Garvey, MD, FACE Best Practices in the Treatment and Management of Relapsed/Refractory Multiple Myeloma George Somlo, MD...26 Improving Outcomes with Individualized Treatment Strategies in Advanced Non-Small Cell Lung Cancer David R. Gandara, MD...31 Improving Outcomes with New Treatment Options in the Management of Cystic Fibrosis Gary Owens, MD...37 Individualizing Treatment Strategies for Effective A1C Reduction and Improved Outcomes in Type 2 Diabetes Daniel Einhorn, MD, FACP, FACE Novel Therapeutic Options in the Management of Epilepsy Joseph I. Sirven, MD Current and Emerging Treatment Paradigms in the Management of Hemophilia Barbara A. Konkle, MD Effective Strategies in Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation Noel G. Boyle, MD...59 Improving Patient Outcomes with Novel Treatments in the Management of Hypertriglyeridemia Harold Bays, MD, FTOS, FACC, FACE, FNLA Vol. 19, No. 3 Journal of Managed Care Medicine 3

4 Provide your members with the option that s FDA APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS Significantly more patients with intermediate-2 risk or high-risk myelofibrosis receiving Jakafi (ruxolitinib) achieved the primary end point compared with placebo (COMFORT-I *) or best available therapy (COMFORT-II ) 1-3 The primary end point was the proportion of patients achieving a 35% reduction in spleen volume from baseline at week 24 as measured by CT or MRI1,2 COMFORT-I Primary End Point: Spleen Volume Reduction at Week 241,2 Patients (%) 40 Jakafi (n = 155) Placebo (n = 154) 42% (P < ) 40 (n = 65) 20 0 Jakafi (n = 146) BAT (n = 73) 50 (P < ) COMFORT-II Primary End Point: Spleen Volume Reduction at Week 481,3 Patients (%) 50 The primary end point was the proportion of patients achieving a 35% reduction in spleen volume from baseline at week 48 as measured by CT or MRI1,3 0.7% (n = 1) 35% Spleen Volume Reduction From Baseline 29% 30 (n = 41) % 0 (n = 0) 35% Spleen Volume Reduction From Baseline BAT, best available therapy. COMFORT-I (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-I) was a randomized, double-blind, placebo-controlled phase 3 study with 309 patients with intermediate-2 risk and high-risk myelofibrosis.1,2 Best available therapy in COMFORT-II included hydroxyurea (46.6%) and glucocorticoids (16.4%), as well as no medication, anagrelide, epoetin alfa, thalidomide, lenalidomide, mercaptopurine, thioguanine, danazol, peginterferon alfa-2a, interferon-α, melphalan, acetylsalicylic acid, cytarabine, and colchicine.4 COMFORT-II (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-II) was a randomized, open-label phase 3 study with 219 patients with intermediate-2 risk and high-risk myelofibrosis.1,3 * Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Severe neutropenia (ANC < /L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Jakafi is a registered trademark of Incyte Corporation. 2016, Incyte Corporation. All rights reserved. RUX /16 Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines

5 Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. Overall survival was a prespecified secondary end point in COMFORT-I and COMFORT-II 1 COMFORT-I: At 3 years, survival probability was 70% for patients originally randomized to Jakafi and 61% for those originally randomized to placebo1 COMFORT II: At 3 years, survival probability was 79% for patients originally randomized to Jakafi and 59% for those originally randomized to best available therapy1 COMFORT-I Overall Survival: Kaplan-Meier Curves by Treatment Group1 COMFORT-II Overall Survival: Kaplan-Meier Curves by Treatment Group1 Jakafi Placebo Survival Probability Median crossover: 9 months 0.4 Jakafi (n = 155) Placebo (n = 154) 0.3 % 1-year survival 91% 84% 0.2 % 2-year survival 80% 69% 0.1 % 3-year survival 70% 61% Time (Months) Median crossover: 17 months Jakafi (n = 146) BAT (n = 73) 0.3 % 1-year survival 96% 94% 0.2 % 2-year survival 86% 81% 0.1 % 3-year survival 79% 0.0 Number of patients at risk Jakafi Placebo Jakafi BATBAT 1.0 Survival Probability Number of patients at risk Jakafi BAT % Time (Months) BAT, best available therapy. Because of progression-driven events or at the physician s discretion, patients randomized to placebo (COMFORT-I) or best available therapy (COMFORT-II) who crossed over to receive Jakafi continued to be grouped within their original randomized assignment for analysis purposes 4 When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following pages. To learn more about Jakafi, visit Jakafi.com/HCP. References: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9): Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9): Data on file. Incyte Corporation. Wilmington, DE.

6 BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 10 9 /L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1) in Full Prescribing Information]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1) in Full Prescribing Information]. Hepatitis B Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. Lipid Elevations Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1) in Full Prescribing Information] Risk of Infection [see Warnings and Precautions (5.2) in Full Prescribing Information] Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3) in Full Prescribing Information] Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4) in Full Prescribing Information]. 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. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 10 9 /L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 10 9 /L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebocontrolled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Adverse Reactions Bruising b 23 < Dizziness c 18 < Headache Urinary Tract Infections d <1 <1 Weight Gain e 7 <1 0 1 <1 0 Flatulence <1 0 0 Herpes Zoster f <1 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dl below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dl below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 10 9 /L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 10 9 /L to 200 X 10 9 /L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 10 9 /L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study a Laboratory Parameter All Grades a (%) All Grades b (%) Jakafi (N=155) Grade 3 (%) Jakafi (N=155) Grade 3 (%) Grade 4 (%) Grade 4 (%) All Grades (%) All Grades (%) Placebo (N=151) Grade 3 (%) Placebo (N=151) Grade 3 (%) Grade 4 (%) Grade 4 (%) Thrombocytopenia Anemia Neutropenia <1 1 a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

7 Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Adverse Events All Grades a (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Headache 16 <1 19 <1 Abdominal Pain b 15 <1 15 <1 Diarrhea <1 Dizziness c Fatigue Pruritus 14 < Dyspnea d Muscle Spasms 12 <1 5 0 Nasopharyngitis Constipation Cough Edema e Arthralgia <1 Asthenia Epistaxis Herpes Zoster f 6 <1 0 0 Nausea a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes abdominal pain, abdominal pain lower, and abdominal pain upper c includes dizziness and vertigo d includes dyspnea and dyspnea exertional e includes edema and peripheral edema f includes herpes zoster and post-herpetic neuralgia Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections. Clinically relevant laboratory abnormalities are shown in Table 4. Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment a Laboratory Parameter Hematology All Grades b (%) Jakafi (N=110) Jakafi (N=110) Grade 3 (%) Grade 4 (%) All Grades (%) Best Available Therapy (N=111) Grade 3 (%) Grade 4 (%) Anemia 72 <1 < Thrombocytopenia 27 5 < <1 Neutropenia 3 0 <1 10 <1 0 Chemistry Hypercholesterolemia Elevated ALT 25 < Elevated AST <1 0 Hypertriglyceridemia a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 Best Available Therapy (N=111) DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The C max and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The C max and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of patients with myelofibrosis in clinical studies with Jakafi, 52% were 65 years and older, while 15% were 75 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl ml/min (N=8)] and in subjects with mild [CrCl ml/min (N=8)], moderate [CrCl ml/min (N=8)], or severe renal impairment [CrCl ml/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pstat3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl ml/min) or severe renal impairment (CrCl ml/min) with a platelet count between 50 X 10 9 /L and 150 X 10 9 /L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl ml/min) or severe renal impairment (CrCl ml/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls ( hours versus 2.8 hours). The change in the pharmacodynamic marker, pstat3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 10 9 /L and 150 X 10 9 /L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos ; ; ; ; ; Incyte Corporation. All rights reserved. Revised: March 2016 RUX-1778

8 Treatment Strategies for the Management of Metastatic Melanoma Kim Margolin, MD For an accredited version of this article, please go to and then click the activity title. Summary One-year survival rates with metastatic melanoma have taken great leaps in recent years with introduction of effective immunotherapy and targeted therapy. Immunotherapy is now the recommended first-line treatment for metastatic disease, unless selected genetic mutations are present and a quick response is needed. Key Points The best first and subsequent therapy for melanoma is enrollment in a clinical trial. If the patient is not in a clinical trial, immunotherapy is the treatment of choice for metastatic melanoma. ALTHOUGH THERE IS NO CURE FOR MAlignant melanoma, the survival rates have increased significantly with the advent of targeted therapy aimed at specific genetic mutations and immunotherapy. Before 2010, the one-year survival rates for patients with Stage IV melanoma were around 30 percent. In 2011, the rate rose to 50 percent in the setting of treatment with ipilimumab, and 70 percent with dabrafenib monotherapy in Perhaps even more impressive are one-year survival rates in light of combination strategies with both targeted therapy and immunotherapy, now exceeding 80 percent. Most melanomas do not arise out of existing moles. They tend to arise out of non-mole skin that develops a mole over a short period of time. The mole takes on malignant appearing features; but it can be difficult for melanoma to be recognized visually. The Ugly Duckling moles are those which look different from the typical pattern of moles seen on a given individual. When seen by dermatologists, those with lots of moles will undergo mole mapping to identify the person s pattern to better identify problem areas. Once diagnosed, the staging system for melanoma is based on prognostic factors. Survival is directly related to the stage at diagnosis. Current prognostic factors include thickness, ulceration, mitotic rate, nodal involvement by number and size, and metastases by site. Nodal tumor location and volume are also prognostic in melanoma. The staging system is constantly undergoing revision as more prognostic factors are identified. It is moving to more molecular basis such as tumor microenvironment and genetic mutations rather than size and numbers. Immuno-oncology is becoming the treatment of choice for many cancers. Immuno-oncology involves giving therapies to activate the innate im- 8 Journal of Managed Care Medicine Vol. 19, No. 3

9 Exhibit 1: T-VEC- HSV-1-Derived Intratumoral Therapy for Local and Systemic Effects Local Effect: Tumor Cell Lysis Systemic Effect: Tumor-Specific Immune Response Healthy cells GM-CSF Dendritic cell activated by GM-CSF CD4+ T cell (helper T cell) CD-8+ T cell (cytotoxic T cell) talimogene laherparepvec Cancer cells Tumor-specific antigens Dying cancer cell Selective viral replication in tumor tissue Tumor cells rupture for an oncolytic effect Systemic tumor-specific immune response Death of distant cancer cells mune response. Therapy is moving away from chemotherapy and radiation as more and more immune and genetic mutation targeted therapies have been developed. Cytotoxics may reappear as immunogenic chemotherapy in strategies of immuno-oncology. Radiotherapy may assume importance as a locoregional immunomodulator of the tumor microenvironment. Immuno-oncology is complicated to discover but may be simple to apply. It is still limited to single agents for the most part, and toxicities are rarely life-threatening or irreversible. Additionally, if toxicity occurs, antidotes are easily available. Abnormal organ function such as kidney disease has less impact on the use and risks of most immune-oncology agents than with chemotherapy. Currently, there are approved or nearly approved immunotherapies for melanoma, lung, and renal cancer. Therapies in melanoma are approved for first-line, second-line, and as adjuvant treatment. Immunotherapy is now the recommended first-line treatment for metastatic disease, unless selected genetic mutations are present and a quick response is needed. 1 High-dose interleukin, the first approved immunotherapy for melanoma, is still used. This rather toxic therapy does produce a long-term response in a small number of patients. There is about a 12 percent response rate. Its ideal place in therapy is not known; at this time, it is unknown whether it should be used before or after other immunotherapies or in combination. Ipilimumab/nivolumab, nivolumab, and pembrolizumab are the preferred first-line immunotherapies. Ipilimumab (Yervoy ) is a monoclonal antibody that binds to cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) to keep T cells activated and is FDA approved for Stage IV melanoma. Although the overall response rate is not high when given as monotherapy, if the patient benefits and has no disease progression for three years, chances of remaining in remission are very high. Similar response can be seen with melanoma that has metastasized to the brain. Higher response rates are seen when ipilimumab is given in combination with nivolumab, so the combination is recommended by the National Comprehensive Cancer Network (NCCN) guidelines. 1 In one trial, the median progression-free survival for the combination was not reached with a minimum follow-up of 11 months versus 3.0 months for the ipilimumab alone arm. The reduction in the risk of progression or death was 61 percent for the combination group when compared with the ipilimumab control group. 2 Programmed death-1 (PD-1) is the other immune target which prevents tumor cells from downregulating T cells. PD-1 antibodies are now approved for melanoma and other cancers. Nivolumab (Opdivo ) and pembrolizumab (Keytruda ) are FDA approved for use in adults to treat metastatic melanoma, following treatment with ipilimumab, or after treatment with ipilimumab and a BRAF inhibitor in patients who carry a BRAF mutation. Giving immunotherapy essentially takes the brakes off the immune system so it can get out of control. The toxicities when combining CTLA-4 and PD-1 can be severe, but are manageable with standard medical principles for immunosuppression. The discontinuation rate for combined treatment is 30 to 40 percent. Eighty percent of the immune adverse effects can be resolved with corticosteroid or other immunosuppressant treatment. Immuno- Vol. 19, No. 3 Journal of Managed Care Medicine 9

10 Exhibit 2: Hypothetical Effects of Targeting Distinct and Potentially Complementary Evasion Pathways 7,8 Schematic of current data curves, advance melanoma The future? Survival Survival Time Time Control Targeted therapies Immune checkpoint blockade Combinations/sequencing Hypothetical slide illustrating a scientific concept, and is beyond data available to date. These charts are not intended to predict what may actually be observed in clinical studies suppression for toxicity does not prevent or curtail ongoing therapeutic benefit. There have been few treatment-related deaths in the trials of the immunotherapy agents for melanoma. Endocrinopathies, especially pituitary damage, tend to be permanent but are easily managed. Pituitary cells appear to have CTLA-4 receptors and treatment with one of the blockers causes cells to die. Pembrolizumab is the other PD-1 inhibitor which works better than ipilimumab. Almost everyone responds to pembrolizumab to a certain extent and over 50 percent of patients have more than 50 percent tumor regression. Additionally, many patients have over 80 percent regression. 3 A new immunotherapy for melanoma is talimogene laherparepvec (T-VEC, Imlygic ). Approved in October 2015, this is the first-in-class of oncolytic viral immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. The herpes simplex virus has been modified to be non-infectious and selective for cancer cells. The virus is also modified to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). When injected into a tumor, the virus replicates, leading to cell lysis and produces GM- CSF which is released and attracts other immune cells to the site of the tumor (Exhibit 1). The GM- CSF may migrate throughout the body to kill other tumor cells. A treatment course of T-VEC consists of a series of injections into the melanoma lesions at start, three weeks later, and then every two weeks for six months. Sixteen percent of study participants had a decrease in tumor and lymph node size compared with 2.1 percent in the control group (injected GM- CSF). 4 It has not been shown to alter overall survival but some data have been published showing effects on un-injected and distant sites. This agent is also being studied in combination with other immunotherapies. There are no strong predictive factors proven at this point to predict response to immunotherapy in the metastatic melanoma setting. There are some data on programmed death ligand (PD-L1) expression on tumor cells as a marker for PD-1 therapy. The data are not yet mature enough in melanoma. One immunotherapy for lung cancer is only indicated for patients with tumors that express PD-L1. For patients who have had surgical removal of their melanoma, adjuvant therapy may be considered. The vast majority of patients with melanoma are diagnosed with early disease, but some have high-risk factors for recurrence, which means they may benefit from adjuvant therapy. Pegylated interferon weekly has been evaluated as adjuvant therapy but it has not been shown to be effective in prolonging survival. 5 Subgroup analysis suggested that this therapy only benefits those with ulcerated tumors. A trial to evaluate that particular use is ongoing. Ipilimumab has been approved as adjuvant therapy 10 Journal of Managed Care Medicine Vol. 19, No. 3

11 at three times the usual dose and for longer duration. 6 At this point, it is difficult to select an adjuvant therapy because the approved agent, ipilimumab, has not been shown to make a difference in overall survival. Also, the treatment is expensive and difficult to endure. Patients just want to be told there is something they should do, but the clinician cannot say this drug is going to save the patient s life. Clinicians are trying to learn how to identify which patients would benefit from adjuvant therapy. At this time, the best treatment for a patient in the adjuvant setting is a clinical trial. A clinical trial is really the best cancer therapy no matter what the stage or disease. Trials are looking at all aspects of treatment agents, dosing schedules, setting (adjuvant, neoadjuvant, salvage), and mechanisms of resistance. There are also therapies targeting specific genetic mutations in melanoma. Single agent BRAF inhibitors (vemurafenib, dabrafenib) therapy improves overall survival compared to chemotherapy. BRAF inhibitor combined with a MEK inhibitor (trametinib, cobimetinib) gives an even higher response rate, duration, progression- free-survival and overall survival and is recommended by the NCCN guidelines. 1 Blocking two areas of cell growth pathways improves response. Unfortunately, resistance almost always develops with targeted therapy and the disease begins to regrow. Targeted therapy is considered backup therapy to immunotherapy, even when patients have proven mutations in BRAF. Many different agents and regimens are being investigated to reduce resistance to targeted therapy. One interesting method being investigated is cyclic therapy. The theory is that efficacy can be restored by taking someone off the medication for a period of time. How to best combine immunotherapy and targeted therapy is also under investigation. One trial is evaluating combination immunotherapy versus combination targeted therapy in patients with BRAF mutation with a crossover to the other therapy at the time of progression. Exhibit 2 illustrates the survival progress in metastatic melanoma that has been made with the advent of targeted therapy and immunotherapy. 7,8 Hopefully, the future will bring additional survival improvements with the use of combinations and sequencing of therapies. Conclusion Enormous progress has been made in improving survival in metastatic melanoma. Immunotherapy and targeted therapy are the main treatments, but their optimal sequence is not yet known. Because there are still many unanswered questions about how best to use the available treatments, clinical trials should carry much greater weight. Kim Margolin, MD, is an Adjunct Clinical Professor at the Stanford Division of Medical Oncology and an Affiliate Member at the Fred Hutchinson Cancer Research Center. References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Melanoma. Version Available at nccn.org. 2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1): Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26): Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25): Eggermont AM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012;30(31): Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5): Ribas A, Hersey P, Middleton MR, et al. New challenges in endpoints for drug development in advanced melanoma. Clin Cancer Res. 2012;18(2): Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23 Suppl 8:viii Vol. 19, No. 3 Journal of Managed Care Medicine 11

12 Advances in the Management of Multiple Sclerosis: A Closer Look at Novel Therapies Lily Jung Henson, MD, MMM, FAAN For an accredited version of this article, please go to and then click the activity title. Summary Therapy for multiple sclerosis (MS) continues to evolve as more is learned about the various disease- modifying therapies, both approved and investigational. The main goal of therapy now is for a patient to have no disease activity. This will require active monitoring and adjustment of therapy over time. Key Points Disease-modifying therapy should be selected and adjusted based on disease course, medication adverse effects, patient preference, and markers of disease activity. Symptomatic therapies should be available for management of patients. No evidence of disease activity (NEDA) is the new goal of MS therapy for relapsing-remitting disease. BECAUSE SO MANY DISEASE-MODIFYING therapies (DMTs) have been approved for MS since the early 1990s (Exhibit 1), it can be difficult for managed care to keep up with all of them and to know how to manage use with each one. The decision process for clinicians to choose an agent is also difficult. Additionally, there are more therapies on the horizon. The DMTs reduce the annualized relapse rate (ARR) and slow the development of disability in relapsing-remitting MS. Exhibit 2 provides a way to think about choosing and adjusting a DMT that considers the disease course, disease activity, and medication adverse effects. At this time, there are no comparative trials available which compare all the agents. The first step in choosing therapy is to determine if the patient has aggressive disease from the onset (Exhibit 2). Those with aggressive disease will have profound neurological symptoms and/or multiple nervous system lesions and enhancing lesions on MRI scans. These patients need more aggressive therapy. Natalizumab (Tysabri ) is the most effective agent in the setting of aggressive disease but carries a risk of progressive multifocal leukoencephalopathy (PML), related to John Cunningham virus (JCV) infection. JCV antibody titers need to be checked to determine if this agent can be used. Many neurologists will use it for at least two years if the antibody titer is low because after that the PML risk increases. If the titer is greater than 0.9 or the patient is frightened of PML, alemtuzumab (Lemtradra ) is the alternative. Alemtuzumab, a humanized monoclonal antibody directed against CD52 (cell surface antigen present on T and B cells) is newer and data are now being accumulated on its long-term efficacy. It is given by an unusual dosing schedule. The first treatment course is given as five consecutive daily infusions; then 12 months later three additional days of therapy 12 Journal of Managed Care Medicine Vol. 19, No. 3

13 Exhibit 1: MS Disease-Modifying Therapies Betaseron (interferon beta-1b sq qod) 1993 Avonex (interferon beta-1a IM qweek) 1996 Copaxone (20 mg/ml glatiramer sq qd) 1996 Novantrone (mitoxantrone IV q3 months) 2000 Rebif (interferon beta-1a sq tiw) 2002 Extavia (interferon beta-1b sq qod) 2009 Tysabri (natalizumab IV qmonth) 2004 Gilenya (fingolimod po daily) 2010 Aubagio (teriflunomide po daily) 2012 Tecfidera (dimethyl fumarate po bid) 2013 Copaxone (40 mg/ml sq tiw) 2014 Plegridy (pegylated interferon beta-1a sq q2 weeks) 2014 Lemtrada (alemtuzumab 5 days IV, then 3 days IV after 12 months) 2014 Glatopa (generic glatiramer 20 mg/ml sq qd) 2015 are given. A low ARR has been seen out to seven years after receiving the two treatment courses. 1,2 Over five years, alemtuzumab lowered the risk of sustained accumulation of disability by 72 percent and the rate of relapse by 69 percent compared with IFNβ-1a. 2 Most patients (52%) required just two cycles of alemtuzumab. 1 Over 67 percent of patients had an improved or unchanged disability compared with baseline. Secondary autoimmunity was the most frequent adverse event occurring in 47.7 percent of patients, most commonly involving the thyroid gland. The majority were also free of MRI scan disease activity and no evidence of disease activity over five years. There was also a significant slowing of brain volume loss over time. A patient with a standard disease course responds well to the treatment of their first attack of MS and has few lesions on scans. The next step for those with a standard course is to assess the patient for injectable agent use (Exhibit 2). The injectable agents, glatiramer and interferons, have been available longer, have more data on use, have known adverse effect profiles, and can be less costly than the oral agents, especially given the availability of the first generic for glatiramer. Unfortunately, about 50 percent of patients with MS are not willing to do injections. If interferon is chosen, there are several options in terms of dosing schedules. Because, in general, all the interferons can be considered equal, the choice would depend partially on which one is covered by the patient s insurance. The depression contraindication for interferon is somewhat relative; it is more of a consideration rather than contraindication. About 80 percent of patients with MS will have depression without exposure to interferon. Once therapy is started, disease activity should be assessed after about six months. The time frame is not fixed and depending on the patient s circumstances can be negotiated. Both silent disease and active symptoms should be assessed. If disease activity is not evident, the therapy is continued with an annual efficacy assessment. The first step in assessing the efficacy of therapy that does not appear to be working is to assess therapy compliance. Medication compliance, particularly with the injectable agents, can be a major issue. If side effects or true lack of efficacy occurs, therapy should be switched to alternative agents. No evidence of disease activity (NEDA) is the new goal of MS therapy for relapsing-remitting disease. This means no relapse, no worsening of disability scores (Expanded Disability Status Scale, EDSS), no new or enlarging T2 lesions on MRI, and no gadolinium-enhancing lesions on MRI. 3 Exhibit 3 illustrates the factors which show disease activity and should lead to therapy adjustment. There are two other two prongs of MS management - treatment of acute relapses and symptomatic treatment. Most neurologists will manage acute relapses with high-dose intravenous methylprednisolone. Repository corticotropin (Acthar ), an ACTH analogue, is an alternative to steroids and indicated for intolerance of high-dose steroids, steroid failure, poor IV access or preference for self-injection. Patients with MS have many symptoms related to their disease which greatly affect their quality of life. Vol. 19, No. 3 Journal of Managed Care Medicine 13

14 Exhibit 2: Choosing MS Therapies Severity of Disease Standard course Aggressive course Able to use injectibles JCV ab yes no + - Depression and/or liver disease yes no Orals Fingolimod (if no cardiovascular risk) Teriflunomide (if no liver disease) Dimethyl fumarate JCV ab index Natalizumab Glatiramer Interferons > 0.9 < 0.9 Reassess disease activity at 6 months Alemtuzumab Natalizumab for 2 years Natalizumab Quiet Active Continue DMT and reassess annually unless new symptoms Assess compliance and/or side effects no yes Aggressive course algorithm Switch to alternative therapy JCV ab = John Cunningham Virus Antibody Symptomatic treatment may be required for fatigue, bladder dysfunction, cognitive dysfunction, bowel dysfunction, pain, sexual dysfunction, dysesthesias, ambulatory dysfunction, and spasticity. The Consortium of Multiple Sclerosis Centers recently released a statement emphasizing that symptomatic management always has been and continues to be the bedrock of patient care in MS as symptoms impact quality of life for patients. 4 The statement advocates for prescribers retaining the right to decide on the best treatment for each individual patient and managed care providing full access to symptomatic management as well as disease- modifying therapies which, in the best judgment of the prescriber, offer optimal treatment outcomes. Further the statement notes that lack of understanding of the disease course and the challenges of MS treatment result in poor decision-making practices by the insurance plans and specialty pharmacies and subsequent denial of prescribed medications. This leads to an inability to adequately serve the people living with MS, negatively affecting the patient s quality of life. Providers have to spend more time arguing with the payers to get coverage for patients. Most of the symptomatic medications are not FDA approved or studied extensively, but on an individual 14 Journal of Managed Care Medicine Vol. 19, No. 3

15 Exhibit 3: Criteria for Considering Treatment Adjustment 3 MRI parameters Multiple new or enlarged T2 lesions (scars) or gad-enhancing lesions (active relapse) Relapse activity - > 1 relapse with incomplete remission - > 1 severe relapse with escalating acute therapy (2 gm. IV solumedrol x 5 days) - > 2 objective relapses without residual symptoms at 1 year Disability progression EDSS score > 3 Fatigue and cognitive parameters are not considered enough EDSS = Expanded Disability Status Scale basis they are effective. Honestly, if they don t work, the patient won t continue them. As more experience has been gained with the disease-modifying agents, more data have accumulated on the possible adverse effects. Natalizumab is a prime example. Five hundred eighty-eight cases of PML (585 MS, 3 Crohn s) in 142,000 patients who have received natalizumab post-marketing had been reported to the manufacturer as of June The global overall incidence is 4.03/1000 patients. Seventy-seven percent of those affected survived with varying levels of disability. The duration of therapy prior to diagnosis ranged from eight to 110 doses; 86 occurred after more than 24 doses. Factors that increase risk of PML include longer treatment duration (> 2 years), prior treatment with an immunosuppressant (e.g. mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate), and positive for the JCV antibody. Clinical vigilance is key to preventing PML. Patients need to understand the risk to themselves and how to monitor for symptoms. Clinicians will typically see patients receiving natalizumab every three months for monitoring. Anti-JCV antibody testing is required before starting and periodically in those receiving natalizumab. The rate of JCV antibody seroconversion is 3 to 8 percent annually. Improved survival is associated with early diagnosis, younger age at diagnosis, less functional disability prior to diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at time of diagnosis. A few cases of PML have also been reported in patients treated with dimethyl fumarate (Tecfidera ). Alteration of immune surveillance, possibly via lymphopenia, for a prolonged time appears critical for development of PML related to this agent. Because lymphopenia is common, those on dimethyl fumarate should have a complete blood count before initiating therapy and then every six months. The medication should be held for signs and symptoms suggestive of PML or lymphocyte counts less than 500. It may take six months or more for resolution of the lymphopenia. Worldwide, more than 18,000 patients have received fingolimod (Gilenya ) after natalizumab use. Twenty cases of PML have been reported with 17 occurring with prior history of natalizumab use and five with MRI evidence before the first dose of fingolimod. There were no immunosuppressive risk factors found in three cases. Adverse events that have emerged with alemtuzumab are infections and delayed autoimmunity. The incidence of infection is greatest after the first course (50% in first year, 40% in year 5). Autoimmune effects include hypothyroidism (10-20%), idiopathic thrombocytopenic purpura (1-2%), and glomerulonephritis and appear to occur fairly early on (i.e., within 3 years). The true incidence for these adverse effects will be known as these patients continue to be monitored over time. Daclizumab high-yield process (DAC HYP, Zinbryta ) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of interleukin-2 [IL- 2] receptor). It reversibly modulates IL-2 signaling, which reduces pro-inflammatory activated T cells, and expands immunoregulatory CD56bright NK cells. It has been submitted to the FDA for approval but had not been approved as of May A 45 percent reduction in ARR compared with interferon has been shown along with other positive benefits. 6 Ocrelizumab is the other promising agent in relapsing and progressive MS. Ocrelizumab is an in- Vol. 19, No. 3 Journal of Managed Care Medicine 15

16 vestigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells. CD20-positive B cells are a specific type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage, which can result in disability in people with MS. Based on preclinical studies, ocrelizumab binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, and therefore important functions of the immune system may be preserved. Trials published or presented so far have been promising. Ocrelizumab is also showing promising results in primary- progressive MS, for which the only approved agent is mitoxantrone, a cardiotoxic chemotherapy. It has been granted Breakthrough Therapy Designation by the FDA and has been submitted for approval for both relapsing-remitting and primary-progressive MS. 7 High-dose biotin is also under study for secondary and primary-progressive MS. A preliminary trial found significant benefit in improving disability and reducing progression. 8 Conclusion The management of MS continues to evolve with the addition of numerous DMTs. These agents are providing dramatic decreases in relapse rates and disability but do have some significant adverse effects. Managed care can help improve MS care by providing coverage for both DMT and symptomatic treatments. Lily Jung Henson, MD, MMM, FAAN, is Chief of Neurology at Piedmont Healthcare in Atlanta, GA. References 1. Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86(2): Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012;78(14): Gold R., Hartung H., Stangel M., et al. Therapeutic goals of baseline and escalation therapy for relapsing-remitting multiple sclerosis. Akt Neurol. 2012;39: CMSC Press Release. CMSC Issues Position Statement on Access to Medications to Treat Symptoms of MS. October 26, Available at mscare.org/news/257256/cmsc-press-release-cmsc-issues-position- Statement-on-Access-to-Medications-to-Treat-Symptoms-of-MS.htm. Accessed 5/16/ Natalizumab and Progressive Multifocal Leukoencephalopathy. Biogen communication. 9/ Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015;373(15): Sorensen PS, Blinkenberg M. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2016;9(1): Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4(2): Online Resources for Members Journal of Managed Care Nursing (JMCN) ArchiTools (case management toolkit) CNE webcasts Career Center Mentor program enewsleeers Join today! asnyder@aamcn.org (804) Journal of Managed Care Medicine Vol. 19, No. 3

17 Overcoming Challenges to Successful Asthma Adherence and Control Charles Vega, MD, FAAFP For an accredited version of this article, please go to and then click the activity title. Summary There are significant challenges in providing quality asthma care. Overcoming these challenges requires use of several strategies which have been studied and shown to improve care. Clinicians can follow best practices and implement these strategies to achieve optimal outcomes for their patients. Key Points Asthma prevalence continues to increase. Asthma exacerbations result in a significant number of hospitalizations and urgent care visits every year. Multimodal approaches utilizing education, best practices, written action plans, and health care teams have all been studied and found to provide asthma care outcome benefits including exacerbation reduction ASTHMA PREVALENCE HAS BEEN INCREASing over the last 36 years. It increased from 3.1 percent of the U.S. population in 1980 to 5.5 percent in 1996, 7.3 percent in 2001, and 8.4 percent in In 2014, 8.6 percent of children and 7.4 percent of adults had asthma. 1 There are many potential reasons for the prevalence increase including rising levels of obesity, pollution, and greater poverty. By age, gender, and race/ethnicity, children, females, and African Americans have higher rates of asthma. Another trend has been a decrease in asthma attacks per person, but there are still lots of attacks per year because of the increasing prevalence. From 2001 to 2010, both children and adults had fewer asthma attacks. 2 In 2001, 61.7 percent of children and 53.8 percent of adults with asthma had at least one asthma attack in the previous 12 months compared with 58.3 percent and 49.1 percent in 2010, respectively. Asthma attacks occurred more often in females (52.7%) than males (49.2%) and, among those with a family income less than 100 percent of the federal poverty threshold (55.1%) than persons with income between 250 percent and less than 450 percent of the poverty threshold (47.9%), and among those living in South and West, than those living in Northeast. This reflects a significant health disparity. Uncontrolled asthma results in approximately 1.8 million emergency room visits and 0.44 million hospitalizations annually. 2 The mortality associated with asthma is low; there are 1.1 deaths related to asthma per 100,000 people. Treatment goals in asthma are to reduce impairment and reduce exacerbations. Reducing exacerbations will reduce the number of ER visits and hospitalizations. To achieve these goals, clinicians should adopt best practices. The first best practice in asthma care is to classify the disease correctly (Exhibit 1). The correct classification leads to the ap- Vol. 19, No. 3 Journal of Managed Care Medicine 17

18 Exhibit 1: Asthma Classification Intermittent Symptoms less than 2 days/week Mild Persistent Symptoms not daily < 4 nighttime awakenings/month FEV 1 /FVC > 80% Moderate Persistent Daily symptoms Awakening at least weekly FEV 1 60% - 80% Severe Persistent Symptoms throughout day Extremely limited function FEV 1 < 60% FEV1 = forced expiratory volume in 1 second FVC = forced vital capacity Exhibit 2: Medication Recommendations by Classification Intermittent SABA only SABA 1 st line for exercise-induced asthma Mild Persistent Low-dose inhaled corticosteroid (ICS) Moderate Persistent Medium-dose ICS, possibly with long-acting beta agonist (LABA) or montelukast Severe Persistent High-dose ICS w LABA or montelukast. May need oral steroids (and referral) SABA = short-acting beta agonist LABA = long-acting beta agnoist propriate medication regimen being selected. Mild asthma accounts for 50 to 75 percent of cases but may constitute 40 percent of exacerbations in urgent care settings. Many times medication nonadherence is the cause of exacerbations at all levels of disease. The second best practice is to initiate hazard reduction. Many times clinicians focus on medications while ignoring the environmental factors that can lead to exacerbations. It is important to identify and avoid triggers and allergens. Patients with persistent asthma may need skin or in vitro testing to identify their issues. Multifaceted approaches for trigger avoidance are most effective and require reinforcement over time. Step 3 of the best asthma practices is to medicate at the level appropriate for the classification. Exhibit 2 outlines the appropriate regimens. Many times clinicians and patients are reluctant to step up therapy to the appropriate level of intensity. Metered-dose inhalers (MDIs) are by far the most popular medication choice, but a large number of all users (~45%) do not use them correctly. 3-4 Improper MDI use is associated with higher asthma symptom scores and frequent ED visits. Because of the difficulty with using MDIs, patients should receive one-on-one instruction when they are prescribed. A good educational resource is com. Spacers should be used for all children to administer their MDIs. Omalizumab (Xolair ), a humanized monoclonal anti-ige antibody, given via subcutaneous injection is an option for managing severe recalcitrant asthma. This agent, which should be prescribed by asthma specialists, can reduce exacerbations by 10 to 20 percent, reduce hospitalization, result in fewer day-today symptoms, lessen use of rescue medications, and help patients no longer need inhaled corticosteroids (ICS) in a very difficult to treat population. 5-6 High acquisition costs are a barrier to the use of this agent, but the overall costs of care need to be considered. In a British cost analysis, cost per quality-adjusted life year (QALY) for omalizumab was above other National Health Service interventions. It was more economical in cases of recent hospitalization, when factoring in ICS use. 7 Step 4 of best practices is active follow-up. Patients should be seen every two to six weeks until adequate control is achieved. Getting the patient rapidly under control is beneficial in preventing exacerbations. Triggers avoidance, MDI technique, and therapy adherence should be assessed at each visit. Education also needs to continue at each visit. Medication adjustments and modification to each individual s asthma action plan should occur over time. Beyond adopting best practices, a large variety of strategies to close the quality gap in asthma care have been studied. Numerous quality interventions have been found to improve the outcomes and processes of care for children and adults with asthma. 8 Young children with asthma benefit most from strategies that are targeted at their caregivers or parents. General populations with asthma can have clinically significant improvements in spirometric measures after participating in patient education interventions, self-monitoring, or self-management especially interventions that are based on theoretical frameworks, are of relatively long durations, and utilize combinations of educational modalities. Patient and caregiver education is an important aspect of asthma care. Education in the emergency 18 Journal of Managed Care Medicine Vol. 19, No. 3

19 Exhibit 3: Effects of a Community-Based Primary Care Asthma Care Program % 80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 77.80% 54.50% 9.90% 19.90% 10.20% 5.50% 62.40% 41.40% 46.40% 25.40% Pre- Post- Exacerbations ER visits School absent Day sx Night sx room can reduce hospital admissions. 9 Education in group visits appears to be modestly effective for reducing health care resource use, symptoms, and inhaler use. 10 Unfortunately, the study quality for group visits is poor overall. In a systematic review of 21 studies with 772 participants, exercise training for asthma was safe (i.e., did not worsen symptoms during training), improved maximum oxygen uptake, and improved health-related quality of life. 11 Improving exercise tolerance can really help improve patient function. Written action plans, for self-monitoring and selfmanagement, are another intervention to improve asthma outcomes. For adults, individualized written action plans based on peak expiratory flow are equivalent to action plans based on symptoms. For children, a symptom-based plan is better than a peak flow-based plan. For children, a written action plan can reduce acute care visits versus having no plan in place. Those with an action plan also have better school attendance, less nocturnal symptoms, and improved symptom scores. The plans need to be periodically reviewed and updated; reducing the intensity of self-management education or the level of clinical review may reduce their effectiveness. 12 Several systems-based interventions have also been studied. Training health care providers in asthma management can improve care. 13 Decision support at the point of prescribing, feedback and audit, and pharmacy support are all moderately effective for improving prescription of controller medications. Decision support and clinical pharmacy interventions are effective in improving patient education and self-management plans. Decision support is also effective for reducing ER visits. Decision support has to be taken in context of a work environment; warning burnout does occur. Organizational change is less effective in improving outcomes. Payfor-performance has not been shown to be effective for reducing exacerbations. Utilizing pharmacists for medication education and monitoring refills and home visits are additional systems-based interventions to improve care. One major area of care gap is outcomes for minority patients with asthma. A review of 24 studies of mostly nonwhite adults (14 in African American) found that the most common intervention to improve outcomes was patient education, but less than half of the education was culturally-focused. 14 Language-appropriate education is most successful. Other successes mirrored that of the general population, including team-based specialty clinics and long-term follow-up for asthma. Surprisingly, health disparities community collaboratives were less effective. 14 A multifactorial model is the most effective way to change outcomes, and this can be done in the primary care setting. As show in Exhibit 3, a community-based primary care asthma care program using a multifactorial approach leads to risk reductions in exacerbations, symptoms, urgent health service use and productivity loss related to asthma. 15 One other area to discuss is management of comorbid conditions. Many different comorbid conditions have been shown to impact asthma symptoms and need to be managed to optimally manage asthma. These include gastroesophageal reflux disease, obesity, obstructive sleep apnea, rhinitis, stress, and depression. Primary care providers, asthma specialists, and other specialists all have to work together to Vol. 19, No. 3 Journal of Managed Care Medicine 19

20 recognize and manage these conditions. Conclusion There are many ways to improve asthma care. Multimodal approaches utilizing education, best practices, written action plans, and health care teams have all been studied and found to provide outcome benefits. Charles Vega, MD, FAAFP, is a Clinical Professor of Family Medicine at the University of California in Irvine, CA. References 1. CDC National Center for Health Statistics. National Health Interview Survey, Available at Accessed May 20, Abinbami LJ, Moorman JE, Bailey C, et al. Trends in Asthma Prevalence, Health Care Use, and Mortality in the United States, NCHS Data Brief No. 94, May Scarfone RJ, Capraro GA, Zorc JJ, Zhao H. Demonstrated use of metereddose inhalers and peak flow meters by children and adolescents with acute asthma exacerbations. Arch Pediatr Adolesc Med Apr;156(4): Al-Jahdali H, Ahmed A, Al-Harbi A, et al. Improper inhaler technique is associated with poor asthma control and frequent emergency department visits. Allergy Asthma Clin Immunol. 2013;9(1):8. 5. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-ige) for asthma in inner-city children. N Engl J Med. 2011;364(11): Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:CD Norman G, Faria R, Paton F, et al. Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation. Health Technol Assess. 2013;17(52): Bravata DM, Sundaram V, Lewis R, et al. Closing the Quality Gap: A Critical Analysis of Quality Improvement Strategies (Vol. 5: Asthma Care). Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Jan. Report No.: 04(07) AHRQ Technical Reviews. 9. Tapp S, Lasserson TJ, Rowe Bh. Education interventions for adults who attend the emergency room for acute asthma. Cochrane Database Syst Rev. 2007;(3):CD Quiñones AR, Richardson J, Freeman M, et al. Educational group visits for the management of chronic health conditions: a systematic review. Patient Educ Couns. 2014;95(1): Carson KV, Chandratilleke MG, Picot J, et al. Physical training for asthma. Cochrane Database Syst Rev. 2013;9:CD Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev. 2003;(1):CD Okelo SO, Butz AM, Sharma R, et al. Interventions to modify health care provider adherence to asthma guidelines: a systematic review. Pediatrics. 2013;132(3): Press VG, Pappalardo AA, Conwell WD, et al. Interventions to improve outcomes for minority adults with asthma: a systematic review. J Gen Intern Med. 2012;27(8): To T, Cicutto L, Degani N, et al. Can a community evidence-based asthma care program improve clinical outcomes?: a longitudinal study. Med Care. 2008;46(12): American Association of Integrated Healthcare Delivery Systems Membership beneets: Receive free subscriptions to the Managed Care E-News, Prevention, Lifestyle and Wellness enews, Genomics Biotech and Emerging Medical Technologies enews, and the Journal of Managed Care Medicine (JMCM). Meet and network with key healthcare executives at AAIHDS educational programs and conferences, including our Spring and Fall Forums. Use our online Career Center and receive free career counseling and job placement services. Become a recognized leader in the industry by writing articles for AAIHDS publications or speaking at AAIHDS programs. wwilliams@aaihds.org (804) Journal of Managed Care Medicine Vol. 19, No. 3

21 Emerging Pharmacologic Treatments and Strategies in the Management of Obesity W. Timothy Garvey, MD, FACE For an accredited version of this article, please go to and then click the activity title. Summary Significant advances have been made in the understanding of obesity pathophysiology and in available treatments. Combating the obesity epidemic in the United States (U.S.) cost-effectively requires adopting a complications-centric approach for selecting therapy. Most patients with complications will be treated with a combination of lifestyle interventions and medication. Key Points Obesity is a life-long disease and requires long-term treatment and follow-up. Treatment involves lifestyle interventions, pharmacotherapy, and surgery. Both BMI and presence and severity of obesity complications need to be considered in selecting treatment. OBESITY IS A PRIMARY DISEASE, AND THE full force of our medical knowledge should be brought to bear on the prevention and treatment of obesity as a primary disease entity. 1 Like other chronic diseases, it is the result of the intersection of environment, behavior, biological factors, and susceptibility genes. To be considered a disease, a condition must have characteristic signs or symptoms, impairment in the normal functioning of some aspect of the body, and results in harm or morbidity. 2 Obesity fits all of these criteria. Excess weight is the primary sign of obesity, which is defined by body mass index (BMI), (Exhibit 1). 3 Dysregulated secretion of various factors from the fat tissue leads to the consequences of obesity. Some of these factors include free fatty acids, leptin, adiponectin, resistin, tumor necrosis factor, and various interleukins. Obesity ultimately leads to the development of metabolic syndrome with hypertension, dyslipidemia, atherosclerosis, and insulin resistance and glucose intolerance which progress to type 2 diabetes. Other consequences of excess weight are polycystic ovary syndrome, depression, cancer, gall bladder disease, sleep apnea, stress incontinence, osteoarthritis, gastroesophageal reflux disease, nonalcoholic fatty liver disease, and mobility issues. 4 In addition to morbidity harm, obese persons face discrimination in employment, college admission, romance, medical care, income, and airline seating. More than 90 percent of obese persons have attempted to lose weight. 5 Greater than 50 percent are currently trying to lose weight. Unfortunately, biology protects humans against weight loss. Signals from the GI tract affect the brain (hypothalamus), leading to increases or decreases in appetite. In obesity, the set point for the desire to eat is upregulated. Hormones that make us eat more (ghrelin) go up and those which make us eat less (leptin, protein YY, cholecystokinin, amylin) go down. Even our psychological food preferences get more oriented toward calorie dense foods. The treatment for obesity is three pronged lifestyle modifications, medications, and bariatric surgery. All patients need lifestyle interventions. Lifestyle interventions that have been proven effective in clinical trials include healthy meal plans, exercise, Vol. 19, No. 3 Journal of Managed Care Medicine 21

22 Exhibit 1: Defining Obesity 3 BMI = weight (kg)/height (m2)* Normal weight BMI Overweight BMI Obesity class 1 BMI Obesity class 2 BMI Obesity class 3 (severe) BMI > 40.0 *World Health Organization defines overweight as BMI 25 kg/m2 and obese as BMI 30 kg/m2. Exhibit 2: Actions of Recently Approved Weight-Loss Medications Decreased Appetite Arcuate Nucleus Paraventricular Nucleus GLP-1 R μ-or POMC/ CART Phentermine α-msh MC4R GABA? Higher Cortical Centers Dopamine NE reuptake 5-HT 2c Naltrexone Topiramate Lorcaserin Bupropion Serotonergic Neurons MC4R = melanocortin 4 receptor GABA = gamma-aminobutyric acid POMC/CART = pro-opiomelanocortin/cocaine-and-amphetamine-regulated transcript and behavior changes. Healthy meal plans, no matter the nutrient composition, should reduce energy intake by 500 to 1,000 kcal/day and reduce portion size. The meal plan should be consistent with the patient s cultural preferences. It does not matter what particular diet is used (low fat, low carbohydrate, etc.); the plan that a patient can be compliant with is the meal plan that will help them lose weight. 6 Meal replacements such as shakes and bars add structure to the diet and can help patients comply with a lowcalorie diet. Physical activity, ideally at 150 minutes per week or more, should be moderate aerobic plus resistance exercise. Behavioral interventions include education, addressing psychological factors, and motivational interviewing. The psychological issues related to eating such as binge eating or depression must be dealt with for weight loss to be successful. Recording food intake, physical activity, and weight can be very helpful to patients to make them aware of their behaviors. 22 Journal of Managed Care Medicine Vol. 19, No. 3

23 Exhibit 3: Contraindications/Warnings with Weight-Loss Medications Contraindications Orlistat Pregnancy, malabsorption syndrome, cholestasis Warnings Drug interactions: cyclosporine, levothyroxine, warfarin Rare severe liver injury, oxalate renal stones, risk of hypoglycemia with diabetes meds Need to restrict dietary fat (< 30% of calories) Need for daily vitamin (especially fat soluble) Lorcaserin Pregnancy Phentermine/Topiramate ER Pregnancy, glaucoma, hyperthyroidism, MAOIs Naltrexone ER/Bupropion ER Pregnancy, uncontrolled HTN, Seizure disorder, Chronic opioid use, MAOIs Liraglutide Pregnancy, personal or family history of MTC or MEN 2, risk of thyroid C-cell tumors Co-administration with other serotonergic or antidopaminergic agents, valvular heart disease, cognitive impairment, psychiatric disorders (euphoria, suicidal thoughts, depression), priapism, risk of hypoglycemia with diabetes meds Fetal toxicity, increased heart rate, suicide and mood and sleep disorders, acute myopia and glaucoma, cognitive impairment, metabolic acidosis, creatinine elevations, hypoglycemia with diabetes medications Angle closure glaucoma, suicidal behavior/ideation, Increased BP and HR, Seizures Risk of hypoglycemia with diabetes medications Acute pancreatitis, acute gallbladder disease, increased HR, renal impairment, hypersensitivity, suicidal behavior and ideation, hypoglycemia There are different ways to implement lifestyle interventions. A physician just telling a patient to lose weight is not effective. Commercial structured programs such as Weight Watchers and multidisciplinary structured programs have been shown to be effective. Physician-driven multidisciplinary structured programs are the most effective. These programs include bariatric surgeons, dieticians, exercise specialists, and psychologists/psychiatrists working together. Losing weight with lifestyle interventions has been shown to reduce the incidence of type 2 diabetes. In the Diabetes Prevention Program (DPP), losing a modest amount of weight reduced the risk of developing type 2 diabetes by 58 percent. 7 Because of the biology discussed earlier, patients will regain weight over time if they do not continue interventions or medications. In the DPP trial, even when weight was regained there were benefits for reduced disease over 10 years. 8,9 Weight-loss medications are an adjunct to lifestyle interventions for patients who are struggling to achieve health benefits through weight loss. Medications can help patients comply with the lifestyle interventions. Addition of a weight-loss medication consistently achieves greater weight loss than that achieved by the lifestyle intervention alone. Medications are indicated for obesity-related complications and need for more aggressive weight-loss therapy. If patients have not lost 5 percent of their body weight by 12 weeks on a medication, the treatment is defined as a primary failure; a different medication should be started at that point. The various obesity management guidelines all advise use of medications for patients who have sufficient health risk, not for cosmetic reasons. Medications may be required long term to prevent weight regain. Phentermine, a sympathomimetic, has been around since Because there are no long-term safety trials, its use as monotherapy is limited to short-term therapy (3 months). This is inconsistent with the fact that obesity is a chronic disease. Orlistat (Xenical, Alli ) is a fat blocker that was FDA approved in It blocks absorption of approximately 30 percent of dietary fat. Four new medications or combinations have been approved since 2012 for treating obesity. These include phentermine/topiramate (Qsymia ), lorcaserin (Belviq ), naltrexone/bupropion (Contrave ), and liraglutide (Saxenda ). Topiramate is an anticonvulsant, which is also used to prevent migraines. Lorcaserin is a serotonin (5-HT 2C ) receptor antagonist, naltrexone is an opioid receptor antagonist, and bupropion is a dopamine/noradrenaline reuptake inhibitor. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, was approved in December 2014 for treating obesity at a much higher dose than what is used to treat type 2 diabetes. Exhibit 2 illustrates where each of these new agents is thought to work in the brain. Vol. 19, No. 3 Journal of Managed Care Medicine 23

24 Exhibit 4: AACE Complication-Centric Model for Care of the Overweight/Obese Patient 18 STEP 1 EVALUATION FOR COMPLICATIONS AND STAGING CARDIOMETABOLIC DISEASE BIOMECHANICAL COMPLICATIONS NO COMPLICATIONS BMI , or BMI > 27 BMI > 27 WITH COMPLICATIONS Stage Severity of Complications LOW MEDIUM HIGH STEP 2 SELECT (i) Therapeutic targets for improvement in complications, (ii) Treatment modality and (iii) Treatment intensity for weight loss based on staging Lifestyle Modification: MD/RD counseling; web/remote program; structured multi-disciplinary program Medical Therapy: phentermine; orlistat; lorcaserin; phentermine/topiramate ER Surgical Therapy (BMI > 35): Lap band; gastric sleeve; gastric bypass STEP 3 If therapeutic targets for improvements in complications not met, intensify lifestyle and/or medical and/or surgical treatment modalities for greater weight loss There are no head-to-head comparison trials with the weight-loss medications. One way to compare the agents is to look at the average weight loss greater than the placebo group in the available clinical trials. In general at one year using the maximum dose, phentermine/topiramate will result in the most weight lost (9% of starting weight) followed by liraglutide, naltrexone/bupropion, orlistat, and lorcaserin Because they have not been directly compared, one cannot say one medication is better than any of the others. The level of weight loss with all these medications does result in significant metabolic benefits. Bariatric surgery is the option for losing the most body weight (~30%, depending on the procedure). Surgery can lead to improvement in cardiovascular risk and induce diabetes remission. 17 It is much easier to put patients into diabetes remission if it is early in the diabetes disease process. Choosing therapy should be done in an evidencebased manner. Clinicians have to balance efficacy, safety, and cost to optimize benefit to risk ratio to achieve best outcomes and cost-effectiveness of care. Patient factors also impact medication selection; the warnings and contraindications for weight-loss medications are shown in Exhibit 3. Numerous clinical guidelines for managing obesity are available; some are BMI centered. Those use BMI cutpoints to choose therapy so all patients who meet the particular cutpoint would be treated. The goal of therapy in BMI-centered guidelines is to lose a given amount of weight (e.g., 5-10%). This is not necessarily a cost-effective option because not every patient with excess weight has or will develop the complications of obesity. At the other end of the spectrum is a complications-centric model for care of the overweight/obese patient. Treatment indications are based on risk, presence, and severity of obesity-related complications with a goal of therapy to treat or prevent the complications. This model is likely to be more cost effective because more aggressive treatments are used in those patients who will derive the highest benefit. The American Association of Clinical Endocrinologists (AACE) has developed such a guideline (Exhibit 4). 18 This guideline does not include the naltrexone/bupropion combi- 24 Journal of Managed Care Medicine Vol. 19, No. 3

25 nation because it has not yet been FDA approved at the time of development. The rationale for a complications-centric model, as opposed to decisions based primarily on the BMI level, includes the fact that nearly 70 percent of American adults are overweight or obese and it is not safe or fiscally feasible to treat everyone with medications or surgery. Risk staging and assessment of obesity-related complications can identify those patients who will most benefit from weight-loss therapy Clinicians should emphasize medical rather than cosmetic outcomes because medications combined with lifestyle interventions often achieve at least a 10 percent weight loss but not necessarily a return to ideal body weight. Ten percent weight loss is sufficient to improve insulin sensitivity, glucose homeostasis, lipid levels, blood pressure, and prevent diabetes development. Overall, benefit to risk and cost-effectiveness are increased when medical and surgical interventions are targeted to obese patients with complications. Patients can be staged to identify those with most risk of developing complications. One staging system is the Cardiometabolic Disease Staging (CMDS) system. 19 In this system, Stage 0 is someone who has no risk factors (i.e., complications from their weight) and Stage 4 is end- stage cardiometabolic disease where the patient already has all the components of metabolic syndrome. The stage indicates both probability of developing type 2 diabetes and survival; those at a higher stage should be treated more aggressively. Primary prevention would be indicated if the patient is at a normal weight; the goal is to prevent development of overweight and obesity. 20 Secondary prevention is when the patient is overweight but has not yet developed a complication. Tertiary prevention is when the patient has a BMI over 25 and already has one or more complication. Conclusion Obesity is a life-long disease and requires long-term treatment and follow-up. Using a complicationscentric model is the most cost-effective way to manage the obesity epidemic in the U.S. W. Timothy Garvey, MD, FACE, is Professor and Chair in the Department of Nutrition Sciences at the University of Alabama at Birmingham and is Director of the UAB Diabetes Research Center. References 1. Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. American Association of Clinical Endocrinologists position statement on obesity and obesity medicine. Endocr Pract. 2012t;18(5): American Medical Association (AMA), Report 4 of the Council on Scientific Affairs (A-05). Recommendations for Physician and Community Collaboration on the Management of Obesity (Resolution 421, A-04), National Heart, Lung and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121(6): Harris Interactive/HealthDay. Many Obese Americans Struggle With Stigma, Discrimination: Poll. August Dansinger ML, Gleason JA, Griffith JL, et al. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005;293(1): Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6): Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702): Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009;360(9): Garvey WT. New tools for weight-loss therapy enable a more robust medical model for obesity treatment: rationale for a complications-centric approach. Endocr Pract. 2013;19(5): Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11): Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1): Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3): Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2): Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741): Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37(11): Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351(26): Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm Endocr Pract. 2013;19(2): Guo F, Moellering DR, Garvey WT. The progression of cardiometabolic disease: validation of a new cardiometabolic disease staging system applicable to obesity. Obesity (Silver Spring). 2014;22(1): Garvey WT, Garber AJ, Mechanick JI, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract. 2014;20(9): Vol. 19, No. 3 Journal of Managed Care Medicine 25

26 Best Practices in the Treatment and Management of Relapsed/Refractory Multiple Myeloma George Somlo, MD For an accredited version of this article, please go to and then click the activity title. Summary Multiple new agents including those with new mechanisms have been approved in the past year for multiple myeloma. Treatment includes immunomodulators, proteasome inhibitors, stem cell transplants, chemotherapy, and clinical trials. Although considered incurable, there are many different lines of treatment which can be used to target relapsed/refractory multiple myeloma. Myeloma is becoming a chronically managed disease, rather than a cured disease. Key Points Relapse is common in multiple myeloma. There are five newer agents that have been FDA approved for the relapsed/ refractory setting. Numerous supportive therapies are also required to manage MM and the adverse effects of treatment. MULTIPLE MYELOMA (MM) IS A CANCER of the plasma cell characterized by excessive numbers of abnormal plasma cells in the bone marrow. The clinical features of MM include bone pain, often with loss of height; constitutional weakness, fatigue, and weight loss; anemia; renal disease; infections secondary to neutropenia and hypogammaglobulinemia; hypercalcemia; hyperviscosity; and neurologic dysfunction secondary to spinal cord or nerve root compression. Most patients present with some type of axial bone pain and fatigue. There are approximately 25, 000 new cases of MM every year in the United States (U.S.), accounting for 10 to 15 percent of hematologic cancers. MM is the second most frequent hematologic malignancy after non-hodgkin s lymphoma. It is considered incurable with a current average survival of four to six years after diagnosis. With better treatment, survival has increased significantly in recent years. The incidence in African Americans is about twice as high as the incidence in Caucasians. It is more common in men than women with a median age at diagnosis of 70 years. Over 70 percent of patients diagnosed with MM had a detectable M protein (monoclonal gammopathy of unknown significance MGUS) previously. Approximately 3 percent of the population over 50 has MGUS. Various genetic features of the disease are prognostic for survival. Depending on genetic markers, patients can be divided into either high or low risk (Exhibit 1). Those with low-risk features have an expected survival greater than six to seven years 26 Journal of Managed Care Medicine Vol. 19, No. 3

27 Exhibit 1: Risk Factors for MM Expected OS > 6-7 years t(11;14); t(6;14) Hyperdiploidy Normal cytogenetics/fish Expected OS 2-3 years t(4;14); t(14;16); t(14;20) Del(17p) Del(1p-) and or amp 1p by FISH Del(13) by cytogenetics Hypodiploidy GEP-high-risk signature Elevated LDH B2 microglobulin > 5.5 OS = overall survival t = translocation FISH = Fluorescence in-situ Hybridization del = deletion GEP = gene expression profile LDH = lactate dehydrogenase B2 = beta-2 compared with two to three year survival for those with high-risk features. It is essential to have the genetic and FISH testing before treatment for prognostic purposes because they may disappear with treatment. The choice of treatment may vary based on whether the patient has high- or low-risk disease. Patients are staged (I to III) based on various measures, including hemoglobin, serum calcium, bone x-ray findings, M protein levels, serum beta-2 microglobulin, serum albumin, and kidney function. 1,2 Exhibit 2 illustrates a patient case. This patient would be Stage III by the International Staging System criteria and is in the high-risk category based on genetic markers. Only patients with active, symptomatic myeloma are treated. 3 Most with smoldering or asymptomatic MM are monitored over time for progression. The first-line treatment plan for the patient in Exhibit 2 includes novel agents for induction, followed by autologous stem cell transplantation (SCT), consolidation, and maintenance. The aim of treatment is complete response (<5% myeloma cells on bone marrow biopsy, normalized free light chain ratio) but at least a very good partial response. 4 Novel agents for MM include immunomodulators [lenalidomide (Revlimid ), and pomalidomide (Pomalyst ), daratumumab (Darzalex ), elotuzumab (Empliciti )] and proteasome inhibitors [bortezomib (Velcade ), carfilzomib (Kyprolis ), ixazomib (Ninlaro )]. Other treatment options include chemotherapy, novel agents in combination with chemotherapy combinations, allogeneic stem cell transplant (SCT), salvage autologous stem cell transplant, and clinical trials. Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem cell reserve prior to stem cell harvesting in patients who may be candidates for transplants. 5 The recommended treatment regimens vary depending on whether the patient is receiving first-line treatment or has relapsed/refractory disease. Exhibit 3 lists the National Comprehensive Cancer Network (NCNN) guideline recommended regimens for relapsed/refractory MM. 5 In patients who are eligible for SCT, initial treatment is induction with combinations of proteasome inhibiting (PI) agents and/or immunomodulators (ImID). Bortezomib, a proteasome inhibitor, and dexamethasone results in greater progression-free survival (PFS) compared with chemotherapy and thus has become the standard regimen. Lenalidomide, an immune modulating agent, combined with dexamethasone also provides benefit over chemotherapy. After the SCT, patients are given maintenance therapy. Those who are not eligible for SCT undergo induction chemotherapy with various agents. Relapse or progression after treatment is common in MM. Primary therapy can be repeated if the relapse occurred longer than six months since completion and there are no other contraindications. There are now numerous agents indicated for relapsed or refractory disease, so a patient can be treated with multiple lines of therapy. In addition to lenalidomide and bortezomib, several newer agents are FDA approved for the relapsed/refractory setting. Carfilzomib, a selective Vol. 19, No. 3 Journal of Managed Care Medicine 27

28 Exhibit 2: Case Study 59-year-old patient presents with back pain and fatigue Hemoglobin 8 g/dl, calcium 11.5 mg/dl, creatinine 1.4 mg/dl, albumin 3.2 g/dl, total protein 10 g/dl β- 2 microglobulin 5.8 mg/l, SPEP shows M spike of 7.2 g/dl, IFE IgGk Bone marrow with 70% monoclonal plasma cells Cytogenetics: Del(13), FISH t(4:14) Skeletal survey: multiple lytic lesions Exhibit 3: MYELOMA THERAPY for Relapsed/Refractory 5 Preferred Regimens for Previously Treated Multiple Myeloma Repeat primary induction therapy (if >6 mo) Dex/cyclophosphamide/etoposide/cisplatin Bortezomib (category 1) Dex/thalidomide/cisplatin/doxorubicin/ Bortezomib/dexamethasone cyclophosphamide/etoposide ± bortezomib Bortezomib/cyclophosphamide/dex Elotuzumab/lenalidomide/dex (category 1) Bortezomib/lenalidomide/dexamethasone Ixazomib Bortezomib/liposomal doxorubicin (category 1) Ixazomib/dex Bortezomib/thalidomide/dexamethasone Ixazomib/lenalidomide/dex (category 1) Carfilzomib High-dose cyclophosphamide Carfilzomib/dex Lenalidomide/dexamethasone (category 1) Carfilzomib/lenalidomide/dex (category 1) Panobinostat/bortezomi b/dex (category 1) Cyclophosphamide/lenalidomide/dex Pomalidomide/dexamethasone (category 1) Daratumumab Thalidomide/dexamethason e irreversible proteasome inhibitor, has been studied in relapsed/refractory MM. Given intravenously, it resulted in a 23.7 percent overall response rate in a heavily pretreated population. 6 The response lasts a median of 3.7 months with overall survival (OS) of 15.6 months. The most commonly reported adverse effects with carfilzomib are thrombocytopenia and anemia. The major distinction from bortezomib, a reversible proteasome inhibitor, is a lower rate of peripheral neuropathy. Pomalidomide, an immunomodulatory lenalidomide analogue, was FDA approved for relapsed/ refractory MM in early When studied in a heavily pretreated population, 31 percent of patients achieved an overall response rate with pomalidomide in combination with dexamethasone. 7 Progressionfree survival was four months compared with 1.9 months for dexamethasone alone. Overall survival was also longer with the combination (12.7 vs 8.1 months). 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 therapy or within 60 days of completion of the last therapy. Three agents (daratumumab, elotuzumab, ixazomib) were approved by the FDA in November 2015 for relapsed/refractory MM under priority review status. Daratumumab is FDA approved to treat patients with MM who have received at least three prior treatments. Daratumumab is the first monoclonal antibody approved for treating multiple myeloma and is an antibody against CD38 protein expressed on MM cells. The safety and efficacy of this agent were demonstrated in two open-label studies. In 28 Journal of Managed Care Medicine Vol. 19, No. 3

29 Exhibit 4: Neuropathic Pain Management in Multiple Myeloma Drug Group Gabapentin, pregabalin Opioids (only by pain specialists) Antidepressants Precautions Interaction with other meds, depression Concomitant use with antidepressants, constipation, substance abuse, driving impairment during treatment Cardiac disease, glaucoma, depression, hepatic disease, renal insufficiency, concomitant use with other antidepressants, withdrawal symptoms those studies, 31 percent of patients experienced a complete or partial reduction in their tumor burden and median PFS and OS was 4.0 months and 20.1 months, respectively. 8 The most common side effects are infusion-related reactions, fatigue, nausea, back pain, fever and cough. Daratumumab may also result in lymphopenia, neutropenia, leukopenia, anemia, and thrombocytopenia. Elotuzumab (Empliciti ) in combination with lenalidomide and dexamethasone is approved for the treatment of patients with MM who have received one to three prior therapies. Elotuzumab is a monoclonal antibody directed against signaling lymphocyte activation molecule family 7 (SLAMF7). SLAMF7 is present on MM cells and is also present on natural killer cells. The median PFS in the elotuzumab-containing arm was 19.4 months and 14.9 months in the lenalidomide plus dexamethasone alone arm. 9 The most common adverse reactions with this agent are fatigue, diarrhea, constipation, peripheral neuropathy, infections, and decreased appetite. Ixazomib (Ninlaro ), the first oral proteasome inhibitor, is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. This agent is a once-weekly pill. It was approved based on data showing PFS benefits (4.5 months). At a median follow-up of approximately 23 months, the median overall survival had not been reached in either study group (ixazomib or placebo), and follow-up is ongoing. 9 Salvage therapy is indicated when there is disease progression following allogeneic or autologous stem cell transplantation, primary progressive disease following initial autologous or allogeneic stem cell transplantation, progressive or relapsing disease after initial induction in patients not eligible for stem cell transplantation, or progressive disease following second- or third-line therapy. Salvage therapy is decided on based on prior responses and the duration of response, completion of prior regimen, organ dysfunction which might rule out particular medications, age, and prior transplants. Numerous adjunctive therapies are also required to keep MM patients relatively healthy. Bone disease may require analgesics for bone pain and/or radiotherapy for palliation. Low-dose localized radiation can be used for bone lesions. Nonsteroidal antiinflammatory agents should be avoided because of renal effects. Bisphosphonates are widely used in the management of lytic bone lesions in MM because they inhibit bone resorption by suppressing osteoclast activity. Pamidronate and zoledronic acid are both primary agents. Anemia is common with MM and is typically treated with transfusions and/or erythropoietin. Hypercalcemia is treated with rehydration and bisphosphonates. Rehydration and plasmapheresis can be used to manage renal dysfunction and hyperviscosity. Medications or procedures such as intravenous contrast dyes, which can worsen renal function, need to be avoided. Because of their risk of infection, MM patients should be up to date on vaccinations. Patients who receive certain medications require infection prophylaxis. Pneumocystis, herpes, and antifungal prophylaxis is recommended for those receiving a high-dose dexamethasone regimen and herpes zoster prophylaxis for patients treated with proteasome inhibitors. Adverse effects of treatment also have to be managed. Peripheral neuropathy, which can be disabling, is a relatively common adverse effect of bortezomib. The subcutaneous injection route leads to lower rates of neuropathy and is the recommended route. 10,11 The pain from neuropathy can be managed with various agents (Exhibit 4). Cytopenias including neutropenia, thrombocytopenia, and anemia are common with lenalidomide and thalidomide. Thrombosis is common with MM and the risk is increased by high-dose dexamethasone and immu- Vol. 19, No. 3 Journal of Managed Care Medicine 29

30 nomodulator therapy. All patients with MM should be on at least aspirin. Prophylactic anticoagulation is recommended for those on immunomodulator therapy. Conclusion The primary treatment for MM is induction to accomplish remission, consolidation-including SCT, and maintenance; a cure may be within reach. Regimens containing lenalidomide or bortezomib have shown efficacy in relapsed/refractory myeloma. Selection of regimens should be a rational process, based upon patient characteristics. Novel agents are useful additions in salvage therapy and are being studied for use earlier in the therapeutic process. Supportive care (bone health, renal, neuroproblems, DVT prophylaxis, infection prophylaxis) are important aspects of the care of these patients. George Somlo, MD, is a Professor in the Department of Medical Oncology and Therapeutics Research with the City of Hope Comprehensive Cancer Center in Duarte, CA. References 1. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer. 1975;36(3): Greipp P, San Miquel J, Durie B, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23: Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e48. 4.Palumbo A, Rajkumar SV, San Miguel JF,et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32: National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Multiple Myeloma Available at Accessed May 27, Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14): San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11): Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016; pii: blood (epub ahead of print). 9. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373(7): Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17): 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: 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): Become an NAMCP Corporate Partner Your company will have unique opportunities to connect with Medical Directors from purchasers, health plans and providers. Benefits ~ Face to face meetings with Medical Directors. ~ Attend meet and greet receptions at the forums. ~ Discounts on Exhibiting fees and JMCM advertising. ~ Complimentary associate memberships. ~ Recognition at the Spring and Fall Forums. ~ Advanced notice on additional sponsorship opportunities and more! For a full list, ask for an application. sreed@namcp.org keads@namcp.org agranet@namcp.org (804) Journal of Managed Care Medicine Vol. 19, No. 3

31 Improving Outcomes with Individualized Treatment Strategies in Advanced Non-Small Cell Lung Cancer David R. Gandara, MD For an accredited version of this article, please go to and then click the activity title. Summary A biomarker-driven approach allows treating only the patients with a particular mutation or other biomarker with an appropriate drug which will be effective. Biomarker-selected therapy in individual patients provides higher value. Lung cancer, particularly non-small cell lung cancer, is moving toward being a chronic disease, which will be treated with multiple lines of therapy based on repeat biomarker testing. Key Points Cancer care, in general, is transitioning from empiric to individualized, biomarkerdriven cancer therapy Biomarker-selected therapy in individual patients provides higher value than an empiric approach. Biomarkers are evolving for both targeted therapy and immunotherapy. EATING AN ELEPHANT, AN ANALOGY THAT can be used for defeating lung cancer, must be done with a strategy and a bite at a time. Never in the history of cancer care have clinicians faced the challenges that are present in the management of lung cancer. In every challenge, there is an opportunity. The greatest opportunity is for our patients because of individualized care. Individualized care is a costeffective way to provide cancer care. Individualized care can also be called precision or personalized care. Cancer care is transitioning from empiric to individualized, biomarker-driven cancer therapy. 1 Empiric therapy has been a clinician using their clinical knowledge to determine a best therapy for a given patient. To move to individualized therapy, for many types of cancer, tumor molecular profiling (also known as genomic analysis) to identify drug targets is required. Adequate tumor tissue is needed for the analysis, but traditional fine needle biopsies many times do not yield enough tissue for testing. Once molecular targets are identified, medications against those targets are needed. The pharmaceutical industry is doing a good job of heading in this direction. For many cancers, including lung cancer, there are now targeted therapies. Additionally, predictive biomarkers for these targeted therapies are needed. New clinical trial designs are needed that define the activity of a medication against its target (predictive biomarkers). Designs that work to allow timely and cost-effective approval of medications are needed. Clinicians have gone from looking at lung cancer as one disease to having histologic subtypes and now to a multitude of genomic subsets. Of 100 patients with lung cancer, 86 will have non-small lung cancer (NSCLC) and the rest will have small cell lung cancer. Within NSCLC, the majority will have adenocarcinoma, of which at least 11 genomic subsets have been identified (Exhibit 1). 2 Squamous cell (SCC) is the next highest group and large cell and Vol. 19, No. 3 Journal of Managed Care Medicine 31

32 Exhibit 1: Evolution of NSCLC Subtyping from Histologic to a Multitude of Genomically-Defined Subsets 2 Other 11% NSCLC as one disease Adenocarcinoma Squamous Cell Cancer ALK HER2 BRAF PIK3CA AKT1 MAP2K1 NRAS ROS1 RET EGFR KRAS Unknown Squamous 34% Adenoca 55% EGFRvIII P13KCA EGFR DDR2 FGFR 1 Amp Unknown Histology Based Subtyping others account for smallest group. Lung cancer with different genetic mutations is as different as breast and colon cancer are from each other. Patients with different lung cancers need different therapies; everyone cannot be treated the same. Using advanced NSCLC as a model, the available tools to facilitate individualized therapy include chemotherapy, targeted therapy, and checkpoint immunotherapy. For choosing chemotherapy, histologic tumor subtyping is used to select therapy. This way of selecting therapy is insufficient but is the best thing available currently. At this point, there are targeted therapies for adenocarcinoma with selected mutations. The best defined genetic biomarkers in NSCLC are epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), proto-oncogene tyrosine-protein kinase (ROS1) for which there are targeted therapies. At this time, there are no targeted therapies against SCC with specific genetic markers. There is a public-private partnership seeking to develop such agents. The checkpoint immunotherapy agents are the most expensive cancer treatments developed to date and parameters for cost-effectively using these agents are needed. These immunotherapy agents may be targeted therapy for selected groups based on a predictive biomarker or empiric therapy. As NSCLC treatment continues to move from empiric therapy (treating everyone with chemotherapy) to individualized treatment, several clinical questions still need to be better answered. These include how to optimize therapy in individual patients (i.e., is there an ideal order of therapy), how can lung cancer be turned into a chronic disease using multiple lines of therapy, and how can new diagnostic testing platforms for targeted therapy or immunotherapy best be integrated into care to achieve optimal results (i.e., next generation sequencing in tissue or cell free[cf]dna in plasma). One way to optimize therapy in individual patients is to select the most appropriate therapy. For those with selected tumor mutations, targeted therapy is the first choice. Targeted therapy is most effective when directed toward patients with cancers expressing the target. Those tumors have oncogenic addiction it is like a light switch, give the correct drug and the patient will have a quick response (typically within 1-2 weeks). Within adenocarcinoma tumors, as mentioned previously, the most common genetic mutations are 32 Journal of Managed Care Medicine Vol. 19, No. 3

33 Exhibit 2: Translating Genomic Profiling Data into Therapeutic Strategies for Lung Adenocarcinoma RET: Cabozantinib : RR = 40% METamp (2.2%) HER2 mutation (0.9%) RIT 1 (2.2%) HER2 mutation: >50% RR to Afatinib ~20% to Dacomitinib ROS1: 70% RR to Crizotinib HRAS (0.4%) NRAS (0.4%) RET fusion (0.9%) MAP2K1 (0.9%) ALK fusion (1.3%) ROS 1 fusion (1.7%) ERBB2 (1.7%) MET ex14 NF1 8.3% 4.3% 24.4% None BRAF (V600E): >60% RR to BRAF + MEK inhibitor combo ALK: 65% RR to Crizotinib: ~70% RR to 2 Gen TKI Ceritinib in resistant cancers BRAF 7.0% 11.3% 32.2% METex14: RR > 50% to Crizotinib EGFR KRAS EGFR: RR > 70% to 1-2 Gen TKIs; ~60% RR to 3 Gen TKIs in resistant cancers KRAS: 35% RR to MEK Inhibitors + Chemotherapy RR = response rate EGFR, ALK, and ROS1. Kirsten rat sarcoma viral oncogene homolog (KRAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations are also found but less commonly. Therapies that are approved for other cancers such as those targeting BRAF mutations in melanoma are effective against BRAF-mutated lung cancer but are not necessarily FDA approved for this indication. Exhibit 2 illustrates translating genomic profiling data into therapeutic strategies for adenocarcinoma. EGFR mutations occur in about 12 percent of NSCLC tumors in the United States (U.S.) and in 40 percent in Eastern Asia. These mutations are most common in adenocarcinoma, never-smokers, East Asians, females, and younger patients, but clinical characteristics are insufficient to select first-line therapy. This is a case of genotype trumps phenotype. In order to identify the mutations, it must be tested for. Several requisites are required to turn lung cancer into a chronic disease. There have to be multiple lines of effective therapy (at least 4 and maybe more). Choices are based on individual patient characteristics. For example, one patient s first-line therapy may be another patient s third-line choice. Patient A with an EGFR mutation may first receive a first-generation EGFR tyrosine kinase inhibitor (TKI). At progression, they may be determined to have a new EGFR mutation such as T790M, which would indicate a third-generation TKI. As thirdline therapy, Patient A would get chemotherapy. Patient B has SCC and would receive chemotherapy as first line and checkpoint immunotherapy as second line. Treating with multiple lines of therapy, especially if there is relatively good response to each, will turn lung cancer into a chronic disease. There are pathways being developed that say after secondline therapy, a patient is moved to palliative care. This is really an issue for oncologists who know there are other possible avenues of therapy and not a wise pathway. Incorporating new diagnostic testing platforms for targeted therapy or immunotherapy to achieve optimal results is another clinical issue to be solved. If single mutations are tested for in a given patient and Vol. 19, No. 3 Journal of Managed Care Medicine 33

34 Exhibit 3: Role of Liquid Biopsy in EGFR-Mutated NSCLC 50 y/o woman with EGFR-mutated adenocarcinoma (E19del) Previously treated with the EGFR TKI Erlotinib with good response for 1 year Now progressive disease in lung, liver and bones A repeat biopsy of a liver lesion is done to determine resistance mechanisms Molecular testing on the repeat biopsy shows the original Exon19del mutation but is negative for the resistance mutation T790M Plasma Next Gen Sequencing for cfdna is positive for T790M Based on cfdna analysis, patient started on clinical trial of 3 rd gen EGFR TKI AZ9291 instead of chemotherapy which was indicated by liver biopsy Repeat PET scan 2 weeks later: Major Response only occur in 1 percent of the population, testing is not cost effective. Doing next-generation sequencing where each possible mutation is part of a panel, the 1, 10, and 40 percenters will be identified. Depending on the number of genes tested for in lung cancer, next-generation sequencing becomes very cost effective. Tumor heterogeneity does occur in lung cancer. 1 The genetic mutations present can be mixed within a tumor at the time of diagnosis. Giving a targeted therapy against one mutation will suppress those cells with the mutation but will allow cells without the mutation to continue to grow and take over the tumor. It is basic Darwinian selection. Because of this change in tumors provoked by treatment, rebiopsy and genomic analysis at the time of relapse or disease progression is recommended by the guidelines to look for actionable oncogenes. The evolution of a patient s cancer over time under the influence of specific therapies (acquired Resistance) has to be understood in order to overcome acquired resistance or even circumventing it from ever occurring. Many research studies are defining these resistance mechanisms and how to overcome them. In lung cancer, resistance appears to occur because of branched evolution. 3 Multiple metastases can develop different mutations (i.e., they evolve independently). Biopsy of a liver metastasis may yield a totally different result from the primary cancer. The original mutation is called the truncal mutation. A single biopsy may not reflect the whole cancer. To get the best information to identify the driving mutations, a growing lesion should be biopsied. There may also be a driver mutation and a backseat driver. The next evolution in care will be to not re-biopsy each time disease progresses but to test cancer cfd- NA in plasma. Multiple commercial tests for cf D- NA are already available in the U.S. If this retesting can be done with a blood test in a cost-effective manner, not only will the patient be saved from an invasive needle biopsy, it will be the way to define how a patient s tumor has evolved over time. It is important to note that everyone has cfdna in their blood from dead cells (~1ng/ml); cancer patients have approximately 4 ng/ml. Plasma cfdna can be considered a liquid biopsy and produces a global result from all the tumor cells in the body. 3 As long as the patient has a high enough tumor load, there are few false positives. Clinicians are now doing plasma cfdna and if nothing shows on that test, they then do a needle biopsy. Exhibit 3 is a case study of the use of cfdna impacting therapy. In this case, the biopsy did not show a secondary EGFR mutation but the cfdna did. This is an example of intratumor heterogeneity. Rather than be treated with chemotherapy, which may not have been effective, the patient received an effective treatment through a clinical trial. In one trial in EGFR mutation-positive patients, if three treatment cycles of an EGFR TKI eliminated the mutation on cfdna testing, the patients had better overall survival and progression-free survival than those who did not have the mutation eliminated by treatment (even in face of lower tumor load on body scans). 4 Not eliminating the mutation was a predictor for early relapse. 4 Elimination of mutations identified by cfdna testing may be very powerful information that can be used to predict early relapse/progression and thus second-line therapy 34 Journal of Managed Care Medicine Vol. 19, No. 3

35 Exhibit 4: Evolution of Biomarker Testing in Clinical Practice: Past, Current and Future 2 Histomorphological Diagnosis: Cancer Empiric Approach (Past) (Compound-Based Therapy): Clinical-histologic factors to select drugs for individual patients Molecular Diagnosis: Current Approach (Target-Based Therapy V1.0): Single gene molecular testing for decision-making in individual patients Evolving Approach (Target-Based Therapy V2.0): Multiplexed molecular tests with increased sensitivity and output for decision-making in individual patients Near-Future Approach (Patient-Based Therapy): Genomic profiling by high throughput next generation sequencing for decision-making in individual patients Use of Plasma instead of tissue samples Representative technologies: Single Biomarker Tests: Sanger DNA Sequencing RT-PCR FISH IHC Multiplex, Hot Spot Mutation Tests: PCR-based SNaPshot PCR-based Mass Array SNP Sequenom Initial High-Throughput Technologies: SNP/CNV DNA microarray RNA microarray Next-Generation Sequencing (NGS): Whole Genome or Exome Capture Sequencing (DNA) Whole or Targeted Transcriptome Sequencing (RNA) Epigenetic profiling Plasma cfdna could be started earlier before acquired resistance occurs. This would require a randomized trial to prove this theory. Exhibit 4 illustrates the evolution of biomarker testing in clinical practice. 2 Checkpoint immunotherapy also plays a role in individualized cancer patient care. Cancer cells have mutations that make them recognizable by the immune system (neo-antigens). Theoretically, the higher the mutational load (e.g., through smoking), the greater the immune recognition. Cancer cells can evade immune surveillance by expressing proteins such as programmed death ligand 1 (PD-L1). Inhibiting PD-L1/PD-1 interaction can restore anti-tumor T cell activity, leading to immune-mediated response. PD-1/PD-L1 antagonists are active in a wide variety of cancers but are currently only approved in a few cancers (melanoma, renal, Hodgkin lymphoma, and NSCLC). Two anti-pd-1 agents are approved for use in lung cancer - nivolumab (Opdivo ) and pembrolizumab (Keytruda ). Anti- PD-1 agents are not effective in cancers with low mutational loads, such as defective DNA mismatch repair colon, myeloma, and pancreatic cancers. In NSCLC, 50 percent of SCC expresses PD-1 and 45 percent of adenocarcinoma (by Genentech/ Roche PD-1 IHC). There are currently six different companies testing for PD-1 and each will produce a slightly different result. An upcoming consensus conference will address the use of these tests as biomarkers for checkpoint immunotherapy. In general, if a tumor has high levels of PD-L1 expression, the response to immunotherapy is better, but there are responses in the PD-L1 negative patients. In SCC, survival benefit of nivolumab in trials has been independent of PD-L1 expression levels. Further data are needed to determine when checkpoint immunotherapy should be used in those who are negative for PD-L1 expression. The NCCN guidelines recommend preferred use of immunotherapy for both metastatic SCC and non- SCC NSCLC after other lines of therapy. 5 There is a unique public-private partnership which is trying to make advances in treating SCC. This partnership includes the FDA, National Cancer Institute, Foundations Medicines and various other groups that will be using a master protocol for research. Each patient will have genomic biomarker testing initially. Depending on the biomarker found, the patients will enter various independent substudies. For those who have no biomarker match, chemotherapy will be given. Conclusion Treatment of NSCLC is becoming ever more so- Vol. 19, No. 3 Journal of Managed Care Medicine 35

36 phisticated. Yet, in the U.S., one in four patients diagnosed with advanced NSCLC receives no treatment. The cost of new anti-cancer therapies is exponentially higher than in the past and can lead to cost-related nonadherence to cancer medications. Determining which patients will benefit most from new therapies is critical. Treating only the subset most likely to benefit (individualized therapy) is cost effective, but predictive biomarkers are essential to appropriately select patients. There is no single solution to defeating lung cancer. Like the elephant, it will take many bites. David R. Gandara, MD, is a Professor of Medicine and is Director of the Thoracic Oncology Group at the University of California Davis Comprehensive Cancer Center. References 1. Gandara DR, Li T, Lara PN Jr, et al. Algorithm for codevelopment of new drug-predictive biomarker combinations: accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer. 2012;13(5): Li T, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31(8): Burrell RA, Swanton C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol Oncol. 2014;8(6): Mok T, Wu YL, Lee JS, et al. Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. Clin Cancer Res. 2015;21(14): NCCN Clinical Practice Guidelines in Oncology. Non-small Cell Lung Cancer Available at nccn.org. Accessed 6/9/ keads@namcp.org (804) Educational Activities Conferences Held biannually during the spring and fall. Earn up to 14 CMEs at each. Archived Webcasts If you can t attend a conference, view the presentations and earn your CMEs online. Live Webinars Attend during your lunch hour. Join our 36 Journal of Managed Care Medicine Vol. 19, No. 3

37 Improving Outcomes with New Treatment Options in the Management of Cystic Fibrosis Gary Owens, MD For an accredited version of this article, please go to and then click the activity title. Summary Cystic fibrosis (CF) is caused by abnormalities in the CF transmembrane conductance regulator (CFTR) gene. There are over 2000 mutations on the CFTR gene, which leads to malfunctioning CFTR protein. Therapies that work to restore function of the problem protein are now available and more are in the wings. Key Points The goal of CFTR modulatory therapy is to improve or restore function to the CFTR protein. CFTR suppressors target Class I mutations. CFTR potentiators target Class II and III mutations. CFTR correctors target Class II mutations. CYSTIC FIBROSIS (CF) IS A GENETIC DISEASE that causes severe lung and digestive problems and results in early death. Pulmonary disease is responsible for the greater share of morbidity and mortality in patients with CF. According to the Cystic Fibrosis Foundation (CFF), 30,000 children and adults in the United States and 70,000 worldwide have CF. 1 The incidence of CF has remained steady over time. The age demographic of the disease has changed over the past several decades. This change is due to an increased understanding of the pathophysiology of the disease and the development of improved treatment strategies. The life expectancy of a patient with CF has dramatically increased. Even though a cure for CF does not exist, with proper management and aggressive treatment, a patient with CF can live well into their 30s or 40s. The CFF Patient Registry reported a median survival of 40.7 years. 2 Because patients with CF are living longer, the number of adults with CF is increasing. The trend is most obvious when the number of children with CF is compared to the number of adults with CF over time. In fact, there are some countries that have a greater number of adults living with CF compared to children with CF. In addition to increased life expectancy, improved pulmonary health has been observed in patients with CF. VanDevanter and colleagues recently analyzed findings from the CFF Patient Registry and found that reductions in respiratory symptoms coincided with improved pulmonary function and improved survival in the analyzed patient population. 3 Unfortunately, lung function declines can still occur in these patients. The rate of decline in lung function, once it begins, remains steep. The rate of decline observed across age groups in 2007 was similar to the rate of decline observed in With newer targeted therapies, the rate of decline may change. Since 2010, routine newborn screening for CF has been mandated and is performed at hospitals in all 50 states. According to the CFF patient registry, 66 percent of new diagnoses of CF are made in the first year of life. 2 A typical newborn screen involves the measurement of immunoreactive trypsinogen (IRT) Vol. 19, No. 3 Journal of Managed Care Medicine 37

38 Exhibit 1: CF-Related Lung Disease Abnormal CFTR Reduced ASL Impaired Mucociliary Clearance Infection Obstruction Inflamation Inflamation Infection Obstruction Structural Damage Bronchiectasis Inflamation Infection Obstruction Pulmonary Insufficiency Respiratory Failure ASL = Airway Surface Liquid with subsequent confirmation via repeat IRT or genotyping. If a genetic mutation is detected, then a sweat chloride test is performed. The sensitivity of the different test combinations differs. Overall, the sensitivity is less than 100 percent; therefore, false negatives are possible. If a patient with CF is not diagnosed via newborn screening, then the diagnosis is often made based on clinical symptoms. Given the imperfect nature of laboratory testing, there is a distinct possibility of patients being missed during routine newborn screening. There are also patients with equivocal results or normal results who do indeed have CF; these patients are often identified later in life. Almost 7 percent are diagnosed after age 16. These patients may have mild or atypical symptoms. Atypical symptoms include infertility and sinusitis. Patients who are diagnosed as adults are more likely to present with respiratory symptoms, compared to younger patients. 4 They may also have pancreatitis, other gastrointestinal symptoms, or infection with typical CF respiratory pathogens. Improved survival of patients with CF is likely due to multiple factors. Widespread newborn screening programs and streamlined diagnostic protocols are capturing patients at the earliest stage of disease. Comprehensive nutritional programs, pancreatic enzyme replacement, and enhanced chest physiotherapy are believed to improve patient outcomes and longevity. Care centers that specialize in the treatment of patients with CF have also been credited with the improved survival rates. Finally, aggressive treatment of airway infection improves patient outcomes. 5 CF is caused by abnormalities in the CF transmembrane conductance regulator (CFTR) gene. There are over 2,000 mutations on the CFTR gene which have been identified and which lead to malfunctioning CFTR protein. The CFTR protein could be completely nonfunctional or have limited functional ability. It takes two mutated genes or alleles, one from each parent, for a person to have CF. As a result of CFTR genetic mutations, the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells is negatively affected. Also, the mutations impair the gating or conductance of chloride and bicarbonate ions through the channel. Overall, CFTR dysfunction results in an ionic imbalance of epithelial secretions in several body systems: the lungs, GI tract, pancreas, and liver. 6 Abnormalities in CFTR are believed to alter the microenvironment of the lung (Exhibit 1). 7 The protein produced by the CFTR gene aids in chloride transport into and out of cells. If the protein is absent or defective, chloride transport is compromised. Under normal circumstances, mucus in the airways is thinned by water and cleared by the lungs. In other words, normal CFTR and epithelial sodium channel (ENaC) activity results in healthy 38 Journal of Managed Care Medicine Vol. 19, No. 3

39 Exhibit 2: Protein Repair: Mutation-Specific Treatment Class I Class II Class III Class IV Class V Defect Result Protein synthesis defects Processing & trafficking defects Defective regulation Altered Clconductance Reduced quantity Mutation Type Nonsense: AA substitution Missence: AA deletion (F508del) Missense: AA change (G551D) Missence: AA change Missense: mrna processing Potential Therapy PTC124 VX-770 VX-809 VX-770 AA = Amino Acid airway surface liquid layer and normal mucociliary clearance. In patients with CF, the lack of chloride ions affects the balance of water in cells. As a result, mucus is left thick, sticky, and difficult to clear. Failure of CFTR to transport chloride and overactivity of ENaC sodium resorption leads to a dehydrated airway surface liquid layer and difficulty in clearing mucus. Thick lung secretions and impaired mucociliary clearance are hallmarks of CF. Impaired mucociliary clearance leads to bronchial obstruction. Persistent inflammation combines with an exaggerated host response and leads to a vicious cycle of pulmonary complications. In fact, the host response does more harm than good. The presence of virulent bacteria strains contributes to the inflammatory process. Chronic inflammation and infection impair the body s natural defense mechanisms. Eventually, this cycle damages the structural integrity of the lungs. As mentioned before, pulmonary insufficiency is responsible for the vast majority of CF-related deaths. The following microorganisms are commonly seen in this patient population - Pseudomonas aeruginosa, Staphylococcus aureus, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Haemophilus influenzae, multi-drug resistant Pseudomonas aeruginosa, Burkholderia cepacia complex, and methicillin-resistant Staphylococcus aureus (MRSA). Over time, the percent of patients colonized with Pseudomonas aeruginosa dramatically increases. Also, the percent of patients with multi-drug resistant Pseudomonas aeruginosa increases. It has been postulated that early infections with viruses and other gateway bacteria may cause substantial inflammation and pave the way for subsequent colonization with Pseudomonas aeruginosa. 8 Overall, bacterial colonization is changing in patients with CF with increasing resistance in Pseudomonas aeruginosa isolates, isolation of MRSA, and emergence of other bacterial species. Multiple treatments used in patients with CF are administered via aerosolization utilizing bronchodilators, mucolytics, and hypertonic saline in an attempt to thin mucus and maintain open airways. Antibiotics for chronic airway infection are also a logical choice for this route of administration. The rationale behind this method of drug delivery is to administer a high dose of medication directly to the impacted area (airways); to minimize systemic absorption and possible toxicity; to overcome sputum binding (especially important with aminoglycoside antibiotics); and to optimize pharmacokinetic and pharmacodynamic parameters (e.g., concentrationdependent killing). 9 Aerosolized antibiotics include tobramycin solution for inhalation (TSI), aztreonam lysine inhalation solution (AZLI), and tobramycin inhaled powder (TIP). Typically, inhaled antibiotics are used for 30 days on and 30 days off. Many CF clinics now alternate aztreonam and tobramycin. Inhaled antibiotics have been shown to improve pulmonary function, decrease need for hospitalization, decrease need for intravenous and oral antibiotics, and reduce Vol. 19, No. 3 Journal of Managed Care Medicine 39

40 Exhibit 3: CFTR Modulation Agent(s) Phase I Phase II Phase III Available Ivacaftor i Ivacaftor + Lumacaftor i Ataluren i Ivacaftor + VX 661 i Riociquat i QBW251 i N91115 i mortality The inhaled antibiotics, of course, are one of the interventions that has helped increase CF life expectancy. Much research has gone into discovering the genetic basis of CF so targeted therapies could be developed. There are six known classes of CFTR mutations. Only five of these are shown in Exhibit 2. Class I are nonsense or premature stop codon mutations that cause defects in protein synthesis. The premature stop codon leads to the production of truncated proteins that are nonfunctional. Nonsense mutation is present in approximately 10 percent of patients with CF. Class II are F508del mutations which cause a folding defect that inhibits intracellular trafficking and enhances degradation of CFTR protein, resulting in significantly reduced cell-surface CFTR expression. F508del is the most common mutation in the Caucasian population. Of note, F508del is not a gating mutation. Class III mutation is a G551D mutation. This gating mutation causes defects in the regulation of salt and water transport through CFTR protein present at epithelial cell surface. G551D is the most common gating mutation; however, it is only present in approximately 4 to 5 percent of patients with CF. Class IV and Class V are gating and conductance mutations that affect the function or quantity of CFTR proteins at the epithelial cell surface. Class VI mutations are considered exceedingly rare. These mutations result in a high turnover of CFTR at the channel surface, because the stability of mature CFTR is reduced. Overall, CFTR mutations reduce the amount or function of CFTR at the cell surface. Patients with Class I, II, or III mutations exhibit severe disease symptomatology. Patients with Class IV, V, and VI mutations exhibit mild symptomatology, typically characterized by pancreatic insufficiency. Ninety-seven percent of patients with CF have had their mutations identified through genetic testing. More than 86 percent of patients with CF have at least one copy of the F508del mutation, with 47 percent having two F508del mutations (homozygotes) and 40 percent having one F508del mutation (heterozygotes). 14 Other less common genetic mutations include G542X, G551D, R117H, N1303K, W1282X, and R553X. CTFR modulators, targeted at restoring the function of the CFTR protein, can be suppressors, potentiators, or correctors. The first one, ivacaftor, was approved in CFTR suppressors (ataluren [Translarna ]) block the premature stop codon and allow full-length, functional proteins to be produced and thus targets Class I mutations. CFTR potentiators (ivacaftor [Kalydeco ]) increase channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. Potentiators increase the flow of ions through CFTR present at the cell surface and target Class II and III mutations. CFTR correctors (e.g. lumacaftor, VX661) increase delivery and amount of functional CFTR protein to the cell surface and targets Class II mutations. Currently, no investigational compounds target Class IV or V mutations. Ivacaftor is indicated for the 5 percent CF patients who have Class III mutations. It is FDA approved for patients with the following genetic mutations: G551D, R117H, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D. This agent increases the time that activated CFTR channels at the cell surface remain open; thereby, restoring CFTR function. Ivacaftor treatment leads to statistically significant improvement in lung function, reduced pulmonary exacerbations, fewer respiratory symptoms, and improved quality of life. 15 From clinical experience, ivacaftor can significantly improve hepatic steatosis, 40 Journal of Managed Care Medicine Vol. 19, No. 3

41 sinus disease, and decline in lung function over time. It can also help patients gain weight. Long-term data are being gathered on the effects, both pulmonary and beyond, of ivacaftor and the other agents. Lumacaftor essentially acts as a chaperone during protein folding and increases the number of CFTR proteins reaching the cell surface. It is FDA approved for use in combination with ivacaftor (Orkambi ) for those who are homozygous for the F508del mutation. The two were combined because ivacaftor doubles the in vitro activity of lumacaftor. Lumacaftor alone only results in 15 percent functional CFTR, whereas addition of the second corrector gets the functional rate near 30 percent. The combination improved lung function and the time to first pulmonary exacerbation compared to placebo. 16 Ataluren, an investigational, orally administered, small-molecule compound, targets Class I nonsense mutations. It is also being evaluated for Duchenne muscular dystrophy and is marketed in the European Union for this indication. A randomized, double-blind, placebo-controlled study was conducted in 238 patients with CF and nonsense mutations to determine the efficacy and safety of ataluren. 17 Unfortunately, the study endpoint of improvement in lung function (forced expiratory volume in one minute percent [FEV1] predicted) was not reached, except in a subpopulation of patients. The group that demonstrated efficacy, improvement in FEV1 and reduced pulmonary exacerbations, was not receiving any aerosolized aminoglycoside antibiotics. This led the investigators to postulate that the reduced efficacy might in fact be due to competitive inhibition of ataluren by the aerosolized antibiotic. Still, the results were promising with a trend toward a lower decline in lung function and fewer pulmonary exacerbations in patients taking ataluren compared to those taking placebo. It remains to be seen if this agent will make it to market. Several other therapies are under investigation for CF (Exhibit 3). Riociguat, approved for pulmonary arterial hypertension, stimulates soluble guanylate cyclase, an enzyme in the cardiopulmonary system and the receptor for nitric oxide. Preclinical data have shown evidence that riociguat can result in improved CFTR channel expression. QBW251 is a CFTR potentiator similar to ivacaftor. A Phase II proof of concept trial is currently underway. This trial will test QBW251 in both healthy subjects and those that have CF. N91115 is an oral compound that modulates the function of the defective CFTR protein and decreases inflammation in the lung. N91115 is the first of a new class of compounds that increase levels of an important signaling molecule in the body, called S-nitrosoglutathione or GSNO. Levels of GSNO have been shown to be decreased in people with CF. Compounds targeting GSNO have been shown to increase the amount of CFTR that reaches the cell membrane and to stabilize CFTR so that its function can be improved. Patients with CF and two copies of F508del CFTR mutation are being enrolled in a Phase II study with N Conclusion CF is an autosomal recessive genetic disease with defects in the CFTR gene. This leads to defects in ion transport of chloride, sodium, and water. Over time the cycle of infection, inflammation, and mucus leads to lung damage. It is treated with antibiotics, mucolytics, anti-inflammatories, and re-hydrators which have increased life expectancy. New medications that are CFTR modulators do not cure the disease but help manage it. These modulators are bringing continued improvements in the lives of those with CF. Other therapies and additional combinations are on the horizon. Gary Owens, MD, is President of Gary Owens Associates. References 1. Cystic Fibrosis Foundation. About Cystic Fibrosis. Available at Accessed 5/16/ Cystic Fibrosis Foundation. Patient Registry Data Available at www. cff.org. Accessed 5/16/ VanDevanter DR, Rasouliyan L, Murphy TM, et al. Trends in the clinical characteristics of the U.S. cystic fibrosis patient population from 1995 to Pediatr Pulmonol. 2008;43(8): Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med. 2002;347(6): Parkins MD, Parkins VM, Rendall JC, Elborn S. Changing epidemiology and clinical issues arising in an ageing cystic fibrosis population. Ther Adv Respir Dis. 2011;5(2): Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev. 2013;22: Chmiel JF, Berger M, Konstan MW. The role of inflammation in the pathophysiology of CF lung disease. Clin Rev Allergy Immunol. 2002;23(1): Starner TD, McCray PB Jr; American College of Physicians; American Physiological Society. 9. Pathogenesis of early lung disease in cystic fibrosis: a window of opportunity to eradicate bacteria. Ann Intern Med. 2005;143(11): Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1): Moss RB. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest. 2002;121(1): Murphy TD, Anbar RD, Lester LA, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4): Sawicki GS, Signorovitch JE, Zhang J, et al. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatr Pulmonol. Vol. 19, No. 3 Journal of Managed Care Medicine 41

42 2012;47(1): Bobadilla JL, Macek M Jr, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations correlation with incidence data and application to screening. Hum Mutat. 2002;19: Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365: Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373: Karem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomized, double-blind, placebo controlled phase 3 trial. Lancet Respir Med. 2014;2: CURRENT Genomics, Biotech & Emerging Medical Technologies Institute (GBEMTI) PROJECTS Medical technologies Dossier Template and Medical Diagnostics Dossier Template. Perspective Papers on Reimbursement for Medical Devices, Impact of ACOs and Emerging Healthcare Delivery Models, Improving Molecular Diagnostics, and Regenerative Medicine. Executive Leadership Webinars on exciting and relevant topics in the GBEMTI space. P (804) F (804) wwilliams@namcp.org Waterfront Dr, Suite 101 Glen Allen, VA Journal of Managed Care Medicine Vol. 19, No. 3

43 Individualizing Treatment Strategies for Effective A1C Reduction and Improved Outcomes in Type 2 Diabetes Daniel Einhorn, MD, FACP, FACE For an accredited version of this article, please go to and then click the activity title. Summary Unlike in years past, today the expectations are that if a patient develops type 2 diabetes (T2DM), they will be well cared for and do well with few long-term complications. It is not difficult for patients today to manage their disease because of the many new medications which are available. Key Points Simple easy regimens that cause little to no hypoglycemia and weight gain should be used for patients with T2DM. Although more than one therapy may be required to achieve control, dual therapy with once a day agents is still easy for a patient to adhere to and be persistent with. With good control, many of the complications of T2DM will be in the past. MANAGING TYPE 2 DM (T2DM) IS MORE than managing glucose. A clinically relevant composite efficacy endpoint for T2DM has been proposed (Exhibit 1). 1 Instead of just focusing on glucose lowering, this endpoint also considers weight gain and hypoglycemia, which many of the older diabetes treatments cause. Using this endpoint and other efficacy components can help clinicians select appropriate therapy. Other efficacy components include accessibility, ease of use, and adverse effects. Accessibility includes cost to the patient, formulary concerns, familiarity of clinicians, and the length of time it takes to educate a patient in use. Ease of use, which affects quality of life and adherence, includes frequency of dosing, timing of dosing in relation to food, requirement for glucose monitoring to adjust dose, requirement to time daily events around the therapy (e.g., food, exercise), and the frequency of needed office visits, phone calls, and lab tests. A lack of real or perceived adverse effects is also important. When considering the costs of a therapy, the initial acquisition cost of medications is only a part of the total cost of care, which includes monitoring requirements, risk of hypoglycemia, weight gain, safety, and other health care utilization. An ideal regimen would be given once daily anytime during the day, resulting in no hypoglycemia or weight gain, having no need for daily self-glucose monitoring, and no need for office visits or lab tests more than twice yearly. Achieving this ideal regimen makes it much easier for patients to be successful and adherent. Many of the medications available now can be used to achieve this type of regimen. Patients do have to accept the idea that one medication may not be enough. Combination therapy is required for most patients. Thus, the goal is to make individual regimens as simple as possible but still achieve glycemic control. The glycemic control target in general is a hemoglobin A1C of less than 7%, but this must be adapted for each patient. Exhibit 2 is a depiction of the elements of decision-making used to determine the intensiveness of efforts to achieve glycemic targets. 2-3 In general, most patients should be targeted to less than Vol. 19, No. 3 Journal of Managed Care Medicine 43

44 Exhibit 1: A Clinically Relevant Composite Efficacy Endpoint in Type 2 Diabetes Mellitus 1 Glycemic control A1C < 7% A1C 6.5% Hypoglycemia No severe hypoglycemia No symptomatic hypoglycemia Weight gain No weight gain < 1 kg weight gain 7%, but tighter targets may benefit younger patients, whereas in older individuals, a more conservative approach is necessary. 3 When possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs, and values. The time to do a great job in managing glucose control in T2DM is as early as possible in the disease process. During the early years, maximal benefits for reducing long-term complications can be achieved with relatively minimal risks. Later in the disease process, therapy may need to be de-intensified. There is less benefit from aggressive glucose lowering and greater risks of hypoglycemia with higher costs. Once complications are present, glucose becomes one of the least important issues. Therapy in T2DM needs to be selected based on the issues already discussed and the mechanism of action, which impacts which agents can be used together. The American Association of Clinical Endocrinologists (AACE) treatment guidelines provide charts listing pros and cons of the various medication classes and algorithms for selecting therapy. 4 The AACE guidelines recommend therapy based on starting A1C; for example, values of 9% or greater should be started on double or triple therapy and those with A1C between 7.5 and 9% should start on two agents. Metformin is still the recommended first agent, if tolerated. Glucagon-like peptide 1 (GLP-1) agonists are the first agents that should be added to metformin. These are either once daily or even once a week and are much easier to use than mealtime insulin but do the same basic thing. Guidelines are now recommending avoiding mealtime short-acting insulin because of the added difficulty for patients, the high rate of hypoglycemia, the time and cost to deal with hypoglycemia, and the additional monitoring costs (blood glucose strips). Pioglitazone has been underutilized because of perceived adverse effects but is making a comeback. Pioglitazone has numerous positive attributes, including excellent efficacy (A1C reduction of 1%), ease of use (1 tablet once daily anytime), generic availability, and no hypoglycemia in monotherapy. It has been shown to improve nonalcoholic fatty liver disease, cardiovascular disease, and cerebrovascular disease outcomes. There are also excellent data available on diabetes prevention and it produces a durable antihyperglycemic effect, which may be related to beta cell preservation. Another positive is that it can be used to treat insulin resistance in polycystic ovary syndrome (PCOS) and can be used independent of renal function. Lastly, it can be combined with any other antiglycemic agent and can be used at any stage of diabetes. Clinicians have many years of experience with pioglitazone, so the pros and cons are well defined The perceived negative attributes of pioglitazone can be minimized. The weight gain with this agent is not visceral fat (i.e., not like sulfonylureas or insulin) and occurs less at low dose and when used without insulin. Fluid retention can occur with this agent, so it should not be used in those with heart failure. Although it does cause fluid retention in HF, there is not an increase in mortality. The fluid retention is less with lower doses and when used without insulin. Bone fractures are rare and atypical. 44 Journal of Managed Care Medicine Vol. 19, No. 3

45 Exhibit 2: Approach to Glycemic Control 2-3 Patient/Disease Features more stringent Hb A1c less stringent Risks potentially associated with hypoglycemia and other drug adverse effects low high Disease duration newly diagnosed long-standing Usually not modifiable Life expectancy long short Important comorbidities absent few/mild severe Established vascular complications absent few/mild severe Patient attitude and expected treatment effects highly motivated, adherent, excellent treatment efforts less motivated, non-adherent poor self care capacities Potentially modifiable Resources and support system Readily available limited Cancer risk from pioglitazone has been disproven. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are moving up in the treatment algorithm. The agents available so far include canagliflozin (Invokana), dapaglifozin (Farxiga), and empagliflozin (Jardiance). Advantages of this class include one tablet once daily anytime, lowers A1C as well as any other oral class, lowers fasting blood glucose as well as any other oral class, no hypoglycemia, weight loss (3-5% body weight), and lower blood pressure. This class has a non-insulin-dependent mechanism and can be used as monotherapy or in any combination. Overall, the class causes minimal adverse effects, except for yeast infections. Other advantages include increases in magnesium levels (fewer cardiac arrhythmias), lowers uric acid, and suppresses sympathetic nervous system activity. Although a new class, the SGLT2 inhibitors are often free or have a very low co-pay for commercial insurance and have better than usual Medicare and related coverage. One big benefit of the SGLT2 inhibitors shown recently is reduction in cardiovascular disease. The SGLT2s modulate various aspects of the development of atherosclerosis and these effects are not necessarily glucose related (Exhibit 3). 5 The number needed to treat in a recent trial of empagliflozin was 39 in those with T2DM and high cardiovascular risk to prevent one event. 6 The majority of subjects in this study were already treated with an ACE inhibitor and statin. The diabetes management guidelines have not been changed because it was only one study. If the CVD benefits are proven for the other agents in this class, it will likely be recommended that every T2DM patient with high risk for CVD be started on one of these. They are also being investigated for type 1 disease. These agents are already being widely used and patients appear to be adherent and persistent with them. Disadvantages of the SGLTs include genital mycotic infections, need for good renal function (estimated glomerular filtration rate [egfr] > 45-60), potential volume loss, potential hyperkalemia (canagliflozin), and the insurance hassles of being new. Genital infections tend to occur more in women and usually in the beginning of treatment. Another disadvantage is the unknowns because the class is new. One unknown is the possibility of bladder cancer which is currently be studied. The GLP-1 agonists are widely used because of their benefits for glycemic control and weight loss without Vol. 19, No. 3 Journal of Managed Care Medicine 45

46 Exhibit 3: Empagliflozin Modulates Several Factors Related to CV Risk 5 BP Arterial stiffness Albuminuria Sympathetic nervous system activity Glucose Insulin Uric acid Weight Visceral adiposity LDL-C HDL-C Triglycerides Oxidative stress the risk of hypoglycemia. There are daily and weekly dose agents. Many different GLP-1s are on the horizon, which will be monthly or yearly injections, oral dosage forms, in combinations with basal insulin, and in combinations with everything else. The disposable insulin pens have revolutionized insulin therapy. It is now easier to give insulin with fewer opportunities for dosing mistakes. The patient also does not feel the injection because of the tiny needle; this can overcome much of the fear of injection. The pens are not only easy to use, but they also protect insulin from light, protect people from needlesticks, and can be used discreetly. It has been shown that using insulin pens reduces rates of hypoglycemia. 7 The current basal insulins are better than NPH insulin but they do all have peaks and troughs. The newer ultra-long acting ones such as U300 glargine and degludec truly produce a flat pharmacokinetic profile. Subcutaneous insulin injection does not exactly mimic endogenous insulin secretion. Ultralong-acting basal insulins have a flatter time-action profile and may be even less likely to cause nocturnal hypoglycemia than first-generation insulin analogues. There appears to be less hypoglycemia and weight gain with these ultra-long-acting agents. Various basal insulins can be combined with GLP-1 agonists to produce less weight gain and hypoglycemia compared to basal plus mealtime insulin; one combination product is already approved. Basal insulins can also be combined with any oral agent. There are more basal long-acting insulins on the horizon, including biosimilar glargine and peglispro. One biosimilar (generic) for insulin glargine was approved in late Several insulins designed for once-weekly administration are in early development, but these may not be ideal in cases where the patient might miss the dose or get sick. Although many clinicians are moving away from mealtime insulin in T2DM, those with type 1 disease will likely still be using it. Several short-acting insulins including biosimilar lispro, ultra-rapid lispro, faster-acting aspart, and another inhaled insulin are under development. Inhaled insulin is almost as fast as intravenous insulin, but adoption 46 Journal of Managed Care Medicine Vol. 19, No. 3

47 has been slow. There are insulin pumps for continuous insulin delivery with the ability to give additional bolus dosing. There are patients with T2DM who require the intensity of an insulin pump to maintain control. Combination therapy is the rule to achieve adequate glucose control. Many combination products are already on the market and more are to come. Every oral medication class can be combined with another class in varying fixed doses and such products are available or coming. Metformin plus every other oral class are available. SGLT2 inhibitors in combination with a dipeptidyl peptidase 4 (DPP-4) inhibitor have been approved and combination with other classes are likely to be approved. Pioglitazone will also be in combination products more frequently. All these different combination products, each with a brand name, do complicate things for the average prescriber. Weekly and monthly therapies will also become more common, especially for injectable products. Injectable combinations are also coming. Novel delivery technologies for insulin and GLP-1 agonists are being investigated. One is an osmotic mini-pump made by Intarcia for continuous subcutaneous delivery of exenatide. This minipump, the size of a small matchstick, provides continuous smooth zero order delivery of medications. A peptide stabilized suspension allows for robust stability at high body temperatures and delivery of peptides for 12 months from just a single device. The mini-pump is placed sub-dermally once/ twice yearly in a short in-office sterile procedure. The implant could be done by specialists, primary care providers, nurses, or physician extenders; there are already approved reimbursement codes for the implant procedure. In addition to improved medications, there are improvements in screening for diabetes. One option for earlier diagnosis of diabetes is an FDA approved device. The ophthalmic lens fluorescence biomicroscope (ClearPath DS-120) measures autofluorescence of the crystalline lens of a patient. This quick, simple, noninvasive eye exam can identify diabetes seven years prior to complications. This avoids the need for a blood glucose test and the required fasting. Many more eye examinations are conducted in the United States annually than blood glucose screenings. Conclusion Clinicians should prescribe simple, easy regimens for patients with T2DM. Although more than one therapy may be required to achieve control, dual therapy with once a day agents is still easy for a patient to adhere to and be persistent with. With good control, many of the complications of T2DM will be in the past. It is all possible with the newer better medications. Daniel Einhorn, MD, FACP, FACE, is Medical Director of the Scripps Whittier Institute for Diabetes in San Diego and is a Professor of Medicine at the University of California San Diego. References 1. Zinman B, Schmidt WE, Moses A, et al. Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme. Diabetes Obes Metab 2012;14: Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med. 2011;154(8): Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1): Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association Of Clinical Endocrinologists And American College Of Endocrinology on the comprehensive type 2 diabetes management algorithm executive summary. Endocr Pract. 2016;22(1): Inzucchi SE, Zinman B2, Wanner C3, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2): Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22): Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21): Vol. 19, No. 3 Journal of Managed Care Medicine 47

48 Novel Therapeutic Options in the Management of Epilepsy Joseph I. Sirven, MD For an accredited version of this article, please go to and then click the activity title. Summary The treatment of epilepsy has changed dramatically over the past 20 years with the development of a dizzying array of medications which also get used for many other disorders. In addition to medications, surgical procedures for focal seizures and devices for treating generalized seizures are also available. Key Points Seizures have a major impact on the patient s life socially, psychologically, and physically. Medications are selected based on the type of seizure and patient characteristics. Partial/Focal seizures can be treated with surgical procedures. Generalized seizures can be treated with surgically implanted devices. A SEIZURE IS THE MANIFESTATION OF AN abnormal, hypersynchronous electrical discharge of a population of cortical neurons. This discharge may produce subjective symptoms or objective signs, in which case it is a clinical seizure, or it may be apparent only on an electroencephalogram (EEG), in which case it is an electrographic (or subclinical) seizure. Epilepsy is having recurrent, unpredictable, unprovoked seizures. Many patients do not want to use or hear the term epilepsy because of negative stigmatizing connotations. They will refer to themselves as having seizures or a seizure disorder. There are two main classifications of seizures partial or generalized. Partial seizures have onset in a discrete part of the brain; focal seizures is the more contemporary term for these seizures in medical literature. Partial seizures are divided into two main types, depending on whether or not consciousness is fully preserved and involve only part of the brain. During simple partial seizures, consciousness is preserved; the person is alert, can respond to questions or commands, and can remember what occurred during the seizure. During complex partial seizures, consciousness is altered or lost. Often, there is no memory of what happened during all or part of the complex partial seizure. The distinction between simple and complex partial seizures is critical because activities such as driving and operating dangerous machinery must be restricted in patients with uncontrolled complex partial seizures; restrictions for people with only simple partial seizures depend on the specific seizure manifestations (and, 48 Journal of Managed Care Medicine Vol. 19, No. 3

49 Exhibit 1: Consequences of Seizures Social - Driving - Employment - Stigma - Sports - Insurance Physical - Injury - Death Cognitive - Short term memory disorders Psychiatric - Depression - Anxiety - Psychosis for driving, on regulations in a particular state). Partial seizures may progress to secondarily generalized seizures. Secondarily generalized seizures ultimately involve motor activity on both sides of the body and can be difficult to distinguish from primary generalized seizures. Primary generalized seizures involve both sides of the brain. Generalized seizures may imply an inherited aspect, whereas partial imply some type of injury to a part of the brain. Everyone has the potential to have seizures, but each person has a different seizure threshold. For example, a stroke may provoke seizures in someone with an inherently low seizure threshold. Where and how seizures originate impact treatment. When a patient has a single first-time seizure, many times they end up in the emergency room for evaluation. Emergency rooms will typically evaluate a first seizure with a plain CT but the test of choice is an MRI, the gold standard, or a CT with contrast to rule out a tumor. ERs typically do not do EEGs. Common causes of seizures such as drugs need to be ruled out. Some drug examples include bupropion, tramadol withdrawal, antiepileptic drug (AED) withdrawal, cocaine, and methamphetamine. Lumbar puncture may be done if ruling out infection. Evaluating a first seizure first involves finding out about the events surrounding the event. Often, the patient is amnestic, and the description must be obtained from relatives, friends, or bystanders. Observers may report behavior consistent with a complex partial seizure immediately preceding or localized motor activity or classic generalized seizure findings. There are serious implications for an individual who has a single seizure. Every state in the United States (U.S.) has a law about driving with a seizure disorder, even after a single seizure. Employers, insurers, and sports coaches have concerns about seizures. Exhibit 1 lists the many psychiatric, social and financial consequences of having a seizure disorder. Multiple seizures cause more issues than single isolated ones. It is common to have shortterm memory loss, physical injuries, and mood disorders. Depression and anxiety can overwhelm the patient s treatment. Once someone has a seizure, a decision on whether to treat them to prevent future seizures must be made. Almost no children should be treated after a first seizure. Recurrence risk is 40 to 50 percent in the two years after a first event. For those with an abnormal exam, EEG or complex partial seizure, the recurrence risk is 80 to 90 percent, so they should be treated. AEDs essentially calm all electrical activity in the brain, which can have significant impact on children academically. In adults, there is a 38 percent risk of recurrence in those with a normal exam after a first seizure. Employment and driving are the two things that impact the treatment decision in adults. The majority of legal cases over seizures are related to adverse effects of AEDs versus not treating the initial seizure. Treatment should be considered after a first seizure in those with a hazardous occupation. Those with a clear precipitating factor such as alcohol withdrawal, drug abuse, acute illness, post impact seizure, specific benign epilepsy syndromes, or seizure from excessive sleep deprivation should not be treated after a single seizure. The groups who should be definitely treated include those with structural lesions, an abnormal EEG, a history of previous symptomatic seizures, a history of a previous brain injury, and status epilepticus at onset. Once someone has two seizures (epilepsy), they should then be treated, if not previously done. The recurrence risk is 80 to 90 percent after two events. There are some exceptions; children with benign rolandic epilepsy, simple partial seizures, or widely spaced seizures (2 years or more apart) are not always treated even after two seizures. Although AEDs are the mainstay of treatment, Vol. 19, No. 3 Journal of Managed Care Medicine 49

50 Exhibit 2: Medication by Example Seizure Types Absence Infantile Spasms Myoclonic Atonic Ethosuximide ACTH Valproate Valproate Valproate Vigabatrin Zonisamide Levetiracetam Lamotrigine Valproate Levetiracetam Phenobarbital Levetiracetam Topiramate Clobazam Zonisamide Levetiracetam Topiramate Felbamate Benzodiazepines Clobazam Rufinamide lifestyle modifications have varying degrees of clinical and experimental support. Lifestyle modifications, particularly avoidance of alcohol and stimulants, sleep deprivation, and known triggers, can be very important in certain syndromes and individuals. Stress can be a contributor but is not a cause of seizures. Relaxation, biofeedback, and other behavioral techniques can help a subset of patients, especially those with a reliable aura preceding complex partial or secondarily generalized seizures. Seizure management with AEDs is like hypertension, when on medication someone is protected from seizures but the underlying pathophysiology is not changed. AEDs control seizures but do not cure them, which is something patients need to understand. There are no head-to-head trials that reveal which medication is best for which seizure type. Choosing a medication requires confirming the diagnosis of epilepsy, determining the seizure type, and considering comorbid conditions, adverse effects, potential for medication adherence, and cost and availability. Agents can be selected by FDA approval by seizure type. Exhibit 2 provides some example seizure types and those agents which are FDA approved for that type of seizure. Agents range from broad spectrum, which cover all seizure types, to narrow spectrum. Some examples of broad spectrum agents are valproate and felbamate. Narrow spectrum agents include gabapentin and carbamazepine. Another example is ethosuximde, which is only useful for absence seizures. Comorbid conditions can also influence medication selection. For example, those patients who also have bipolar disorder may benefit from lamotrigine, valproate, or carbamazepine. Topiramate, gabapentin, and valproate can also be used to treat migraine. Exhibit 3 lists the newer AEDs and some of their characteristics. Two of these agents (ezogabine and perampanel) represent new classes of AEDs. Several of the older AEDs now have long-acting, oncedaily formulations (lamotrigine, levetiracetam, oxcarbazepine, topiramate, and gabapentin). Theoretically, the extended-release formulations have fewer adverse effects compared with multiple daily doses due to more steady blood levels. Also the extendedrelease formulations and other AEDs dosed once a day have better adherence rates than multiple dosing per day agents. Adverse effects are also a consideration in selecting an AED. Almost all of the AEDs can cause Stevens-Johnson syndrome. Any rash that occurs should immediately lead to the discontinuation of AEDs. Weight gain or loss with medications is another major adverse effect consideration. Weight gain occurs with gabapentin, pregabalin, perampanel, vigabatrin, and valproate. It can be as much as 40 pounds with valproate. Topiramate, felbamate, and zonisamide all lead to weight loss. For women in childbearing years, the teratogenic potential for AEDs is an especially important consideration. Phenytoin, carbamazepine, phenobarbital, topiramate, lamotrigine, and valproate are known teratogens (Category D). All the secondgeneration AEDs are currently Category C (teratogenic in animals but human risk is unknown). It can take two decades of an agent being on the market before enough patients are exposed and enough data can be collected to determine if a given new agent is teratogenic. Folic acid is important for preventing early teratogenic effects (first trimester) with AEDs when an unplanned pregnancy occurs. All women of childbearing age on AEDs should receive daily folic acid supplements. The American Academy of Neurology guidelines on pregnancy and seizures recommend avoiding use of polytherapy, avoiding valproate for monotherapy or polytherapy, and limiting dosage of valproate and lamotrigine if they must be used. 1 Valproate has been shown to lower the IQ in children of mothers who are on the drug during pregnancy, but the effect is less with lower 50 Journal of Managed Care Medicine Vol. 19, No. 3

51 Exhibit 3: Newest Anti-Epileptic Medications in the U.S. Drug MOA Adverse Effects Comments Clobazam (Onfi, Frisium) Eslicarbazepine (Aptiom) Ezogabine (Potiga) Lacosamide (Vimpat) Perampanel (Fycompa) Long acting benzodiazepine Sodium channel First potassium channel modulator Acts as long acting sodium channels First AMPA part of glutamate receptors Drowsiness Dizziness Poor coordination Drooling Restlessness or aggressiveness Dizziness, nausea and vomiting, somnolence and diplopia Same side effects as carbamazepine and oxcarbazepine Reportedly better tolerated Less hyponatremia and rash Urinary retention Neuropsychiatric symptoms ( hallucinations, irritability, anxiety, depression) Dizziness and sleepiness Mild changes in heart rhythm Suicide thoughts Dizziness, nausea, diplopia, vertigo, mood PR prolongation Dizziness, somnolence, nausea, imbalance, vertigo, weight gain Anxiety, irritability BID dosing Low dependence/addiction potential Used very commonly in Mexico and Canada Limited FDA inidication Once a day dosing Indicated for partial seizures Closely related to oxcarbazepine and carbamazepine Slow titration Indicated for partial epilepsy Rare reports of blue skin discoloration of fingers/toes and visual loss Not frequently used Indicated for partial epilepsy Some data in generalized BID dosing Renal excretion Indicated for partial and generalized epilepsy Hepatic metabolism dose. 2 Kidney and liver function and potential for drug interactions can also impact AED selection. A few agents depend on renal elimination, including gabapentin, topiramate, levetiracetam, pregabalin, and lacosamide. All the other AEDs are predominately metabolized by the liver. Another AED consideration is the effect on the patient s mood. Some agents can elevate mood, while others tend to cause anxiety, depression, and irritability. The number of daily doses of an AED required is also vitally important to adherence. Studies have shown that missing a single dose of an AED increases risk of having a seizure by 40 percent. Those agents with only once or twice daily dosing are easier for the patient to be adherent with. Cost and availability are also important. Some AEDs, such as gabapentin, are easy to replicate, and there are no problems with generics. Lamotrigine, zonisamide, oxcarbazepine, and carbamazepine generics have had some issues. This issue is being examined by the FDA and seizures may be one instance where generics may not be the best choice. When combination therapy is required to control seizures, it may be most rational to use agents with different mechanisms of action. This is still a theory and has not yet been proven. AED mechanisms of action include affecting sodium channels, interacting with glutamate receptors, interacting with GABA, and potassium channels. A trial using newer agents in 523 untreated patients with epilepsy showed that 47 percent responded to their first AED monotherapy, 13 percent were seizure-free on the second AED monotherapy, and 1 percent on the third monotherapy choice. 3 Only 3 percent were controlled with two AEDs, and none with three. Prevention of drug resistant epilepsy should be the goal of treatment when the first AED is prescribed. The International League Against Epilepsy defines drug resistant epilepsy as a failure of adequate trials of two tolerated and appropriately chosen and used AEDs (whether as monotherapies or in combination) to achieve sustained seizure freedom. About 15 percent of epilepsy patients have drug resistance, but this small percentage accounts for over 80 percent of the cost of treating seizures. When a patient is deemed as drug resistant by the neurologist and has partial or focal disease, surgical candidacy should be assessed. Risks from uncontrolled seizures include declining IQ or other cognitive impairment, socioeconomic effects (cannot drive, cannot work), impaired quality of life, increased mortality, sudden death, re- Vol. 19, No. 3 Journal of Managed Care Medicine 51

52 Exhibit 4: The Clinical Trajectory 1 st Seizure No further seizures 2 nd + Seizure Seizures well controlled by single AED Seizures continue and poorly controlled AED withdrawl and no relapse AED withdrawl and relapse Continued seizures and no surgical option Continued seizures but response to surgery Continued seizures and poor response to surgery peated trauma, accidental injuries, and medication/ emergency room/hospital expense. The mortality rate in those with uncontrolled seizures is two times the general population rate. The sudden death rate is eight times higher. There are curative and palliative surgical procedures for seizure disorders. There is a potential for cure with partial/focal seizures. Several trials have found that surgical treatment outperforms medical treatment for temporal lobe epilepsy for seizure-free rates. 4-6 Temporal lobe surgery results in a long-term 70 percent or greater seizure-free rate with a 2 to 4 percent complication rate. Complications include memory, mood, and visual field issues. Mortality risk with this type of surgery is less than risk from seizures. Temporal lobe surgery results in improved quality of life and survival. Surgery for extra-temporal epilepsy has a 60 to 65 percent seizure-free rate. Thermal ablation is one of the new surgical techniques that is minimally invasive. This procedure is done through a burr hole in the skull versus a craniotomy with older techniques. The hospital length of stay has been reduced from over a week to one day with thermal ablation. It can be done for patients with focal epilepsy where the focus is eloquent or with a high risk of surgical complications. For patients who are drug resistant but are not surgical candidates, there are brain stimulators. These are like pacemakers for the brain. Responsive neurostimulation (NeuroPace RNS System) is a chip with an EEG computer embedded in it which is implanted into the skull. The electrodes are placed over the area of the likely seizure origin. The device detects seizures as they occur and sends a stimulation to break up the seizure. This device is not a cure but does lead to a 44 to 66 percent long-term seizure reduction. 7 Patients will either respond dramatically or will have no benefit. Vagal nerve stimulation (Aspire SR ) and trigeminal nerve stimulation (TNS) work in a similar manner. Vagal nerve stimulation, through an implanted device, results in a 45 percent reduction in seizure frequency and may elevate mood. Patients in the vagal stimulator clinical trials experienced seizure cessation, shorter seizures, and improved postictal recovery. 8 TNS, using an external device, is approved in the European Union and in trials in the U.S. A 30 percent responder rate was shown in one trial. 9 Deep brain stimulation is approved in Europe for seizures but not in the U.S. When done in the deep thalamus, it can be helpful for epilepsy not controlled by any other means. The clinical trajectory for patients with seizures is given in Exhibit 4. Any patient with a single seizure or epilepsy will be treated this way. About 10 percent of the world population will have a single seizure. One in 26 Americans develop epilepsy. Overall, 60 percent of those with epilepsy are controlled with a single agent. Fifteen to 20 percent are poorly controlled and may or may not have a surgical option. Conclusion It is an exciting time in the management of epilepsy with many new medications, surgical treatments, and device- 52 Journal of Managed Care Medicine Vol. 19, No. 3

53 based treatments available. Managing seizures appropriately can help preserve a patient s quality of life. Although some patients remain poorly controlled, the majority can be controlled on a single antiepileptic medication. Joseph I. Sirven, MD, is a Professor of Neurology and Chairman of the Department of Neurology at the Mayo Clinic in Arizona. References 1. Harden CL, Meador KJ, Pennell PB, et al. Management Issues for Women with Epilepsy Focus on Pregnancy (an evidence based review): Teratogenesis and perinatal outcomes. Neurology. 2009;73(2): Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360(16): Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology. 2002;58(8 Suppl 5):S2-S8. 4. Choi H, Sell RL, Lenert L, et al. Epilepsy surgery for pharmacoresistant temporal lobe epilepsy: a decision analysis. JAMA. 2008;300(21): Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5): Helmstaedter C, Kurthen M, Lux S, et al. Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol. 2003;54(4): Heck CN, King-Stephens D, Massey AD, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014;55(3): Data on file, Cyberonics Inc. Houston, TX 9. DeGiorgio CM, Soss J, Cook IA, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology. 2013;80(9): The Oncology Institute NAMCP Oncology Proole Purchasers, health plans and integrated systems transform their oncology data into oncology information (costs, resources used, patient severity, guideline concordance and benchmarks) to manage change. NAMCP PAVE the Way to Quality in Cancer Care (Patients, Value, Answers, Expectations) Purchasers, health plans and integrated systems provide patients with questions to open, clear conversations with their care team on expectations, care and treatment to empower patients in decisions around their journey. NAMCP Medical Directors Guide: Palliative Care in Oncology Clear information on issues and trends in palliative care for oncology patients to help Medical Directors from purchasers, health plans and integrated systems. jmcmpub.org/pdf/ palliative-care-guide P (804) F (804) keads@namcp.org Waterfront Drive, Suite 101 Glen Allen, VA Vol. 19, No. 3 Journal of Managed Care Medicine 53

54 Current and Emerging Treatment Paradigms in the Management of Hemophilia Barbara A. Konkle, MD For an accredited version of this article, please go to and then click the activity title. Summary Hemophilia is an expensive to treat but rare disorder. Improvements in care of these patients have led to increases in survival and reductions in disability. Additional improvements with clotting factor replacements and possibility gene therapy will continue to make strides in enhancing care. Key Points Long-term complications include joint destruction, muscle atrophy, and decreased quality of life. Inhibitor development is the most severe complication. Prophylactic factor replacement avoids or reduces musculoskeletal impairment, decreases death from bleeding, and enhances quality of life. Longer-acting factor replacement products and gene therapy will change treatment models. The Hemophilia Treatment Center model offers improved clinical and economic outcomes via multidisciplinary, comprehensive care. HEMOPHILIA IS AN X-LINKED RECESSIVE bleeding disorder that leads to bleeding following trauma or surgery or spontaneous bleeding. It is typically expressed in males, but female carriers can have symptoms. It is characterized by a deficiency of Factor VIII (hemophilia A) or Factor IX (hemophilia B). Hemophilia A is about four times more common than hemophilia B. Hemophilia is a rare disease and affects about 20,000 males in the United States (U.S.). It occurs in about one of every 5,000 live male births. Approximately 30 percent of cases are new mutations. Because of new mutations, it affects individuals from all racial and ethnic groups and it is not unusual to see a child born with hemophilia who has no family history. The clinical manifestations of this disorder include bleeding into joints (hemarthrosis), muscles, soft tissues, and other locations anda life-threatening bleeding in the central nervous system, retroperitoneum, and neck. Large joints are the most common joints that get bleed into in moderate to severe hemophilia. Intracranial bleeding is the main cause of death in hemophilia. Long-term sequelae, if bleeding is not prevented, include flexion contractures, arthropathy, chronic pain, muscle atrophy, loss of mobility, and neurologic impairment. Patients can have interference with normal activities and with the ability to participate fully in school or work. Older patients in hemophilia clinics demonstrate all the impact of not having good disease control with multiple joint replacements, need for assistive 54 Journal of Managed Care Medicine Vol. 19, No. 3

55 Exhibit 1: Clinical Classification Classification (% of affected patients) Severe (50% - 70%) Moderate (10%) Mild (30% - 40%) FVIII or FIX activity < 1% 1% - 5% 6% - 40% Pattern of bleeding episodes ~2-4 per month* ~4-6 per year** Uncommon Cause of bleeding episodes Spontaneous Minor trauma Major trauma, surgery *If not on prophylactic therapy **Patients with moderate disease may bleed like those with severe or mild disease devices for walking, and lots of disability. Younger patients have the benefit of better disease control, so the disability rates from hemophilia are going down. Patients can be classified as having severe, moderate, or mild disease based on factor levels (Exhibit 1). Classification predicts risk of spontaneous bleeding. Those with severe disease, who essentially have no clotting factor, will bleed several times a month without treatment. Factor levels above 5 percent prevent spontaneous bleeding. Those with mild disease ( 6%) will need factor replacement for several weeks in cases of surgery or major trauma. Women with a family history of hemophilia should be tested to see if they are carriers. Those women who are identified as carriers need preconception counseling. Any male offspring of carriers will have their cord blood tested at birth. Even mild disease should be identified early to prevent bleeding with surgery or injury. In infants without a family history, bleeding with birth, circumcision, or immunizations; excessive bleeding following trauma/injury; or joint bleeds and hematomas would be indications for hemophilia testing. Only about 50 percent of males born with severe hemophilia will bleed before the age of two. Once boys are walking is when episodes increase. There are two treatment approaches for hemophilia - episodic or on-demand factor replacement and prophylaxis. The treatment goal of hemophilia today is to prevent bleeding episodes through use of prophylactic factor therapy. This is a shift from years ago when patients were only treated when they had an episode of bleeding. If bleeding episodes occur, even on prophylaxis, they are treated with rapid and effective replacement of the missing coagulation factor. Significant advances have been made in the past six decades in factor replacement. Years ago, the only choice for therapy was hospital-based factor infusion. Now there are many different options which are routinely given in the home. High purity virally inactivated factors (which eliminated the risk of HIV and hepatitis transmission) was one significant advance. The factors are all still given intravenously, so parents or the patient themselves have to be taught how to give the infusions. By preteen years, patients should be giving themselves their own infusions. Patients have great control over their disease when they do their own infusions. The improvements in factor replacement has led to improvements in survival. 1 The hemophilia population is also aging as a result of improved survival. The life expectancy for someone with severe hemophilia is almost that of someone without. Prophylaxis is infused factor replacement before the occurrence of, and to prevent, bleeding and is the mainstay of therapy for most patients. Since the 1990s, prophylaxis has been supported by the World Health Organization, the National Hemophilia Foundation, and the World Federation of Hemophilia as first-line treatment for children with severe hemophilia. 2,3 Prophylaxis in adult patients with moderate to severe disease has been increasing. 4 In the U.S., most children are allowed to have one bleed or reach a particular age where infusion is easier before prophylaxis is started. In Europe, the practice is to start prophylaxis before any bleeds ever occur. When prophylaxis is started at a young age, the demonstrated benefits of prophylaxis include prevention of chronic arthropathy and sequelae, prevention of intracranial and other serious bleeds, prevention of pain, improvement in quality of life, and reduction in long-term disability. 5-8 If a child receives aggressive on-demand replacement initially and is switched later in life to prophylaxis, the child will always have more disability than someone who was given prophylaxis from the beginning. In adults, bleeding rates are reduced by prophylaxis. It is more difficult to demonstrate benefits Vol. 19, No. 3 Journal of Managed Care Medicine 55

56 Exhibit 2: Factor VIII and IX Products Parameter Factor VIII Factor IX Intravenous infusion IV push Contiuous infusion Dose units/kg body weight units/kg body weight Half-life 8-12 hours hours Expected change in Factor level with each unit infused Parameter +2% +1% Factor VIII Recomb-inant Plasmaderived Plasmaderived Factor IX Recomb-inant Easy to store and prepare May contain immuno-modulatory proteins /-* /-* Increase dose up to 1.5 vs. plasma-derived * variable depending on level of purity on joints because most already have some damage. Today, young men coming into adult hemophilia programs are already on prophylaxis and have good joints. Most adult programs will try to continue prophylaxis in these patients to continue to preserve function over time. In adults who have never been on prophylaxis, the rate of bleeding episodes and worsening joint damage will be used to decide on whether to switch to prophylaxis. Seventy percent of adults are currently on prophylaxis. To achieve the best long-term outcomes, most children are started aggressively with three times per week infusions and decreased to twice a week if possible. To reduce the interference with daily life, many adults are started at two times a week and increased if necessary. The development of factor replacement has progressed over the years from high purity factor concentrates (eliminating risk of HIV and hepatitis transmission) to recombinant factor concentrates to increasing use of prophylaxis to new long actingfactors, which reduce the frequency of administration and gene therapy. The recombinant factors appear to have fewer immunomodulatory proteins which may lead to inhibitor formation which is discussed later. The half-life of standard hemophilia therapies results in frequent injections. Factor VIII is given three times per week to every other day depending on patient response and factor IX is given two to three times per week. Benefits of replacement products with a longer half-life could include reduced frequency of administration, ability to achieve higher trough factor levels in certain clinical situations, and potentially improved adherence. Giving fewer times per week should improve quality of life. Fewer infusions weekly are of significant benefit in very young children and older patients with poor venous access. The first longer-lasting rfviii and rfix have obtained FDA approval. Additional ones are also under study. Longer-lasting FVIII (rfviiifc) increases factor half-life by one and a half times, whereas the longer-lasting FIX (rfixfc) increases half-life by five times. With the longer lasting FIX, this may mean once a week or even every other week infusion. Clinicians are now struggling with where these fit in therapy and which patients will achieve the most benefit from a reduced dosing frequency. Exhibit 2 illustrates some of the differences between the plasma-derived and recombinant factor replacement products. Measurement of factor levels is a key for management. The ability to measure can be used to minimize costs of factor replacement. An albumin fusion protein (rix-fp) was FDA approved in mid This is a long- acting fusion protein linking recombinant coagulation factor IX with recombinant albumin designed to preserve the native function of the coagulation factor in the fusion protein, while benefiting from recombinant albumin s long physiological half-life. In clinical trials in hemophilia B, rix-fp maintained factor IX activity levels above 5 percent over 14 days, resulting 56 Journal of Managed Care Medicine Vol. 19, No. 3

57 in a median annualized spontaneous bleeding rate of 0.00 when used as prophylaxis. 9 Neutralizing antibody (inhibitor) development to factor replacement therapy is a major complication of current treatment. Infusion of an exogenous clotting factor can trigger an immune response. IgG antibodies (inhibitors) directed against Factor VIII or IX protein neutralizes the procoagulant effect of the infused factor. The incidence is highest in patients with severe disease (Hemophilia A, 20-30%; Hemophilia B, 1-4%). Inhibitors typically develop early in life (median age years). The greatest risk for inhibitor development occurs within the first 50 days of exposure to infused product, but risk continues throughout the lifetime and may increase in older age. 10,11 Regular laboratory monitoring for inhibitors is needed. Those who develop inhibitors have more bleeding and joint damage. There are several strategies to manage inhibitors. Bypassing agents include activated prothrombin complex concentrates and recombinant factor VIIa. Bypassing agents have unpredictable efficacy (50 90%), are not as effective as replacement therapy, and cost more. Patients often need access to both products. Immune tolerance therapy (ITT) is a method to eradicate inhibitors with a 70 percent overall effectiveness. This involves giving high doses of factor replacement daily. If the inhibitors can be cleared, the patient can then go back to a regular replacement schedule. Overall, the cost of treating inhibitors is significant. Instead of factor replacement, desmopressin acetate (IV, intranasal) can be used in mild FVIII deficiency. Patients need to be tested to ensure that desmopressin effectively increases FVIII levels. Antifibrinolytic agents, aminocaproic acid, and tranexamic acid may be used adjunctively during bleeding episodes or surgical procedures. For example, adjunctive antifibrinolytics are needed when a prostate biopsy is done. Supportive measures such as joint icing, immobilization, and rest along with physical therapy by a physical therapist with hemophilia experience can help reduce the damage from joint bleeds. New agents for treatment are under study, including a thrombin inhibitor and a bispecific antibody that takes the place of factor VIII. Both of these agents are being studied as subcutaneous injections, which would be a significant improvement over current products. Gene therapy is in late-phase clinical trials. Clinicians need better ways to predict which patients will have complications. This may be better defining genetic and clinical factors to predict those who will develop inhibitors and predict those who will bleed less (or more). A current initiative is My Life, Our Future, a collaboration between the National Hemophilia Foundation, the American Thrombosis and Hemostasis Network, BloodworksNW and Biogen. This program offers free or very low-cost genotyping to people with hemophilia and their families, with the goal of improving hemophilia care by increasing understanding of the disorder today and building the scientific foundation for the breakthrough treatments of tomorrow. There are many ongoing clinical questions that need to be answered. In prophylaxis, traditionally trough values of 1 percent factor levels have been targeted. This trough value was chosen because those with moderate hemophilia (1-5% activity) bleed less than those with values less than 1 percent. One percent probably is not the right number for everyone. Studies need to be conducted to determine the best trough for personalized care. The cost to benefit ratio of targeted higher levels would have to be determined and so would the impact on patient outcomes and quality of life. Another issue is defining the benefit of prophylaxis in various age groups not just for pediatrics. When treating bleeding episodes, the best target peak factor level and optimal length of hemostatic coverage need to be determined. For individualized treatment, pharmacokinetic parameters are needed to inform dosing of new factor products and tools for prediction of levels are needed. Using factor activity levels may be the way to go in individualizing factor replacement. With the aging of the hemophilia population, greater research is needed in the management of comorbidities of aging. For example, as a hemophilia patient ages, there are challenges with treating cardiovascular diseases where anticoagulants have been the recommended therapy. With new hepatitis C medications, there is an opportunity to cure hepatitis C. It is less expensive to treat hepatitis C than to pay for clotting factor use in liver failure. A hemophilia treatment center (HTC) is a federally recognized comprehensive care facility featuring a multidisciplinary team of experts experienced in the care of patients with bleeding disorders and whose staff spends a majority of their time caring specifically for these patients. Key features of an HTC are expertise in coagulation disorders, development and provision of individual treatment plans, preventive medicine, access to multiple health care disciplines, and optimization of care. These centers may have an associated 340B factor program that reduces cost of factor replacement. Treatment via the HTC model results in more comprehensive care with efficiencies that drive improved outcomes. 12 For patients receiving care outside of an HTC, the mortality rate increases by 70 percent and the hos- Vol. 19, No. 3 Journal of Managed Care Medicine 57

58 pitalization rate rises by 40 percent To optimize care, comprehensive HTCs should be managing all patients with hemophilia. New options for measuring outcomes in hemophilia are coming. Evidence-based clinical practice guidelines, being developed independently by a Mc- Master University led group under the direction of the National Hemophilia Foundation, should be published in Several groups have large databases for outcomes research. The American Thrombosis and Hemostasis Network (ATHN) is a nonprofit organization maintaining a secure database of information from over 130 HTC affiliates. The National Hemophilia Program Coordinating Center for Health and Human Services is an evaluative program underway to establish best practices. CDC Public Health Surveillance has data on over 27,000 patients in a HIPAA compliant database. It is hoped these resources will provide data to identify the best treatment processes/ regimens which produce the best outcomes. Conclusion Hemophilia is an X-linked recessive bleeding disorder. A common symptom is bleeding into joints and muscles. Long-term complications include joint destruction, muscle atrophy, and decreased quality of life. Inhibitor development is the most severe complication. Prophylactic factor replacement may avoid or reduce musculoskeletal impairment, decreases death from bleeding, and enhances quality of life. Longer-acting factor replacement products and gene therapy will change treatment models. The HTC model offers improved clinical and economic outcomes via multidisciplinary, comprehensive care. Barbara A. Konkle, MD, is the Associate Director at the Washington Center for Bleeding Disorders and the Director of Clinical and Translational Research at Bloodworks Northwest (formerly Puget Sound Blood Center). She also serves as a Professor of Medicine/Hematology at the University of Washington in Seattle, WA. 1. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007;110(3): Carcao M, Chambost H, Ljung R. Devising a best practice approach to prophylaxis in boys with severe haemophilia: evaluation of current treatment strategies. Haemophilia. 2010;16 Suppl 2: Rodriguez NI, Hoots WK. Advances in hemophilia: experimental aspects and therapy. Hematol Oncol Clin North Am. 2010;24: Collins PW, Björkman S, Fischer K, et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost. 2010;8: Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6): Brown DL, Shapiro AD. The Role of Prophylaxis in Managing Hemophilia in Adult and Pediatric Populations. Available at: viewarticle/703176_print. 7. Berntorp E, Astermark J, Björkman S, et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia. 2003;9 Suppl 1: Manco-Johnson MJ, Kempton CL, Reding MT, et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost. 2013;11(6): Santagostino E, Martinowitz U2, Lissitchkov T3, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rix-fp) in hemophilia B: results of a phase 3 trial. Blood. 2016;127(14): Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood. 1994;83(9): Hay CR, Palmer B, Chalmers E, et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011;117(23): Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood. 2000;96(2): Soucie JM, Symons J 4th, Evatt B, et al. Home-based factor infusion therapy and hospitalization for bleeding complications among males with haemophilia. Haemophilia. 2001;7(2): References 58 Journal of Managed Care Medicine Vol. 19, No. 3

59 Effective Strategies in Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation Noel G. Boyle, MD For an accredited version of this article, please go to and then click the activity title. Summary Stroke prophylaxis must be addressed in every patient with atrial fibrillation (AF). The novel oral anticoagulants provide improved risk reduction with similar or lower risk of bleeding complications compared with warfarin. Therapy choice will depend on the other risk factors for stroke, risk factors for bleeding present in the patient, and other concomitant conditions such as kidney dysfunction. Key Points Stroke prophylaxis is very important in patients with AF. Stroke risk scores determine whether prophylaxis is needed. Novel anticoagulants offer several advantages over warfarin. ATRIAL FIBRILLATION (AF) IS TREATED with cardioversion, antiarrhythmics, rate control, and prevention of thromboembolism. This article focuses on thromboembolism prevention. Approximately, 15 percent of all strokes are related to AF. In those over 75 years of age, up to 25 percent of strokes are caused by AF. Stroke from AF has a higher morbidity rate and long- term morbidity than strokes from other causes. The risk of stroke is the same whether someone has paroxysmal, persistent or permanent AF. Thus, the thromboembolism prevention guidelines apply to all types of AF, and everyone with AF needs to be evaluated for prophylaxis. 1 Stroke risk can be estimated with the CHA 2 DS 2 -VASc scoring system (Exhibit 1). 2 As the score increases, the stroke risk increases. Exhibit 2 lists the recommended regimens based on risk scoring. 1 For many years, warfarin and aspirin were the only choices for anticoagulation and antiplatelet therapy. Overall, warfarin reduces risk of stroke by 66 percent and aspirin by 21 percent. 3 The guidelines have moved away from the use of aspirin for AF indication. Novel oral anticoagulants (NOACs) were first approved in The currently approved agents are dabigatran (Pradaxa ), rivaroxaban (Xarelto ), apixaban (Eliquis ), and edoxaban (Savaysa ). Many times patients and clinicians will ask whether clopidogrel and aspirin, used for another indication such as stent placement, can be used in place of anticoagulation. Unfortunately, they are not a substitute. In one trial comparing the combination with warfarin in AF, the risk of stroke was significantly higher with the combination. 4 Warfarin does have some advantages it is effective, familiar for clinicians, and inexpensive. The effect can be measured (international normalized ratio, INR) and rapidly reversed with vitamin K. It is well known that procedures such as pacemaker and ICD implants can be done safely if the INR is less than 3.0. There are rare adverse effects apart from bleeding. There is also the social aspect of warfarin clinic visits. The disadvantages of warfarin are also well Vol. 19, No. 3 Journal of Managed Care Medicine 59

60 Exhibit 1: Stroke Risk and the CHA 2 DS 2 -VASc Score 2 CHA 2 DS 2 -VASc Risk Score CHA 2 DS 2 -VASc Score Adjusted stroke rate (%/year) 0 0 CHF or LVEF <40% Hypertension Age > Diabetes Stroke/TIA/ Thromboembolism Vascular Disease Age Female CHF = congestive heart failure TIA = transient ischeic attack LVEF = left ventricular ejection fraction known, including a narrow therapeutic window. The risk of stroke dramatically increases if the INR falls below 1.8, and the risk of bleeding increases with an INR above 3.0. Other issues include interaction with many drugs including alcohol, interaction with vitamin K containing foods, slow onset and offset of action, and an initial modestly prothrombotic state through decreased protein S levels when therapy is initiated. The effect must be measured and the dose adjusted frequently, resulting in trips to a warfarin clinic, which can be inconvenient or impractical and expensive. Additionally, the time spent adjusting therapy is not reimbursed by Medicare. Probably the most important disadvantage is the fear of warfarin among patients and doctors. These disadvantages have led to low rates of anticoagulation in high-risk AF patients. 5 For those who do get anticoagulated with warfarin, about 60 percent will be in the therapeutic range the majority of the time. 6 The other 40 percent are either over or under-anticoagulated. Patients who have risk factors for bleeding can be identified by HAS-Bled scale (Exhibit 3). 7 Clinicians need to document high risk for bleeding or refusal of anticoagulation in patients with stroke and AF. The NOACs have several advantages over warfarin in nonvalvular AF. These include predictable effect without need for monitoring, fewer medication interactions, no food interactions, more predictable half-life and elimination, very quick onset of effect, and an improved safety to efficacy ratio. In large efficacy trials, the NOACs have been shown to have at least equal efficacy in reducing the risk of stroke and systemic embolization and lower rates of major bleeding (hemorrhagic stroke) All agents reduce the risk of bleeding (fatal for rivaroxaban, major for apixaban, major at 110 mg for dabigatran) and intracranial hemorrhage. The directionality and magnitude of the mortality reduction is consistent and approximates a relative risk reduction of 10 percent per year. Differentiators among the agents include that dabigatran at a dose of 150 mg was associated with a reduction in ischemic stroke, rivaroxaban is a once a day drug associated with a lower rate of fatal bleeding, and apixaban was associated with a reduction in all-cause mortality, but not in cardiovascular mortality. Exhibit 4 provides suggestions for selecting a NOAC in selected situations. Apixaban and warfarin are the agents of choice when a patient requires dialysis. Clinicians need to be confident that the patient is compliant with a NOAC because nothing can be measured to make sure they are taking it. The European Heart Rhythm Association (EHRA) Practical Guide to NOACs recommends having patients bring their medication to each visit for tablet counts to assess adherence. 12 Other assessment at each visit should include circulation assessment for thromboembolism, adverse effects including bleeding, current medication list, and periodic laboratory monitoring. Renal function tests are especially important because each NOAC must be dose adjusted based on 60 Journal of Managed Care Medicine Vol. 19, No. 3

61 Exhibit 2: Approach to Thromboprophylaxis in Patients with AF 1 Risk Category One major risk factor or 2 clinically relevant non-major risk factors One clinically relevant non-major risk factor CHA 2 DS 2 -VASc Score No risk factors Recommended Antithrombotic Therapy OAC a Either OAC a or aspirin mg daily. Preferred: OAC rather than aspirin Either aspirin mg daily or no antithrombotic therapy. Preferred: No antithrombotic therapy rather than aspirin. Exhibit 3: Clinical Characteristics Comprising the HAS-BLED Bleeding Risk Score 7 Letter Clinical Characteristic a Points Awarded H Hypertension 1 A Abnormal renal and liver function (1 point each) S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (e.g. age > 65 years) 1 1 or 2 D Drugs or alcohol (1 point each) 1 or 2 High Risk: Score > 3 Maximum 9 points creatinine clearance. When the NOACs were initially promoted, they had the reputation for having no medication interactions but, as they were used in a wider population, some important ones have been identified. Plasma levels of NOACs can be altered by p-glycoprotein inducers or inhibitors. P-glycoprotein is involved in the absorption and renal clearance of these agents. Cytochrome P450 3A4 is involved in the hepatic clearance of rivaroxaban and apixaban; thus, plasma levels can be altered by 3A4 inducers or inhibitors. Inducers include anticonvulsants and rifampicin. Inhibitors include antivirals for HIV, macrolide antibiotics, antifungals, cyclosporine, amiodarone, dronedarone, and verapamil. Some of these can be very significant increases such as 150 percent increase of dabigatran and rivaroxaban with fluconazole. There is now a reversal agent (idarucizumab, Praxbind ) for dabigatran. This agent will reverse the effects within minutes. Reversal agents for the other NOACs should be coming in the near future. Patients need to be educated on the NOACs and what to do if they have bleeding. There are several excellent guidelines or resources for clinicians managing patients with AF. These include the AHA/ACC/HRS 2014 Guidelines, EHRA Practical Guide on the use of the novel oral anticoagulants (NOACs), Heart Rhythm Society Practical Management of Atrial Fibrillation, and the World Heart Federation tool for bringing practice 1, closer to guidelines. The guidelines recommend that patients be involved in decision-making when selecting AF thromboembolism prophylaxis. 1 There are several good resources available for patients, including the American Heart Association Patient Guide for taking the NOACs. 15 Many health systems also have patient guides. Vol. 19, No. 3 Journal of Managed Care Medicine 61

62 Exhibit 4: CHOOSING between the NOACs Once per day dosing Age > 80 Drug Rivaroxaban, edoxaban Dabigatran 110 mg, apixaban, rivaroxaban, edoxaban Consideration Dabigatran 150 associated with excess bleeding in those over 80 History of stroke Apixaban, rivaroxaban Apixaban has largest reduction compared with warfarin; rivaroxaban has largest studied population with previous stroke Previous gastrointestinal bleeding High stroke risk, high bleeding risk Apixaban Dabigatran 150 mg Only NOAC with reduced GI bleeding compared with warfarin Largest reduction in ischemic stroke with this dose Concomitant coronary disease Rivaroxaban Only NOAC with mortality reduction after acute coronary syndromes. Concomitant kidney disease Apixaban, rivaroxaban, enoxaban Least renal elimination (25%, 35%, 50% respectively) Intended electrocardioversion Rivaroxaban Only NOAC with prospective trial versus warfarin for intended cardioversion Conclusion Anticoagulation of those with AF has been underutilized in the past because of real or perceived issues with warfarin. Appropriate preventive therapies should be prescribed for those patients with AF at significant stroke risk. The newer anticoagulants provide clinicians with additional choices for anticoagulation and should be available for selection. Noel G. Boyle, MD, is a Professor of Medicine with the UCLA Cardiac Arrhythmia Center at the Ronald Reagan UCLA Medical Center in Los Angeles. References 1. January CT, Wann LS, Alpert JS, Calkins H, et al AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol. 2014: 64: Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2): Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7): ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526): Ogilvie IM, Newton N, Welner SA, et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(7): e4. 6. Ansell J, Hollowell J, Pengo V, et al. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM). J Thromb Thrombolysis. 2007;23(2): Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS- BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5): Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12): Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10): Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22): Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Available at Accessed 6/20/ Heart Rhythm Society. Practical Management of Atrial Fibrillation. Available at Accessed 6/20/ World Heart Federation. Atrial Fibrillation in Primary Care. Bringing atrial fibrillation practice closer to guidelines. A tool for primary care physicians. Available at awareness/atrial-fibrillation/tools-materials. Accessed 6/20/ Lane DA, Wood K. Patient Guide for Taking the Non Vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation. Circulation. 2015;131:e412- e Journal of Managed Care Medicine Vol. 19, No. 3

63 Improving Patient Outcomes with Novel Treatments in the Management of Hypertriglyceridemia Harold Bays, MD, FTOS, FACC, FACE, FNLA For an accredited version of this article, please go to and then click the activity title. Summary Hypertriglyceridemia (HTG) is a known risk factor for atherosclerosis. Treatment is somewhat controversial because of lack of specific trial data. Trials underway may provide some clarity for use of at least omega-3 fatty acids. Key Points Although HTG has been treated with fibrates, statins, and omega-3 fatty acids for many years, data supporting their use are from trials which did not enroll HTG only subjects. Omega-3 fatty acid trials in patients with HTG alone are underway. Non-HDL-C values need to be measured to determine the ultimate benefit of triglyceride lowering. HIGH TRIGLYCERIDE (TG) LEVELS ARE IMportant for two main reasons pancreatitis and atherosclerotic cardiovascular disease (ASCVD). Values greater than 500 mg/dl and particularly over 1000 mg/dl increase the risk of pancreatitis. Treating elevated TG levels is important to reducing ASCVD risk because TG-rich lipoproteins are atherogenic. 1-2 Additionally, TG lipolysis by lipoprotein lipase causes proinflammatory free fatty acid formation. Hypertriglyceridemia (HTG) causes atherogenic changes in low-density lipoprotein (LDL) and highdensity lipoprotein (HDL) particles. HTG is often associated with high apolipoprotein (Apo) B levels. Apo C-III in TG-rich particles enhances vascular endothelial activation and monocyte adhesion. Primary and secondary causes of increased TG are numerous. 1,3 Familial combined hyperlipidemia (FCHL) and familial HTG are common primary causes. FCHL is associated with increased central obesity and Hyper-Apo B levels. HTG manifests as increased TG alone and not total cholesterol. It is associated with increased CVD if central obesity and metabolic syndrome are present. It is largely due to increased hepatic VLDL production and Apo B is usually normal. Secondary causes include excess intake of saturated fat, high glycemic index foods, and simple sugars; diabetes; hypothyroidism; nephrotic syndrome; alcohol (fatty liver); marijuana; and certain medications. Medications known to increase TGs include antiretroviral regimens (for HIV), some phenothiazines and second-generation antipsychotics, nonselective beta-blockers, thiazide diuretics, oral estrogen, tamoxifen, glucocorticoids and isotretinoin. Exhibit 1 illustrates the classification for TG values. 4-6 An elevated triglyceride level is not a target of therapy per se, except when very high (>=500 mg/dl). 7 When the triglyceride concentration is very high (>=500 mg/dl, and especially if >=1000 mg/dl), reducing the concentration to <500 mg/ dl to prevent pancreatitis becomes the primary goal of therapy. When triglycerides are between 200 and Vol. 19, No. 3 Journal of Managed Care Medicine 63

64 Exhibit 1: Triglyceride Level Classifications 4-6 American Heart Association National Lipid Association Endocrine Society TG Level* mg/dl TG Level* mg/dl TG Level* mg/dl Optimal < 100 Normal < 150 Normal < 150 Normal < 150 Borderline High Borderline High Mild High High Moderate Very High 500 Very High 500 Severe** *Fasting levels **> 2000 mg/dl is very severe Exhibit 2: Non-HDL-C Includes Cholesterol in All Atherogenic Lipoproteins VLDL Very-low-density lipoprotein Made in the liver, takes lipids to periphery Apo-B, C-I, C-II, C-III, -E TG >> CE Non-HDL-C = TC - HDL-C IDL LDL Intermediate-density lipoprotein Formed from VLDL with loss of TG Apo E>>Apo B TG CE Low-density lipoprotein Formed from IDL with loss of TG; main plasma cholesterol carrier; Apo B CE >> TG Lp(a) Lipoprotein (a) Formed from LDL plus apo(a) Atherogenic/pro-oxidative CE = cholesterol ester TC = total cholesterol Apo = apolipoprotein HDL High-density lipoprotein Apo-AI Removes cholesterol from peripheral tissue 499 mg/dl, the targets of lipid therapy are non HDL-C and LDL-C. 7 Elevated TGs lead to increased levels of small dense LDL particles, low levels of HDL, and increased non-hdl-c. Non-HDL-C is the totality of cholesterol carried on atherogenic lipoproteins (Exhibit 2). Some groups (National Lipid Association) and clinicians believe that non-hdl should be another primary target of therapy and not just LDL- C. Two patients can have the same LDL and have vastly different atherogenic lipid profiles if one also has elevated TG. Elevated TGs respond well to lifestyle changes. Among major lipid parameters, physical activity most consistently reduces triglyceride levels. Weight loss in individuals with overweight or obesity may have the greatest impact on improving triglyceride levels; substantial weight loss is required for lowering LDL levels. Managing the secondary causes such as diabetes and hypothyroidism or stopping offending medications can also reduce levels. Even after lifestyle changes, many patients will still need medi- 64 Journal of Managed Care Medicine Vol. 19, No. 3

65 Exhibit 3: Lipid Effects of Drug Classes in Subjects with Primary Hyperlipidemia/Mixed Dyslipidemia and Isolated HTG 9 Type of Dyslipidemia Medication Mixed dyslipidemia TG* LDL-C* HDL-C* Non- HDL-C* Statins -10 to to to to -60 OM-3 fatty acids -19 to to to +7-1 to -7 Fenofibrate, fenofibric acid and gemfibrozil -24 to to to Niacin -5 to to to +26 NR Isolated HTG Statins -21 to to to to -52 OM-3 fatty acids -26 to to to to -14 Fenofibrate, fenofibric acid and gemfibrozil * Range % NR = Not Recommended -46 to to to +23 NR cations to lower TGs. Exhibit 3 illustrates the effects of TG specific treatment on the various lipid levels. 8 The effect of fibrates on lipid levels is dependent upon baseline TGs. If baseline TG values are less than 200 mg/ dl, fibrates will lower LDL-C. If they are greater, LDL will increase. This effect can be dramatic in those with very high TGs. Omega-3 fatty acids (OM-3s) can also increase LDL. If patients are also treated with statins, the effect of OM-3s on LDL is minor. The rise in LDL-C with one of these therapies means that VLDL is being removed and more cholesterol is being carried on LDL. As long as non- HDL-C is going down with a therapy, atherosclerotic risk is being decreased. The effective components for TG lowering of OM-3s are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). OM-3s can be obtained from fatty fish such as salmon, herring, mackerel, and halibut. There are various fish oil supplements and prescription omega- 3s list these. They have slightly different effects on the lipid profile. Icosapent ethyl (pure EPA) lowers non-hdl-c the most and lowers apolipoprotein B and LDL-C. Exhibit 4 illustrates the differences between omega-3 supplements and prescription products. To get an accurate dose of EPA and DHA, patients must read the supplement label. Many are labeled as 1 gm of omega-3 but may have substantially less than one gram of EPA and DHA. If clinicians recommend an OM-3 supplement, they need to educate the patient on reading the supplement facts label to achieve the correct dosing. A major factor contributing to the uncertainty in treating HTG is that no prospective coronary disease outcome trial conducted in hypertriglyceridemic patients has ever shown as a primary endpoint that lowering TG levels (and only TG levels) reduces CHD events. 9 Many epidemiologic (fish or fish oil consumption) and prospective trials of OM-3s done in those who already have heart disease find cardiovascular benefit, but not all do. Some of the studies have been discredited because some of data were made up. There are no trials where fibrates were given in those with only high TGs even though the fibrates have been used for many years for this purpose. Post-hoc analyses of statins, fibrates, and EPA trials for general lipid lowering or CVD benefit do show improvement in those who had high TGs at baseline but these trials did not enroll people with very high TGs. Two trials are currently testing whether 4 grams of EPA per day (REDUCE-IT) or 4 grams combined of EPA and DHA/day (STRENGTH) in those with high CV risk who are at LDL-C goal on a statin improves CV outcomes. TGs are greater than 200 mg/ dl in these trials. The results of these prospective trials should hopefully add some clarity for the role of omega- 3s. No trials are being done with fibrates. There are a many other possible indications for OM-3s from fish oils. These include inflammation, rheumatologic and bone, neuropsychiatric, eye health, women s health, and cancer. OM-3s also have effects which theoretically are beneficial in preventing cardiovascular disease other than TG lowering. These include anti-dysrhythmic, anti- Vol. 19, No. 3 Journal of Managed Care Medicine 65

66 Exhibit 4: Prescription vs Dietary Supplement OM OM-3 acid etyl esters (Lovasa, generics) Icosapent ethyl (Vascepa ) Dietary OM-3 Supplements FDA product classification Drug Drug Food FDA approval Yes Yes No Ingredients DHA + EPA EPA Variable amounts of DHA + EPA (may include other PUFAs) Quantity of OM-3 per capsule 1g 1g Typically 300 mg 800 mg EPA and DHA Typically EPA Capsules/day to achieve 4g OM Recommanded dose 4 g/day 4 g/day Tested in clinical trials Yes Yes Not required PUFA = polyunsaturated fatty acid CHD = coronary heart disease Typically 5 13 for EPA & DHA Typically EPA In patients with CHD: Consume ~1 g of EPA+DHA per day, preferably from oily fish. EPA+DHA supplements could be considered in consultation with the physician. In patients requiring TG lowering: 2 4 grams of EPA+DHA per day provided as capsules under a physician s care thrombotic, and anti-inflammatory effects. These are all theoretical but need to be proven in randomized, placebo- controlled trials. One other target contributing to HTG being investigated is apolipoprotein C-III (ApoC-III), a small protein that resides on various lipoproteins. It inhibits lipoprotein and hepatic lipases, impairs hepatic uptake of triglyceride (TG)-rich lipoproteins (such as lipoprotein remnants), and generally promotes HTG. It may contribute to insulin resistance and may contribute to atherosclerosis. There are medications being developed against ApoC-III. Conclusion Trials of the OM-3s in patients with hypertriglyceridemia alone are finally being done. Other options for lowering triglycerides include fibrates, for which there are no clinical trials, and statins. Non-HDL-C values need to be measured in addition to TG and LDL levels in order to determine the ultimate benefit of triglyceride lowering. Harold Bays, MD, FTOS, FACC, FACE, FNLA, is Medical Director and President of the Louisville Metabolic and Atherosclerosis Research Center in Louisville, KY. References 1. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014; 371(1): TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1): 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): Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20): National Lipid Association. Recommendations for Patient-Centered Management of Dyslipidemia. Available at Accessed 6/20/ Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9): Bays HE, Jones PH, Brown WV, Jacobson TA. National lipid association annual summary of clinical lipidology J Clin Lipidol. 2014;8(6 Suppl):S1-S Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol. 2012;6(5): Bays HE. Rationale for prescription omega-3-acid ethyl ester therapy for hypertriglyceridemia: a primer for clinicians. Drugs Today. 2008;44(3): Journal of Managed Care Medicine Vol. 19, No. 3

67 NAMCP Medical Directors Institute Corporate Partners 2016 Abbott Vascular AbbVie Acelity (KCI) Acorda Therapeutics Actelion Pharmaceuticals US, Inc. Allergan Amarin Corporation Ambry Genetics AmerisourceBergen Amgen Inc. Apobiologix Ariad Pharmaceuticals Assurex Health Astellas Pharma US, Inc. Baxalta Bayer HealthCare Pharmaceuticals Biodesix BioFire Diagnostics Biogen BioReference Laboratories Bioventus, LLC Boehringer Ingelheim Boston Scientific Braeburn Pharmaceuticals Bristol-Myers Squibb Company CareNational Castle Biosciences CVS Caremark Celgene Corporation Counsyl Courtagen Life Sciences Dendreon Corporation DiaTech Oncology, LLC Eisai Foundation Medicine GE Healthcare Genentech Genomic Health Gilead Sciences Genoptix HeartFlow Heron Therapeutics Incyte Corporation Infinity Pharmaceuticals Intarcia Therapeutics J & J Health Care Systems, Inc. Janssen Biotech Kaléo Lilly Oncology Lilly USA, LLC Merck & Co, Inc. Merrimack Pharmaceuticals Merz North America Myriad Genetic Laboratories NanoString Technologies NantOmics Natera Novartis Oncology Novartis Pharmaceuticals Novo Nordisk NovoCure Omeros Corporation Osiris Therapeutics, Inc. Pfizer Inc. PharMedQuest Philips Healthcare Purdue Pharma, L.P. Regeneron Sandoz Pharmaceuticals Seattle Genetics Sunovion Pharmaceuticals Taiho Oncology Takeda Oncology Teva Pharmaceuticals Tolmar Pharmaceuticals VITAS Healthcare Corporation Veracyte, Inc. Vermillion ZOLL Medical Corporation

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