Journal of Managed Care Medicine Volume 19, Number 4 by Jeremy Williams

Vol. 19, No. 4, 2016

Educating Medical Directors of Employers, Health Plans and Provider Systems

FEATURED ARTICLES INCLUDE: Novel Targets and Evolving Therapies to Improve Outcomes in Lipid Management Overcoming Challenges in the Treatment and Management of Overactive Bladder Updates in the Treatment and Management of Metastatic Breast Cancer Developing Appropriate Evidence for Demonstrating the Value of Diagnostics: Where are We Now and What is Appropriate for the Future State?

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

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

Gary Owens, MD Principal Gary Owens Associates

Devena Alston-Johnson, MD Medical Director CIGNA

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

Philip Painter, MD Chief Medical Officer Humana

E. Paul Amundson, MD Chief Medical Officer Dakotacare

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

Linda Ash-Jackson, MD Medical Director Hometown Health

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

Paul Bluestein, MD Chief Medical Officer Connecticare

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

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

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

Anthony Bonagura, MD Chief Medical Officer Aetna, Inc.

Karen Knowles, MD Internal Medicine Physician HCA/Emcare

Salil V. Deshpande, MD Market Medical Officer United Healthcare

Catherine Marino, MD Chief Medical Officer MagnaCare

Michael Fine, MD Medical Director Health Net 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

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 Oâ&#x20AC;&#x2122;Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans

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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

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Vol. 19, No. 4, 2016

TABLE OF CONTENTS Best Practices in the Management of Hepatitis C (HCV): Individualizing Therapy with Emerging Options David H. Winston, MD, FACP, AGAF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Jeremy Williams

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Grant Menard American Medical Communications gmenard@americanmedicalcomm.com 267-614-6809

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Custom Article Reprints High quality reprints of individual articles are available in print and electronic formats. Contact Jeremy Williams, jwilliams@namcp.org, 804-527-1905 for reprints. ISSN: 1094-1525. 1094-1525. The Thev is Journal published of Managed by Association Care Services Corporate and Circulation offices: Medicine Inc. is published by NAMCP Medical Directors 4435 Waterfront Drive, Suite 101, Glen Allen, VA Institute. Corporate and Circulation offices: 4435 23060; Tel (804) 527-1905; Fax (804) 747-5316. EditoWaterfront Drive, Suite 101, Glen Allen, VA 23060; rial and Production offices: 2613 N. Parham Rd., Tel (804) 527-1905; Fax 747-5316. Editorial and Suite B, Richmond, VA(804) 23294; Tel (804) 272-9100; Production offices: Advertising P.O. Box 71895, Richmond, VA Fax (804) 272-1694. offices: Jack Klose, 23255-1895; TelW. (804) 387-7580; (703) 997-5842. 804 Broadway, Long Branch, Fax NJ 07764; Tel (732) 229-8845; Fax (856) 582-9596. Subscription Rates: Advertising offices: Sloane Reed, 4435 Waterfront one the United States; oneTel year $105 in Driveyear Ste$95 101,inGlen Allen, VA 23060 (804) 527Canada; one year $120 international. Back issues 1905, Fax (804) 747-5316. All rights reserved. Copyare available for $15 each. All rights reserved. right 2016. 2010. No part thisof publication may bemay reproCopyright Noofpart this publication be duced or transmitted in any in form by any reproduced or transmitted anyorform or means, by any means, electronic or mechanical, including photoelectronic or mechanical, including photocopy, recopy, recording, or any information storage orsysrecording, or any information storage or retrieval trieval system,written without writtenfrom consent from the tem, without consent the publisher. publisher. The publisher does not guarantee, eiThe publisher does not guarantee, either expressly ther expressly or by implication, the factual accuor by of implication, the and factual accuracy ofherein, the articles racy the articles descriptions nor and descriptions nor does the publisher does the publisherherein, guarantee the accuracy of any guarantee the accuracy ofby anythe views or opinions views or opinions offered authors of said ofarticles fered or by descriptions. the authors of said articles or descriptions. POSTMASTER: Send address changes to The POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 WaterJournal of Managed Waterfront Drive, Suite 101,Care GlenMedicine, Allen, VA4435 23060. front Drive, Suite 101, Glen Allen, VA 23060.

Novel Targets and Evolving Therapies to Improve Outcomes in Lipid Management Karol E. Watson, MD, PhD, FACC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Overcoming Challenges in the Treatment of OAB David A. Ginsberg, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Reducing Exacerbations in the Treatment and Management of COPD Charles Vega, MD, FAAFP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Update in the Management of Venous Thromboembolism (VTE) Darrell W. Harrington, MD, FACP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Updated Therapeutic Strategies in the Management of Pulmonary Arterial Hypertension David B. Badesch, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Treatment of Metastatic Breast Cancer Joanne Mortimer, MD, FACP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Optimal Treatment Strategies in the Management of Castration-Resistant Prostate Cancer Julie N. Graff, MD, MCR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Improving the Management of Hyperkalemia Biff F. Palmer, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Developing Appropriate Evidence for Demonstrating the Value of Diagnostics: Where are We Now and What is Appropriate for the Future State? Eric Faulkner, Daryl S. Spinner and Joshua Ransom. . . . . . . . . . . . . . . . . . . . . 66

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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

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

COMFORT-I Primary End Point: Spleen Volume Reduction at Week 241,2

COMFORT-II Primary End Point: Spleen Volume Reduction at Week 481,3

Patients (%)

42%

(P < 0.0001)

(n = 65)

Jakafi (n = 146) BAT (n = 73)

Patients (%)

Jakafi (n = 155) Placebo (n = 154)

0.7% (n = 1)

≥35% Spleen Volume Reduction From Baseline

29%

(n = 41)

20 10

(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 <0.5 × 10 9/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

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

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

0.9

0.8 0.7 0.6

Median crossover: 9 months

0.5

Jakafi (n = 155)

0.4

Placebo (n = 154)

0.3

% 1-year survival

91%

84%

0.2

% 2-year survival

80%

69%

0.1

% 3-year survival

70%

61%

0.0

0.8 0.7 0.6

Number of patients at risk Jakafi 155 145 Placebo 154 142

102 82

29 32

0 0

Time (Months) 134 117

122 101

111 92

Median crossover: 17 months

0.5

Jakafi (n = 146)

BAT (n = 73)

% 1-year survival

96%

94%

% 2-year survival

86%

81%

% 3-year survival

79%

0.4 0.3 0.2 0.1 0.0

Jakafi BAT

1.0

Survival Probability

1.0

Number of patients at risk Jakafi 146 135 BAT 73 58

59%

104 33

33 9

0 0

Time (Months) 126 50

115 47

107 42

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):799-807. 3. 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):787-798. 4. Data on file. Incyte Corporation. Wilmington, DE.

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 109/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 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/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 Jakafi Placebo (N=155) (N=151) All Gradesa Grade 3 (%) (%)

Adverse Reactions Bruisingb

Grade 4 All Grades Grade 3 (%) (%) (%)

Grade 4 (%)

Dizzinessc

Headache

Urinary Tract Infectionsd

Weight Gaine

Flatulence

Herpes Zosterf

a b c d e f

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present includes weight increased, abnormal weight gain 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 109/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 109/L to 200 X 109/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 109/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 Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

a b

Presented values are worst Grade values regardless of baseline 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.

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 Jakafi (N=110) Adverse Events

Best Available Therapy (N=111)

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

Constipation

Cough

Edemae

Arthralgia

Asthenia

Epistaxis

Herpes Zosterf

Nausea

a b c d e f

Grade 3-4 (%)

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema 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 Treatmenta Jakafi (N=110) Laboratory Parameter

All Gradesb Grade 3 (%) (%)

Best Available Therapy (N=111) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Hematology Anemia

Thrombocytopenia

Neutropenia

Chemistry Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

a b

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

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 Cmax 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 Cmax 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 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 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 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 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 (4.1-5.0 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 109/L and 150 X 109/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. 7598257; 8415362; 8722693; 8822481; 8829013; 9079912 © 2011-2016 Incyte Corporation. All rights reserved. Revised: March 2016 RUX-1778

Best Practices in the Management of Hepatitis C (HCV): Individualizing Therapy with Emerging Options David H. Winston, MD, FACP, AGAF For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary This is an exciting time to be involved in treating hepatitis C. Many new therapies which can cure the infection and prevent long-term complications are now available and more are on the horizon. More people need to be screened for this infection and treated to prevent an expensive public health issue from large numbers of cirrhosis and liver cancer cases. Key Points • Chronic HCV is a progressive disease that increases morbidity and mortality which can be reduced with successful treatment. • Primary care physicians should screen all patients with risk factors and all baby boomers for HCV. • High cure rates, short duration of treatment, and few adverse effects are all possible with new all-oral combinations. • The cost of oral therapy is offset by future savings through the prevention of liver related complications.

ALMOST FOUR MILLION AMERICANS ARE known to be infected with hepatitis C (HCV), but the true prevalence is much higher.1,2 Of those known to be infected, 2.7 to 3.9 million have chronic disease.1 Chronic HCV cases not included in this estimate include those who are homeless, incarcerated, veterans, active military, health care workers, nursing home residents, chronic hemodialysis patients, or hemophiliacs; thus the true prevalence of chronic disease is probably closer to 5.1 million. Of those with chronic disease who get diagnosed, only 41 percent get treated. The majority of people who get infected with HCV acutely will develop chronic HCV (75-85%). Twenty to 30 percent of those with chronic HCV will develop cirrhosis. Some will develop hepatocellular carcinoma (HCC) and decompensated cirrhosis. HCV infection is the reason for 60 percent of all cases of HCC in the United States (U.S.).

The health care system is currently in a tsunami of HCV-induced cirrhosis and its complications (hepatic decompensation, portal hypertension, ascites, variceal bleeding, and encephalopathy) as a consequence of under-diagnosis and under-treatment of HCV. The peak of chronic HCV prevalence was in 2001. Because of the time lapse for development, the highest prevalence of cirrhosis and HCC is projected to be around 2020 (Exhibit 1).3 Without HCV treatment, by 2030, over a million people are going to develop cirrhosis, 254,664 will develop HCC, and 537,928 will die.3 Since the late 1990s, the mortality rates related to HCV have climbed while those for hepatitis B and human immunodeficiency virus (HIV) have either remained steady or declined.4 In addition to cirrhosis and liver cancer, HCV infection has many other systemic effects. Chronic persistence of the virus leads to the circulation of immune complexes and autoimmune phenomenon

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Exhibit 1: The Tsunami of HCV Cirrhosis Decompensation and Increased HCC 3

160,000

Hepatocellular Cancer Decompensated Cirrhosis

Number of Cases

140,000 120,000 100,000 80,000 60,000 40,000 20,000

2030

2020

2010

2000

1990

1980

1970

1960

1950

Exhibit 2: Extrahepatic Manifestations of HCV5 Hematologic - Mixed cryoglobulinemia - Thrombocytopenia - Non-Hodgkin’s B-cell lymphoma

Dermatologic - Porphyria cutanea tarda - Lichen planus - Vasculitis

Vascular - Necrotizing vasculitis - Polyarteritis nodosa

Ocular - Corneal ulcers - Uveitis

Renal - Glomerulonephritis - Nephrotic syndrome

Neuromuscular - Weakness/myalgia - Peripheral neuropathy - Arthritis/arthralgia

Endocrine - Hypothyroidism - Diabetes mellitus type 2 (Insulin resistance)

Autoimmune - Sjogren (sicca) syndrome Neuropsychiatric - Depression

(Exhibit 2).5 Unlike the DNA viruses HIV and hepatitis B, HCV infection can be cured. This is possible because the virus resides in the cytoplasma of the cell rather than the nucleus or incorporated into DNA like HBV and HIV, respectively. To be cured though requires that the infection has to be identified. The goal of HCV treatment is to reduce all-cause mortality and liver-related health adverse consequences such as end-stage liver disease and HCC by achievement of a virologic cure or a sustained virologic response (SVR).6 A SVR is an undetectable HCV RNA three months after completion of treatment. A SVR is synonymous with “cure.” SVR rates with current recommended oral regimens are

greater than 90 percent in those who have never been treated before (treatment naïve). HCV infection needs to be treated for several reasons. Chronic HCV is a progressive disease that increases morbidity and mortality which can be reduced with successful treatment. Treatment delays can decrease the benefit of SVR and allow for the development of severe liver disease and liver-related complications. In a major change in recommendations, the guidelines state that treatment deferral practices based on fibrosis stage alone are inadequate and shortsighted.6 Curing HCV at any stage regardless of baseline fibrosis results in decreased all-cause mortality, decreased liver-related death, decreased need for liver transplantation, decreased hepatocellu-

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 9

lar carcinoma rates, decreased liver-related complications, improvement or prevention of extrahepatic complications, and quality of life improvements.6-9 The guidelines no longer recommend prioritizing patients for treatment. Because of the many benefits associated with successful HCV treatment, “treatment is recommended for ALL patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV.”6 The goal is to treat all patients as promptly as feasible to improve health and to reduce HCV transmission. Unfortunately, there are a significant number of undiagnosed cases of HCV infection and what is undiagnosed cannot be treated. Primary care providers (PCPs) have an opportunity to make a diagnosis of HCV early and refer for treatment before the development of cirrhosis and its complications. Early diagnosis and treatment can improve survival, improve quality of life, and will reduce the economic burden of HCV and result in cost savings. Although HCV screening is the first step to a cure, there are both patient and provider barriers to screening. Persons infected with HCV are usually asymptomatic, unaware of their infection, and are unaware of the risk factors for HCV.10 Fifty-six percent of infected people are asymptomatic. For those that are symptomatic, the most common symptom is nonspecific fatigue. In general, PCPs do not include routine HCV risk factor assessment in their practice. Elevated liver function tests (LFTs), not risk factors, are typically the reason for PCPs to screen patients for HCV. There is so much fatty liver disease in the U.S. that the curve of “normal” LFTs has shifted (40-70) even though normal in males is really 30; thus, many PCPs are not recognizing elevated LFTs. The common risk factors for HCV infection are contaminated needles, intranasal cocaine use with shared implements, body piercing with contaminated needles, tattooing with contaminated needles or ink, and incarceration. Intravenous drug use now accounts for two- thirds of the HCV cases in the U.S. Other risk factors include receiving blood or blood products or solid organ transplant or hemodialysis before 1992. Less common are sharing of household items that could carry infected blood, traumatic contact with blood, perinatal transmission, and high-risk sexual behavior (i.e., multiple sex partners, prostitutes, man to man sex). PCPs should be looking for these risk factors in everyone. Since 75 percent of HCV cases are found in baby boomers, the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force (USPSTF) recommend a one-time screening for all persons born between 1945 and

1965.10,11 The rates are very high in baby boomers because HCV was not even diagnosed when this population was young, the blood supply was contaminated and there was no way to screen blood products, and there were no universal precautions in health care settings. Thus, PCPs should screen all baby boomers, all patients with risk factors regardless of age, and all patients with elevated liver function tests. Choosing treatment requires knowing the virus genotype, prior treatment experience, stage of disease (i.e., degree of fibrosis and presence or absence of cirrhosis), presence of hard-to-treat conditions, or presence of conditions that place patients at high risk for getting complications that require treatment before they get worse. The majority of cases in the U.S. are genotype 1 (70%). The other five genotypes are less common and some are more difficult to eradicate. Disease staging to assess the degree of fibrosis and cirrhosis is traditionally done with a liver biopsy, but there are disadvantages of this method. It only samples a very small portion of the liver, is anxiety provoking, and can have complications. Biopsies can cost $2,500 to $3,000. A noninvasive option is a device (Fibroscan, Aixplorer) that measures the velocity of the ultrasonic shear wave as the wave passes through the liver. The propagation velocity of the shear wave correlates with the elasticity of tissue. The velocity increases with increased stiffness of the liver parenchyma. This is the test of choice if available. There are also blood fibrosis tests (Fibrosure, Fibrotest, Hepascore, Fibrospect) which measure variations in biomarkers caused by changes in liver stiffness. These are good for staging patients with zero or minimal fibrosis and those with advanced fibrosis or cirrhosis but are less accurate for assessing mid-range fibrosis. Populations at high risk for having complications with chronic HCV infection include those with advanced liver disease, HIV or hepatitis B coinfection because of greater risk for rapidly progressive fibrosis and cirrhosis, other coexistent liver disease (e.g., nonalcoholic steatohepatitis), or a prior liver transplant. Those with advanced liver disease have substantial risk of developing complications which may occur in a relatively short time frame. Another group at high risk for complications is those with severe extrahepatic manifestations regardless of their stage of fibrosis including cryoglobulinemia, nonHodgkin’s lymphoma, type 2 diabetes with insulin resistance, proteinuria and nephrotic syndrome, or debilitating fatigue. High-risk groups need to be treated before their concomitant conditions or HCV infection gets worse.

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Hard to treat populations include those with decompensated cirrhosis, renal impairment, genotype 3 HCV infection, HCV/HIV coinfection, and postliver transplant. Patients with decompensated cirrhosis ideally should be treated in a liver transplantation center because they can become ill quickly. The SVR rates in this population are 83 to 86 percent; this is an area where new regimens are needed. At lower levels of renal function, medication doses may need to be adjusted; ribavirin is one that has to be adjusted. At levels of 30 ml/min, most agents can be used except sofosbuvir. Safety and efficacy of many of the medications have not been determined at very low levels of renal function (<15 ml/min). Genotype 3 has been the most difficult genotype to treat. Fibrosis progression occurs more rapidly than with other genotypes and there is a higher prevalence of severe steatosis and a higher incidence of HCC. The same treatment recommendations (naïve and treatment experienced) as in patients without HIV are recommended for those coinfected with HIV. The primary consideration in selecting a HCV treatment is potential drug-drug interactions with antiretroviral therapy. It is important to coordinate with the patient’s HIV specialist. Post-liver transplant is the last hard to treat population. HCV accounts for almost 50 percent of liver transplants in the U.S. All patients with detectable HCV RNA at the time of transplant will infect the graft liver. Reinfection occurs as soon as reperfusion of the allograft takes place in the operating room and viral titers reach pretransplant levels within 72 hours. The likelihood of developing cirrhosis in the newly transplanted liver over three to five years posttransplant is 10 to 30 percent. The goal in those who are awaiting transplant is to suppress HCV RNA to an undetectable level for at least 30 days prior to the transplant and prevent the graft liver from becoming infected with the HCV virus. Patients with longer periods of undetectable HCV RNA prior to transplant have better post-transplantation SVR rates In recent years, there has been an explosion of available agents to treat HCV infection. Interferon and ribavirin were the first two therapies approved for HCV management. Because of the multiple issues with interferon and the availability of newer more effective therapies, guidelines for treatment naïve patients no longer recommend interferon as first-line therapy. The unsatisfactory response rate in genotype 1 (54-56%) to interferon and ribavirin led to the development of the direct-acting antivirals (DAAs) that directly inhibit viral replication. The DAAs have revolutionized chronic HCV therapy by being oral agents, very tolerable, have high

cure rates, and are aimed at very specific targets in the life cycle of the HCV virus. A combination of DAAs must be used to prevent the emergence of resistance. The standard of care for treating HCV infection in treatment-naïve patients is an all-oral regimen of at least two agents; ribavirin is recommended to be added in some instances. The current duration of therapy is eight to 24 weeks, depending on which therapy is selected and presence of cirrhosis. An eight-week duration of treatment can be considered when sofosbuvir/ledipasvir is used in treatment-naïve patients without cirrhosis with genotype 1 who have pretreatment HCV RNA less than 6 million IU/mL. Regimens for the various genotypes, those with cirrhosis, and those who are naïve or have had prior treatment are specified in the treatment guidelines.6 Because therapy for HCV is changing rapidly, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in collaboration with the International Antiviral Society–USA (IAS–USA) have developed a web-based process for the rapid formulation and dissemination of evidence-based, expert-developed recommendations for HCV management. These up-to-date guidelines can be found at hcvguidelines.org. Because the recommendations change rapidly, a table of recommended regimens is not published here. An example of how rapidly treatment is changing is the fact that two new combination products have already been approved in 2016. Approved in January, elbasvir/grazoprevir fixed dose combination (Zepatier ®), with or without ribavirin, is FDA approved for patients infected with genotype 1, as well as the less common genotype 4. The most recent combination product (Epclusa®) approved ( June 28, 2016) is a fixed-dose combination tablet containing sofosbuvir and velpatasvir and is the first to treat all six major genotypes. The combination is FDA approved to treat adult patients with chronic HCV, both with and without cirrhosis. For patients with moderate to severe cirrhosis, the combination is approved for use in combination with ribavirin. The DAAs are very expensive in terms of acquisition costs and have led to significant debate about the costs of treatment. When considering the costs of HCV treatment, the cost of not treating the infection is important to consider. While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease, cirrhosis, and HCC and associated health care costs continue to rise. HCV health care costs are substantial and increase as liver disease progresses.12,13 Most costs will be incurred both short term and long term.

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 11

Although the DAA regimens are expensive in terms of acquisition costs, they are cost effective. Curing HCV markedly reduces the national cost of treating cirrhosis and hepatocellular carcinoma ($30,000-$70,000 annual cost x 5 to 10 years/ patient) and markedly reduces the need for liver transplantation ($350,000-$577,000/transplant + $145,000 year maintenance).14 On an individual health plan basis, the per member per month health care costs are 24 to 35 percent lower in those who receive treatment compared to an untreated population.15 The higher SVR rates with the oral regimens compared with older interferon-based regimens provide significant benefits. An SVR in non-cirrhotic HCV patients prevents the development of cirrhosis and its complications. A SVR in compensated cirrhosis patients lowers the rate of complications, liver cancer, and transplant. SVR improves all-cause mortality, quality of life, and increases life expectancy.16-18 The U.S. is unique among Western countries in that it does not regulate drug prices. Actual U.S. drug costs paid are rarely known. Pharmaceutical companies determine the wholesale acquisition cost (WAC) of a drug; pharmacy benefit managers and insurance companies negotiate for rebates and discounts that decrease the actual price paid. Negotiations of drug prices are considered confidential business contracts, so there is almost no transparency regarding the actual prices paid. Market-based competition has driven down the cost of HCV drugs. The average negotiated discount has been reported to be 46 percent off the WAC in 2015 and greater than 50 percent for some Medicaid programs and the Veterans Administration.19 Cost-effectiveness studies published in 2015, even using the higher WAC prices, have shown that DAA regimens are cost effective for most patients, within the range of other accepted medical therapies.20-22 Cost-effectiveness does not take into account affordability. Affordability refers to whether a payer has sufficient resources in its annual budget to pay for a therapy for all who need it. The challenge is to pay for HCV drugs which have high upfront costs incurred over a short period of time. Many payers have limited coverage to only those with advanced fibrosis and cirrhosis because of budgetary constraints. Many clinicians and bioethics professionals have called this rationing. HCV coverage limitations have raised some serious ethical questions. There is a large number of people with HCV for which we have a cure for almost everybody; yet, many are not being treated. There are not many other curable conditions

where many patients are told that they have to be sicker before they can be treated. â&#x20AC;&#x153;Triag(ing) access as a way to cope with price... seems to me to be strikingly immoral. What we have to do is drive down the price.â&#x20AC;?23 Insurers, government, and pharmaceutical companies should work together to bring medication prices to the point where all of those in need of treatment are able to afford and readily access it. There are more DAAs under study which will hopefully continue to raise the SVR rates closer to 100 percent, further reduce adverse effect rates, and allow increasingly shorter treatment regimens. It is hoped the future will bring less costly but better regimens. Conclusion

HCV is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Clinicians should screen all patients with risk factors and all baby boomers for HCV. A dramatic paradigm shift in HCV treatment with new DAA combinations that promise higher cure rates, shorter treatment duration and fewer side effects is here. Virtually every patient with chronic HCV should be treated. David H. Winston, MD, FACP, AGAF, is Section Head of Gastroenterology and Hepatology at CIGNA HealthCare of Arizona in Sun City, AZ.

References 1. Centers for Disease Control and Prevention. Hepatitis C Information for Health Professionals. Available at http://www.cdc.gov/hepatitis/HCV/index. htm. Accessed June, 29, 2016. 2. Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090-101. 3. Davis G, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-21. 4. Ly KN1, Xing J, Klevens RM, et al. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156(4):271-8. 5. Ali A., Zein NH. Hepatitis C infection: a systemic disease with extrahepatic manifestations. Cleve Clin J Med 2005;72(11):1005-8. 6. AASLD/IDSA/IASâ&#x20AC;&#x201C;USA. Recommendations for testing, managing, and treating hepatitis C. Available at/www.hcvguidelines.org. 7. Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology. 2008;135(3):821-9. 8. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122(5):1303-13. 9. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147(10):677-84.

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10. Smith BD, Jorgensen C, Zibbell JE, Beckett GA. Centers for Disease Con-

Hepatol. 2011;9(6):509-16.

trol and Prevention initiatives to prevent hepatitis C virus infection: a selective

17. Wong JB. Hepatitis C: cost of illness and considerations for the economic

update. Clin Infect Dis. 2012;55 Suppl 1:S49-53.

evaluation of antiviral therapies. Pharmacoeconomics. 2006;24(7):661-72.

11. US Preventive Health Services Task Force. Screening for Hepatitis C Virus

18. McAdam-Marx C, McGarry LJ, Hane CA, et al. All-cause and incremental

Infection in Adults. Available at www.uspreventiveservicestaskforce.org/usp-

per patient per year cost associated with chronic hepatitis C virus and associated

stf/uspshepc.htm. Accessed 6/29/2016.

liver complications in the United States: a managed care perspective. J Manag

12. Gordon SC, Pockros PJ, Terrault NA, et al. Impact of disease severity on

Care Pharm. 2011;17(7):531-46.

healthcare costs in patients with chronic hepatitis C (CHC) virus infection.

19. Pollack, A. Sales of Sovaldi, New Gilead Hepatitis C Drug, Soar to $10.3

Hepatology. 2012;56(5):1651-60.

Billion. The New York Times. 2/3/15

13. Younossi ZM, Singer ME, Mir HM, et al. Impact of interferon free regi-

20. Chhatwal J, Kanwal F, Roberts MS, Dunn MA. Cost-effectiveness and

mens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients.

budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in

J Hepatol. 2014;60(3):530-7.

the United States. Ann Intern Med. 2015;162(6):397-406.

14. Reau NS, Jensen DM. Sticker shock and the price of new therapies for

21. Najafzadeh M, Andersson K, Shrank WH, et al. Cost-effectiveness of novel

hepatitis C: is it worth it? Hepatology. 2014;59(4):1246-9.

regimens for the treatment of hepatitis C virus. Ann Intern Med. 2015;162(6):407-19.

15. Gordon SC, Hamzeh FM, Pockros PJ, et al. Hepatitis C virus therapy is as-

22. Linas BP, Barter DM, Morgan JR, et al. The cost-effectiveness of sofosbu-

sociated with lower health care costs not only in noncirrhotic patients but also in

vir-based regimens for treatment of hepatitis C virus genotype 2 or 3 infection.

patients with end-stage liver disease. Aliment Pharmacol Ther. 2013;38(7):784-93

Ann Intern Med. 2015;162(9):619-29.

16. Backus LI, Boothroyd DB, Phillips BR, et al. A sustained virologic response

23. Caplan A. HCV Drugs Cost-effective, but Who Should Get Them? Med-

reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol

scape 3/17/2005.

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Can Individualized Therapy Improve IBD Outcomes? Joel R. Rosh, MD For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Improving outcomes in inflammatory bowel disease (IBD) requires risk stratification of patients based on risk factors of progression and degree of disease and choosing therapy based on this assessment. Aggressive therapy with biologics and immunomodulators from the onset is important for those with moderate to severe disease. Those with mild disease can usually be treated with less aggressive therapy. Key Points • IBD is a chronic inflammatory disease. • “Step in” therapy, rather than sequential therapy, is the best strategy to improve outcomes. • Along with a personalized approach of risk stratification, treat to target is emerging as a best practice. • Therapeutic drug monitoring, optimization of therapy, and tight monitoring of actual disease activity (not just symptoms) are critically important goals.

INFLAMMATORY BOWEL DISEASE (IBD) IS chronic intestinal inflammation from a dysregulated immune response to the intestinal microbiome in a genetically predisposed host. In addition to a genetically susceptible host, IBD likely requires an appropriate environmental trigger(s). Today, IBD is labeled as Crohn’s disease (CD) and ulcerative colitis (UC), though numerous overlapping phenotypes are recognized. Presenting symptoms range from mild to severe and the clinical course is often unpredictable, ranging from easily controlled to fulminant disease. IBD is really a family of diseases and the classification is evolving to label patients as having IBD1, IBD2, and so forth. Clinical features of UC include continuous, superficial inflammation of the colon mucosa. CD is characterized by patchy but transmural inflammation and mouth to anus involvement. Fistulas and strictures are common in CD. Both UC and CD increase the risk of colon cancer and have extra-intestinal manifestations.

As IBD is a lifelong disease. The emphasis of treatment is ultimately to bring the disease into remission, maintain remission, deal with the variety of emotional, psychological and medical issues, and encourage the patient to be involved. To personalize care, therapy should be based on the whole person rather than just symptoms. In caring for the whole person, it is critical to look beyond a clinical remission. Even with no symptoms there can be underlying inflammation continuing. Overall, there is little correlation between GI symptoms and the actual amount of inflammation in the gut. GI symptoms on therapy should trigger an evaluation why the symptoms are occurring rather than just a knee jerk increase in medications. Patients with compromised mucosa one year after diagnosis have ongoing damage and may be more likely to need IBD-related surgeries.1 Mucosal healing is the ultimate goal; healing results in better remission rates (Exhibit 1).2 Patients should have both a clinical remission (patient feels

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Exhibit 1: Mucosal Healing After Therapy Predicts Improved Outcomes1

100

SES 0 SES 1 - 8

70.8

Patients (%)

62.5 60

40 27.3 18.2

0 Remission off steroids

Remission off steroids and anti-TNF

SES = Simple Endoscopic Score TNF = tumor necrosis factor

better) and inflammation remission (turn off the inflammation to reduce the damage to the bowel). Inflammation remission, as evidenced by low serum markers of inflammation and normalization of the gastrointestinal mucosa on endoscopy, reduces the long-term complications of the disease â&#x20AC;&#x201C; fistula, cancer, and strictures. Aggressive initial â&#x20AC;&#x153;step inâ&#x20AC;? therapy is better for achieving mucosal healing. Therapy can then be stepped down. Risk stratification based on risk factors for progressive disease and degree of disease on endoscopy can be used to determine whether aggressive therapy is needed; aggressive therapy is most likely only needed for those with moderate to severe disease. It is important to aggressively manage IBD early in the disease process. The impact of therapy depends on the degree of structural damage and the velocity of progression. Early in the disease inflammation levels are highest and structural damage is lowest.3 There are several predictors for poor outcomes with IBD. They include deep colonic ulcerations on endoscopy, persistent severe disease despite adequate induction therapy, extensive (pan-enteric) disease, marked growth retardation (> -2.5 height Z scores), severe osteoporosis, stricturing or penetrating disease at onset, and severe perianal disease.4Each of these would indicate a need for aggressive therapy. Treating to target is an emerging best practice in

IBD management. Treat to target means the regular assessment of disease activity using objective clinical and biologic outcome measures with subsequent adjustment of treatment if the desired goals, primarily mucosal healing, are not being accomplished. Treat to target has been shown to result in better outcomes in rheumatoid arthritis, hypertension, diabetes, and hypercholesterolemia. Treatment of IBD can be both nonpharmacologic and pharmacologic. One option for CD is dietary therapy. Exclusive enteral nutrition (EEN), which is only giving liquid whole protein dietary replacements, is a valid treatment option which can be used for a steroid-free induction and is more effective than corticosteroids in inducing remission. The efficacy of EEN seems independent of the disease location. Partial EEN may be a valid adjunct to other therapies. The mechanism of action is still to be fully established but may be related to altered gut microbiota. The efficacy of EEN proves that diet does matter in IBD. Unfortunately, drinking only liquids is difficult for patients to maintain, and they may have a disease flare-up when a regular diet is restarted. In a comparison of studies of corticosteroids versus various types of dietary therapy, corticosteroids are slightly better.5 Indirect evidence in CD supports a low dietary intake of animal fat, insoluble fiber and processed fatty foods containing emulsifiers.6 In

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Exhibit 2: Efficacy of Combination Therapy 9

P < .001

100

P = .006

Patients (%)

P = .022

56.8

60 44.4 40

30.0

20 51/170

75/169

96/169

0 AZA + placebo

IFX + placebo

IFX + AZA

AZA = azathioprine IFX = infliximab

UC, weak evidence suggests that high meat intake correlates with increased likelihood of relapse. Pharmacologic therapy of IBD involves both induction and maintenance therapies. Induction therapy is used to bring the patient into remission and then maintenance therapy is given to maintain the remission. IBD is a disease of remission and relapse, so long-term maintenance therapy is required. Various agents are used to treat IBD. Because of long-term adverse effects, systemic corticosteroids should be used for induction only, if possible. Local acting agents include oral and rectal 5-aminosalicylic acid/mesalamine, budesonide rectal foam, and budesonide oral formulations designed specifically to release in the intestines (UcercisÂŽ, Entocort ÂŽ). Local acting agents are most effective for UC, which is more localized. Immune-modifying therapies include thiopurines, methotrexate and the anti-tumor necrosis factor (TNF) and anti-adhesion biologics. Those with CD have more extensive, systemic disease and most will require immune-modifying therapies. One mainstay of treatment has been various formulations of aminosalicylates. These agents release 5-aminosalicylic acid (5-ASA) at various points in the gastrointestinal tract by pH- dependent release, timed release, and bacterial cleavage. 5-ASA agents work on the mucosa of the bowel and thus are most appropriate for those patients who have only mucosal disease (UC) and primarily in the colon. In pediatric UC, 40 percent of patients can achieve a ste-

roid-free remission at one year with 5-ASA. Rectal therapy combined with oral therapy is the best way to utilize 5-ASA, especially in children. Patients on the combination will feel much better because the rectal formulation reduces many of the problematic symptoms. The evidence for effectiveness of 5-ASA in CD is very limited and would not be expected given that CD is a transmucosal disease. In the short term, 5-ASA agents reduce the inflammation in the bowel but do nothing to improve CD disease outcomes long term. Adherence and persistence with 5-ASA agents is abysmal. Even with medication monitoring devices, adherence is only about 50 percent.7 At one year, about 15 to 30 percent of patients will still be on an agent.8 Optimizing 5-ASA agents through combination oral and rectal therapy and adherence/persistence support can lead to improved outcomes. The immunomodulators azathioprine and 6-mercaptopurine have been used in IBD since the 1980s. They have a delayed onset of action and are used for maintenance. Measurement of a patientâ&#x20AC;&#x2122;s ability to metabolize these agents (pharmacogenomics) and therapeutic drug monitoring are required when these two agents are used to ensure safe dosing. There are long-term adverse effects with these agents which are of concern, including higher risk of non-melanoma skin cancers and lymphomas. There are data to say that patients who have never been infected with Epstein-Barr virus should not receive these two immunomodulators because of very high

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

Exhibit 3: Monitoring Biologics: What Factors Influence the Pharmacokinetics of TNF Antagonists?10

Impact on TNF agonist pharmacokinetics • Decreases in drug concentration Presence of anti-drug antibodies

Increases clearance Worse clinical outcomes • Reduces anti-drug antibody formation

Concomitant use of immunosuppressives

Increases drug concentration • Decreases drug clearance Better clinical outcomes • Increases drug clearance

Low serum albumin concentration

Worse clinical outcome

High baseline CRP concentration

• Increase drug clearance • May decrease drug concentration by

High baseline TNF concentration

increasing clearance

High body size

• May increase drug clearance

Gender

• Males have higher clearance

CRP = C-reactive protein TNF = tumor necrosis factor

risk of lymphoma. Methotrexate is increasingly being used in IBD because of lower rates of long-term adverse effects compared with the other immunomodulators. It is being used as a primary immune modifier, secondary immune modifier, and in combination with the biologics. TNF-alpha plays a crucial role in sustaining chronic mucosal inflammation. Four anti-TNF biologics are approved for use in IBD. These include adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), and infliximab (Remicade®). Each have different FDA approved indications. The best results with anti-TNF agents is seen when they are combined with an immunomodulator such as azathioprine or methotrexate (Exhibit 2).9 The combination should be continued for at least the first six months of biologic therapy. In addition to using combination therapy, there are several other issues which can impact the pharmacokinetics and thus the efficacy of anti-TNF agents (Exhibit 3).10 Some safety issues which have to be

considered when using anti-TNF agents include infections, immunogenicity, and heart failure. Approximately 40 percent of patients who initially benefit from anti-TNF agents ultimately lose response.11 Development of antibodies to anti-TNF agents correlate with decreased drug concentrations, decreased clinical response, and shorter duration of response. Dosing these agents effectively can reduce the development of antibodies. Adherence is also important because missing doses can also lead to antibodies. If a patient does not respond to anti-TNF therapy or loses response, anti-adhesion biologics are available. Natalizumab (Tysabri®) and Vedolizumab (Entyvio®) are two anti-adhesion biologics approved for IBD. Natalizumab is an anti-alpha 4 beta 1 agent and does carry the risk of potentially fatal progressive multifocal leukoencephalopathy (PML). Because of this risk, additional agents were investigated. Vedolizumab is a gut selective anti-alpha 4 beta 7 agent approved in 2014. Vedolizumab binds to the alpha 4 beta 7 integrin, blocking its interaction with

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Exhibit 4: Vedolizumab at Six Weeks in UC12

100 Placebo Vedolizumab

80 Patients (%)

P < .0001

P = .0010

60 47.1

40.9

40 25.5

24.8 16.9

20 5.4 0 Clinical Response 95% Cl:

Clinical Remission

∆ 21.7 11.6, 31.7

mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is mainly expressed on gut endothelial cells. This interaction facilitates lymphocyte homing to the gut and is an important contributor to inflammation. Exhibit 4 shows the results from one trial with vedolizumab.12 Approximately 3,000 patients have been treated with vedolizumab in clinical trials, including about 1,000 treated for two years or more. The main adverse effect has been nasopharyngitis. Infusion reactions with this agent are infrequent. Abnormal liver function tests are seen rarely. No PML cases have been reported to date because vedolizumab is gut specific. Because IBD is a chronic disease, it has to be treated chronically. Unfortunately, when patients are feeling well, they don’t worry about the complications of their disease and they are less likely to take their medications. Clinicians need to help patients understand that IBD is a progressive disease that can lead to complications in the future and that maintenance therapy has to be continued. Adherence and persistence with medications is important to have good outcomes. If the medication is not taken, it cannot be effective. There are plenty of educational resources available to help clinicians provide patient education and involve their patients in treatment decisions. Two excellent resources are the Crohn’s and Colitis Foundation (www.ccfa.org) and Option Grids (www. optiongrid.org). Option Grids are brief easy-to-read tools to help patients and providers compare alternative treatment options and are evidence based. Agents under study for IBD include an interleukin 12 and 23 antagonist (ustekinumab [Stelera®]),

∆ 11.5 4.7, 18.3

Mucosal Healing ∆ 16.1 6.4, 25.9

which is currently approved for psoriasis treatment. In one trial, 69.4 percent of those treated with ustekinumab had a response and 41.7 percent had remission compared with 42.5 percent and 27.4 percent, respectively for placebo.13 Tofacitinib (Xeljanz®) is a novel, small-molecule, oral JAK inhibitor under investigation for treating IBD. It is currently FDA approved for treating rheumatoid arthritis. Tofacitinib, directly or indirectly, modulates signaling for an important subset of pro-inflammatory cytokines, including IL-2, -4, -7, -9, -15, and -21 and has shown promising results in early trials. Conclusion

IBD is chronic intestinal inflammation from a dysregulated immune response to the enteric microbiome in a genetically predisposed host. It is a family of diseases currently simplified to two umbrella terms: Crohn’s disease and ulcerative colitis. “Step in” therapy, rather than sequential therapy, is the best strategy to change the natural history and disabling outcomes of surgery, hospitalization, cancer, and lowered quality of life. Along with a personalized approach of risk stratification, “treat to target” is emerging as a best practice. Therapeutic drug monitoring, optimization of therapy and tight monitoring of actual disease activity (not just symptoms) are critically important goals. Treatment of the whole patient will result in the best overall outcomes. Joel R. Rosh, MD, is Director of Pediatric Gastroenterology at the Goryeb Children’s Hospital/Atlantic Health and Professor of Pediatrics at the Icahn School of Medicine at Mount Sinai.

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

References

7. LeLeiko NS, Lobato D, Hagin S, et al. Rates and predictors of oral medicaInflamm Bowel Dis.

1. Frøslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory

tion adherence in pediatric patients with IBD.

bowel disease: results from a Norwegian population-based cohort. Gastroenterol-

2013;19(4):832-9.

ogy. 2007;133(2):412-22.

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

2. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained

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

clinical remission in patients with early-stage Crohn’s disease. Gastroenterology.

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

2010;138(2):463-8; quiz e10-1.

9. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or

3. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior

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

of Crohn’s disease. Inflamm Bowel Dis. 2002;8(4):244-50.

10. Ordás I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor

4. Ruemmele FM, Veres G, Kolho KL, et al. Consensus guidelines of ECCO/

necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol

ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohns

Hepatol. 2012;10(10):1079-87; quiz e85-6.

Colitis. 2014;8(10):1179-207.

11. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF

5. Heuschkel RB, Menache CC, Megerian JT, Baird AE. Enteral nutrition and

treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33(9):987-95.

corticosteroids in the treatment of acute Crohn’s disease in children. J Pediatr

12. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and

Gastroenterol Nutr. 2000;31(1):8-15.

maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710.

6. Richman E, Rhodes JM. Review Article: evidence based dietary advice for

13. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and mainte-

patients

with

inflammatory

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Aliment

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nance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519-28.

2013;38(10):1156-71.

AbbVie Acelity (KCI) Acorda Therapeutics Actelion Pharmaceuticals US, Inc. Allergan Amarin Corporation Ambry Genetics Amgen Inc. Apobiologix Ariad Pharmaceuticals Assurex Health Astellas Pharma US, Inc. Bayer HealthCare Pharmaceuticals Biodesix BioFire Diagnostics Bioventus, LLC Boston Scientific Braeburn Pharmaceuticals Bristol-Myers Squibb Company CVS Caremark CareNational Castle Biosciences Celgene Corporation Courtagen Life Sciences Eisai Foundation Medicine GE Healthcare Genentech Genomic Health Genoptix Gilead Sciences HeartFlow

Heron Therapeutics Incyte Corporation Infinity Pharmaceuticals InSightec Intarcia Therapeutics J & J Health Care Systems, Inc. Janssen Biotech Kite Pharmaceuticals Lilly Oncology Lilly USA, LLC LIM Innovations Merck & Co, Inc. Merrimack Pharmaceuticals Merz North America Myriad Genetic Laboratories Natera Novartis Oncology Novo Nordisk NovoCure Pfizer Inc. PharMedQuest Philips Healthcare Regeneron Sandoz Pharmaceuticals Seattle Genetics Sunovion Pharmaceuticals Taiho Oncology Teva Pharmaceuticals VITAS Healthcare Corporation Veracyte, Inc. Vermillion ZOLL Medical Corporation

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

Current and Emerging Therapeutic Options in the Management of CINV Susan Urba, MD For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Control of chemotherapy-induced nausea and vomiting (CINV) continues to improve with better understanding of various neurotransmitters involved in the process and availability of medications targeting those neurotransmitters. Control of CINV related to highly and moderately emetogenic chemotherapy requires medication combinations to cover both acute and delayed episodes. Several recent changes to the management guidelines have occurred and new agents have been approved. Key Points • Prevention of CINV is the goal. • Guidelines for prevention and treatment should be followed. • Risk lasts for at least four days for highly or moderately emetogenic chemotherapy. • Combinations of a serotonin antagonist, a neurokinin 1 (NK1) antagonist or olanzapine, and dexamethasone are recommended when highly emetogenic chemotherapy is given. • Costs of uncontrolled CINV (financial and human) are substantial.

CHEMOTHERAPY CAN CAUSE NAUSEA AND vomiting by two major ways – peripheral or central mechanisms. In response to chemotherapy, enterochromaffin cells in the gastrointestinal tract release serotonin, which starts the syndrome of chemotherapy-induced nausea and vomiting (CINV). Serotonin stimulates vagal afferent nerves which communicate with the brain. Through the dorsal vagal complex, the brain communicates back to stomach causing reverse peristalsis, which results in nausea and vomiting. Centrally, stimulation of the neurokinin 1 (NK1) receptors by substance P in the brainstem can also lead to CINV. Although many other neurotransmitters are involved, serotonin and substance P are the primary neurotransmitters targeted with medications. Acute CINV is nausea and vomiting that occurs within the first 24 hours after administration of chemotherapy. It occurs in 70 to 80 percent of patients

given emetogenic chemotherapy without preventive medications. Delayed CINV starts more than 24 hours after administration of chemotherapy and typically lasts three to four days. Without prophylaxis, delayed CINV can occur in up to 80 percent of patients. Acute CINV is predominately mediated by serotonin-dependent mechanisms, whereas delayed is predominately substance P mediated, but there is some overlap.1 The overlap of differential involvement of neurotransmitters supports combination therapy to enhance prevention of emesis. Both acute and delayed mechanisms need to be covered from the first day chemotherapy is given. There are three other types of CINV. Anticipatory CINV is a conditioned response that happens after a negative past experience with chemotherapy and has been reported in an average of 33 percent of patients. Breakthrough CINV is that which occurs despite prophylaxis and requires rescue medications.

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Exhibit 1: Classification of Acute Emetogenic Potential of Single Chemotherapeutic Agents

Emetogenicity

Percentage of Emesis

High

> 90%

Moderate

30 - 90%

Low

10 - 30%

Minimal

< 10%

When there is repeated need for rescue when prior rescue efforts have failed is refractory CINV. There are patient and chemotherapy-related risk factors for CINV. Patient factors which predispose to the development of CINV include low alcohol consumption (< 10 drinks/week), younger age (< 50), female gender, history of motion sickness, and poor control with prior chemotherapy. The most important factor for determining whether CINV will occur is the emetogenic potential of the chemotherapy being given. Chemotherapy agents can be classified as having high, moderate, low, or minimal potential for inducing emesis (Exhibit 1). Examples of highly emetogenic agents are cisplatin and doxorubicin. Some agents are only considered highly emetogenic if given in certain doses. Because combinations of chemotherapy agents are commonly given, the emetogenic potential of all the agents used have to be considered in choosing prophylactic therapy. Additionally, there are now many oral chemotherapy agents which can also cause CINV. Some highly emetogenic oral agents include olaparib and crizotinib. The National Comprehensive Cancer Network (NCCN) guidelines provide guidance on emetogenic category for every chemotherapy agent.2 Clinicians can significantly over estimate the efficacy of antiemetic therapy, particularly for moderately emetogenic agents. This is particularly true for delayed nausea and vomiting.3 Clinicians need to determine the true effects on the patient of both chemotherapy and the prophylactic antiemetic regimen. The Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool is a tool that has a patient rate their nausea and vomiting acutely over the four subsequent days after chemotherapy. These ratings are done during the treatment rather than asking the patient to remember how they did at a follow-up visit. The major agents used for CINV prevention when

highly emetogenic chemotherapy is given are serotonin antagonists, neurokinin 1 (NK1) antagonists, olanzapine, and corticosteroids. The recommended regimens include at least three agents; omission of the steroid is the most common mistake that clinicians make when prescribing these regimens. Dolasetron (Anzemet®), granisetron (Kytril®), ondansetron (Zofran®, generic), and palonosetron (Aloxi®) are the available serotonin antagonists. These are given on the same day as highly emetogenic chemotherapy to prevent acute CINV and are available in a variety of dosing forms – intravenous, oral, and transdermal patch – which varies by agent. The granisetron transdermal patch, which works for seven days, can be especially beneficial in patients with very prolonged nausea or vomiting or difficulty swallowing. In the NCCN guidelines, palonosetron intravenous is listed as the preferred agent for highly emetogenic chemotherapy.2 Palonosetron has a longer half-life (40 hours versus 4 to 8 hours for others) and higher receptor binding affinity, but it has not been shown to be significantly more effective than the other serotonin antagonists for acute CINV related to highly emetogenic chemotherapy.4,5 Because of purchasing contracts, some institutions use one particular agent as the preferred agent for most patients. Three antagonists of NK1 receptors are available, including aprepitant/fosaprepitant (oral/intravenous, Emend®), rolapitant (Varubi®), and netupitant. Netupitant is only available in a fixed-dose oral combination with palonosetron (Akynzeo®). Aprepitant is given once on the day of highly emetogenic chemotherapy administration. The intravenous formulation of aprepitant has a long enough duration of action so a single dose covers delayed CINV. If the oral form is used, doses need to be given for two to three days after chemotherapy. Rolapitant has a 180hour half-life and has greater than 90 percent receptor occupancy rate for five days, so a single dose on

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 21

Exhibit 2: NCCN Guidelines for Acute/Delayed CINV Highly Emetogenic Chemotherapy (HEC)2

Acute

Delayed

Aprepitant or rolapitant containing regimen NK1 antagonist • Aprepitant 125 mg PO, or • Fosaprepitant 150 mg IV once, or • Rolapitant 180 mg PO once

• If a aprepitant PO given on day 1, aprepitant 80 mg PO on days 2 and 3 • If fosaprepitant IV given on day 1, no further aprepitant needed on days 2 and 3

AND Serotonin (5-HT3) antagonist • Dolasetron 100 mg PO once • Granisetron 2 mg PO once, or 0.01 mg/kg (max 1 mg) IV once, or 3.1 mg/24 hrs transdermal patch applied 24 - 48 hrs before chemotherapy • Ondansetron 16-24 mg PO once or 8 - 16 mg IV once • Palonosetron 0.25 mg IV once AND

AND • If aprepitant PO given on day 1, dexamethasone 8 mg PO/IV daily on days 2, 3 and 4 • If fosaprepitant IV given on day 1, dexamethasone 8 mg PO/IV once on day 2, then 8 mg PO/IV twice daily days 3 and 4 • If rolapitant is given on day 1 dexamethasone 8 mg PO/IV twice daily days 2, 3 and 4 AND • Dexamethasone 8 mg PO/IV on days 2, 3 and 4 • Olanzapine 10 mg PO on days 2, 3 and 4

Steroid • dexamethasone 12 mg PO/IV once Netupitant-containing regimen • Netupitant 300 mg/palonosetron 0.5 mg PO once • Dexamethasone 12 mg PO/IV once Olanzapine-containing regimen • Olanzapine 10 mg PO once • Palonosetron 0.25 mg IV once • Dexamethasone 20 mg IV once

the day of chemotherapy can be given. Netupitant has a 96-hour half-life, so the combination product (netupitant 300 mg/palonosetron 0.5 mg) is given once, one hour before chemotherapy. Aprepitant is both an inducer and inhibitor of the CYP3A4 liver enzymes, netupitant inhibits this pathway, and rolapitant does not affect; this may impact agent selection if a chemotherapy or other concomitant medication metabolized by 3A4 is also being given. The response rate to serotonin antagonists is greatly improved when these agents are combined with dexamethasone, which is the standard of care.6 Dexamethasone is given on the day of highly emetogenic chemotherapy administration and for three to four days afterwards to prevent both acute and delayed CINV. A meta-analysis of 32 randomized, controlled trials with 5,613 patients suggested superiority of dexamethasone over a serotonin antagonist for preventing delayed emesis.7 In the NCCN guidelines, olanzapine is listed as an alternative to NK1 antagonists and is substantially less expensive.2 This atypical antipsychotic blocks

multiple neurotransmitters, including dopamine, serotonin, catecholamines, acetylcholine, and histamine. Olanzapine 10 mg once a day is given on days one to three instead of aprepitant. Combined with a single dose of dexamethasone and a single dose of palonosetron, olanzapine was comparable to aprepitant at controlling acute and delayed CINV in patients receiving highly emetogenic chemotherapy.8 Olanzapine may be better for delayed nausea than aprepitant. Olanzapine is approved by the FDA as an antipsychotic and does not have an FDA indication as an antiemetic. Combining the three classes of agents (serotonin antagonist, NK1 antagonist or olanzapine, and dexamethasone) leads to the best control of both acute and delayed CINV.2 For highly emetogenic chemotherapy, a regimen including three classes is recommended (Exhibit 2).2 For moderately emetogenic chemotherapy, the recommended regimens are now almost identical to those for highly emetogenic. The regimens for netupitant and olanzapine-containing regimens are

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

identical. The rolapitant-containing regimen has a small difference in dosing of dexamethasone on days two to three. Regimens containing aprepitant are similar, but the addition of aprepitant is only recommended for select patients with additional risk factors or who have failed previous therapy with a serotonin antagonist and steroid alone.2 Most clinicians will go ahead and use aprepitant for at least the first cycle of chemotherapy to prevent anticipatory CINV from occurring. For moderately emetogenic chemotherapy, the guidelines should be consulted for the recommended treatment regimens.2 For chemotherapy regimens with low emetic risk, the NCCN guidelines recommend dexamethasone, a serotonin antagonist, metoclopramide, or prochlorperazine started before chemotherapy and given daily during therapy.2 For minimal emetogenic potential chemotherapy, no prophylaxis needs to be given. Oral chemotherapy is now commonly used and can cause significant CINV. Prophylactic regimens are recommended for moderate or highly emetogenic oral chemotherapy. Because oral chemotherapy is given for a longer duration, only oral agents are recommended. Oral serotonin antagonists are typically the first choice.2 If the regimen has low or minimal emetogenic potential, metoclopramide, a serotonin antagonist, prochlorperazine, or haloperidol can be prescribed for as needed use. Prevention of CINV with optimal antiemetics at the first chemotherapy treatment is the best way to prevent anticipatory CINV. If patients develop anticipatory CINV, they can be taught behavioral techniques, such as relaxation techniques or guided imagery to manage symptoms. Antianxiety agents such as alprazolam or lorazepam can be started the night before treatment to lessen this type of CINV. Breakthrough CINV is treated with a class of agent not previously used. An agent should be prescribed for as needed use for breakthrough. There are many different choices to add to the regimen, including benzodiazepines, cannabinoids, metoclopramide, haloperidol, phenothiazines, olanzapine, or scopolamine. When a patient is having breakthrough CNV, it is important that clinicians check that the correct regimens were originally prescribed and that the patient was adherent. CINV has a significant effect on quality of life.9 Chemotherapy may have to be stopped or delayed because of uncontrolled CINV. This can have an impact on the ultimate treatment outcome. It can also lead to loss of work days. The dread of future chemotherapy can lead to anticipatory nausea, which requires significant health care provider time to manage. The major financial costs of uncontrolled CINV

include nursing time, physician time, antiemetic rescue medication, additional office visits, emergency room visits, intravenous hydration, and hospital admission. In a retrospective cohort study, 13.8 percent of patients receiving chemotherapy had a CINV-associated hospital visit.10 The majority of these visits were because of delayed CINV, and the mean costs were $5,299 per patient. In another study, 25 percent of patients who received highly or moderately emetogenic chemotherapy required medical care for uncontrolled CINV.10 Two percent of the patients had emergency room visits. The total direct costs for patients with uncontrolled CINV exceeded controlled patients by $2,000 to $4,000; work loss days were also significantly higher.11 After controlling for demographics, geographic regions, and comorbidities, the difference in monthly medical costs between the controlled and uncontrolled group was $2,619 (p<0.001). However, the difference in work loss was no longer significant. Nonprescription agents have also been studied for CINV. Ginger has been studied in a large randomized trial in combination with a serotonin antagonist and dexamethasone.12 For acute nausea, all doses of ginger studied were more effective than placebo; 0.5 gm and 1.0 gm were most effective. It was not as effective for delayed CINV. Acupressure has also been studied in nine controlled trials. A review of the trials concluded that the effect of acupressure is strongly suggestive but is still not conclusive.13 The trials studied different emetic potential agents and different acupressure modalities (wrist bands and finger acupressure). It can be recommended as a nonpharmacologic intervention in addition to pharmacologic regimens. Conclusion

Because of the substantial costs of uncontrolled CINV, prevention of CINV is the goal. To achieve this goal, the antiemesis guidelines should be followed. Optimal control for highly or moderately emetogenic chemotherapy will require combination therapy to prevent both acute and delayed CINV. Susan Urba, MD, is Professor of Medicine in the Division of Hematology and Oncology at the University of Michigan Comprehensive Cancer Center.

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12. Ryan JL, Heckler CE, Roscoe JA, et al. Ginger (Zingiber officinale) re-

7. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of

duces acute chemotherapy-induced nausea: a URCC CCOP study of 576 pa-

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chemotherapy-induced nausea and vomiting control. J Pain Symptom Manage.

tion of Chemotherapy-Induced Nausea and Vomiting: A Randomized Phase III

2008;36(5):529-44.

www.NAMCP.org keads@namcp.org (804) 527-1905

Educational Activities Conferences Held biannually during the spring and fall. Earn up to 14 CMEs at each. Archived Webcasts If you canâ&#x20AC;&#x2122;t attend a conference, view the presentations and earn your CMEs online. Live Webinars Attend during your lunch hour. Join our list @ www.namcp.org/joinemail.htm

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

How to Improve Depressing Statistics in Major Depressive Disorder Jair C. Soares, MD, PhD For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Major depressive disorder (MDD) is the disease that causes more disability than any other disease; yet, it is underdiagnosed and undertreated. There are effective antidepressants and psychiatric treatments available, but a significant portion of patients will have refractory depression. For those patients, other therapies may be necessary. Key Points • MDD is underdiagnosed and undertreated. • MDD can lead to changes in the brain. • Electroconvulsive therapy and transcranial magnetic stimulation are options for refractory depression. • Several investigational treatments are under study, including ketamine, immunotherapy, and deep brain stimulation.

IN ANY GIVEN YEAR, 19 MILLION AMERICAN adults, or 9.5 percent of the population in the United States (U.S.), suffer from depressive disorders. The point prevalence of depression varies from country to country. In the U.S., the point prevalence is 4.45 percent. An individual has a lifetime prevalence of 17 percent and 7 percent over one year. Major depressive disorder (MDD) is a costly disease, both financially and personally. It is the number one cause of years lost due to disability, the number three contributor to overall burden of disease, and the number one contributor to overall burden of disease in middle- and high-income countries.1 Depression doubles an individual’s overall health care costs. Depressed patients can have severely impaired quality of life.2 Depression is also deadly and is the number one mental illness contributing to suicide.3 Few people with depression receive adequate treatment. In one study of 12-month use of mental health services in the U.S., only 19.6 percent of

those with depression were receiving minimally adequate treatment.4 Inadequately treated depression has a progressive course and may be associated with functional and structural changes in the brain.5 Structural neuroimaging studies are now being examined for diagnostic and monitoring purposes. These noninvasive studies have allowed science to prove that depression is a brain disease. The size and structure of key areas of the brain related to emotion (fronto-limbic regions) are altered in depression. The changes probably perpetuate the disease. Because of the effects on the brain of a depression episode, after two to three episodes, patients probably should be treated for a lifetime. Mental health is gaining acceptance as a medical problem, but progress in finding treatments is still hampered by stigma. If depression was viewed like cancer, there would significantly more research dollars spent on this disorder.

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 25

Exhibit 1: Classification of Mood Disorders

Mood disorders

Bipolar disorders

Bipolar I disorder

Cyclothymic disorder

Depressive disorders

Bipolar disorder NOS

Bipolar II disorder

Exhibit 1 illustrates the classification of mood disorders. The focus of this discussion is MDD. Some people with depression will have a single episode, but many will have recurrent episodes. Those with recurrent depression are at higher risk for many chronic diseases, such as cardiovascular and diabetes, and for brain disorders, including dementia. Twenty to 30 percent of those with recurrent depression will have refractory or difficult to treat depression. Depression is likely the result of biological vulnerability interacting with psychosocial factors. There is significant study into the genetics of depression, but this is complicated by the large number of genes likely involved (polygenic). It has been proposed that a chronic inflammatory process in the brain may be related to the brain changes that occur with depression. Studies have shown increases in inflammatory measures in those with depression. This theory and the tools to measure the effects of the immune system and inflammation in depression is in its infancy. Comprehensive treatment strategies for MDD include relieving acute symptoms and preventing/ reducing recurrences, assessing and treating comorbid psychiatric and/or medical conditions, assessing relevant psychosocial issues and intervening when appropriate, maximizing treatment compliance, and preventing negative outcomes. The American Psychiatric Association has published treatment guidelines.6 There are a large number of medication options for treating depression, including the tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibi-

Major depressive disorder

Single episode

Dysthymic disorder

Depressive disorder NOS

Recurrent

tors (SNRIs), monoamine oxidase inhibitors, and serotonin modulators. There is no one effective agent for all patients. It is really a trial and error process to find an effective antidepressant. Typically, one agent is started for which only about 30 percent of patients will respond. The next step may be to switch classes or add an additional agent for augmentation. Examples of agents used for augmentation include the atypical antipsychotics, lithium, thyroid hormone, pindolol, or buspirone. Cognitive behavioral therapy (CBT) is very effective and can be the sole treatment for some patients. CBT, combined with antidepressants, is the best treatment combination for those who have had more than one episode of depression. Current medications and psychotherapy are no more effective than they were in the 1950s.7,8 Electroconvulsive therapy (ECT, circa 1938) is still the most effective antidepressant treatment, with a 50 to 70 percent remission rate but a greater than 50 percent relapse rate in six months.9,10 ECT is still the gold standard for refractory depression. Since about 30 percent of patients with depression have refractory depression, clinicians need to understand why this occurs. Several factors contribute to treatment refractoriness. These factors include alcoholism; substance abuse; other comorbid psychiatric illnesses including anxiety disorders, attention deficit disorder, and personality disorders; poor social support; poor adherence to treatment; and neurocognitive impairment. Poor treatment adherence may occur because of denial, medication adverse effects, and financial barriers. One newer therapy for MDD is transcranial mag-

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

netic stimulation (TMS), which is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve symptoms of depression. TMS is FDA approved for MDD in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode. TMS efficacy is comparable to atypical antipsychotics in treatment-resistant depression and antidepressants, but ECT is still superior to TMS.11-13 This treatment is given five times weekly for three to six weeks. For patients who have to pay a copay for each treatment, this therapy may be unaffordable. Several novel treatments for MDD are under study. One of these is transcranial direct- current stimulation (tDCS), which is emerging as one of the most promising approaches because of its relative ease of use, safety and neurobiological effects. This procedure involves the use of weak electric currents (1–2 mA) which are passed through brain tissue via electrodes placed on the scalp for 20 to 40 minutes per treatment. The stimulation is too weak to directly cause neuronal firing, but is thought to interact with the neuronal membrane and background neural activity. Effect size for tDCS is similar to TMS and antidepressant medications.14 Deep brain stimulation (DBS) of the subcallosal cingulate is also under investigation.15 DBS is currently being used to treat Parkinson’s disease. Immune modulators such as infliximab have shown early promise in patients with documented inflammation (i.e., high C reactive protein).16 Ketamine, an anesthetic, has been studied in MDD, treatment-resistant bipolar disorder, and people in a suicidal crisis in emergency rooms.17 It is given intravenously, has a very rapid onset of action, and a short duration of benefit. It appears to work by blocking N-methylD-aspartate (NMDA) receptors for glutamate, a different mechanism from current antidepressants.

References 1. Unützer J, Schoenbaum M, Katon WJ, et al. Healthcare costs associated with depression in medically Ill fee-for-service Medicare participants. J Am Geriatr Soc. 2009;57(3):506-10. 2. Papakostas GI, Petersen T, Mahal Y. Quality of life assessments in major depressive disorder: a review of the literature. Gen Hosp Psychiatry. 2004;26(1):13-7. 3. Centers for Disease Control. Risk Factors for Suicide. Available at http:// www.cdc.gov/violenceprevention/suicide/riskprotectivefactors.html. Accessed 7/13/2016. 4. Wang PS, Lane M, Olfson M, et al. Twelve month use of mental health services in the United States. Arch Gen Psych. 2005;62(6):629-40. 5. Bremner JD. Structural changes in the brain in depression and relationship to symptom recurrence. CNS Spectr. 2002;7(2):129-30,135-9. 6. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. 2010. Available at http://psychiatr yonline.org/pb/assets/raw/sitewide/practice_guidelines/ guidelines/mdd.pdf. Accessed 7/13/2016. 7. Holtzheimer PE, Mayberg HS. Stuck in a Rut: Rethinking Depression and its Treatment. Trends Neurosci. 2011; 34(1): 1–9. 8. Holtzheimer PE, Nemeroff CB. Novel targets for antidepressant therapies. Current Psychiatry Reports 2008;10:465-73. 9. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285(10):1299-307. 10. Kellner CH, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006 ;63(12):1337-44. 11. Schutter DJ. Nosce te ipsum: On the efficacy of transcranial magnetic stimulation in major depressive disorder. Biol Psychiatry. 2010;67(5):e27; author reply e29. 12. Gaynes BN, Lloyd SW, Lux L, et al. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis. J Clin Psychiatry. 2014;75(5):477-89; quiz 489. 13. Ren J, Li H, Palaniyappan L, Liu H, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:181-9. 14. Shiozawa P, Fregni F, Benseñor IM, et al. Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014 ;17(9):1443-52. Erratum in: Int J Neuropsychopharmacol. 2014;17(9):1539.

Conclusion

15. Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingulate deep

Depression is likely etiologically heterogeneous and polygenic. Regional abnormalities in fronto-limbic regions involved in mood regulation have been shown on brain imaging studies. Clinicians need to look for and treat depression. Beyond CBT and antidepressants, ECT and TMS are options for refractory depression. Research is needed to better understand the causes/mechanisms of this disease and better treatments need to be developed.

brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69(2):150-8. 16. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41. 17. Fond G, Loundou A, Rabu C, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology (Berl). 2014;231(18):3663-76.

Jair C. Soares, MD, PhD, is the Pat R. Rutherford, Jr. Professor and Chair of the UT Center of Excellence on Mood Disorders in the Department of Psychiatry and Behavioral Sciences at the UTHealth Medical School, in Houston, TX.

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 27

Novel Targets and Evolving Therapies to Improve Outcomes in Lipid Management Karol E. Watson, MD, PhD, FACC For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Four new lipid-lowering agents with unique mechanisms of action have recently been approved in the United States (U.S.). Although effective for reducing atherogenic lipids, long-term benefits for reducing mortality and cardiovascular events have not yet been proven. Clinicians await the long-term studies before significantly adopting these agents. Key Points • Clinicians should consider familial hypercholesterolemia (FH) in patients with LDL-C over 190 mg/dL. • Mipomersen and lomitapide are FDA approved agents for the treatment of homozygous FH under a REMS program. • Evolocumab and alirocumab are FDA approved as adjuncts to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. • Outcomes studies with the new agents are needed before they will be adopted widely.

THE AMERICAN COLLEGE OF CARDIOLOgy/American Heart Association guidelines for managing cholesterol were published in 2013.1 These guidelines were an update to the prior National Cholesterol Education Program (NCEP) guidelines. Exhibit 1 provides the overall algorithm from the guidelines.1 The guidelines target the four groups who benefit the most from statin therapy – clinical atherosclerotic cardiovascular disease (ASCVD), low-density lipoprotein cholesterol (LDL-C) greater than 190 mg/dl, diabetes, and estimated 10-year risk of cardiovascular disease (CVD) of 7.5 percent or higher. Statins are the mainstay of lipid-lowering therapy but are not effective or appropriate for all patients. Those groups that will likely need additional or al-

ternative therapies include statin-resistant patients, statin-intolerant patients, those with familial hypercholesterolemia (FH), and those with low highdensity lipoprotein cholesterol (HDL-C). Even though statins are robust LDL-C lowering drugs, there is significant inter-individual response to statins.2 Most likely these differences are related to genetics and not lack of adherence. An estimated 5 to 20 percent of patients cannot tolerate statin treatment. Statin intolerance (most commonly muscle pain, aching, and weakness) commonly leads to discontinuation. Most statinintolerant patients can be successfully re-challenged without adverse effects. Intolerance may be the result of perception or expectation. Muscle adverse events without significant elevation of creatine kinase lev-

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Exhibit 1: Lipid Management Algorithm1 Heart healthy lifestyle habits are the foundation of ASCVD prevention (See 2013 AHA/ACC Lifestyle Management Guideline)

Age ≤ 75 years High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin)

Yes Adults aged > 21 years and a candidate for statin therapy

Yes

Clinical ASCVD

Yes

Age > 75 years OR if not candidate for high-intensity statin Moderate-intensity statin

Yes

High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin)

No Definitions of High and Moderate Intensity Statin Therapy High Daily dose lowers LDL-C by approx. ≥ 50%

Moderate Daily dose lowers LDL-C by approx. 30% to 50%

LDL-C ≥ 190 mg/dL

Diabetes Type 1 or 2 Age 40 - 75 years

Yes

Moderate-intensity statin

Yes

Estimated 10 year ASCVD risk ≥ 7.5% High-intensity statin

DM age < 40 or > 75 years

Primary prevention (No diabetes, LDL-C 70 - 189 mg/dL and not receiving statin therapy Estimate 10 year ASCVD Risk every 4 - 6 years Pooled Cohort Equations

< 5% 10 year ASCVD risk

Age < 40 or > 75 years and LDL-C < 190 mg/dL

≥ 7.5% 10 year ASCVD risk (Moderate or highintensity statin)

5% to < 7.5% 10 year ASCVD risk (Moderate-intensity statin)

In selected individuals, additional factors may be considered to inform treatment decision making Emphasize adherence to lifestyle Manage other risk factors Monitor adherence Clinician-Patient Discussion Prior to initiating statin therapy, discuss: 1. Potential for ASVCD risk reduction benefit 2. If decision is unclear, consider primary LDL-C ≥ 160 mg/dL, family history of premature ASCVD, lifetime ASCVD risk, abnormalCAC score or ABI, or hs-CRP ≥ 2 mg/dL 3. Potential for adverse effects and drug-drug interactions 4. Healthy lifestyle 5. Management of other risk factors 6. Patient preferences

No to statin Yes to statin Encourage adherence to lifestyle Initiate statin at appropriate intensity Manage other risk factors Monitor adherence

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 29

Exhibit 2: Comparing Mipomersen and Lomitapide

Mipomersen

Lomitapide

Mechanism of action

Antisense apoB synthesis inhibitor

MTP inhibitor

FDA approved

Yes - for HoFH

Administration

20 mg SC injection, once weekly

5, 10 and 20 mg oral capsules, once daily

Drug interactions

Minimal

CYP3A4 substrate ↓ absorption of fat soluble vitamins

Safety concerns

Black box warning: Risk of hepatotoxicity*; ↑ LFT abnormalities; hepatic fat accumulation

Pregnancy

Cost

~ $175,000/yr

~ $250,000/yr

* Available through the Risk Evaluation and Mitigation Strategies (REMS) program.

els are unlikely to be related to the statin. There is a subset of patients who are truly statin intolerant. Familial hypercholesterolemia (FH) is a heritable disorder, caused by mutations in the LDL-receptor gene that result in receptor absence or malfunction.3 FH is the most common inherited disorder.4,5 Inheritance may be autosomal dominant or recessive. Heterozygous FH occurs in about 1:500 patients. Over 900 mutations in the LDL-receptor gene have been identified as causing FH. Most mutations are of the LDL-receptor gene. Mutations in apolipoprotein B (Apo B) and, proprotein convertase subtilisin/kexin type 9 (PCSK9) are less common that those in LDL receptor (1:2,500 and 1:1,000, respectively). The common consequence of the possible genetic mutations is a decreased clearance of LDL from the plasma, resulting in a clinically recognizable pattern of severe hypercholesterolemia, cholesterol deposition in the tendons and skin, and high risk of atherosclerosis, which manifests mainly as coronary artery disease (CAD). Clinical manifestations include severe hypercholesterolemia (LDL-C > 190 mg/dl) and CVD early in life (Men: 42–46 yrs; Women: 50–52 yrs). Those with homozygous FH can have LDL-C values in the thousands. FH is underdiagnosed and undertreated. Over 600,000 people in the U.S. have FH, but only 10 percent are diagnosed. FH is difficult to treat and a highpotency statin is often not enough. Novel strategies to address unmet needs in lipid lowering include antisense oligonucleotides, microsomal triglyceride transport protein (MTP) inhibition, PCSK9 inhibition, and cholesteryl ester transfer protein (CETP) inhibition. Since patients with

FH have abnormal or nonexistent LDL-Rs, these classes are another avenue for reducing LDL-C rather than statins. One avenue to reduce LDL-C is to alter production of very low-density lipoprotein (VLDL) from which LDL is produced. Apo B-100 is an important structural and functional component of lipoproteins. Blocking Apo B-100 production blocks VLDL and subsequent LDL production. Apo B antisense oligonucleotides block Apo B production by preventing RNA translation. Mipomersen (Kynamro®), the first Apo B antisense oligonucleotide, reduces LDLC by 28 percent in homozygous FH.6 Another mechanism is to target MTP. MTP plays an essential role in lipoprotein assembly and its inhibition disrupts particle formation. Lomitapide (Juxtapid®) is the first MTP inhibitor. It significantly reduces LDL-C by 25 to 50 percent and other atherogenic lipoproteins.7 It also modestly raises HDL-C. Without LDL to carry fat away from the liver, it can accumulate in the liver. The liver does not respond well to fat accumulation, so liver function tests (LFTs) increase. A black box warning exists for lomitapide and mipomersen regarding the risk for transaminase elevations and hepatic steatosis. Fatty liver can lead to the development of cirrhosis. Mipomersen and lomitapide are only indicated for homozygous FH and are available under an FDA Risk Evaluation and Mitigation Strategy (REMS) program, so only certified physicians can prescribe and certified pharmacies can dispense them. Outcomes with these two will be followed by the manufacturers and the FDA. Exhibit 2 provides some additional information on these two agents.

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

Exhibit 3: PCSK9-Directed Therapies in Development

Drug (Alternate Name)

Agent

Indication

Phase

LGT-209

Monoclonal antibody

Hypercholesterolemia

Pfizer/Rinat

RN316 (Bococizuab)

Monoclonal antibody

Hypercholesterolemia

Genentech

RG7652 (MPSK3169A)

Monoclonal antibody

Hypercholesterolemia

Alylam Pharmaceuticals

ALN-PCS02

siRNA oligonucleotide

Hypercholesterolemia

Adnexus Therapeutics/ Bristol Myers Squibb

BMS-962476

Fusion protein using Adnectin technology

Cardiovascular disease

Idera Pharmaceuticals

TBD

Antisense oligonucleotide

Hypercholesterolemia

Preclinical

SX-PCK9

Small peptide mimetic LDLR antagonist

Hypercholesterolemia

Preclinical

TBD

Small molecule PCSK9 modulator

Metabolic disorders

Preclinical

Company Novatis

Serometrix Shifa Biomedical Corp.

PCSK9 is a secreted protein which targets the LDL receptor for degradation. Gain of function mutations causes high LDL-C; increased activity or levels of PCSK9 reduces the number of LDL receptors available to bind and clear LDL-C, leading to a reduction of LDL-C catabolism and elevated LDL-C levels. Loss of function mutations cause low LDL-C. People with loss-of-function mutations in PCSK9 or total lack of PCSK9 have naturally low levels of LDL-C and reduced CHD and are generally healthy with no other apparent metabolic abnormalities. Inhibition of PCSK9 lowers LDL-C levels. PCSK9 inhibition provides an effective option for patients (with and without FH) who cannot achieve their target LDL-C levels. Monoclonal antibody-mediated mechanisms have been the primary focus for PCSK9 inhibition. The monoclonal antibodies are as effective as statins for lowering LDL-C.8-11 Reductions in LDL-C of 60 to 70 percent have been seen. So far these agents have been well tolerated and appear safe in clinical trials to date, but they must be administered via subcutaneous injection. Adverse effects include injection-site reactions, myalgia, neurocognitive events (memory loss), and ophthalmologic events. The FDA is continuing to monitor the neurocognitive and ophthalmologic events. Evolocumab (RepathaÂŽ) and alirocumab (PraluentÂŽ) are the first two PCSK9 monoclonal antibodies approved by the FDA. Both are indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic cardiovascular disease, who require

additional lowering of LDL-C. The recommended dose for evolocumab is 140 mg every two weeks via subcutaneous administration. An every fourweek dosed product is in development. Alirocumab is dosed as 75 mg subcutaneously once every two weeks; the majority of patients achieve sufficient LDL-C reduction with this dosage. If the LDL-C response is inadequate, the dosage may be increased to the maximum dosage of 150 mg every two weeks. No trial designed to show cardiovascular benefit of these agents has been published. A post-hoc analysis of an alirocumab trial showed a lower incidence of major cardiovascular events in those who received alirocumab in combination with statins compared with those who received statins alone.10 Several long-term outcome studies are underway and likely will be published in 2018. Non-antibody PCSK9 inhibition compounds and additional monoclonal antibodies are in development. Exhibit 3 shows the additional PCSK9 agents currently under development. Managing low HDL-C is another unmet need in lipid management. Low HDL-C is the most common risk factor found in patients with premature coronary heart disease. Even in statin- treated patients with low LDL-C (even less than 70 mg/dl), low HDL-C is a dangerous risk factor.12 Lifestyle measures are very effective for increasing HDL-C. Aerobic exercise, smoking cessation, weight loss, healthy diet, and moderate alcohol intake can each raise HDL-C in the 10 to 15 percent range. When lifestyle measures are not enough, pharmacologic measures are another way to raise HDL-C. Unfor-

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 31

tunately, trials studying statins plus niacin or fibrates specifically for HDL-C raising have not shown cardiovascular benefits. One avenue of raising HDL-C under investigation is targeting cholesteryl ester transfer protein (CETP). CETP exchanges cholesterol from HDL and LDL to VLDL in the bloodstream, resulting in smaller, denser HDL and LDL. Small, dense LDL is more atherogenic than larger LDL particles. Small, dense HDL is more rapidly cleared than larger HDL particles. Inhibiting CETP leaves more cholesterol attached to HDL and LDL. CETP inhibitors or modulators are being developed to target HDL-C. Torcetrapib, dalcetrapib, and evacetrapib were investigational CETP inhibitors or modulators which produced significant increases in HDL. Unfortunately, the clinical trial results with these agents have been disastrous. In one torcetrapib trial, although LDL-C was decreased 25 percent and HDL-C was increased 72 percent, the trial was terminated early due to increased risk of death and cardiac events with torcetrapib. The increased risks with torcetrapib were thought to be due to “off-target” effects, including increased blood pressure, decreased potassium, and increased sodium, bicarbonate, and aldosterone.13 Trials of dalcetrapib and evacetrapib were terminated early due to lack of efficacy. Anacetrapib is the last CETP inhibitor left standing. The published trial of anacetrapib found significant HDL-C rising, LDL-C lowering, and a lowering of cardiovascular events.14 Interim safety analyses have been conducted and no adverse mortality issues have been seen. Final results will likely be published in the next year.

Karol E. Watson, MD, PhD, FACC, is Professor of Medicine in the Division of Cardiology at the David Geffen School of Medicine at UCLA, Co-director of the UCLA Program in Preventive Cardiology and Director of the UCLA Barbra Streisand Women’s Heart Health Program.

References 1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45. 2. Pedro-Botet J, Schaefer EJ, Bakker-Arkema RG, et al. Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner. Atherosclerosis. 2001;158(1):183-93. 3. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111(12):1795-803. 4. Genetic Alliance UK. http://www.geneticalliance.org.uk/education3.htm 5. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007;4(4):214-25. 6. Gouni-Berthold I, Berthold HK. Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia. Atheroscler Suppl. 2015;18:28-34. 7. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med. 2007;356(2):148-56. 8. Lambert G, Charlton F, Rye KA, Piper DE. Molecular basis of PCSK9 function. Atherosclerosis. 2009;203(1):1-7. 9. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367(20):1891-900 10. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-99 11. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500-9

Conclusion

Several novel lipid-altering drugs are now available and more are currently in development. Although these new agents lower lipids, cardiovascular benefit has to be proven before they will be FDA approved for wider indications or widely adopted by clinicians.

12. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301-10. 13. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-22. 14. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406-15.

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Overcoming Challenges in the Treatment of OAB David A. Ginsberg, MD For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title

Summary Overactive bladder (OAB) has a serious impact on quality of life, but it is treatable. Treatment typically begins with behavioral interventions and pharmacotherapy. If those do not provide adequate symptom relief, treatment can then move to more invasive therapies. Key Points • Urgency, with or without urgency incontinence, usually with frequency and nocturia, characterizes OAB. • Behavioral therapy and pharmacotherapy are first-line and second-line therapies. • Neurostimulation and onabotulinum toxin injections are additional options.

OVERACTIVE BLADDER (OAB) IS A CLINICAL, symptom-based diagnosis and is defined as urinary urgency, usually accompanied by frequency and nocturia with or without urgency urinary incontinence, in the absence of urinary tract infection or other pathology.1 Those affected by OAB will frequently complain of a frequent urge to void, they are up several times at night to void, they “can’t make it” to bathroom in time, and they may leak large volumes of urine. Overactive bladder is a prevalent disease affecting approximately 16 percent of the adult population in the United States (U.S.) and is as prevalent as chronic diseases such as arthritis, allergic rhinitis, and sinusitis.2,3 It is more prevalent than heart disease, asthma, diabetes, and peptic ulcers. OAB does not just occur in women; the prevalence is similar in men, approximately 16 percent and women, approximately 16.9 percent. The incidence of OAB increases with age in both genders. However, it may be surprising

to note that many patients are younger than some people may believe, with high rates in the 45 to 65 age range. Women appear more likely to seek care for OAB symptoms, possibly because they are more likely to be incontinent from the condition. OAB is a financially and personally costly condition. Total annual costs of OAB are estimated at $12 billion.4 Seventy percent of that is from community residents and 30 percent from institutionalized individuals. Routine care costs for institutionalized care of OAB are $2.77 billion annually or $15/day per person for diapers, laundry, etc.5 Consequence costs of OAB in community dwelling adults include $49 million for skin conditions, $1.37 billion for urinary tract infections, $54 million for falls, $368 million for broken bones, $1.9 billion for nursing home admissions, and $62 million for hospital stays.6 For some of these consequences, the costs are higher if the person also has urinary incontinence. In addition to these consequences, OAB has a tremendous

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Exhibit 1: Impact on Quality of Life Medical Social

Sleep

Physical

Sexual

QOL Work life

Emotional

Economic

Psychological Home life

impact on all aspects of quality of life (Exhibit 1). Clinical practice guidelines for screening, diagnosis, and management of OAB are available.7 A presumptive diagnosis of OAB can be made on the basis of the patient’s history, an assessment of the symptoms, a physical examination, and a urinalysis. An extensive workup may not be required for the initiation of noninvasive treatment such as behavioral therapy and medications. If other causes of the OAB symptoms are suspected, then an additional workup is suggested. These include pelvic organ prolapse, interstitial cystitis, urinary tract infection, carcinoma in situ, bladder outlet obstruction, polyuria, and medication induced. The perceptions of physicians and patients about OAB differ. In 85 percent of cases of women discussing their incontinence symptoms with their physician, the patient had to raise the issue. Only 34 percent of patients with diagnosed OAB receive treatment. Greater than 50 percent of women who discussed OAB with a health care provider waited more than a year to seek treatment.8,9 OAB diagnosis has a positive impact on knowledge, communication with spouse/partner and medical professionals, and management of symptoms.10 Exhibit 2 outlines some questions to help detect OAB and its impact on a given patient.11,12 It is also important to recognize significant comorbidities of OAB, which include urinary tract infection, chronic constipation and fecal incontinence, overweight (BMI 25–30 kg/m2) and obesity (BMI >30 kg/m2), type 2 diabetes mellitus (T2DM) and depression. In a survey of 1,359 patients with T2DM, who were screened at a dedicated diabetes center, 22.5 percent had OAB and 48.0 percent of those with OAB had incontinence.13 Behavioral therapies are first-line treatment for OAB. These include bladder training, bladder con-

trol strategies, pelvic floor muscle training, and dietary changes. Bladder training focuses on modifying bladder function by having the patient maintain a bladder diary. The diary is reviewed and the patient’s voiding interval should be increased gradually by 15- to 30-minute intervals based on the voiding pattern, and the patient should be taught bladder coping strategies. Bladder training is used primarily for urge incontinence, urgency, and frequency. Bladder training can be very effective, but it requires ongoing commitment by the patient. Pelvic floor muscle training with urge suppression techniques can also be taught. Avoiding bladder irritants such as spicy foods, citrus fruits and juices, tomato-based foods, alcohol, drinks with caffeine, and nicotine can be helpful. Avoiding constipation can also help. Limiting fluid intake after dinner can reduce nocturia. Behavioral therapy can lead to a 50 to 80 percent reduction in the frequency of incontinence. Behavioral therapies may be combined with pharmacologic therapy, and typically the combination has improved results compared with behavioral therapy alone. The issue is maintaining adherence over time with the behavioral therapies. “No treatment” is an acceptable choice made by some patients and caregivers when the symptoms are not majorly bothersome.7 Weight loss can improve urinary incontinence and other OAB symptoms. Several trials have found that even modest weight loss of 5 to 10 percent is effective.14 Some have suggested that weight loss should be the initial treatment of OAB for those who are overweight. Education about the condition and helping set appropriate patient expectations about treatment are important aspects of management. Patients need to understand that OAB is not cured with treatment but is managed. They also need to understand that the goal of therapy is to reduce the

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

Exhibit 2: Useful Questions to Direct the Diagnosis of OAB11,12

Do you have to rush to go to the toilet? Do you do this because of a sudden intense feeling so you have to urinate IMMEDIATELY?

Urgency

Do you feel that you urinate too often during the day?

Frequency

Do you have to get up during the night to urinate? Does the urge to urinate wake you?

Nocturia

When you feel the urge to go to the bathroom, do you have leaks or wetting accidents?

Urgency urinary incontinence

symptoms to a manageable level. Complete elimination of symptoms, including urinary incontinence, may not be possible. Pharmacologic therapy is second-line therapy after behavioral management. Antimuscarinics and beta agonists are the two available classes of therapy. The guidelines recommend oral antimuscarinics or the beta agonist, mirabegeron.7 The guidelines state that extended release (once daily dosing) formulations should preferentially be prescribed over immediate release formulations. Clinicians need to use caution in prescribing antimuscarinics in those using other medications with anticholinergic properties and in the frail OAB patient. Antimuscarinic agents block binding of acetylcholine to muscarinic receptors on the smooth muscle membrane. By doing so, they stabilize bladder smooth muscle, making it relatively refractory to the stimulation via parasympathetic neural impulses. Through this mechanism, antimuscarinic therapy decreases the frequency of involuntary bladder contractions. Antimuscarinic therapy also increases bladder capacity and delays the initial urge to void. Oxybutynin (generic, Ditropan XL®, Gelnique®), tolterodine (Detrol® LA), trospium (Sanctura®), solifenacin (Vesicare®), darifenacin (Enablex ®), and fesoterodine (Toviaz®) are all antimuscarinic agents. All are effective for treating OAB symptoms, but there are differences in their adverse effect profiles and thus tolerability. There are also now multiple different dosage forms including extended release oral, liquids, topical patches, topical gels and bladder instillation. Finding an effective and tolerable antimuscarinic can require trying several different agents.

Beta agonists are the other class of medications for OAB treatment. Mirabegron (Myrbetriq®) is a selective beta-3 adrenoceptor agonist. It activates beta-3 adrenoceptors on the detrusor muscle of bladder to facilitate filling of the bladder and improved storage. Essentially, this is a bladder relaxant which does not affect detrusor muscle contractility. Mirabegron has efficacy similar to antimuscarinic agents without the anticholinergic adverse effects. The traditional approach to OAB pharmacotherapy has been starting naïve patients on an antimuscarinic as the first pharmacotherapy choice. If expense is a concern, the antimuscarinics tend to be less expensive than mirabegron. Choosing an antimuscarinic that is dosed once daily and can be titrated is preferable. If the patient’s symptoms are not controlled on the antimuscarinic or they have intolerable adverse effects, treatment can then move on to the beta agonist. Trials of several different antimuscarinics may be required to find one that is effective with tolerable adverse effects. In a retrospective analysis of a California managed care organization prescription database, patients used one to six antimuscarinics during the period reviewed. There was a high discontinuation rate (88-100%) and dissatisfaction rate (82 – 100% among those still on agents).15 No matter how many different agents were tried, there was a similar daily incontinence rate (3.3-3.9 episodes/day). This analysis suggests that continual antimuscarinic cycling is not an optimal treatment approach following failure of the first prescribed agent. Options for lack of antimuscarinic efficacy include titrating up on antimuscarinic (same or different), adding mirabegron, switching to mirabegron

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 35

alone, or taking more invasive options. A combination of mirabegron and solifenacin has been studied and found to be more effective than either agent alone.16 With the combination, there was no significant impact on urinary retention. The two most common adverse effects were dry mouth and minor increase in blood pressure. The anticholinergic adverse effects (dry mouth, constipation) had a dose relationship with the solifenacin dose. There was no increase in these with the combination therapy. Patients who should be started on mirabegron as first choice include those who have significant baseline dry mouth from other medications or Sjögren’s syndrome, significant baseline constipation, baseline cognitive concerns, and the frail elderly. Baseline cognitive concerns are especially an issue in those who are already on medications with anticholinergic adverse effects. Third-line treatments include intradetrusor onabotulinum toxin A, sacral neuromodulation (SNS), and percutaneous tibial nerve stimulation (PTNS). Intradetrusor onabotulinum toxin A (100 U) is the first choice of the third-line treatments in carefully-selected and thoroughly-counseled patients who are refractory to first- and second-line OAB treatments.7 Candidates for botulinum toxin A injection have to be able and willing to return for frequent post-void residual evaluation because urinary retention is common, and they also have to be able and willing to perform self-catheterization if necessary. SNS is recommended in a carefully selected patient population characterized by severe refractory OAB symptoms, are not candidates for second-line therapy, and are willing to undergo a surgical procedure. PTNS is an external device treatment that is given in the physician’s office for 30 minutes once a week for 12 weeks. It is FDA approved for refractory OAB that has failed two antimuscarinics. Patients who respond may require occasional OAB medication to sustain response.

David A. Ginsberg, MD, is an Associate Professor of Urology at the USC Institute of Urology.

References 1. Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29(1):4-20. 2. National Center for Health Statistics. Health, United States. 2015. Available at http://www.cdc.gov/nchs/data/hus/hus15.pdf. Accessed 7/12/2016. 3. Stewart W, Herzog R, Wein A, et al. The prevalence and impact of overactive bladder in the U.S.: results from the NOBLE program. Neurourol Urodynam. 2001;20:406–8. 4. Hu TW, Wagner TH, Bentkover JD, et al. Estimated economic costs of overactive bladder in the United States. Urology. 2003;61(6):1123-8. 5. Hu TW, Wagner TH, Bentkover JD, et al. Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology. 2004;63(3):461-5. 6. Mullins CD, Subak LL. New perspectives on overactive bladder: quality of life impact, medication persistency, and treatment costs. Am J Manag Care. 2005;11(4 Suppl):S101-2. 7. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. 2012. Available at www.auanet.org. 8. Dmochowski RR. The puzzle of overactive bladder: controversies, inconsistencies, and insights. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(6):650-8. 9. Dmochowski RR, Newman DK. Impact of overactive bladder on women in the United States: results of a national survey. Curr Med Res Opin. 2007;23(1):65-76. 10. Muller N. What Americans understand and how they are affected by bladder control problems: highlights of recent nationwide consumer research. Urol Nurs. 2005;25(2):109-15. 11. Rosenberg MT, Dmochowski RR. Overactive bladder: evaluation and management in primary care. Cleve Clin J Med. 2005;72(2):149-56. 12. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006;50(6):1306-14; discussion 1314-5. 13. Liu RT, Chung MS, Lee WC, et al. Prevalence of overactive bladder and associated risk factors in 1359 patients with type 2 diabetes. Urology. 2011;78(5):1040-5. 14. Pomian A, Lisik W, Kosieradzki M, Barcz E. Obesity and Pelvic Floor Dis-

Conclusion

In OAB, it is important that clinicians ask questions to identify the condition. There are many different treatment options and clinicians need to choose the right treatment for the right patient. Expectations for symptom reduction need to be managed because complete elimination of symptoms may not be possible. Cycling of the same drug is not effective and should be avoided.

orders: A Review of the Literature. Med Sci Monit. 2016;22:1880-6. 15. Chancellor M, Pulicharam R, Cheng I-N, et al. Anticholinergic cycling and treatment outcomes in overactive bladder patients with urinary incontinence. American Urological Association 2014. Abstract: MP33-20. 16. Abrams P, Kelleher C, Staskin D, et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol. 2015;67(3):577-88.

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

Reducing Exacerbations in the Treatment and Management of COPD Charles Vega, MD, FAAFP For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Published studies and management guidelines can be used to select optimal therapy for chronic obstructive pulmonary disease (COPD) patients. There are numerous interventions, including self-management plans and integrated disease management programs, which have been shown to improve symptoms and outcomes in this disease. Managed care can improve COPD care by targeting some of these interventions. Key Points • COPD is a common, costly disease which is managed with smoking cessation, comorbid condition management, pulmonary rehabilitation, medications, and other medical interventions. • Guideline-based management can improve outcomes. • An integrated disease management approach can improve outcomes, especially hospitalizations for exacerbations.

CHRONIC OBSTRUCTIVE PULMONARY disease (COPD) is characterized by airflow limitation that is not reversible.1 It is an abnormal pulmonary inflammatory response to noxious stimuli and is usually progressive. Objectively, it is defined as a forced expired volume in one second (FEV1) to forced vital capacity (FVC) ratio of less than 0.7. Fifteen million Americans have diagnosed COPD, which causes significant morbidity, mortality, and costs.2,3 Over 23 million hospitalizations per 10,000 with COPD occur annually. Hospitalizations are slightly more common in women and much higher among adults over 65 years of age. The disease is estimated to cost $36 billion (2010 dollars) annually. This includes $32 billion in direct medical costs. It results in 16.4 million days of work lost every year. The costs are expected to rise to $49 billion annually by 2020 as our population ages.

Eighty percent of COPD cases are related to smoking. There is a general, but not exact, correlation between smoking pack-years and COPD diagnosis. Another important risk factor is environmental particulate exposure, which is especially important among immigrants. The diagnosis of COPD needs to be accurate. Asthma is frequently mistaken for COPD but can develop into COPD. Symptoms and smoking history alone are not sufficient for a diagnosis. Spirometry is critical for an accurate diagnosis; the FEV1/ FVC ratio should be less than 0.7 with little or no reversal with bronchodilator treatment. The most important treatment for COPD is smoking cessation. Even quitting after many years of smoking is beneficial. In a trial determining the 25year absolute risk of developing COPD in men and women from the general population, quitting 15

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 37

Exhibit 1: Comparing Devices for Inhaled Medications14 Device

Pros

Cons

MDIs

Convenient Fast to use Cheap

Some lack dose counter Hardes to use properly Spacer helps but takes space

Nebulizer

Easy technique Tidal breathing only Reassuring to patients Easy to teach No propellants

Not portable Requires compressed air Requires maintenance Drug delivery can be unreliable

Dry Powder Inhalers

Ease of use - breath activated Portable Dose counters No spacer necessary

Relies on moderate inspiratory flow

years into the study was associated with significantly reduced risk of moderate to severe COPD.4 Death from COPD is also reduced by smoking cessation.5 Pulmonary rehabilitation is an effective treatment for COPD and improves quality of life (QOL), respiratory symptoms, and exercise tolerance.6 Adding other interventions within the rehabilitation program beyond exercise does not further improve outcomes. Although pulmonary rehabilitation is effective, best practices (i.e., type, duration, and setting) still need to be defined. Vaccinations are important in preventing COPD exacerbations. Influenza and pneumococcal are the two vaccines which should be kept up to date. Comorbid conditions also need to be managed to achieve the best outcomes in COPD. Depression is especially important. The prevalence of depression is 24.6 percent in COPD compared with 11.7 percent in controls without COPD.7 Depression in COPD leads to worse health-related QOL, a 77 percent higher risk of hospitalization, a 48 percent higher risk of emergency room visits, and an approximate twofold increase in mortality.7 Up to 40 percent of patients with COPD will have significant anxiety. Pulmonary rehabilitation improves depression and anxiety symptoms; cognitive behavioral therapy is less effective than rehabilitation for both. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines are evidencebased recommendations for managing COPD.1 Despite these guidelines, there is more variability in how clinicians treat COPD with medications compared with asthma. Stepped care and guidelinebased therapy is well accepted for asthma but not necessarily for COPD.

Like asthma, all patients should have a rescue inhaler for acute symptom management. In general, either a single short-acting beta agonist, a short-acting antimuscarinic, or the combination are all acceptable for rescue use. In terms of spirometry, the combination of albuterol and ipratropium (Combivent ®) is superior for spirometry results versus either medication alone, but the combination does not result in a difference in QOL, symptom scores, or physician ratings.8 Most of a clinician’s time related to medications in COPD should be focused on long- term control of the disease with controller medications. The options include long-acting beta agonists (LABAs), longacting muscarinic antagonists (LAMAs), inhaled corticosteroids (ICSs), or phosphodiesterase (PDE) inhibitors. LABAs include salmeterol (Serevent®, Advair ®) and formoterol (Foradil®). Tiotropium (Spiriva®) and glycopyrrolate are LAMAs available in the United States (U.S.). Beclomethasone (QVAR®), budesonide (Pulmicort®), ciclesonide (Alvesco®), flunisolide (Aerospan®), fluticasone (Flovent®), and mometasone (Asmanex ®) are example ICSs. Numerous combination products are also available. Example combinations of ICS and LABA include budesonide/formoterol (Symbicort®), fluticasone/salmeterol (Advair ®), fluticasone/vilanterol (Breo®), and mometasone/formoterol (Dulera®). Combination LABA/LAMA inhalers include glycopyrrolate/formoterol (Bevespi Aerosphere®) and tiotropium/olodaterol (Stiolto®). Roflumilast (Daliresp®) is a PDE-4 inhibitor. Choosing between the various classes of therapies can be challenging. In a large study of moderate to severe COPD patients randomized to a LABA (sal-

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

Exhibit 2: Effect of Integrated Disease Management Programs for COPD on Hospitalizations16

Mean number of hospital admissions over 3 to 12 months per 100 participants: 30

25 20

15 10 5 0 DZ Mgt

meterol) or a LAMA (tiotropium), tiotropium was better for reducing moderate to severe exacerbations and time to first severe exacerbation with similar adverse effects between groups.9 A Cochrane review of seven randomized trials with 12,223 participants found that tiotropium was superior for exacerbation prevention, regardless of which LABA was chosen.10 Hospitalizations and spirometry values were similar in tiotropium and LABA groups. Combination of tiotropium and a LABA are slightly better for health-related QOL and FEV1 improvement.11 There are no differences in mortality, exacerbations, symptom scores, and serious adverse effects. For patients with major QOL impact from their COPD, clinicians can consider using the combination. The GOLD guidelines do not state a preference for beta-agonists or antimuscarinics as a bronchodilator, but do state that long-acting agents are better for symptom relief.1 They note that bronchodilators also improve risk of exacerbation, risk of hospitalization, and QOL. They suggest the combination of LABA/LAMA is probably better than increasing the dose of a single agent. ICSs are another option in COPD. A Cochrane review of 55 randomized trials in over 16,000 participants found that the main benefits of ICSs were fewer exacerbations (-0.19 episodes/year) and slower reduction in QOL.12 Only one trial showed improvement in FEV1 and no difference in mortality was shown in any of the trials. There is a risk of oral candidiasis if patients do not follow prevention instructions and pneumonia. No negative effects on bone were seen over three years of use. Overall, studies have found that the more severe the COPD,

Control

the better the effectiveness and benefit of ICSs. The GOLD guidelines note that ICS are best proven among patients with FEV1 less than 60 percent of predicted.1 The GOLD guidelines are more positive on lung function improvements with ICS compared with the Cochrane review. The guidelines do agree that ICS can improve exacerbations. Long-term monotherapy with ICS is not recommended by the guidelines, but they should be combined with LABA/LAMA. A once-daily triple combination therapy inhaler containing fluticasone, umeclidinium, and vilanterol is under investigation. Exhibit 1 compares the devices for inhaled medications.13 Patients tend to like to use nebulizers because of ease of use, seeing the medication being inhaled, and the act of slowly breathing in can be soothing and can reduce anxiety. Because there is a high rate of improper inhaler technique, patients should bring their inhalers to each health care visit and demonstrate their use. Improper inhaler use can be due to lack of education, lack of outpatient follow-up, and physical difficulties. It is harder for older patients with COPD to use their inhalers than for younger asthma patients. COPD patients are more likely to have arthritis or cognitive impairment. Combination inhaler products can be used to reduce the number of inhalers a patient has to use which will help improve adherence. Although rarely used to treat COPD in the U.S., theophylline works by targeting multiple phosphodiesterases (PDEs) and other inflammatory markers. Roflumilast is like a â&#x20AC;&#x153;targeted theophyllineâ&#x20AC;? because it only affects PDE-4 but is better tolerated and easier to give. It is FDA approved for severe COPD

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 39

with chronic bronchitis and frequent exacerbations and is probably not appropriate for primary care prescribing. Patients with severe enough disease to require this agent should be managed by a pulmonary specialist. Pooled data from two trials found it reduces exacerbations in severe COPD.14 The guidelines suggest this agent for preventing exacerbations among patients with a history of exacerbations and FEV1 less than 50 percent of predicted.1 Oxygen is the only therapy that has been shown to improve survival in patients with COPD. It is indicated for oxygen saturation less than 88 percent at least twice over a three-week period.1 Oxygen is also beneficial if pulmonary hypertension, high hematocrit ( > 55%), or heart failure are present. Self-management plans need to be part of COPD care. Twenty-nine studies with nearly 3,700 participants found that typical self-management plans required at least two contact points and at least two of the following elements: smoking cessation, exercise advice, diet advice, medication advice, and how to recognize and treat exacerbations.15 Fifty-two percent of interventions were offered individually, 26 percent in small groups, and 22 percent in both. Most interventions were multidimensional and included action plans. Health-related QOL and dyspnea were improved when a self-management plan was used compared with usual care. Self-management plans can reduce the number of hospitalization; having a plan can prevent one hospitalization for every eight high-risk patients and every 20 low-risk patients. No improvement was seen in mortality, all-cause hospitalization, or exercise tolerance when selfmanagement plans were used. If exercise had been included in all the plans, there likely would have been an improvement in exercise tolerance. Integrated disease management programs have been studied for impacting COPD outcomes.16 Twenty-six trials involved secondary care (17) or primary care (8). The programs had a mean of three types of health care providers involved and a mean of four components. The most common interventions were exercise (13 studies), self-management or exacerbation plan (5), and structured follow-up with a HCP (5). These programs reduced hospital admissions for exacerbations over 12 months (Exhibit 2).16 Hospital stays were reduced by 3.78 days per year in the integrated disease management groups compared with control groups. There was no difference in overall mortality. Improvements in QOL domains of dyspnea, fatigue, and emotional impact were seen with the programs. There were also improvements in patient 6-minute walking distances. The American College of Chest Physicians/Canadian Thoracic Society COPD guidelines suggest

that education or case management alone may improve QOL but are insufficient to prevent exacerbations.17 Education and action plans without case management are also insufficient. The guidelines state that education and case management with monthly access to a health care provider works. Intensive interventions are important until the patient demonstrates an understanding of their disease and how to manage it and achieves disease control. Barriers to medical therapy can also impact outcomes. Risk factors for medication nonadherence in COPD include low belief in medication effectiveness, higher number of comorbid conditions, depression, and higher numbers of perceived barriers to care.18 Clinicians need to be on the watch for barriers and subsequent nonadherence. Conclusion

COPD is a common disease which can be managed in many different ways. Using the management guidelines and published reviews of various interventions, the most appropriate therapies can be selected. Smoking cessation is the most important aspect of COPD treatment. Controller medications are required for most patients to prevent exacerbations. Managing these patients in a multidisciplinary disease management program can help improve outcomes. Charles Vega, MD, FAAFP, is a Health Sciences Clinical Professor at UC Irvine Department of Family Medicine in Irvine, CA.

References 1. Global Initiative for Chronic Obstructive Lung Disease, Inc. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. 2014. Available at www.goldcopd.org. Accessed 7/21/2016. 2. CDC Behavioral Risk Surveillance System. Chronic Obstructive Pulmonary Disease among Adults â&#x20AC;&#x201D; United States, 2011. MMWR 2012; 61(46):938-43. 3. CDC Work-Related Lung Disease Surveillance System. COPD Death Rates in the United State. Available at http://www.cdc.gov/copd/data.htm. Accessed 7/21/2016. 4. LĂ¸kke A, Lange P, Scharling H, et al. Developing COPD: a 25-year followup study of the general population. Thorax. 2006;61(11):935-9. 5. Li Y, Yamagishi K, Yatsuya H, et al. Smoking cessation and COPD mortality among Japanese men and women: the JACC study. Prev Med. 2012;55(6):639-43. 6. McCarthy B, Casey D, Devane D, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;2:CD003793. 7. Panagioti M, Scott C, Blakemore A, Coventry PA. Overview of the prevalence, impact, and management of depression and anxiety in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:1289-306. 8. The COMBIVENT Inhalation Solution Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest. 1997;112(6):1514-21. 9. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103.

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

10. Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists

COPD frequent exacerbator phenotype. Chest. 2013;143(5):1302-11.

for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev.

15. Zwerink M, Brusse-Keizer M, van der Valk PD et al. Self management for

2012;(9):CD009157.

patients with chronic obstructive pulmonary disease. Cochrane Database Syst

11. Karner C, Cates CJ. Long-acting beta(2)-agonist in addition to tiotropium

Rev. 2014; CD002990.

versus either tiotropium or long-acting beta(2)-agonist alone for chronic ob-

16. Kruis AL, Smidt N, Assendelft WJ, et al. Integrated disease management

structive pulmonary disease. Cochrane Database Syst Rev. 2012;4:CD008989.

interventions for patients with chronic obstructive pulmonary disease. Cochrane

12. Yang IA, Clarke MS, Sim EH, Fong KM. Inhaled corticosteroids for stable

Database Syst Rev. 2013; CD009437 .

chronic

obstructive

pulmonary

disease.

Cochrane

Database

Syst

Rev.

17. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerba-

2012;7:CD002991.

tions of COPD: American College of Chest Physicians and Canadian Thoracic

13. Geller DE. Comparing clinical features of the nebulizer, metered-dose in-

Society Guideline. Chest. 2015;147(4):894-942.

haler, and dry powder inhaler. Respir Care. 2005;50(10):1313-21; discussion

18. Khdour MR, Hawwa AF, Kidney JC, et al. Potential risk factors for medica-

1321-2.

tion non-adherence in patients with chronic obstructive pulmonary disease

14. Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the

(COPD). Eur J Clin Pharmacol. 2012;68(10):1365-73.

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www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 41

Update in the Management of Venous Thromboembolism (VTE) Darrell W. Harrington, MD, FACP For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Venous thromboembolism (VTE) events are relatively common and many are preventable. Prevention in hospitalized patients at risk for these events is important but does not always occur. Evidence-based guidelines are available to guide both the prophylaxis and treatment of VTE. Key Points • VTE is the most common preventable cause of hospital death. • Despite effectiveness, VTE prophylaxis is underused. • Risk assessment can be used to identify those who would benefit the most from prophylaxis while hospitalized. • Standardized protocols for diagnosis of VTE, prophylaxis, and treatment are necessary within institutions. • Evidence supports use of the new oral anticoagulants for the management of acute VTE.

VENOUS THROMBOEMBOLISM (VTE) REfers to a continuum of disease that begins with a deep vein thrombosis (DVT) and can progress to a pulmonary embolism (PE). DVT is a condition in which a thrombus forms in one of the deep veins of the calf or thigh, such as the popliteal or femoral vein. DVT can sometimes lead to a PE, which can be life-threatening. PE results when a thrombus in the deep veins detaches from the vessel wall and travels as an embolus through the inferior vena cava into the right side of the heart, ultimately obstructing blood flow in the pulmonary arteries. Approximately one million VTEs occur every year.1 Each year in the United States (U.S.), one person in 1,000 will experience his/her first VTE. One-third will have a PE (with or without DVT]). Six percent of those with DVT and 12 percent with PE will die within one month of diagnosis. VTE is the most common preventable cause of hospital

death; it accounts for up to 10 percent of deaths.2 VTE can be a recurrent disease. Recurrent DVT occurs in 17 percent of DVT patients within two years after initial treatment and 30 percent within eight to 10 years.3,4 Health burden associated with VTE is expected to grow dramatically during coming years, in part due to an aging population. It is estimated that the rate of VTE will increase 25 to 30 percent over the next 20 years. Being hospitalized is a significant risk factor for VTE. It is more than 130 times greater among hospitalized patients than among community residents.5 Half of community-based cases occur in nursing home patients or within 90 days of hospital discharge. Sixty percent of all cases occur in either hospitalized, recently discharged, or nursing home patients. Hospitalization for acute medical illness is associated with up to an eightfold increase in relative risk for

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

Exhibit 1: Padua Score11

Active cancer*

Previously deep VTE

Reduced mobility †

Thrombophilic condition‡

Trauma or surgery (≤ 1 month)

≥ 70 years old

Heart or respiratory failure

Acute MI or stroke

Acute infection or rheumatologic disorder

Obesity (BMI ≥ 30)

Ongoing hormonal treatment

High Risk = 4+ Low Risk = 3 or less

*mets or Rx in last 6mo † bathroom mobility or less, 3+ days ‡ antithrombin, Protein C+S, F V Leiden, G20210A, antiphospholipid syndrome

VTE. Unprevented VTE may lead to increased morbidity and mortality, including recurrent disease and significantly increased health care costs. VTE prophylaxis in hospitalized patients is very effective. It results in the reduction in fatal PE by 62 percent, and reduces both DVT and PE by more than 50 percent.6 Despite effectiveness, VTE prophylaxis is underused. In one study, only 50 percent of those at risk received prophylaxis.7 Even when used, evidencebased guideline recommendations are often not followed. In one study, recommendations were followed from 45 percent (hip fracture surgery) to 84 percent (elective total hip replacement) of the time.8 In another study, overall guideline compliance was 13.3 percent in greater than 120,000 hospital admissions.9 The compliance rates were 2.8 percent in neurosurgery, 52.4 percent in orthopedic surgery, and 13.3 percent in general medicine. The American College of Chest Physicians (ACCP) guidelines recommend VTE prophylaxis in several groups during hospitalization.10 Because of immobility and surgery, orthopedic surgery patients are at high risk for VTE. They should receive prophylaxis with low-molecular weight heparin (LMWH), fondaparinux, dabigatran/apixaban/rivaroxaban (if total knee or total hip replacement, not hip fracture surgery)], unfractionated heparin (UFH), or adjusted dose warfarin.10 The guidelines also recommend aspirin or intermittent pneumatic compression if medications cannot be used, but both of these recommendations are controversial because of lack of reduction in mortality data com-

pared to the other agents which reduce mortality by 25 percent. General surgery patients should be assessed for risk of VTE. The guidelines specify cutpoints for identifying very low, low, moderate, and high risk and which prophylactic strategies are recommended.10 Those with high risk of VTE should receive LMWH, low-dose UFH, or mechanical prophylaxis, if they also have high risk of bleeding. Beyond those who have had orthopedic or general surgery, other acutely ill hospitalized medical patients are at increased risk of VTE. Risk can be assessed based on the Padua Score (Exhibit 1) or other risk assessment system.11 About 40 percent of acutely ill hospitalized patients will be high risk by the Padua Scoring system. Those at high risk (score of 4 or more) have an 11.8 percent risk of VTE if not given prophylaxis and a 2.2 percent risk if given prophylaxis. Those with a score of less than 4 only have a 0.3 percent risk of VTE and thus need no prophylaxis. Presence of a central venous catheter is one possible risk which is controversial and not accounted for in the Padua Scoring system. There are few absolute contraindications to prophylaxis, but there are a few relative ones. Absolute are history of anaphylaxis with a particular agent; that agent or class should be not used. Active bleeding and thrombolytic therapy in the last 24 hours are the other absolutes. Cautions include excessive risk of bleeding, age greater than 85, and liver or renal failure. It is important to identify those who would most benefit from prophylaxis (i.e., high risk for VTE but low risk of adverse events from

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 43

Exhibit 2: Pharmacological Characteristics of TSOAc

DRUG

DABIGATRAN ETEXILATE

RIVAROXABAN

APIXABAN

EDOXABAN

Mechanism of Action

direct thrombin inhibitor

direct factor Xa inhibitor

6.50%

80 - 100%

50%

62%

Time to Max Inhibition

0.5 - 2 hours

1 - 4 hours

1 - 2 hours

Half-life

12 - 14 hours

5 - 13 hours

8 - 15 hours

10 - 14 hours

85%

66% (36% unchanged and 30% inactive metabolites)

27%

50% (of the absorbed drug)

Inhibitors of P-gp: verapamil --> avoid Potential inducers P-gp avoid

Potent inhibitors of CYP3A4 and P-gp: avoid Potent inducers of CYP3A4 and P-gp: use with caution

Potent inhibitors of P-gp: reduse dose Potent inducers of P-gp: avoid

200mg OD or 150mg OD (prev.) 150 BID (treat.)

10mg OD (prev.) 15mg BID, then 20mg OD (treat.)

2.5mg BID (prev.) 5 mg BID (treat.)

60mg OD (treat.)

Oral Bioavailability

Renal Excretion (fraction of absorbed dose)

Potential Metabolic Drug Interaction

Dose in VTE prevention and treatment

CYP 3A4 inducer – phenytoin, carbamazepine, phenobarbitol, and St. Johns wart P-gp inducers – Refampicin, St. Johns wort, phenytoin, carbamazepine P-gp inhibitors – verapmil, amiodarone, quinidine, clarithromycin also cyclospone and other antineoplastic increase levels of TSOAcs

prophylaxis) to most cost-effectively manage VTE prophylaxis. Prophylaxis for six to 21 days, until full mobility is restored, or until discharge from hospital, whichever comes first, is the recommended duration of prophylaxis.10 There are some high-risk populations who might benefit from longer term prophylaxis; some cancer patients fall in this category. Diagnostic testing for VTE is overused. In one emergency room study, diagnostic management was inappropriate in 43 percent of suspected VTE patients, including 8 percent of confirmed PE and 57 percent who had a PE ruled out.12 Inappropriate diagnostic management had a negative impact on the patient; there were higher rates of thromboembolic events, nonfatal events, and sudden death in the three months after inappropriate exclusion of PE. Clinical assessment should be driven by pretest probability of VTE. There are two evidence-based clinical probability scoring systems that can be used in patients with suspected PE to help improve testing selection.13,14 The guidelines recommend that D-dimer should not be used as the first test in high pretest probability patients but is the first test recommended in those with lower probability.10 A negative highly sensitive D-dimer adequately excludes VTE in non-high-risk patients. Patients with a positive D-dimer must go on to a confirmatory test. Once an acute episode of VTE is diagnosed, treat-

ment is initiated either in the emergency room or the hospital. Parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) is typically first started with oral anticoagulants for prevention of recurrence, and it should be started as soon as possible. The ACCP guidelines also address treatment; the treatment portion of the guidelines were updated in 2016.15 A key change in the treatment guidelines includes the use of target-specific oral anticoagulants (TSOACs) over warfarin for initial and long-term treatment of VTE in patients without cancer. This is only a 2B recommendation (weak/moderate) rather than a 1A (strong/high) or B (strong/moderate) recommendation. 2B recommendations are clinical judgement suggestions rather than standard of care. Recent studies have shown that TSOACs are as effective as warfarin therapy with a reduced risk of bleeding and an increased convenience for patients and health care providers. TSOACs are also referred to as non-vitamin K antagonist or novel oral anticoagulants (NOACs). Much treatment of VTE has moved to the home setting, which reduces hospitalization costs and reduces adverse effects. In patients with acute DVT of the leg and whose home circumstances are adequate, the guidelines recommend initial treatment at home over treatment in the hospital (Grade 1B).15 In patients with low-risk PE and whose home circumstances are adequate, the guidelines suggest

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

early discharge over standard discharge (e.g., after first 5 days of treatment) (Grade 2B).15 Treating PE in the home results in a lower rate of major bleeding and death.16 There are validated criteria for selecting patients for home treatment.17,18 A score of zero on these criteria can result in either an early hospital discharge or discharge directly from the emergency room. The majority of studies being conducted currently in PE are being done in the home setting. Much of the long-term anticoagulation for VTE is moving from warfarin to TSOACs. The TSOACs include dabigatran (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Savaysa®). Each has different FDA indications. Dabigatran and edoxaban are FDA approved for acute VTE treatment after five to 10 days of heparin. Apixaban is FDA approved for VTE prophylaxis after major orthopedic surgery. Rivaroxaban is approved for treatment and prophylaxis of VTE. Exhibit 2 compares the agents. TSOACs are as good as, if not better than, other treatment options. Compared with LMWH after total hip or knee arthroplasty, they result in fewer thrombotic events but more bleeding.19,20 In VTE treatment, they result in lower bleeding rates than warfarin.21 Compared with warfarin treatment of VTE, the TSOACs are considered cost effective.22 The TSOACs have significant advantages, including oral administration, rapid onset and offset of action, predictable pharmacokinetics, fixed doses, wide therapeutic index, easy to use with no need for monitoring, and low propensity for food and drug interactions. At this time, there is only a reversal agent for dabigatran. Reversal agents for the others should be approved in coming years. Some considerations in switching from warfarin to TSOACs, which are not yet clarified, include their role in extended treatment beyond six to 12 months. Only dabigatran has an indication for reduction of the risk of recurrence of VTE following the initial six months of treatment. Other issues to consider include patient preference, adherence with therapy (which cannot be proven with any blood tests with the TSOACs), and lack of long-term safety data for the TSOACs. Additionally, the inability to assess treatment failure, the cost of the new agents, the difficulty in using in those with renal dysfunction, and the lack of ability to titrate dose to a lower or higher level of anticoagulation are other issues with the TSOACs.

remain with patient selection and provider compliance. Optimization of diagnostic strategies (i.e., avoiding unnecessary tests and properly interpreting tests) in VTE management ensures highquality cost-effective outcomes for providers and systems. Most patients with VTE can be readily treated as an outpatient. Good evidence supports use of TSOAC agents for the management of acute VTE. They are efficacious, safe, and likely cost effective. However, provider knowledge of individual nuances is important in assuring high-quality and reliable outcomes. Darrell W. Harrington, MD, FACP, is a Professor of Medicine at the David Geffen School of Medicine at UCLA.

References 1. Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol. 2011;86(2):217-20. 2. Pendleton R, Wheeler M, Rodgers G. Venous thromboembolism prevention in the acutely ill medical patient: a review of the literature and focus on special patient populations. Am J Hematol. 2005;79(3):229-37. 3. Prandoni P, Villalta S, Bagatella P, et al. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica. 1997;82(4):423-8. 4. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257-64. 5. Heit JA, Melton LJ 3rd, Lohse CM, et al. Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin Proc. 2001;76(11):1102-10. 6. Dentali F, Douketis JD, Gianni M, et al. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med. 2007;146(4):278-88. 7. Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;371(9610):387-94. 8. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160(3):334-40. 9. Yu HT, Dylan ML, Lin J, Dubois RW. Hospitals’ compliance with prophylaxis guidelines for venous thromboembolism. Am J Health Syst Pharm. 2007;64:69-76. 10. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e494S. 11. Barbar S, Noventa F, Rossetto V, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010;8(11):2450-7.

Conclusion

12. Roy PM, Meyer G, Vielle B, Le Gall C, et al. Appropriateness of diagnostic

Effective evidence-based regimens for VTE prophylaxis exist, and there are significant opportunities to improve prophylaxis. Challenges still

management and outcomes of suspected pulmonary embolism. Ann Intern Med. 2006;144(3):157-64. 13. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in

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the emergency department: the revised Geneva score. Ann Intern Med.

of right ventricular function. J Thromb Haemost. 2013;11(4):686-92.

2006;144(3):165-71.

19. Adam SS, McDuffie JR, Lachiewicz PF, et al. Comparative effectiveness of

14. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism

new oral anticoagulants and standard thromboprophylaxis in patients having

at the bedside without diagnostic imaging: management of patients with sus-

total hip or knee replacement: a systematic review. Ann Intern Med.

pected pulmonary embolism presenting to the emergency department by using

2013;159(4):275-84.

a simple clinical model and d-dimer. Ann Intern Med. 2001;135(2):98-107.

20. Huo MH. New oral anticoagulants in venous thromboembolism prophy-

15. Kearon C, Akl EA, Ornealas J, et al. Antithrombotic therapy for VTE Dis-

laxis in orthopaedic patients: are they really better? Thromb Haemost.

ease: CHEST guideline and expert panel report. Chest. 2016;149(2):293-294.

2011;106(1):45-57.

16. Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for

21. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleed-

deep vein thrombosis. Cochrane Database Syst Rev. 2007;(3):CD003076.

ing complications in patients receiving target-specific oral anticoagulants: a

17. Zondag W, Mos IC, Creemers-Schild D, et al. Outpatient treatment in pa-

systematic review and meta-analysis. Blood. 2014;124(15):2450-8.

tients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost.

22. Amin A, Lingohr-Smith M, Bruno A, et al. Economic Evaluations of Med-

2011;9(8):1500-7.

ical Cost Differences: Use of Targeted-Specific Oral Anticoagulants vs. Warfa-

18. Zondag W, Vingerhoets LM, Durian MF, et al. Hestia criteria can safely

rin among Patients with Nonvalvular Atrial Fibrillation and Venous Thrombo-

select patients with pulmonary embolism for outpatient treatment irrespective

embolism in the U.S. J Heamtol Thrombo Dis. 2015;3:209 epub.

The Oncology Institute

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Updated Therapeutic Strategies in the Management of Pulmonary Arterial Hypertension David B. Badesch, MD For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although rare, pulmonary arterial hypertension (PAH) is a costly disease, both financially and personally. Survival rates have improved with targeted therapies but are not yet optimal. Management of these patients requires complex, expensive regimens which are likely best managed by a multidisciplinary team in a pulmonary hypertension center. Key Points • Clinical research can inform the development of evidence-based treatment guidelines for patient care. • PAH is more common in women and affects a broad age range. • Delays in diagnosis persist, so most patients are diagnosed with late symptoms. • PAH has a very poor prognosis if untreated. • A multidisciplinary approach should be used to optimize long-term outcomes.

PULMONARY ARTERIAL HYPERTENSION (PAH), although rare, has become more important as awareness of the symptoms has become more common and medications targeting the disease have been approved for use in the United States (U.S.). PAH is a disease of the pulmonary vasculature and primarily occurs in the small pulmonary arteries prior to the pulmonary capillary bed. It is just one type of pulmonary hypertension (PH) and can be idiopathic, heritable, drug- and toxin-induced, persistent PH of the newborn or associated with connective tissue disease, HIV infection, portal hypertension, coronary heart disease, schistosomiasis, or chronic hemolytic anemia. Most drug-induced cases in the U.S. are from methamphetamine and cocaine. In the early stage of PAH, pulmonary vascular resistance (PVR) and pulmonary arterial pres-

sure (PAP) rise, but cardiac output (CO) remains stable and the pulmonary vasculature shows minimal changes (if any). As PAH progresses, PVR and PAP continue to rise, and CO starts to decline. The pulmonary vasculature develops intimal proliferation and smooth muscle hypertrophy. With advanced PAH, CO starts to decline in the face of continued increase in PVR; this may result in a decrease in mean PAP. The pulmonary vasculature shows smooth muscle hypertrophy, intimal hyperplasia, thrombosis, and plexiform lesions. Exhibit 1 illustrates what happens over time as the disease progresses.1 Symptoms increase and patient function declines as the disease progresses; the World Health Organization (WHO) classification system can be used to place people in functional categories one to four.

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Exhibit 1: Hemodynamic and Clinical Course of PAH1

BNP PAP PVR

WHO I

III

Time CO = cardiac output PAP = pulmonary arterial pressure PVR = pulmonary vascular resistance BNP = b-type-natriuretic-peptide WHO = World Health Organization

PAH is about four times more common in women compared to men.2 The reasons for this disproportionate gender distribution are unknown. It occurs in all age groups, but the most common age at diagnosis is between 45 and 57. Untreated PAH is a highly lethal disease. In the absence of effective therapy, median survival is 2.8 years from diagnosis.3-5 Over 50 percent of untreated patients will die within five years. It is imperative that clinicians actively screen for it in order to improve outcomes. Unfortunately, most patients are not diagnosed with PAH until late in the disease. PAH registries reveal that 75 percent or more of patients are in WHO class III or IV at the time of diagnosis. Dyspnea, fatigue, syncope or near syncope, chest pain, palpitations, and leg edema are the most common symptoms of PAH. These nonspecific symptoms are often mistaken for cardiac disease, asthma, or chronic obstructive pulmonary disease (COPD) and are a major reason for delayed diagnosis. Special attention should be given to patients presenting with dyspnea and syncope. Dyspnea, in a relentless and progressive fashion over a period of months to a couple of years, suggests PAH as compared with dyspnea that waxes and wanes from week to week or varies according to the season. Entities such as asthma are more likely to explain variable dyspnea. Syncope when it is exercise- or activity-related suggests PAH. Patients who feel like â&#x20AC;&#x153;passing outâ&#x20AC;? after going up a flight of stairs are more likely to have limited CO and brain perfusion (caused by severe PAH and other serious entities) as compared with

people who feel they might pass out while sitting down watching TV or when they turn their heads too fast. The latter more likely reflects some other types of vertigo/dizziness and less likely related to decreased brain blood flow because of cardiac issues. A right heart cardiac catheterization is necessary to determine the diagnosis of PAH. Hemodynamically, it is defined as a mean PAP greater than or equal to 25 mm Hg plus a pulmonary capillary wedge pressure to left ventricular end diastolic pressure (LVEDP) ratio of less than or equal to 15 mm Hg. Cardiac catheterization is also used to exclude congenital heart disease, measure wedge pressure and LVEDP, establish the severity and prognosis, and test for vasoreactivity with vasodilator therapy. An appropriate diagnosis is necessary to select the most appropriate therapy. The approved medications are only effective for PAH and not for most other forms of PH. There is one therapy discussed later which is effective for both PAH and chronic thromboembolic pulmonary hypertension (CTEPH). For some types of PH, the medications can even be harmful. The very expensive PAH medications tend to be inappropriately used for those who do not have actual PAH. PAH treatment goals include reduction in severe symptoms, improvement in exercise capacity, improvement in hemodynamics, prevention of clinical worsening, improvement of quality of life, and improvement of survival. Targeted therapies discussed later improve each of these outcome measures. Although survival rates have improved with targeted therapies, the life expectancy of someone with PAH

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

is still not the same as if they did not have the disease. Patients with PAH require several general care measures. Women with PAH need to avoid pregnancy because of the high maternal mortality rate (30-60%) and teratogenicity of many PAH medications. All fertile women with PAH require counseling on pregnancy avoidance and reliable contraception. Because respiratory illnesses can worsen the disease, all those with PAH should receive influenza and pneumonia vaccinations. Oxygen therapy may be required in these patients because hypoxic vasoconstriction aggravates PAH. It is important to keep patients’ oxygen saturation at 90 percent or greater. Anticoagulation, diuretics, and digoxin are also occasionally used to prevent thromboembolism and to manage symptoms. Pulmonary rehabilitation is recommended because it can significantly improve functional ability as measured by the six-minute walk distance (6MWD). Sometimes patients get more functional improvement with pulmonary rehabilitation than with the medications. Acute vasoreactivity testing is done during the diagnostic right heart catheterization procedure to determine if vasodilator therapy with calcium channel blockers is appropriate. Ten to 15 percent of patients with PAH are vasoreactive and respond well to calcium channel blockers long term. A positive vasodilator challenge is defined as a drop in mean pulmonary artery pressure by 10 mm Hg to a value of 40 mm Hg or less. A positive vasodilator challenge does have prognostic value; responders have better longer term survival. The majority of patients are not going to be vasoreactive and will require PAH- specific therapies. There are oral, parenteral, and inhaled PAH-specific therapies. The first class of PAH-specific agents are the prostacyclin analogues—epoprostenol, treprostinil, and iloprost. These agents provide prostacyclin-like activity with vasodilation, platelet inhibition, antiproliferative effects, and inotropic effects. Trials have shown improvements in symptoms, 6MWD over 12 weeks, hemodynamics, and survival. Epoprostenol (Flolan®, Veletri®), the first PAHspecific therapy, has a very short half-life (2 minutes), so it is delivered via continuous parenteral infusion. Treprostinil (Remodulin®) is available as subcutaneous or intravenous continuous infusion and has a longer half-life than epoprostenol (4 hours). Treprostinil is also available as an inhaled therapy (Tyvaso®) that is dosed four times daily and an extended release oral formulation (Orenitram®) given two to three times daily. Iloprost (Ventavis®), an inhaled agent, is administered nine times daily

with each inhalation taking five to eight minutes. There are patients who have been on prostacyclin analogues for 15 to 20 years, which is tremendous given the life expectancy of untreated disease. The adverse events of the prostacyclin analogues include flushing, headache, diarrhea, nausea, vomiting, jaw pain, leg pain, hypotension, dizziness, syncope, cough (inhaled products), and delivery site complications (intravenous products). The adverse effects vary according to the medication and the route of delivery. Another avenue of treating PAH is to target endothelin, a small peptide hormone produced in the vascular endothelium which leads to vasoconstriction and smooth muscle cell proliferation. Endothelin receptor antagonists (ETRA) work by blocking receptors on the endothelium and vascular smooth muscle. The available agents are bosentan (Tracleer ®), ambrisentan (Letairis®), and macitentan (Opsumit®). These agents improve the 6MWD, hemodynamics, functional class, and survival. All agents in this class are oral and teratogenic. All women on an ETRA must have a monthly negative pregnancy test to continue these agents. Adverse effects of these agents include nasal congestion, abnormal hepatic function, and edema. Reversible transaminase elevations greater than three times the upper limit of normal may require dose adjustment or discontinuation. Monthly liver function tests are recommended when bosentan is used. Lower extremity edema may require diuretics to manage. A third area to target in PAH is phosphodiesterase. Phosphodiesterase 5 (PDE-5) inhibitors augment cyclic guanosine monophosphate (cGMP) which has vasodilatory and antiproliferative actions in the pulmonary arteries. These agents improve the 6MWD, functional status, hemodynamics, and time to worsening. Sildenafil (Revatio®) was the first FDA approved PDE-5 inhibitor. The FDA approved dose is 20 mg three times daily but higher doses (80-100 mg tid) have been shown in trials to improve hemodynamic findings. Tadalafil (Adcirca®), with an FDA approved dose of 40 mg once a day, has similar efficacy to sildenafil. Its once daily dosing is a slight advantage over sildenafil. PDE-5 inhibitors do cause more adverse effects than the ETRAs. Many of the adverse effects are related to vasodilation and include headache, epistaxis, dyspepsia, flushing, diarrhea, and visual changes. These agents are contraindicated in combination with nitrates because of systemic hypotension. Riociguat is a new class of medication– soluble guanylate cyclase stimulator. It has a dual mode of action, directly stimulating soluble guanylate cyclase (sGC) independently of nitric oxide (NO), and in-

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creasing the sensitivity of sGC to NO. It is approved in both PAH and PH secondary to chronic thromboembolic pulmonary hypertension (CTEPH), a vascular disorder characterized by organized thrombotic obstructions in the pulmonary arteries and can be associated with small vessel vasculopathy indistinguishable from idiopathic PAH. Like PAH, CTEPH is associated with significant increased risk of mortality. Riociguat improved the 6MWD and hemodynamics in both types of PH.6 CTEPH may be under-recognized and underdiagnosed. Approximately 600,000 individuals in the U.S. have an acute pulmonary embolism (PE) annually.7 The incidence of CTEPH is about 4 percent within two years in patients after a first episode of PE.8 A significant proportion of patients with CTEPH have no history of clinically overt PE. Like PAH, patients with CTEPH have a poor prognosis without early treatment. Pulmonary thromboendarterectomy (PTE) is the standard treatment for CTEPH and the only potentially curative treatment. Surgery is not an option for those with occlusion of distal vessels, coexisting conditions, or lack of access to expert surgical centers. Operability should be assessed at an experienced PTE center. Some patients who undergo PTE have persistent or recurrent PH. In addition to riociguat, anticoagulation is the other nonsurgical treatment for CTEPH. Evidence-based treatment guidelines are available to guide clinicians in selecting therapy.9 Overall, PAH functional class should be improved by therapy. In general, those with low risk for progression and functional class II are usually treated with oral therapies. Those with moderate risk and class III may be treated with oral, inhaled, or infused therapy and those with high-risk disease and class IV will need inhaled or infused therapy. While current therapies are effective as monotherapy, many patients are left with significant exercise limitations, and survival is not normal, despite treatment. Although the mortality rate has improved, it remains very high. Even patients who improve with therapy rarely achieve normal physical function, and quality of life remains impaired. With so far yet to go, physicians have started combining available drugs, hoping that their beneficial effects will be additive or even synergistic. The guidelines recommend combination therapy when monotherapy is not sufficient; this recommendation may change to early use of combination therapy based on some ongoing trials and a recently published trial of early use of an ambrisentan and tadalafil combination.9-11 Combination therapy might allow lower dosages of individual drugs with reduced toxicity or cost. Because PAH involves several signaling pathways,

combination therapy with different classes also modifies multiple pathways. Therapy and perhaps even cure might logically require multiple avenues of attack. Initial data from the REVEAL Registry found more than a third of over 1,200 patients were on two medications, and 9 percent were on three. Preliminary evidence from controlled clinical trials of combination therapy has been promising.12 Some information can be gleaned from other trials where at least half of the patients studied were on background therapy at the time of randomization, such as PHIRST (53% on background ERA), SERAPHIN (64% on background PDE-5 inhibitor or prostanoid), and PATENT-1 (50% on background ERA or prostanoid).6, 13-17 In PHIRST, in which 53 percent of patients were on combination therapy, treatment-naïve patients had a more robust response to the addition of a PDE-5.13 Of note, there are more published studies of prostacyclins—IV or inhaled—in combination with oral therapy than there are of dual oral therapies. Ongoing studies of combination oral therapy will hopefully provide useful information about these regimens. Managing those with PAH requires a multidisciplinary team to manage all the various medical, physical, and social issues and complex medication regimens. Patients with all types of pulmonary hypertension should be seen in centers of excellence where these teams are most often located. Typically, the centers will see the patient every three months and their local primary care providers will see them in between. Conclusion

The nonspecific nature of symptoms of PAH contributes to significant delays in diagnosis, and those delays likely have an impact on prognosis, which is poor in the absence of therapy. While the diagnostic work-up is not difficult, it must be performed methodically so as to be certain of the diagnosis. Different etiologies of PH have very different treatment approaches and prognoses. While PAH remains a potentially life-threatening disease, better diagnosis and treatment of PAH can make a substantive difference. Effective therapies which improve prognosis now exist. A multidisciplinary approach should be used to optimize long-term outcomes. David B. Badesch, MD, is a Professor of Medicine at the University of Colorado School of Medicine in Denver, CO.

References 1. Gaine S. Pulmonary hypertension. JAMA. 2000;284(24):3160-8. 2. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary Arterial Hypertension:

Baseline

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

Characteristics

From

the

REVEAL

Registry.

Chest.

2010;137(2):376-87.

lege of Cardiology Foundation Task Force on Expert Consensus Documents and

3. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol

the American Heart Association developed in collaboration with the American

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College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmo-

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

4. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary

10. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmo-

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

nary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.

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

11. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tada-

5. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary

lafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9):834-44.

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

12. Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term

2004;126(1 Suppl):78S-92S.

intravenous epoprostenol therapy in patients with pulmonary arterial hyperten-

6. Ghofrani HA, Simonneau G, Rubin LJ, et al. Riociguat for pulmonary hy-

sion: a randomized trial. Ann Intern Med. 2008;149(8):521-30.

pertension. N Engl J Med. 2013;369(23):2268.

13. Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary

7. Tapson VF, Humbert M. Incidence and prevalence of chronic thromboem-

arterial hypertension. Circulation. 2009;119(22):2894-903..

bolic pulmonary hypertension: from acute to chronic pulmonary embolism.

14. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding

Proc Am Thorac Soc. 2006;3(7):564-7.

inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J

8. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboem-

Respir Crit Care Med. 2006;174(11):1257-6315.

bolic pulmonary hypertension after pulmonary embolism. N Engl J Med.

15. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil

2004;350(22):2257-64.

to oral therapy for pulmonary arterial hypertension: a randomized controlled

9. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert

clinical trial. J Am Coll Cardiol. 2010;55(18):1915-22

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

16. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and

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.

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wwilliams@aaihds.org (804) 747-5823

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 51

Treatment of Metastatic Breast Cancer Joanne Mortimer, MD, FACP For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Although considered incurable, there are many treatment options for metastatic breast cancer. Advances continue to be made in managing breast cancer, including agents for resistance to hormonal therapy and increasing research in how best to tackle triple-negative breast cancer. Key Points • Therapy is selected based on tumor biology and markers. • Hormone receptor-positive disease is treated primarily with antiestrogen therapies. • Resistance to hormonal therapy presents a major clinical challenge in managing breast cancer. • HER2-positive disease is treated with targeted therapies in addition to chemotherapy. • Triple-negative disease is treated with chemotherapy. • Targets for therapy in triple-negative disease are being identified.

THE WOMEN WITH METASTATIC BREAST cancer are a very diverse group. It is estimated that there are 250,000 women alive in the United States (U.S.) with metastatic breast cancer. Breast cancer is divided up based on the presence of markers for response to targeted therapy. Seventy- two percent of breast cancer cases in the U.S. are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2) negative.1 Smaller percentages are triple negative (not positive for estrogen or progesterone receptors or HER2, 13%), HER2+ and HR+ (10%), and HER2+ and HR- (5%). Although considered incurable, there are many different treatment options for metastatic breast cancer. Women with HR+ and HER+ disease may live for many years with the disease and go through many different lines of treatment. At this time there are no approved targeted therapies for triple-negative breast cancer (TNBC), which has a median survival of 12 months.

Exhibits 1 and 2 outline the approach to treating premenopausal and postmenopausal women with metastatic HR+ breast cancer, respectively. If the patient does not respond to the first hormonal therapy, then they will not respond to subsequent ones and should move directly to chemotherapy. For those who respond to hormonal therapy, there are multiple lines of therapy which can be given before resistance to all hormonal therapies occurs and chemotherapy becomes the only option. Resistance to hormonal therapy presents a major clinical challenge in managing breast cancer. Significant research is ongoing to identify the mechanisms of resistance and how to target these with medications. The growth of HR+ breast cancer is dependent on cyclin D1, a direct transcriptional target of the estrogen receptor. Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein (D1) dimerizes with CDK4/6 to regulate cell growth and DNA replication. Cell

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

Exhibit 1: Treatment of Metastatic Premenopausal Hormone Receptor-Positive Breast Cancer

LHRH agonist + tamoxifen

No Response

Response with subsequent progression Chemotherapy Estrogen

Aromatase Inhibitor/Fulvestrant + Palbociclib

No Response Response with subsequent progression Aromatase Inhibitor + Everolimus

Androgen

Progesterone *Continue LHRH agonist if still premenopause

line models of hormonal resistance remain dependent on cyclin D1 and cyclin-dependent kinase 4 and 6 (CDK4/6) for growth, so this is a target for overcoming resistance. Palbociclib (IbranceÂŽ) is an inhibitor of CDK4/6. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER) positive breast cancer cells. Palbociclib is FDA approved for use in combination with letrozole for the treatment of postmenopausal women with ER+ and HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease. In the trial that led to its approval, palbociclib combined with letrozole improved mean progression-free survival (PFS) by 10 months compared with letrozole alone.2 There was no improvement in overall survival (OS) with palbociclib. It has also been studied as second-line therapy in combination with luteinizing hormone-releasing hormone (LHRH) agonists, tamoxifen, or fulvestrant (Faslodex ÂŽ) in pre and postmenopausal women with ER+/HER2- metastatic disease at relapse or progression on first-line therapy who had one or fewer rounds of chemotherapy previously.3 The combination increased the mean PFS by 4.4 months. The major adverse effects of palbociclib are neutropenia and fatigue. Because the neutropenia can

be fatal, patients must have their white counts done every two weeks while on treatment, so dose modification can occur if neutropenia develops. At this point, there is not a particular marker (other than ER+ disease) which predicts response to palbociclib. In the 1980s, HER2 was discovered as a driver of breast cancer. HER2-targeted therapy, with the first approved agent trastuzumab in 1998, was a significant advance because these agents have been shown to improve survival when added to chemotherapy in women with metastatic HER2+ breast cancer. Lapatinib, pertuzumab, trastuzumab/emtansine are the other HER2-targeted agents. HER2 targetedtherapy is given with chemotherapy and continued in patients with metastatic disease even at progression because second-, third-, and fourth-line chemotherapy has better outcomes when combined with trastuzumab versus chemotherapy alone. Because the HER2 agents have different mechanisms of action, they can be combined to improve response in HER2+ metastatic breast cancer. In the trial studying trastuzumab and pertuzumab, PFS and OS were both improved by the combination.4 There are no major increases in toxicity when trastuzumab, pertuzumab, and docetaxel are used in combination. Because of the benefits seen with the

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 53

Exhibit 2: Treatment of Metastatic Postmenopausal Hormone Receptor-Positive Breast Cancer

Letrozole + Palbociclib

No Response

Response with subsequent progression Chemotherapy Estrogen

Exemestane + Everolimus

No Response Response with subsequent progression 2nd line Fulvestrant + Palbociclib (if no prior Palbociclib)

Androgen

Progesterone

triple therapy, this is now the recommended firstline therapy for metastatic HER2+ disease. Lapatinib and trastuzumab have also been studied in combination with a 14 percent improvement in OS.5 Exhibit 3 outlines the treatment of advanced HER2-positive breast cancer. Importantly, following systemic therapy, the HER2 status of the tumor may change in 5 to 30 percent of patients. Retesting for HER2 status should occur intermittently. There are some limitations of identifying and treating HER2+ patients. Concordance between labs for HER2 testing is only 80 percent. There are also data that some HER2-negative patients may benefit from HER2-directed therapies.6 Presence of a V777L activating mutation may be a factor in HER2-targeted therapy response.7 Neratinib, an epidermal growth factor receptor (EGFR)/HER2 agent, is under study for patients with this HER2 activating mutation. TNBC is really a group of different subtypes of breast cancer (Exhibit 4).8 Many people think of TNBC as a very aggressive disease, predominately in African American women, but it is really many different diseases that respond to treatment differently. Although in the past, clinicians have not thought of TNBC as having targets for therapy, data are showing there are possible targets. One target is modulation of homologous recombination repair

mechanism deficiency (BRCA1 and BRCA2) using platinum-based chemotherapy. The standard of care for TNBC has been platinum-based (cisplatin, carboplatin, oxaliplatin) single agent chemotherapy as first line, but it is controversial among oncologists whether all patients with TNBC should receive it.9 In metastatic disease, high response rates are seen with platinumbased therapies, but these agents are very difficult to tolerate. As neoadjuvant therapy (reduce tumor burden before surgery), platinum-based therapies produce high pathologic response rates, primarily in BRCA-associated cancers.10,11 This makes sense because platinum-based agents prevent DNA repair and BRCA mutations cause defects in homologous DNA repair. Unfortunately, there are no data to say that platinum-based chemotherapy in TNBC alters survival. Giving platinum chemotherapy can damage the bone marrow, which can make giving myelosuppressive therapy in subsequent lines of therapy more difficult. Androgen receptor-positive TNBC accounts for 10 percent of all TNBCs. These tumors typically are low grade lesions, occur in older patients, and are associated with programmed death ligand-1 (PDL1) expression. Targeting PD-L1 is being investigated. Another option in these patients may be to use androgen antagonists. Enzalutamide, an andro-

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

Exhibit 3: Treatment of Metastatic HER2 Positive Breast Cancer

Presents with Metastatic Disease

> 6 months

Metastatic Disease after Adjuvant Trastuzumab

Chemo + trastuzumab + pertuzumab Dz Progression or No Response Ado-trastuzumab/Emtansine (TDM-1) or Trastuzumab + lapatinib Dz Progression or No Response Capecitabine + lapatinib or Trastuzumab + lapatinib or Chemo + trastuzumab Dz Progression or No Response

gen antagonist approved for treating prostate cancer, has shown promising results in preclinical analysis and in a small clinical trial.12 The androgen-based therapies are much less toxic than platinum-based chemotherapy. For those with immunomodulatory driven TNBC, pembrolizumab (KeytrudaÂŽ), a monoclonal antibody against the programmed death-1 (PD-1) receptor, is under investigation. This agent prevents binding to ligands (PD-L1 and PD-L2), thus restoring immune surveillance. It is already approved for treating metastatic melanoma and non-small cell lung cancer that expresses PD-L1. Again, promising results have been seen in one small trial.13 When using personalized medicine to select breast cancer therapies, a few things are important to note. Platforms such as Foundation One testing may identify therapies that one might not otherwise select (i.e., agents approved for other cancers). Additionally, as discussed previously, with HER2+ disease molecular profiles of tumors change as a result of treatment. This likely necessitates re-biopsy and retesting at relapse to identify new agents to use. Bone-directed therapy with bisphosphonates and denosumab is a significant advance in treating metastatic breast cancer. This has helped improve quality of life by preventing bone fractures, reduced need

for radiation and orthopedic surgery, reduced incidence of hypercalcemia that requires treatment, and reduced pain. The current standard of care is monthly zoledronic acid, pamidronate, or denosumab injections. The hardest part of treating metastatic breast cancer is understanding when to stop therapy. Although this recommendation is not frequently adhered with, the National Comprehensive Cancer Network (NCCN) guidelines do specify stopping treatment in patients who have no response after three sequential lines of chemotherapy or their functional status is that they are in bed more than out of bed.9 Trials in metastatic cancers, but not necessarily breast cancer, have found that best supportive/palliative care provides longer survival than chemotherapy. Clinicians may be rushing death by giving women treatment when they are already in poor physical health. A recent trial of patients with endstage disease (15% with breast cancer) found that chemotherapy was associated with a worse quality of death.14 Quality of death is a new and upcoming functional measure for cancer treatment. Conclusion

Patients with certain types of metastatic breast cancer can live for many years with their disease. This

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 55

Exhibit 4: Triple Negative Subtypes8 Androgen, oestrogen or steroid metabolism genes

Cell cycle or DNA repair genes

Luminal androgen

Basal-like

Unstable

Immunomodulatory

Immune response genes

Mesenchymal-like

Cellular differentiation motility or growth factor pathways

will require moving through multiple lines of therapy to keep the cancer at bay. Not as much progress has been made with TNBC, but numerous targets for therapy in various subtypes are being identified. Hopefully, within the next few years, targeted therapies for TNBC will be available and will prolong survival.

study. Lancet Oncol. 2013;14(6):461-71. 5. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30(21):2585-92. 6. Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358(13):1409-11. 7. Ellis MJ, Perou CM. The genomic landscape of breast cancer as a therapeutic

Joanne Mortimer, MD, FACP, is Director of the Women’s Cancer Pro-

roadmap. Cancer Discov. 2013;3(1):27-34.

gram and Vice Chair of Medical Oncology and Therapeutics at the City

8. Moran MS. Radiation therapy in the locoregional treatment of triple-nega-

of Hope Comprehensive Cancer Center.

tive breast cancer. Lancet Oncol. 2015;16(3):e113-22. 9. National Comprehensive Cancer Network. NCCN Clinical Practice Guide-

References

lines in Oncology. Breast Cancer. Version 2.2016. Available at www.nccn.org.

1.Kohler BA, Sherman RL, Howlader N, et al. Annual Report to the Nation on

Accessed 7/27/2016.

the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes

10. von Minckwitz G, Blohmer JU, Costa SD, et al. Response-guided neoadju-

by Race/Ethnicity, Poverty, and State. JNCI. 2015;107(6):1-25

vant chemotherapy for breast cancer. J Clin Oncol. 2013;31(29):3623-30.

2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor

11. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant Cis-

palbociclib in combination with letrozole versus letrozole alone as first-line

platin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145-53.

treatment of estrogen receptor-positive, HER2-negative, advanced breast can-

12. Cochrane DR, Bernales S, Jacobsen BM, et al. Role of the androgen recep-

cer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol.

tor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res.

2015;16(1):25-35.

2014;16(1):R7.

3. Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor-Positive

13. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in Patients With Ad-

Advanced Breast Cancer. N Engl J Med. 2015;373(3):209-19.

vanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin

4. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel

Oncol. 2016;34(21):2460-7.

for HER2-positive metastatic breast cancer (CLEOPATRA study): overall sur-

14. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy Use, Performance

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

Status, and Quality of Life at the End of Life. JAMA Oncol. 2015;1(6):778-84.

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

Optimal Treatment Strategies in the Management of Castration-Resistant Prostate Cancer Julie N. Graff, MD, MCR For a CME/CNE version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.

Summary Hormonal therapy remains first-line therapy in advanced prostate cancer; however, many men will develop castration-resistant prostate cancer (CRPC). These patients will ultimately require multiple lines of therapy over time. There are unanswered questions about the best use of various therapies which will hopefully be answered in the near future. Key Points â&#x20AC;˘ In addition to taxane-based chemotherapy, sipuleucel-T, abiraterone, and enzalutamide are newer options approved for treating mCRPC. â&#x20AC;˘ Unanswered questions in managing mCRPC include which agents should be used when, how best to combine the agents, effects of longer term androgen suppres sion therapy on the body, and the effect of multiple treatments on tumor characteristics.

PROSTATE CANCER IS THE MOST COMMON cancer in men and the second most common reason for death in men.1 Exhibit 1 illustrates the possible paths of prostate cancer. Most men diagnosed in the United States (U.S.) have localized disease, which is potentially curable. Four percent of men initially present with metastatic disease, which is not curable. The majority of metastases with prostate cancer are seen in bone; other common sites are the liver and lungs. Many more men develop metastatic cancer after presenting with localized cancer. A biochemical recurrence is an increase in the prostate specific antigen level (PSA) without any evidence of disease on bone or CAT scan. The initial treatment of metastatic prostate cancer would be androgen suppression with LHRH agonists (medical castration) and/or surgical castration. These treatments decrease androgens by 90 percent, which causes apoptosis of many of the cancer cells, but not all. The adrenal glands continue to produce testosterone. The goal with androgen suppression is to have a testosterone level less than 50 ng/dl. Even-

tually, cancer cells learn to survive on very small amounts of androgens. Once androgen suppression is no longer effective, the patient is considered to have metastatic castration-resistant prostate cancer (mCRPC). This can also be considered androgen resistant. Mechanisms of androgen resistance include upregulation of androgen receptors, use of estrogen to make testosterone, and constantly activated androgen receptors (which do not require testosterone).2 mCRPC is defined as a positive body scan for tumor and tumor growth despite an optimal testosterone level (<50 ng/dl). The treatment options for mCRPC have dramatically increased since 2004 when docetaxel was first FDA approved (Exhibit 2). Chemotherapy with the taxanes, docetaxel and cabazitaxel, have been shown to improve median overall survival by 2.4 months, reduce pain, and improve quality of life.3-5 Taxanes are the only chemotherapy effective for prostate cancer. Adverse effects of the taxanes include fatigue, allergic reactions, alopecia (50%), tear duct scarring, myelosuppression (neutropenic fever 2-3%), and

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 57

Exhibit 1: Disease States in Prostate Cancer

mHSPC

Localized Disease

mCRPC

Biochemical Recurrence (BCR)

nmCRPC

mHSPC = metastatic hormone sensitive prostate cancer nmCRPC = non-metastatic castrate resistant prostate cancer mCRPC = metastatic castrate resistant prostate cancer

Exhibit 2: Timeline for FDA Approvals in mCRPC

2004

Docetaxel

2010 Sipuleucel-T Cabazitaxel 2011

Abiraterone post-chemotherapy

2012

Enzalutamide post-chemotherapy Abiraterone pre-chemotherapy

2013

Radium-223

2014

Enzalutamide pre-chemotherapy

sensory neuropathy. Sipuleucel-T (Provenge) is an immunotherapy. Essentially, this therapy trains the patient’s white blood cells to train T cells to kill the cancer. It is recommended as first-line treatment for asymptomatic or minimally symptomatic metastatic CRPC.6 A course of sipuleucel-T treatment consists of three basic steps. A patient’s white blood cells, primarily antigen-presenting cells (APCs), are extracted in a leukapheresis procedure. The blood product is incubated with a fusion protein (PA2024) consisting of two parts, the antigen prostatic acid phosphatase (PAP), which is present in 95 percent of prostate cancer cells, and immune signaling granulocytemacrophage colony-stimulating factor (GM-CSF)

that helps the APCs to mature. The activated blood product (APC8015) is returned to the infusion center and infused into the patient to cause an immune response against cancer cells carrying the PAP antigen. A complete sipuleucel-T treatment repeats three courses, with two weeks between successive courses. The cost is about $31,000 per infusion and $93,000 for a complete treatment. Acute infusion reaction is the most common adverse effect, thus patients have to be premedicated with acetaminophen and diphenhydramine before re-infusion of their treated white blood cells to prevent cytokine release. Sipuleucel-T provides a median of 4.1 month OS benefit over placebo.7 No significant prostate-specific antigen (PSA) decreases or tumor size decreases occur with this therapy. Because it is a modest effect and very expensive, the procedure is not extensively used. Even though mCRPC is hormone resistant, there are two second-generation options to further reduce androgen effects. More complete suppression of androgen production can be accomplished with abiraterone (Zytiga®). Enzalutamide (Xtandi®) provides a more complete blockade of androgen receptor signaling. Abiraterone blocks glucocorticoid and androgen hormone productions and increases mineralocorticoid production. In the prechemotherapy population, abiraterone improves median OS by 4.3 months, improves progression-free survival (PFS) by 8.2 months, and decreases PSA.8,9 Common adverse effects include increased liver function tests and mineralocorticoid excess. Everyone treated

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

Exhibit 3: Considerations for the Elderly

Agent

Analysis

Conclusion

Sipuleucel-T

Survival: > 71 years vs ≤ 71 years Product integrity: 80 ≥ vs 80 years old

No difference in survival or product integrity based on age

Cabazitaxel/Prednisone

19% in study were ≥ 75 years

No analysis

Abiraterone/Prednisone

Adverse events ≥ 75 years vs < 75 years

Similar adverse effects with equal benefit from treatment

Enzalutamide

Post-chemotherapy, survival: < 75 years and men ≥ 75 years

No difference in survival, More fatigue, edema, falls and diarrhea men ≥ 75 years

Radium-223

Survival < 67 years, 67 - 74 years and ≥ 75 years

Good in all groups

Exhibit 4: Toxicities from Androgen Suppression

Those you can see

Those you can feel

Other

Weight gain

Hot flashes

Bone density loss

Muscle loss

Fatigue

Lipid changes

Hair pattern changes

Depression

Decreased insulin sensitivity

Fat redistribution

Mental slowing

Heart disease (?)

Resticle/penis size decrease

Anemia

with abiraterone also has to receive prednisone to prevent hypertension, low potassium, high sodium, and heart failure exacerbations. Enzalutamide is an androgen receptor (AR) inhibitor at three different places. It inhibits binding of testosterone to AR, inhibits AR nuclear translocation, and inhibits AR-mediated DNA binding. Enzalutamide improves overall survival and radiographic progression-free survival in patients with mCRPC post-docetaxel.10,11 It also improved time to the first skeletal event. Toxicities include seizures, fatigue, hypertension, and falls. Older radiation therapies were used in the past for palliation of pain. Radium-223 (Xofigo®) has the same valiance as calcium. Bones take this agent up instead of calcium and thus this agent is effective for painful bone metastatic disease. It actually improved survival, provided pain relief, and reduced the number of fractures and other skeletal-related events.12 Toxicities of radium-223 include flare in bone pain, myelosuppression, nausea, emesis, and dehydration. There are several unanswered questions in man-

aging mCRPC. These include which agents should be used when, how best to combine the agents, effects of longer term androgen suppression therapy on the body, and the effect of multiple treatments on tumor characteristics. Prostate cancer is primarily a disease of elderly men and most men who die from prostate cancer are 80 or older.1 Exhibit 3 enumerates some considerations with the therapies just discussed in the elderly population. It does not appear that age impacts efficacy, but the adverse effects of some agents may be worse in the oldest old. A multidisciplinary team can be helpful in managing those with mCRPC. Because these patients can live a very long time on hormone suppression, they may have many short- and long- term effects (Exhibit 4). Physical therapists, dieticians, and individual or couples therapists are all helpful in managing the adverse effects of hormone suppression. Conclusion

Although considered incurable, mCRPC can be

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 59

treated with multiple lines of therapies. Because there are so many different treatment options available today, patients may live for many years with their disease. The long-term effects of these treatments are just now being understood.

5. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-54. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. 3.2016. Available at www.nccn.org. Accessed 7/28/2016.

Julie N. Graff, MD, MCR, is with the Portland VA Medical Center and

7. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for

is an Assistant Professor of Medicine at the Knight Cancer Institute at

castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-22.

the Oregon Health and Science University.

8. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-48.

References

9. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin.

versus placebo plus prednisone in chemotherapy-naive men with metastatic

2015;65(1):5-29.

castration-resistant prostate cancer (COU-AA-302): final overall survival anal-

2. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen depriva-

ysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet

tion therapy: progress in understanding mechanisms of resistance and optimiz-

Oncol. 2015;16(2):152-60.

ing androgen depletion. Nat Clin Pract Urol. 2009 Feb;6(2):76-85.

10. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in

3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mito-

prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-97.

xantrone plus prednisone for advanced prostate cancer. N Engl J Med.

11. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic

2004;351(15):1502-12.

prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-33.

4. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine

12. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and sur-

compared with mitoxantrone and prednisone for advanced refractory prostate

vival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-23.

cancer. N Engl J Med. 2004;351(15):1513-20.

Online Resources for Members Journal of Managed Care Nursing (JMCN)

CNE webcasts Career Center Mentor program

ArchiTools (case

management toolkit) Join today! www.AAMCN.org asnyder@aamcn.org (804) 747-9698

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

eNewsleeers

Improving the Management of Hyperkalemia Biff F. Palmer, MD

Summary Hyperkalemia is a frequent and important clinical problem. It limits the use of many medications which affect the renin-angiotensin-aldosterone system (RAAS). A newly approved potassium binder given daily provides sustained lowering of potassium, which can allow many patients to continue receiving guideline-recommended therapy. Key Points â&#x20AC;˘ Hyperkalemia is an important clinical concern. â&#x20AC;˘ Hyperkalemia limits use of guideline-recommended RAAS inhibitor therapy in heart failure, diabetes, and chronic kidney disease. â&#x20AC;˘ Patiromer use may allow patients to stay on RAAS inhibitor therapy.

HYPERKALEMIA IS A VERY COMMON ELECtrolyte disorder. The incidence of hyperkalemia is as high as 40 to 55 percent in patients with chronic kidney disease (CKD).1-3 Even in specialized CKD clinics, the incidence is as high as 55 percent. Normally, most of the potassium in the body is within cells with about 3500 mEq in intracellular fluid [140-150 mEq/L)]. There are only 70 mEq in the extracellular fluid [3.5-5.5 mEq/L)]. This large potassium gradient sets cell voltage, which is very important in electrically excitable tissues such as the heart and nerve tissue. Potassium homeostasis is regulated by renal and gastrointestinal excretion. When people lose kidney function, the GI tract, particularly the colon, becomes increasing important for managing potassium. It is estimated that in a dialysis patient with no renal function as much as 50 percent of potassium that enters the body is excreted by the colon. Interestingly, people on dialysis who have a colectomy have major issues with hyperkalemia.

Because it takes the kidneys about four hours to clear a potassium load, the body has the ability to buffer that load by shifting potassium into cells under the influence of insulin and the adrenergic nervous system. If it were not for the effects of insulin after a meal, a human might die of hyperkalemia. The development of hyperkalemia has prognostic significance. The mortality rate within one day of a hyperkalemic event is six to 17 times higher in patients with serum potassium greater than or equal to 5.5 mEq/L than in those with values less than 5.5 mEq/L.1 Hyperkalemia can be caused by excess potassium intake, cell shifts, and impaired renal excretion, which is the only cause of sustained hyperkalemia. Pseudohyperkalemia can also occur when blood samples are not properly collected, stored, or transported to a laboratory. Excess intake can occur through use of salt substitutes and consuming large amounts of juice (coconut, orange, and noni) or bananas. In one case

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 61

Exhibit 1: Affecting Potassium Excretion through the Kidneys6

Angiotensin I

Angiotensin II

ANGIOTENSIN RECEPTOR BLOCKERS

ANGIOTENSINCONVERTING ENZYME INHIBITORS

Aldosterone IMPAIRED ALDOSTERONE METABOLISM

Adrenal Gland

DIRECT RENIN INHIBITOR Afferent Arteriole

SODIUM CHANNEL BLOCKERS Amiloride Triamterene Trimethoprim Pentamidine

Renin Juxtaglomerular cells IMPAIRED RELEASE OF RENIN

Adrenal Disease Heparin Ketoconazole Collecting Duct (principal cell)

Na+

NSAIDs Beta Blockers Cyclosporine, Tacrolimus Diabetes Elderly

Na+

Lumen

K+ K+

ALDOSTERONE RECEPTOR BLOCKERS Spironolactone Eplerenone Drospirenone

report a 51-year-old man had values of 9 mEq/L after drinking 2.5 L of orange juice daily.4 He had consumed 1,125 mEq/d for three weeks. Over consumption of bananas has also been reported to lead to hyperkalemia. Eating unusual items including river bed clay (100 mEq/100 g clay) and burnt match heads (cautopyreiophagia) can led to elevated potassium levels.5 White clay (kaolin) consumption can reduce potassium levels. Cell shifts are primarily due to metabolic acidosis, insulin deficiency, and alpha-adrenergic stimulation. Impaired renal excretion is caused by a decrease in mineralocorticoid activity (aldosterone, renin, angiotensin, Exhibit 1).6 Impaired release of renin can occur with certain medications (nonsteroidal anti-inflammatories, beta blockers, cyclosporine, tacrolimus), diabetes, and with age. Age-related changes in renin and aldosterone release make the elderly much more likely to develop hyperkalemia. Sodium restriction in the elderly worsens decreased plasma renin activity and decreased aldosterone levels. The elderly have less of an aldosterone response to a potassium infusion when compared with young people.7 Other medications including angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and direct renin inhibi-

tors also increase serum potassium. Impaired aldosterone metabolism can also occur with adrenal disease, heparin, and ketoconazole. Spironolactone, eplerenone, and drospirenone increase potassium by blocking aldosterone receptors. Impaired potassium excretion can also occur because of a decrease in distal sodium delivery with oliguric acute renal failure and acute glomerulonephritis. Amiloride, triamterene, trimethoprim, and pentamidine are sodium channel blockers and impair sodium delivery. An additional reason for impaired potassium excretion is abnormal cortical collecting ducts. This can be caused by tubulointerstitial nephritis and urinary obstruction. The clinical consequences of hyperkalemia include cardiac toxicity, muscle weakness, and impaired renal acidification. Unfortunately, the electrocardiogram (ECG) is not always sensitive enough to pick up myocardial changes with high potassium levels. In 127 patients with serum potassium between 6 and 9.3 mEq/L, changes on the ECG were only found in 46 percent of cases.8 In another series of 90 cases, only 24 were noted to have characteristic T-wave changes as read by a cardiologist.9 Only one in 14 who presented with arrhythmias or cardiac arrest had characteristic changes on ECG. Muscle weakness related to hyperkalemia can be severe and is not

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

Exhibit 2: Guideline Recommendations for RAASi Modifications at Various Serum K+ Levels13-18

> 6.0

Serum K+ (mEq/L)

NICE: Stop RAASi if > 6.0

> 5.5

ACC/AHA, ESC HF, K/DOQI: Reduce dose of/stop ACEi/ARB, AA if > 5.5

K/DOQI: don’t start RAASi if > 5.0 NICE: don’t start RAASi if > 5.0 HFSA HF: MRA not recommended > 5.0 ACA/AHA HF: Maintain MRA 4.0-5.0

> 5.0 Serum K+ Threshold Before Change in RAASi Guideline Recommendation

MRA = mineralocorticoid receptor antagonist RAASi = renin-angiotensin-aldosterone inhibitor

always appreciated. It can even progress to paralysis. Hyperkalemia impairs renal acidification, which leads to metabolic acidosis. Less ammonia is reabsorbed and available for interstitial hydrogen buffering, thus net urinary acid excretion is reduced. Low level chronic metabolic acidosis is a risk factor for progression of chronic kidney disease (CKD). One of the standards of care in CKD is to avoid metabolic acidosis by keeping the serum bicarbonate levels above 22. Correcting hyperkalemia is another way to treat metabolic acidosis in CKD. Although beneficial for many disease states, there are numerous medications which lead to hyperkalemia. Renin-angiotensin-aldosterone system inhibitor (RAASi) medications are well known to have kidney-saving and life-saving benefits in patients with CKD, heart failure, hypertension, or diabetes mellitus but a limiting side effect of these agents is hyperkalemia. One consequence of using RAASi medications is hospitalizations. Hospitalizations for hyperkalemia dramatically increased in the years after the publication of a trial showing the benefits of spironolactone in heart failure.10 Hyperkalemia is a common reason for patients having to discontinue RAASi therapy.11 Clinicians have to balance out the benefits of a RAASi agent versus the risk of hyperkalemia. In

one study, hyperkalemia was the leading reason for not starting RAASi agents and the major reason for discontinuation of RAASi in CKD.12 Current guidelines for HF and CKD tend to lessen the use of full recommended doses of RAASis because of concerns related to hyperkalemia (Exhibit 2).13-18 The Kidney Disease Improving Global Outcomes (KDIGO) guidelines do not provide recommendations for stopping at any particular potassium value but instead recommend a maximum tolerated RAASi dose.17,18 Only about 25 percent of CKD patients are on optimal RAASi dose. Ninety percent of nephrologists say hyperkalemia is a top concern with use of RAASi medication. Overall, hyperkalemia prevents use of guideline-recommended RAASi therapy in several important diseases. Treating hyperkalemia falls into two general areas – acute and chronic. Acute management can be done by cell membrane stabilization to prevent cardiac toxicity, potassium redistribution, and potassium elimination from the body. Cell membrane stabilization is done with calcium gluconate to decrease the threshold potential of cardiac myocytes and, in hypovolemic patients, hypertonic solution infusion increases action potential rising the velocity of cardiac myocytes. Potassium redistribution can be accomplished with insulin which activates

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 63

the sodium/potassium ATPase pump and beta adrenergic agonists. Several agents can be used to acutely eliminate potassium. These include sodium bicarbonate which alkalinizes the urine, thereby enhancing urinary potassium excretion; loop diuretics, with adequate renal function, enhance urinary potassium excretion; binding agents (sodium polystyrene sulfonate, patiromer) enhance potassium removal through the colon; and hemodialysis removes potassium from the blood. In addition to the measures listed above, chronic management of hyperkalemia includes stopping exogenous potassium supplements, discontinuing any medications affecting potassium levels (if possible), and instituting dietary potassium restriction. Although used for many years for chronic management of hyperkalemia, sodium polystyrene sulfonate (SPS, KayexalateÂŽ) has limited data to substantiate its efficacy. It was approved for treatment of hyperkalemia in 1958, before well-controlled studies were required. There is concern that SPS may not be effective unless it is given with osmotically active amounts of sorbitol and that sorbitol may actually be the effective agent.19,20 Others have noted that there is no convincing evidence that SPS increases fecal potassium losses in experimental animals or humans and no evidence that adding sorbitol to the resin increases its effectiveness.21 There are also toxicity concerns with SPS in certain patients. Cases of intestinal necrosis, which may be fatal, and other serious gastrointestinal adverse events (bleeding, ischemic colitis, perforation) have been reported in association with SPS use. The majority of these cases reported the concomitant use of high-dose sorbitol. Risk factors for gastrointestinal adverse events were present in many of the cases, including infant prematurity, history of intestinal disease or surgery, hypovolemia, and renal insufficiency and failure.22 The FDA issued a warning about intestinal necrosis with SPS in 2009. Concomitant administration of sorbitol is not recommended by the FDA; however, without the sorbitol, SPS may not be effective. Additionally, there are potential issues with SPS and medication binding. The FDA is requiring the manufacturer to conduct studies to investigate this agentâ&#x20AC;&#x2122;s potential to bind to other medications administered by mouth. Prescribers and patients should consider separating SPS dosing from other medications taken by mouth by at least six hours.23 In the past, SPS was the only option in the United States (U.S.) for potassium binding but in 2015 a new agent was approved, patiromer (VeltassaÂŽ). Patiromer is a sodium-free, non-absorbed, potassiumbinding polymer that exchanges calcium for potas-

sium in the lumen of the gastrointestinal tract.24 It increases fecal potassium excretion, resulting in a reduction of serum potassium levels. The recommended starting dose is 8.4 grams administered orally once daily with food.24 The dose can be adjusted upward by 8.4 grams daily as needed at one week intervals to obtain the desired serum potassium target range. The maximum recommended dose is 25.2 grams per day. In clinical trials, patiromer was effective in lowering potassium levels in hyperkalemic participants with chronic kidney disease.25-27 It has been shown to be effective out to at least one year of use.27 Importantly, in this clinical trial, all the subjects were on a RAASi and were able to remain on it because patiromer lowered their serum potassium and kept it under control.27 A recently published trial found that patiromer use decreased aldosterone levels and blood pressure in patients with CKD and hyperkalemia on a RAASi.28 In clinical trials, the most common adverse reactions were constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort, and flatulence.24-28 Patiromer should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.24,29 Patiromer binds to many orally administered medications, which could decrease their absorption and reduce their effectiveness. It should be separated from other medications by at least six hours before or after doses. Another gastrointestinal lumen potassium binder, sodium zirconium cyclosilicate (ZS-9), is still investigational. In the U.S., regulatory approval of ZS-9 was rejected by the FDA in May 2016 due to issues associated with manufacturing.30 It is likely this agent will be resubmitted to the FDA for approval. ZS-9 has a higher potassium binding capacity and much greater selectivity for potassium than SPS. This agent has been studied as three doses per day for two days to lower potassium and then continued for 28 days as a single daily dose.31,32 In a multi-center, randomized trial of this agent, it was effective in reducing potassium quickly in patients having HF (36.4% of study population), diabetes (65.9%), and on a RAASi (69.8%), and the reduction was durable out to 28 days. If this agent makes it to market, it will be another option for lowering potassium chronically in those who require RAASi therapy but develop hyperkalemia. Conclusion

Hyperkalemia is an important clinical concern and is common in CKD patients and in those with conditions that disrupt the renin-angiotensin-aldosterone

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

system or treated with medications affecting this system. Despite known life-saving benefits, many medications get underused in CKD, diabetes, and HF because of hyperkalemia. Hyperkalemic events are associated with cardiac events, muscle weakness, and impaired acidification. Strategies to limit development of hyperkalemia would be of clinical utility and newer therapies may provide a safer, more consistent management strategy.

15. Heart Failure Society of America. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):e1-e194. 16. National Institute for Health and Care Excellence (NICE) [UK]. Chronic kidney disease in adults: assessment and management. January 2015. Available at https://www.nice.org.uk/guidance/cg182. Accessed 7/28/16. 17. KDIGO Clinical Practice Guidelines for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int Suppl. 2012;2(5). Available at http:// www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO_BP_GL.pdf 18. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1).

Biff F. Palmer, MD, is a Professor of Internal Medicine at the University

19. Kamel KS, Schreiber M. Asking the question again: are cation exchange

of Texas Southwestern Medical Center in Dallas, TX.

resins effective for the treatment of hyperkalemia? Nephrol Dial Transplant. 2012;27(12):4294-7.

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20. Gruy-Kapral C, Emmett M, Santa Ana CA, et al. Effect of single dose resin-

1. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its

cathartic therapy on serum potassium concentration in patients with end-stage

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renal disease. J Am Soc Nephrol. 1998;9(10):1924-30.

2. Hayes J, Kalantar-Zadeh K, Lu JL, et al. Association of hypo- and hyperkale-

21. Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-exchange resins for

mia with disease progression and mortality in males with chronic kidney dis-

the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol.

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3. Sarafidis PA, Blacklock R, Wood E, et al. Prevalence and factors associated

22. Kayexalate (sodium polystyrene sulfonate) powder. Safety Labeling Chang-

with hyperkalemia in predialysis patients followed in a low-clearance clinic.

es Approved By FDA Center for Drug Evaluation and Research (CDER). Janu-

Clin J Am Soc Nephrol. 2012;7(8):1234-41.

ary 2011. Available at http://www.fda.gov/Safety/MedWatch/SafetyInforma-

4. Palmer BF, Sterns RH. Fluid, electrolytes, and acid-base disturbances. Neph-

tion/ucm186845.htm. Accessed 7/28/2016.

SAP. 2009;8:70-167.

23. Kayexalate (sodium polystyrene sulfonate): Drug Safety Communication –

5. Sterns RH, Palmer BF. Fluid, electrolytes, and acid-base disturbances. Neph-

FDA requires drug interaction studies. 10/22/2015 Available at http://www.

SAP: 2007;6.

fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedi-

6. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angio-

calProducts/ucm468720.htm. Accessed 7/28/2016.

tensin-aldosterone system. N Engl J Med. 2004;351(6):585-92.

24. Veltassa package insert. Relypsa, Inc. Redwood City, CA. June 2016.

7. Mulkerrin E, Epstein FH, Clark BA. Aldosterone responses to hyperkalemia

25. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kid-

in healthy elderly humans. J Am Soc Nephrol. 1995;6(5):1459-62.

ney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med.

8. Acker CG, Johnson JP, Palevsky PM, Greenberg A. Hyperkalemia in hospi-

2015;372:211-221.

talized patients: causes, adequacy of treatment, and results of an attempt to im-

26. Bushinsky DA, Williams GH, Pitt B, et al. Patiromer induces rapid and

prove physician compliance with published therapy guidelines. Arch Intern Med.

sustained potassium lowering in patients with chronic kidney disease and hy-

1998;158(8):917-24.

perkalemia. Kidney Int. 2015;88(6):1427-1433

9. Montague BT, Ouellette JR, Buller GK. Retrospective review of the frequen-

27. Bakris GL, Pitt B, Weir MR, et al. Effect of patiromer on serum potassium

cy of ECG changes in hyperkalemia. Clin J Am Soc Nephrol. 2008;3(2):324-30.

level in patients with hyperkalemia and diabetic kidney disease: the AME-

10. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after

THYST-DN randomized clinical trial. JAMA. 2015;314(2):151-61.

publication of the randomized aldactone evaluation study. N Engl J Med.

28. Weir MR, Bakris GL, Gross C, et al. Treatment with patiromer decreases

2004;351(6):543-51.

aldosterone in patients with chronic kidney disease and hyperkalemia on renin-

11. Lopes RJ, Lourenço AP, Mascarenhas J, et al. Safety of spironolactone use in

angiotensin system inhibitors. Kidney Int. 2016;pii:S0085-2538(16)30186-7

ambulatory heart failure patients. Clin Cardiol. 2008;31(11):509-13.

[Epub ahead of print]

12. Yildirim T, Arici M, Piskinpasa S, et al. Major barriers against renin-angio-

29. FDA approves new drug to treat hyperkalemia. Available at http://

tensin-aldosterone system blocker use in chronic kidney disease stages 3-5 in

w w w.fda.gov/newsevents/newsroom/pressannouncements/ucm468546.

clinical practice: a safety concern? Ren Fail. 2012;34(9):1095-9.

htm. Accessed 7/28/2016.

13. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the

30. Adams B. Updated: AstraZeneca’s $2.7B hyperkalemia drug ZS-9 rejected by

management of heart failure: a report of the American College of Cardiology Foun-

FDA. May 27, 2016. Available at http://www.fiercebiotech.com/biotech/astra-

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Cardiol. 2013;62(16):e147-239.

31. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosili-

14. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the di-

cate in hyperkalemia. N Engl J Med. 2015;372(3):222-31.

agnosis and treatment of acute and chronic heart failure 2012: The Task Force

32. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclo-

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www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 65

Developing Appropriate Evidence for Demonstrating the Value of Diagnostics: Where are We Now and What is Appropriate for the Future State? Eric Faulkner, Daryl S. Spinner and Joshua Ransom

Key Points for Decision Makers

Current evidence expectations for diagnostics are highly variable and not well aligned to health system incentives, resulting in lack of clarity on diagnostics value demonstration and potentially limiting patient access to new tests emerging in the marketplace. Unlike with pharmaceutical products, randomized controlled trials are not always the best or most practical study design for demonstrating diagnostic value, and payers do not have guidance on what constitutes sufficient evidence to apply consistent technology assessment practices to diagnostics. Development of a clear set of evidence expectations for diagnostics has been discussed for some time in the global community involved in diagnostics development and value assessment â&#x20AC;&#x201C; this much needed activity would have broad reaching benefits for payers, physicians, manufacturers and patients and help improve consistency of access decisions relevant to diagnostics. This paper provides perspectives on rethinking diagnostic evidence expectations to support consistent and practical decision making.

DIAGNOSTICS PLAY A FUNDAMENTAL ROLE in health care decision making at all stages and have tremendous potential to improve the efficiency, quality, and costs of care. Diagnostic tests include a broad range of techniques varying in their (1) level of complexity (from a simple clinical assessment to complex multi-marker assays) and (2) purpose (disease risk assessment, disease screening, diagnosis and staging, treatment selection, and monitoring).1 Diagnostics are well-known to inform many health care decisions, though their costs are relatively low. Yet, for technologies with such high impact, characterizing the value of diagnostics is

currently highly uncertain. While diagnostic tests have been integrated into clinical practice for many years, it is only in recent years, due to increasing reliance on testing and emergence of more complex and costly tests, that payers have devoted more resources toward assessing their impact. This paper evaluates the current state of diagnostic evidence development and health technology assessment (HTA), including challenges and opportunities, and discusses approaches to value demonstration that may be more in line with this unique technology type and the future state of diagnostics.

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

Exhibit 1: Common Limitations of Applying RCT Designs to Diagnostics 46-51

• Blinding is not always feasible. • Statistical powering to associate test use with one or more treatment/patient management actions may not be feasible. • RCT designs do not readily allow for assessment of change in patient management decisions. • RCTs are best applied when the outcomes of interest are narrowly defined, but diagnostics may inform multiple decisions about the patient’s health state and treatment. • RCTs that include both testing and a treatment or patient management intervention by default blend the impact of both interventions. • It may be unethical to randomize treatment solely to determine the implications of test use.

Current State of Diagnostics Evidence Development and Value Demonstration

Current payer evidence expectations for diagnostics are highly variable and not aligned with methodological and practical realities associated with diagnostic test development.1-5 A 2013 study conducted by the National Association of Managed Care Physicians (NAMCP) showed that only 38 percent of U.S. commercial payers properly defined the clinical utility of a diagnostic, suggesting that payers are still coming up the learning curve on diagnostics.3 This uncertainty and “moving target” evidence problem not only makes it challenging for manufacturers to develop evidence for tests, but it also risks variability in patient access to beneficial tests. Reasons for the inconsistency among stakeholder expectations and for test value assessment have been well documented, include but are not limited to: • variable understanding of terms and concepts associated with assessing diagnostics, • limited consensus on appropriate/accepted study designs for diagnostics, • limited consensus on what constitutes a suffi cient evidence base to support testing, • lack of value-based reimbursement for diag nostics that supports extensive evidence development, and • limited intellectual property protections versus other technology-types and lower barriers to market entry for laboratory developed tests.1,6-9 Though the answer to the diagnostic value assessment challenge is multi-factorial, one key issue is that the majority of current evidence-based medicine (EBM) approaches used by managed care evolved with an emphasis on treatments and do not take into account issues surrounding diagnostic evidence development. As a consequence, consistently

agreed upon study designs and HTA approaches have not yet emerged for diagnostics, resulting in a highly variable evidence base across marketed tests and complicating payer decision making. In general, evaluating the impact of treatments (e.g., medication) or interventions (e.g., surgery) can often be more straightforward than for diagnostics because the link to patient outcomes is more direct. There are practical and methodological issues associated with applying a “single yardstick” approach to measuring diagnostics value that does not take into account unique considerations found with diagnostics. First of these issues is that evidence expectations are not aligned to evidence questions, particularly for different test applications. Secondly, there has been a lack of evolution with respect to evidence requirements for the different core test applications (e.g., screening, diagnosis, treatment selection, and monitoring), all of which may have different associated patient management goals.46 The following highlights the three core areas that currently complicate evidence development and evaluation for diagnostics: 1. Uncertainty Around Diagnostic Terminology and Dimensions of Test Value

In general, evidence on the performance and value of diagnostic tests in clinical settings is most often considered along the following three dimensions that are unique to diagnostics: 63 • Analytical validity: How accurate (i.e., sensi tive and specific) a test is in detecting a specific biomarker/diagnostic target, including the rate of false negatives and false positives • Clinical Validity: How accurate a test is in detecting a specific condition or disease (e.g., cancer or heart disease).

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 67

Exhibit 2: Examples of Prospective and Retrospective Solutions for Diagnostic Value Characterization Across Key Test Applications31-41

Screening PKU Testing in Newborns

Diagnosis/Treatment Selection: KRAS Testing to Predict Colorectal Cancer Treatment Response

•

In 1989, the USPSTF recommended screening of all newborns for PKU, and published a systematic review conducted by AHRQ to update this recommendation as necessary in 1996 and 2008.

•

Initial pivotal RCT studies of cetuximab monotherapy and in combination with irinotecan in irinotecan-resistant mCRC expressing EGFR showed a modest benefit in overall survival and was approved for use in early 2004.

•

The 1989 recommendation was based almost entirely on retrospective observational studies published over the prior 7 year period. In the 2008 update, which confirmed the evidence and reiterated the original recommendation for PKU screening, a chain of evidence was essentially used to indirectly link test clinical validity (sensitivity and specificity) with the benefit of PKU intervention (clinical utility).

•

Subsequent retrospective analyses on archived mCRC tumor samples from the pivotal studies published in 2006 and 2008 indicated that presence of a non-mutated KRAS gene predicted significantly greater response rates and progressionfree survival (PFS).

•

After further confirmation in retrospective studies and single arm trials, by the close of 2008 the National Comprehensive Cancer Network (NCCN) incorporated KRAS testing into colorectal cancer guidelines and the American Society of Clinical Oncology recommended testing in published provisional opinion

•

In essence there was no way to create a randomized study design for PKU screening tests that would not cause harm to patients. The only way to demonstrate the value of PKU screening was to demonstrate the accuracy of the test in detecting the disease on the one hand, and indirectly.

•

The National Comprehensive Cancer Center (NCCN) currently cites only the retrospective analysis conducted in 2008 as the supporting evidence for recommending KRAS testing in colorectal cancer guidelines (NCCN 2013)

• Clinical Utility: How useful a test is in inform ing clinical and/or treatment decisions and im proving the health outcomes of patients (e.g., mortality, morbidity, and quality of life). These dimensions of test value are not included in conventional evidence development approaches for treatments as the connection between treatment use and outcomes is often more direct than for diagnostics. Overall, the terminology associated with diagnostics is confusing to many stakeholders, as highlighted in prior NAMCP member surveys.58 Clinical utility, for example, as a term has been interpreted in a variety of ways, adding to the confusion surrounding what constitutes sufficient evidence for diagnostics.39 Another consideration is that direct evidence of clinical utility is not always relevant for particular test scenarios. For example, a payer may be justified

Monitoring: BCR-ABL Monitoring for CML •

Initial data from pivotal RCT studies of imatinib treatment in CML (post interferon-alpha failure) demonstrated high response rates as measured by hematologic and cytogenetic testing.

•

Subsequent retrospective analysis of molecular monitoring by quantitative real time polymerase chain reaction (qRT-PCR) on archived bone marrow and peripheral blood samples demonstrated a potential for monitoring patient leukemia burden by 100 to 1000-fold greater sensitivity.

•

Guidelines (including NCCN) were updated based on a systematic literature review of clinical lab research and method comparison studies for protocols and optimal timing of molecular monitoring.

•

The National Comprehensive Cancer Network (NCCN) and AHRQ each reviewed and updated recommendations based on further retrospective analysis that refined the clinical utility evidence for BCR-ABL molecular monitoring.

in seeking clinical utility information on a test when there is no predicate test that has already established clinical utility. In cases where an indirect evidence base around a predicate test already exists that can be anchored to test performance and possibly patient management information for a new test, studies of accuracy may be sufficient to meet decision maker needs. Where predicate tests exist, overly complex or repetitive evidence may not be necessary. Other dimensions of test benefit may include, but are not limited to, the ability of a test to: (a) “rule out” or “rule in” disease status or treatment options, (b) guide patient management decisions, (c) better target treatments based on individual patient factors (e.g., personalized medicine), (d) help avoid adverse events or safety outcomes, and (e) increase the efficiency and “flow” of patient triage through clinical pathways and health systems. Not all of these di-

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

Exhibit 3: Evidentiary Questions for Demonstrating Main Value Criteria for Diagnostic Test Applications2,9,10,15,18,20 Test Type

Key Questions to Establish Test Value Criteria Analytic Valiidity

Screening

Diagnosis

Diagnostic Applications that Provide Prognostic Information

Clinical Validity

Clinical Utility

•

Does the test accurately identify target biomarker or analyte in a large number of well characterized samples (reliability/ robustness)?

•

Do results coorelate with the target condition in an experimental study (few false negatives/high clinical sensitivity and false positives/high clinical specificity)?

•

Do test results add incrementally to, or result in patient care decisions outside of existing standard of care approaches to diagnosis?

•

Is the test sufficiently sensitive to detect the analyte at the required level (few false negatives)?

•

Do results correlate with the target condition in the population represeting the true asymptomatic condition prevalence (predictive value)?

•

In the absense of the test, do patients remain undiagnosed or misdiagnosed?

•

Is the test sufficiently specific to detect the analyte and nothing else (few false positives?

•

Can results be linked to improved health outcomes in patients with a chain of indirect evidence?

•

Can results be linked to changes in clinical management in patients with the condition (actionable in terms of change in treatment, patient behavior/adherence or monitoring frequency?

•

For what percent of tested patients is treatment impacted?

•

How many patients need to be screened to identify one with the disease or predisposition to the desease?

•

How are at risk populations defined so as to limit unnecessary testing in the broader population?

•

What are the potential harms associated with the test and test results?

•

Do diagnostic results add incrementally to, or result in patient diagnosis decisions outside of to diagnosis?

•

In the absense of the test, do patients remain undiagnosed or

•

Can results be linked to improved health outcomes in patients with the condition either directly or with clinical management in patients with the condition (actionable in terms of change in treatment, patient behavior/

•

Do results correlate with the target condition in an experimental study (few false negatives/sensitive and false positives/specific)?

•

Do results correlate with the target condition in a population representing the true condition prevalence (predictive value)?

•

Do results observed early in the course of disease correlate with a particular health outcome in an experimental trial (few false negatives/ sensitivity, few false positives/ specific)?

•

Do results observed early in the course of disease correlate with a particular health outcome in patients with the target disease in a population representing the true prevalence of the disease (predictive value)?

www.namcp.org | Vol. 19, No. 4 | Journal of Managed Care Medicine 69

Exhibit 3: Continued… Test Type

Key Questions to Establish Test Value Criteria Analytic Valiidity

Diagnostic Applications that Provide Predictive/ Treatment Selection Information

Monitoring

Clinical Validity •

Do results correlate with treatment response in patients with the target condition in an experimental trial (few false negatives/sensitive, few false positives/specific)?

•

Do results correlate with treatment response in patients with the target condition in a population representing the true condition prevalence (predictive value)?

•

Do results correlate with target condition in an experimental study (few false negatives/sensitive and few false positives/specific) and in a population representing the true condition prevalence (predictive value)?

•

Do results observed early in the course of disease correlate with a particular health outcome in patients with the target disease in an experimental trial and in a population representing the true condition prevalence (predictive value)?

•

Color Key

Clinical Utility

•

Do monitoring results add incrementally to, or result in patient diagnosis decisions outside of existing standard of care approaches those predicted by the tested biomarker?

•

Can results be linked to improved health outcomes in patients with the condition either directly or with a clinical management in patients with the condition (actionable in terms of change in treatment, patient behavior/

•

What is the relative risk-benefit for conducting the test in the target population (e.g., potential benefit of identification/early identification of relapsing disease versus the adverse effects impacts of additional or high risk or invasive testing/ monitoring in the target population, potential impact of non-adherence to testing, emotional or physical stress, lifestyle changes)?

•

What are the risks associated with a false positive or false negative test result (e.g., risks of changing or not changing treatment in a patient who is misclassified by the test)?

Do results correlate with treatment response in patients with the target condition in an experimental trial or in a population representing the true condition prevalence (predictive value)?

Light teal = Diagnosis, Screening or Monitoring Applications Teal = Prognosis Test Dark teal = Prediction/Treatment Selection Grey = All diagnostic Test Types

mensions are adequately captured in conventional HTA expectations. In practice, different study types would be required to adequately assess test value for different applications. Reevaluating what constitutes “good” evidence of diagnostics is a fundamental need in this technology sector to ensure appropriate alignment of understanding and expectations between payers, physicians and test developers. 2. Inconsistent Impressions of What “Good” Diagnostic Evidence Looks Like

As emphasis on evidence-based medicine (EBM)

has grown over the past two decades, payers increasingly seek scientific information documenting the impact of medical interventions, including diagnostics, on patient health outcomes. In HTA processes, the strength of the available evidence is usually characterized in terms of an evidence hierarchy with randomized controlled trials (RCTs) at the top of the hierarchy and case series and case reports placed lower in the grading system. Payers and HTA agencies prefer evidence from RCTs versus other study types (e.g., prospective and retrospective observational studies) because RCTs are of-

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

Exhibit 4: Evidence to Demonstrate the Value of Diagnostic Tests with an Already Accepted Comparable Predecessor (Predicate)14,21-24

Key Questions to Establish Test Value Criteria Analytic Valiidity •

Does the new test identify target analyte/biomarker as well as predecessor?

•

Is the new test as sensitive as predecessor?

•

Is the new test as specific as predecessor?

Clinical Utility

Clinical Validitya No new evidence required unless the new test:

No new evidence required unless the new test:

•

Uses a different test method, platform, tissue sample/process or interpretation versus predecessor.

•

Is anticipated to result in changes to how patients are chosen for testing or in the resulting treatment versus predecessor.

•

Is anticipated to result in a change in tested patient characteristics or treatment versus predecessor.

•

Is anticipated to change tested patient behavior/adherence versus predecessor.

May subsume analytic validity evidence when unavailable

ten less subject to bias and confounding than other study designs. On the other hand, a well-designed observational study is often viewed as preferable to a poorly designed RCT. It is generally unconventional for most diagnostics developed as standalone tests to conduct RCTs. Methodological challenges with leveraging RCT designs for diagnostics have been previously described (see Exhibit 1). In addition, the practical challenge in an environment that does not provide value-based reimbursement for diagnostics, is that expectations for RCT evidence are also often financially impractical for test manufacturers that do not have the pricing latitude to recoup costs of developing evidence. While some stakeholders accept this rationale, the question of what constitutes acceptable study designs for diagnostics in a commoditized payment environment remains a central conundrum in this technology area. Expectations for emerging multi-marker tests that have the potential to alter care paradigms and improve care efficiency are even less clear. Additionally, expansion of drug-diagnostic co-development, where the test is validated in the context of a drug development study, has the potential to skew evidence expectations towards models more applicable to treatment valuation but less feasible for standalone diagnostics. This is because co-development trials are virtually always RCTs that regulators require to characterize the value of the drug. These scenarios further result in uncertainty and misperceptions around diagnostic evidence.

Additionally, there is the challenge of developing direct evidence that links test use to outcomes (including potential confounding where multiple treatment options may apply). Many groups, such as the Center for Evaluation of Genomic Applications in Practice and Prevention (EGAPP), U.S. Preventive Services Task Force (USPSTF) and others, have developed analytic frameworks recognizing methods for assembling both direct and indirect evidence.2, 14-19 In many cases, a story linking test use to patient outcomes is often built by constructing an indirect ‘chain of evidence’ using multiple studies with a combination of designs. While such approaches have been long used by groups like the USPSTF to demonstrate the clinical utility of diagnostics, application of this approach can be inconsistent where broad gaps in the diagnostic evidence base are apparent. Arriving at a consistent vision of what constitutes an appropriate diagnostics evidence set and applying this more consistently would also benefit all stakeholders involved in reimbursement and use of diagnostics. 3. Lack of Value-based Reimbursement Limits Evidence Development Options

In addition to unclear evidentiary requirements and variable evidence-grading approaches, product innovation is further hindered by payment mechanisms that do not reflect the value of the test.1,6,7,9 At present, diagnostic tests are often paid for on a flat fee schedule typically dictated by test type (e.g.,

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Exhibit 5: Diagnostic Evidence Approaches by Study Type and Test Application23-25

Evidence ConsiderationsA

Screening/Risk Assessment

Clinical Lab Research (preclinical validation/ analytical validation)

Method Comparison (Prospective)

Case Series

Cross-sectional Study

Case-control Study (Retrospective)

Diagnosis

N/A

Monitoring

N/A

B Ž

• More appropriate for analytical validity, especially with predicate device

• Can require large sample if rare condition for screening and Dx

N/A

• More appropriate for CER on tests method • Insufficient

N/A

Limitations/Issues

• Only applicable for biomarker test with history of use

N/A

• Can be done as observational

Longitudinal Cohort Study (Prospective)

Retrospective Tissue Registry Study

Prospective Observational Study

• Less costly/real world applicability

Naturalistic/Pragmatic Trial

• Can be complex and costly

Randomized Controlled TrialC

N/A

• Limited to already collected samples

N/A

• Too complex/costly for most applications

= Evidence package can include meta-analysis from multiple studies, including predicate devices

B = Screening only, not risk assessment C

= Arms of RCT for screening test should be test versus don’t test while arms of RCT for predictive test should be treat versus don’t treat

Sufficient and recommended for (if well designed): = Analytical Validity

= Most appropriate evidence approach for analytical validity

= Clinical Validity

= Most appropriate evidence approach for clinical validity

= Clinical Utility

= Most appropriate evidence approach for clinical utility

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

polymerase chain reaction, immunohistochemistry) and test payment does not typically reflect the value provided by an individual diagnostic test. The Medicare Clinical Laboratory Fee Schedule (CLFS), as with other global lab test fee schedules, has struggled to keep pace with the rapid innovation in diagnostics and expansion of multi-marker molecular panels. For more than 30 years, the CLFS has remained relatively static compared to other Medicare fee schedules, further challenging diagnostic economic incentives.2 Additionally, some diagnostics are subject to payment reductions well below payment rates established on the CLFS – the basis for most U.S. diagnostic payment, further compromising the potential for test providers to offer the test profitably under some payer fee schedules.8 Recent statutory and regulatory changes will affect the way payment amounts are established and updated for tests that are paid under the CLFS1, however CMS is currently in the process of implementing these changes in the law, and it is too early to tell what the impact may be on payment for those tests. In the absence of value-based reimbursement mechanisms for diagnostics, it is difficult (and in some cases perhaps impossible) to financially support the same evidence development approaches required for evaluation of therapeutic technologies. Overall, given the current state of affairs, there is a need for (a) new approaches for grading evidence, (b) methods/study designs that are appropriate to diagnostics to demonstrate value, (c) alignment of HTA preferences to address these more consistently, and (d) changes in reimbursement that reflect value. The remainder of this paper will focus on discussion of new approaches for diagnostic evidence development and assessment, but will not consider steps necessary to advance value-based payment paradigms. Real-World Examples of Evidence Used to Inform Diagnostic Acceptance

The following provides three real-world examples of how diagnostic tests have been evaluated and reimbursed using non-RCT evidence methods. All three examples are considered standard of care in today’s health system. Example 1: Phenylalanine Testing in Newborns to Screen for PKU (Screening): Screening of newborns for PKU has been accepted in U.S. clinical practice since the 1960s to prevent long term brain damage. As highlighted in Exhibit 2, formal recommendations by the USPSTF in 1989 confirming, and in 1996 and 2008 reconfirming the value of PKU screening in newborns were based almost entirely on cross-sectional and retrospective

observational data used to indirectly link evidence of test performance (clinical validity) with evidence for usefulness of identifying and treating patients with PKU.31,32,33 Only studies on the PKU interventions presented RCTs. The appropriateness of retrospective and/or observational study designs in demonstrating test clinical utility has been detailed in a variety of studies 34,37,39 Example 2: KRAS Biomarker Testing in Predicting Cancer Drug Response (Diagnosis/Treatment Selection): Current use of the anti-EGFR drug cetuximab in metastatic colorectal cancer (mCRC) has evolved since it first launched for EGFR biomarker-expressing mCRC. Today cetuximab is indicated for mCRC with non-mutated (or wild-type) KRAS biomarker. This evolution was prompted and largely driven by evidence generated through retrospective studies on banked tissue samples as highlighted in Exhibit 2 and was further substantiated based on evidence established in codevelopment trials of another anti-EGFR agent – panitumumab.35,36 Example 3: Hematologic, Cytogenetic, and Molecular (BCR-ABL Gene Product) Monitoring in Chronic Myelogenous Leukemia (Monitoring): Current guidelines recommend regular quantification of BCR-ABL gene expression levels but evidence is still in development to monitor the occurrence and development of resistance mutations in patients receiving tyrosine kinase inhibitor therapy. As highlighted in Exhibit 2, the evidence for BCR-ABL molecular monitoring initially was driven by retrospective analyses using archived samples that had been intermittently collected from patients. Additional RCT and metaanalysis from drug trials though were not able to differentiate therapeutic clinical utility due to the low incidence and high number of BCR-ABL resistance mutations. An assessment by the Agency for Healthcare Research and Quality (AHRQ) recently recommended large prospective observational registries as the only feasible and cost-effective approach to collect the broad base of evidence necessary to clarify optimal timing and frequency of monitoring testing to leverage results for disease management.40-45,59 While payer stakeholders have expressed concern regarding evidence supporting some test applications and it is inarguable that quality and consistency of evidence development approaches can improve, these examples highlight the flexibility that can be applied in characterizing the value of diagnostics. The examples also show solutions that have been applied in a manner that balances evidence “need to know” with practical realities, patient factors, and

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health system incentives and drivers. Rethinking Diagnostics Evidence Expectations: Where Do We Go From Here?

Given the aforementioned challenges associated with the development of diagnostic evidence and with value assessment, where do we go from here? Many factors must be considered in characterizing the value of new diagnostic tests, and these set the stage for development of an appropriate evidence evaluation framework. Some of the key questions to ask include: • What core evidence questions must be answered to characterize the value of a specific test or test application? • What are the benefits (e.g., addresses an unmet need in patient management) and risks associ ated with use of a test for the patient? What considerations may be different for single vs. multi-marker tests? • How certain do we need to be about the evi dence to inform a sound decision for test adop tion and ensure performance and clinical utility of the test? How does this vary by test applica tion (e.g., screening, diagnosis, treatment selec tion, and monitoring)? • Which study designs are best suited to address key payer and provider questions? What evi dence development approaches may be needed to fill these gaps and round out the body of evi dence on test value? Many HTA experts have begun to agree that reliance on a single evidence hierarchy/grading approach is too rigid for technology assessment of all medical interventions, including diagnostics, due to concerns around external validity, cost, time and other constraints associated with evidence development.60-62 In recent years, several stakeholders have advanced new approaches for diagnostic value assessment. These include the Blue Cross Blue Shield Technology Evaluation Center (BCBS TEC), Palmetto (a Medicare Administrative Contractor, or MAC), WellPoint, AHRQ, the Institute of Medicine, and EGAPP of the Centers for Disease Control. The Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) has also considered diagnostic evidence issues in the past couple of years; however, the committee is only advisory to CMS and has not issued any official Medicare guidance. Other groups such as the Center for Medical Technology Policy (CMTP) 56 and MEDC have also taken interest in reshaping diagnostic evidence expectations, including consideration of observational and hybrid studies, registries and database approaches, and decision analytic modeling.

The challenge is that these contributing organizations have advanced different and broad ranging perspectives on the evidence needed to characterize the value of new tests, yet none has emerged as industry guidepost, resulting in even greater market confusion.1,10-14 Three keys to solving this problem are (1) identifying what questions are important to characterize the value of a particular test application, (2) being flexible in terms of study approaches that can reasonably address the test application scenario, and (3) linking this back to an easily understandable, consistent evidence grading approach that can be consistently implemented by HTA agencies and payers. Questions Important to Characterize the Value of a Particular Test Application

One key factor that has generally been missing from the application of EBM for diagnostics to date is a consensus on what evidence questions are most important in test assessment. This remains a fundamental reason why application of HTA practices to diagnostics has experienced a slow and complex evolution over the past decade. It is also a contributing factor to the confusion and inconsistency among access and uptake by health decision makers faced with a rapid increase in diagnostic market entry. While there are often scenario-specific factors associated with diagnostics value assessment, some overarching evidence questions are outlined by primary type of test in Exhibit 3.2,9,10,15,18,20 This is not intended to be the complete or comprehensive list, but instead a starting point in moving towards a consistent diagnostic value assessment framework. Consideration of such questions ideally should result in [or lead to] development of core study designs that can practically address those questions. Reasonable Flexibility in Acceptance of Value Demonstration Approaches for Diagnostics

As noted previously, there has been a shift by some U.S. and outside the U.S. HTA and payer bodies away from the concept that RCTs are the de facto standard for evidence development. In practice, there should be flexibility of study designs for diagnostics to assemble/address evidence around value. While the body of evidence supporting the value of a test must address key questions around test performance and impact (as noted in Exhibits 3 and 4), such evidence can be achieved using an array of study types and designs, including assembly of available studies into a chain of test value evidence as has long been supported by the USPSTF. Exhibit 5 depicts multiple study design alternatives that may be sufficient to address decision maker needs to characterize test performance, clinical

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validity and clinical utility.23-25 Each of these study approaches has tradeoffs in terms of internal versus external validity, potential for bias and confounding, and ability to link test use to patient management and treatment outcomes (either directly or indirectly). For example, analytical validation studies are often required to determine test performance, but often do not address patient management decisions. On the other hand, RCT-based designs may be appropriate for some screening or diagnostic applications (e.g., some treatment selection applications where the treatment has substantial side effects such as oncology agents) where test outputs may direct the patient to downstream additional tests and services that may result in potential harms to a potentially large patient population. Well-designed observational studies (e.g., casecontrol, longitudinal cohort, cross-sectional) have been most consistently applied in efforts to build an evidence base around diagnostics. Properly designed observational studies have the advantage of being more reflective of real-world patient situations as compared to RCTs given the often narrower patient inclusion criteria. Hybrid approaches, that integrate some of the design controls of RCTs into observational study methods or that blend retrospective and prospective data analytical approaches, may be a better fit with diagnostic development models because they balance payer needs against the limited incentives for evidence development on tests.21,26 Other approaches, such as meta-analysis, may support/permit evaluation of a broader body of evidence supporting specific diagnostics.27 One or more such studies may be required to comprise a broader body of evidence characterizing test value. Clinical modeling may also be appropriate to assemble an existing body of evidence to link studies of test performance to patient management to outcomes. When a diagnostic predicate exists, the evidence needed is more straight forward (Exhibit 4).14, 21-23 For many tests with predicates using a common testing method (e.g., PCR, IHC), the only new evidence required is often to prove analytic validity – for example, a simple single marker follow-on RT-PCR test for an established molecular biomarker or a follow-on standard blood chemistry test. In order to get to a point where “good diagnostic evidence” is clear and accessible to all stakeholders, a next step required will be to link the fundamental questions that must be addressed to characterize the value of a test application to the range of study designs best suited to address those questions. Such a schematic would enable decision makers to evaluate a new diagnostic with the understanding that an ap-

propriate methodology has been used. As with any framework, to ensure adequate uptake and broad application, a comprehensive diagnostic decision framework must also be simple and easy to apply. It is also important to note that all evidencebases for health technologies have gaps and no single study design methodology will address all real world use questions. Clarity on acceptable economic modeling approaches should also be anticipated in an optimal diagnostics evidence decision framework. Consensus on economic modeling best practices focused on testing may be particularly valuable to help decision makers understand appropriate methodologies to address gaps common to diagnostics (e.g., use of complex multimarker tests). Linking Evidence Expectations to a Consistent Evidence Grading and Technology Assessment Approach

Rigid application of our conventional evidence hierarchy creates challenges for diagnostics due to a variety of limitations described below, suggesting that an alternative evidence evaluation framework aligned to diagnostic value assessment considerations is warranted.13, 28 This is also likely true for medical devices more broadly, as they also have unique benefit and risk considerations that differ from pharmaceuticals. Evolution of such a framework for diagnostics, if properly developed, should not be construed as a lessening of evidence expectations, but instead a rethinking that addresses unique considerations associated with various health technology types and aims to continually improve our approaches to HTA. A novel evidence hierarchy and HTA process that is better aligned to diagnostics would include the following: • Anticipation of special evidentiary consid erations unique to specific test applications (e.g., screening, diagnosis, treatment selection, moni toring) • Evidence tiers that encompass the range of study designs most frequently viable for diagnostics; early work by authors such as Simon have begun to contemplate this path37 • Alignment of study designs with evidence ques tions key to diagnostics; • Guidance on developing a chain of evidence linking different health decision points, similar to the approaches pioneered by the USPSTF Harmonization of the evidence expectations and HTA processes for diagnostics should improve consistency of outputs and ensure rational use of these key health technologies. Given the key role that

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tests play in guiding patient management decisions and supporting favorable treatment outcomes, this would benefit all stakeholders, including payers, providers and patients. Preparing for the Future

Even though requirements for demonstrating the value of diagnostics remain largely inconsistent and are still evolving in most global markets, we are at the same time rapidly moving towards a shift in the complexity of molecular testing -- namely, the movement from simple or single marker tests to multi-marker panels and next generation testing approaches (that may involve dozens to hundreds of biomarkers) or evaluation of multiple biomarker types (e.g., genetic composition and DNA/RNA/ protein expression of an individual patient). At present, only a limited number of technology assessments and policy evaluations have explored early evidence and the implications of next generation testing, and payer organizations are only in the initial stages of considering these tests.52-56 Several unique considerations may warrant further consideration beyond simple diagnostics, including but not limited to: • Expectations around validation of individual biomarkers in a panel, including in scenarios where the output of the panel is algorithmic vs. a read out of individual markers • Expectations around how unanticipated testing results are managed, • How information from biomarkers in a panel that may not be directly involved in patient management may be used or communicated (particularly if they subject patients to additional testing or treatment) • Expectations for comparison of broader ap proaches to less comprehensive or simpler test ing approaches (e.g., a single marker KRAS test vs. a next generation sequencing test that in cludes KRAS but offers information beyond just KRAS status) • Efficiencies in management of broader clinical pathways (e.g., identification of patient candi dacy for multiple available treatment alterna tives) beyond single care decisions • Evaluation of cost-effectiveness of complex vs. standard of care testing • Scenarios where simple and/or complex testing data may be integrated with other population/ patient data (e.g., database information, pub lished literature) to develop novel decision sup port solutions As we evolve a clear and more comprehensively used set of evidence expectations for diagnostics, addressing unique issues associated with next generation diagnostic evidence and HTA frameworks

will also be important. Payers and HTA agencies are already beginning to consider an initial vanguard of such tests that are beginning to enter the marketplace and have substantial potential to augment the way we manage patients in the future. Conclusions

Lack of agreement on what constitutes a sufficient evidence base for test development remains a fundamental problem for diagnostics. This makes it difficult for test manufacturers to target the appropriate study designs to characterize diagnostics value and inadvertently results in a widely variable evidence base. Inappropriately aligned and inconsistent evidence models also may miss opportunities for improving care efficiencies and outcomes given the foundational role that tests play in a majority of health care decisions. Greater clarity and consistency would also benefit the payers and providers facing a rapidly evolving wave of test information that will reshape practices of patient management. Conventional approaches toward diagnostic evidence requirements and value assessment need to evolve. To improve decision making, it is necessary to move away from a more “static” evidence evaluation framework that does not (a) adequately align the appropriate study type to the key questions that must be answered and (b) does not consider differences associated with the variety of health technologies that exist (e.g., drugs, devices, biologic products, diagnostic tests). A new hierarchy of evidence would use a combination of controlled trials and observational studies to provide the data necessary to evaluate value. In terms of diagnostic evidence development and evaluation, this paper has highlighted some of the key considerations for moving towards workable solutions for all key stakeholders. However, additional work will be necessary to clarify a workable and consistent diagnostics evaluation framework (including health economic data expectations/approaches) that addresses differences in test applications and real world use scenarios, helps define a range of study designs that are sufficient for appropriate decision making, and improves homogenity of test evaluation and adoption decisions. Given our exponentially expanding knowledge of systems biology and ability to weave multiple biomarkers and health information inputs into a more comprehensive and evidence-based decision tapestry, the time to align on decision criteria and fundamentals in the diagnostics arena has never been more important. Eric Faulkner, Executive Director, NAMCP Genomics, Biotech, and Emerging Medical Technology Institute; Vice President, Precision and Transformative Technology Solutions, Evidera; Associate Professor, Es-

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

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