March/April 2012, Vol 5, No 2 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MARCH/APRIL 2012

VOLUME 5, NUMBER 2

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

A New Beginning David B. Nash, MD, MBA BUSINESS

Trends in Biologic Therapies for Rheumatoid Arthritis: Results from a Survey of Payers and Providers ™

Rhonda Greenapple, MSPH Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

Impact of the Removal of the Monthly Liver Function Test Requirement for Ambrisentan Louise A. Durst, RN; John Carlsen, MHA; Megan Kuchinski, MPH; Lauren Harner, JD; Daniel Neves, BA; Stephanie J. Harris, RN, BSN; Glenna L. Traiger, RN, MSN, CNS-BC Stakeholder Perspective by James T. Kenney, Jr, RPh, MBA CLINICAL

Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis after Total Hip or Knee Arthroplasty Richard J. Friedman, MD, FRCSC Stakeholder Perspective by Atheer A. Kaddis, PharmD

DEXILANT MAY BE COADMINISTERED WITH PLAVIX (CLOPIDOGREL BISULFATE) DEXILANT had no clinically important impact on the antiplatelet activity of Plavix in healthy volunteers t DEXILANT 60 mg had no clinically important effect on Plavix active metabolite pharmacodynamics, as measured by Inhibition of Platelet Aggregation (IPA) and inhibition of Platelet Reactivity Index (PRI) based on co-primary endpoints of the study1 t DEXILANT minimally reduced the mean AUC of the Plavix active metabolite by 9%2 t No dose adjustment of Plavix is necessary when administered with an approved dose of DEXILANT2 % decrease in IPA* with Plavix and PPI coadministration (day 9)1

DATA PRESENTED AT ACC IN 2011

% decrease in inhibition of PRI with Plavix and PPI coadministration (day 9)1

0.2% 4.7% 22.5% DEXILANT 60 mg (n=40) Positive control (omeprazole 80 mg; n=40)

35.2%

Results from a Phase 1, open-label, multiple-dose, 2-period crossover study (n=160) of CYP2C19 extensive metabolizers receiving once-daily administration of Plavix 75 mg alone or concomitantly with 1 of 4 PPI agents. Co-primary endpoints were the measurement of PRI and Mean Platelet Aggregation (MPA) of Plavix + PPI vs Plavix alone. *ADP 5ÂľM.

Conclusions of comparative efficacy cannot be drawn from this information. The clinical relevance of these data has not been established. Indications for DEXILANT t Healing all grades of erosive esophagitis (EE) for up to 8 weeks t Maintaining healing of EE and relief of heartburn for up to 6 months t Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks

Important Safety Information t DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. t Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. t Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. t Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. t Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). t Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. Please see accompanying brief summary for DEXILANT. References: 1. Data on file, Takeda Pharmaceuticals North America, Inc. 2. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANT and DEXILANT (with design) are trademarks of Takeda Pharmaceuticals North America, Inc., registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Plavix is a registered trademark of sanofi-aventis Corp.

ÂŠ2011 Takeda Pharmaceuticals North America, Inc. LPD-01954 11/11 Printed in U.S.A.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed-release capsules for oral use INDICATIONS AND USAGE DEXILANT is indicated for: • the healing of all grades of erosive esophagitis (EE) for up to 8 weeks • maintaining healing of EE and relief of heartburn for up to 6 months • the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks. CONTRAINDICATIONS DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Gastric Malignancy Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosisrelated fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Adverse Reactions]. Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions]. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of DEXILANT was evaluated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 patients on lansoprazole 30 mg once daily. Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%) that occurred at a higher incidence for DEXILANT than placebo in the controlled studies are presented in Table 2. Table 2: Incidence of Adverse Reactions in Controlled Studies Placebo DEXILANT DEXILANT DEXILANT Lansoprazole 30 mg 60 mg Total 30 mg (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4.0 4.0 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory 0.8 2.9 1.7 1.9 0.8 Tract Infection Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy was diarrhea (0.7%). Other Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy; Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial

infarction, palpitation, tachycardia; Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo; Endocrine Disorders: goiter; Eye Disorders: eye irritation, eye swelling; Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching; General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia; Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly; Immune System Disorders: hypersensitivity; Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvovaginal infection; Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn; Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase; Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia; Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia; Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia; Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes; Renal and Urinary Disorders: dysuria, micturition urgency; Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder; Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat; Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria; Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to DEXILANT by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis. Other adverse reactions not observed with DEXILANT, but occurring with the racemate lansoprazole can be found in the lansoprazole prescribing information, ADVERSE REACTIONS section. Postmarketing Experience The following adverse reactions have been identified during post-approval of DEXILANT. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders: deafness Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema, pancreatitis General Disorders and Administration Site Conditions: facial edema Hepatobiliary Disorders: drug-induced hepatitis Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal) Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremia Musculoskeletal System Disorders: bone fracture Nervous System Disorders: cerebrovascular accident, transient ischemic attack Renal and Urinary Disorders: acute renal failure Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir.

DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Warfarin Co-administration of DEXILANT 90 mg and warfarin 25 mg did not affect the pharmacokinetics of warfarin or INR [see Clinical Pharmacology]. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with DEXILANT and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Tacrolimus Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Clopidogrel Concomitant administration of dexlansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed. A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole [see Nonclinical Toxicology]. Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established. Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of DEXILANT 60 mg. Non-serious adverse reactions observed with twice daily doses of DEXILANT 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

CLINICAL PHARMACOLOGY Pharmacodynamics Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment. Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months. During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology]. Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, SpragueDawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day. Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology]. In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA). A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive. Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test. Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test. The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats. PATIENT COUNSELING INFORMATION To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved Patient Information Leaflet should be discussed with the patient. Inform the patient to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.

Advise the patient to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions]. Advise the patient to tell their health care provider if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes [see Drug Interactions]. Advise the patient to follow the dosing instructions in the Patient Information Leaflet and inform the patient that: • DEXILANT is available as a delayed release capsule. • DEXILANT may be taken without regard to food. • DEXILANT should be swallowed whole. • Alternatively, DEXILANT capsules can be administered as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed. – Do not store for later use. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. Trademark registered with the U.S. Patent and Trademark office. All other trademark names are the property of their respective owners. ©2009, 2011 Takeda Pharmaceuticals America, Inc. DEX006 R15_BS Revised: October 2011 L-LPD-1011-2

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MARCH/APRIL 2012

VOLUME 5, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS EDITORIAL

A New Beginning David B. Nash, MD, MBA

BUSINESS

Trends in Biologic Therapies for Rheumatoid Arthritis: Results from a Survey of Payers and Providers Rhonda Greenapple, MSPH

Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

101 Stakeholder Perspective by James T. Kenney, Jr, RPh, MBA

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton 732-992-1892 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry

CLINICAL

Mission Statement

115 Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis after Total Hip or Knee Arthroplasty Richard J. Friedman, MD, FRCSC 122 Stakeholder Perspective by Atheer A. Kaddis, PharmD Continued on page 78

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March/April 2012

Vol 5, No 2

MARCH/APRIL 2012

VOLUME 5, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

OPINION

106 No, You Can’t Keep Your Health Plan: Think the Contraception Decision Was Bad? Wait Until Bureaucrats Start Telling Your Insurer Which Cancer Screenings to Cover Scott Gottlieb, MD 111 The End of Health Insurance Companies Ezekiel J. Emanuel; Jeffrey B. Liebman

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March/April 2012

Vol 5, No 2

EDITORIAL BOARD EDITOR-IN-CHIEF

GOVERNMENT

PHARMACY BENEFIT DESIGN

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Senior Counselor, Fleishman-Hillard

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

HEALTH INFORMATION TECHNOLOGY

DEPUTY EDITORS

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Harvard Vanguard Medical Associates

Joseph E. Couto, PharmD, MBA Assistant Professor, Jefferson School of Population Health Director, Health Economics and Outcomes Research Fellowship Program Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy

Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson HEALTH OUTCOMES RESEARCH

ACTUARY

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Immediate Past President, ACCC Past Chair, NCCN Board of Directors

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL HEALTH & VALUE PROMOTION

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Milwaukee

CARDIOLOGY RESEARCH

MANAGED MARKETS

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA

EMPLOYERS

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare, Sharon, MA ENDOCRINOLOGY RESEARCH

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA

Vol 5, No 2

March/April 2012

Leslie S. Fish, PharmD Senior Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

Charles E. Collins, Jr, MS, MBA RESEARCH & DEVELOPMENT Executive Vice President, Managing Director Michael F. Murphy, MD, PhD Engage Managed Markets Chief Medical Officer and Scientific Officer Worldwide Clinical Trials PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardProfessor of Pharmacy Law & Ethics MIT Division of Health Sciences and Vice Chair, Dept. of Pharmacotherapy Technology, Cambridge, MA College of Pharmacy, Washington State University, Spokane, WA SPECIALTY PHARMACY Atheer A. Kaddis, PharmD PERSONALIZED MEDICINE Vice President, Managed Markets Wayne A. Rosenkrans, Jr, PhD Diplomat Specialty Pharmacy Chairman and President, Personalized Swartz Creek, MI Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager PHARMACOECONOMICS Harvard Pilgrim Health Care Jeff Jianfei Guo, BPharm, MS, PhD Wellesley, MA Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

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It’s flu season. Which one’s the culprit?

DATA INDICATE IT MAY BE THE B STRAIN

Influenza B causes flu morbidity every season, yet predicting the dominant circulating B strain is not an exact science. Current flu vaccines protect against two A strains, and one of the two B strain lineages.2 In 5 out of 10 influenza seasons (2001-2011), the predominant circulating B strain was different from the one included in the influenza vaccine.3 When the incorrect B strain is predicted in an annual vaccine, the mismatch can leave a portion of your membership unprotected.

Percent Circulating Influenza Virus (%)

Many of your members may be vaccinated against influenza, yet still may not be protected against all circulating strains this coming season. Why? There are different strains of influenza—A strains and B strains. Protecting against influenza depends, in part, on predicting the circulating strains each season, and then ensuring the vaccination covers those strains.1

Influenza B Strain Prevalence Is Variable3 100

80 70 60 50 40 30 20 10 0

2001-02 2002-03 2003-04 2004-05 2005-06 2006-07 2007-08 2008-09 2009-10 2010-11

B strain mismatch occurred in this year’s flu vaccine

A strain

B strain

References: 1. World Health Organization. Influenza (Seasonal) Fact Sheet No 211, April 2009. http://www.who.int/mediacentre/factsheets/fs211/en/#. Accessed January 4, 2012. 2. Centers for Disease Control and Prevention. Seasonal Influenza (Flu). 2011-2012 Influenza Vaccine Information. http://www.cdc.gov/flu/flu_vaccine_ updates.htm. Accessed January 4, 2012. 3. Centers for Disease Control and Prevention. Seasonal Influenza (Flu). Past Weekly Surveillance Reports. http://www.cdc.gov/ flu/weekly/pastreports.htm. Accessed January 4, 2012. 4. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292(11):1333-1340. 5. Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal influenza in the US: measuring disease burden and

VACCINATED, YET NOT OPTIMALLY PROTECTED

POTENTIAL IMPACT OF PROTECTION

What does this mean for your health plan?

Protecting against both influenza B strain lineages avoids the challenge of predicting which one will predominate in upcoming influenza seasons. In fact, a recent CDC model§ estimated that protecting against both B strains may have helped avoid 2.7 million cases of influenza illness over ten flu seasons.7

• In seasons where mismatched circulating B strains predominate, your vaccinated members may be more susceptible to influenza illness ESTIMATED ANNUAL IMPACT OF INFLUENZA A AND B

§The

• 200,000 hospitalizations4*

model used in the analysis is dependent on variables such as overall burden of influenza, annual vaccine capacity and coverage, and proportion of influenza burden due to circulating B strains.

• 31 million outpatient visits5† • 44 million lost working days5† • 38 million lost school days in one year6‡ *Based

on 2003 population demographics. annual average based on data from influenza seasons from 1979-1980 through 2000-2001. ‡Estimated figure pertains to 1996 only. †Estimated

costs. Vaccine. 2007;25:5086-5096. 6. Adams PF, Hendershot GE, Marano MA. Current estimates from the National Health Interview Survey, 1996. Vital Health Stat 10. 1999;(200):1-203. 7. Reed C, Meltzer MI, Finelli L, Fiore A. Public health impact of including two lineages of influenza B in a quadrivalent seasonal influenza vaccine. [Published online ahead of print January 4, 2012.] Vaccine. (2012),doi:10.1016/j.vaccine.2011.12.098. © 2012 MedImmune. All rights reserved. 10116-22956

INAUGURAL EDITORIAL

A New Beginning David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health

t is with a great deal of pride and humility that I have accepted this new role as the Editor-in-Chief of American Health & Drug Benefits (AHDB). Let me outline what I hope to accomplish in the coming months and years and solicit your input and support. First, some background about my professional journey. I have been at Thomas Jefferson University for the past 22 years. During that tenure, I have had essentially 3 jobs. I came on board in 1990 in a staff role to the hospital CEO, directing the Office of Health Policy. Thirteen years later, this office evolved into the first Department of Health Policy within Jefferson Medical College, the nation’s largest private medical school. After 5 years as a medical school department chair, having achieved what I thought was my professional zenith, I was asked by the President of Jefferson University, Robert Barchi, MD, PHD, to take on a new challenge, namely, to create a brand new school, aptly named the Jefferson School of Population Health (JSPH). JSPH was formed through a unanimous vote of the Jefferson University Board of Trustees, and we opened our doors to a unique school on September 9, 2009. During this journey, I have had the privilege of editing nearly 2 dozen books, and I currently serve as an editor for several peer-reviewed journals. As a result, I have a steady hand when it comes to steering a journal in new and choppy waters. To hold on to this helm, I have asked 2 seasoned colleagues to join me as deputy editors. Joseph E. Couto, PharmD, MBA, is Assistant Professor in the JSPH. Dr Couto also directs our very successful postdoctoral Health Economics and Outcomes Research Fellowship program. Laura T. Pizzi, PharmD, MPH, RPh, is Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy. Dr Pizzi has significant experience in researching the costs and outcomes of pharmaceuticals. I am grateful to Dr Couto and Dr Pizzi for their willingness to join me in this endeavor. Our mission is to take AHDB to new heights. With your help, and with steady leadership, we will continue to further AHDB as a trusted source of new information and position it as the “go-to” journal within the realm of health and drug benefits, the functioning of benefit managers, value-based patient care, and the role of these functions in the context of healthcare reform. Who should be reading the revitalized AHDB? I

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believe decision makers in all sectors will be interested in our content. Our target audience encompasses key persons, such as members of pharmacy and therapeutics committees, leaders within the pharmacy benefit management realm, executives in managed care organizations and integrated delivery systems, and providers who have leadership aspirations. I would also like AHDB to increasingly engage policymakers in the public and the private sectors. Along with Dr Couto and Dr Pizzi, I intend to reenergize the journal and invite new collaborators to join us. We will recruit senior leaders from every relevant sector of our audience—industry, academia, the purchaser community, and the government. I am confident that our revitalized editorial board will help accomplish several key goals: strengthening the editorial focus of AHDB; recruiting timely, credible, and informative articles; and stimulating a broader and deeper conversation regarding contemporary issues in line with our editorial mission. Our healthcare system, especially as it applies to the evaluation of health and drug benefits and value-based healthcare, is at a crossroads. It is also a new era for the pharmaceutical industry and its sister industries, biotechnology and medical devices. All this offers a wonderful opportunity to reshape AHDB in a way that would prepare it for greater recognition by authoritative medical bodies. The challenges of and changes to our healthcare system today present this real opportunity for AHDB. To accomplish these goals, we need your help. First, I hope you will personally turn to AHDB as a go-to source for cutting-edge, relevant, and timely information in our field. Second, I hope you will consider AHDB a publication venue when you are evaluating programs and conducting research. Third, I hope you will recommend our content to many colleagues. Finally, I hope that you will join us in a revitalized national conversation about America’s healthcare system and the benefits that are critical to our nation’s health. With this national conversation in mind, I invite you to communicate directly with me via e-mail at david.nash@jefferson.edu. I hope to hear from many of you. A journal is only as good as the conversation it engenders in print and on the web. AHDB is looking forward to your participation in a robust and honest conversation. Thank you for the privilege of this new editorial responsibility. ■

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March/April 2012

Vol 5, No 2

BUSINESS

Trends in Biologic Therapies for Rheumatoid Arthritis: Results from a Survey of Payers and Providers Rhonda Greenapple, MSPH Background: Advances in therapies for rheumatoid arthritis (RA), particularly biologics, have transformed the treatment paradigm for RA. However, the associated costs of these therapies result in a significant economic burden on the healthcare system. As a chronic disease requiring lifelong treatment, most health plans now position RA drugs as a highpriority therapeutic category. Objective: To identify provider and payer practices and perceptions regarding coverage of RA biologics in the current marketplace, as well as emerging trends in reimbursement practices. Method: In November 2011, Reimbursement Intelligence, a healthcare research company, collected and analyzed quantitative and qualitative data via parallel-structure online surveys of 100 rheumatologists and 50 health plan payers (medical and pharmacy directors) who represent more than 80 million covered lives. The surveys included approximately 150 questions, and the surveys were designed to force a response for each question. Results: Payers reported using tier placement, prior authorization, and contracting in determining coverage strategies for RA biologics. Among providers, experience with older RA agents remains the key driver for the choice of a biologic agent. A majority of payers and providers (68% and 54%, respectively) reported that they did not anticipate a change in the way their plans would manage biologics over the next 2 to 4 years. Payersâ&#x20AC;&#x2122; responses indicated uncertainty about how therapeutic positioning of newer, small-molecule drugs at price parity to biologics would affect the current reimbursement landscape. Survey responses show that approval of an indication for early treatment of RA is not likely to change the prescribing and reimbursement landscape for RA biologics. This survey further shows that payers and providers are generally aligned in terms of perceptions of current and future treatments for RA. Conclusion: Advances in RA therapies allow patients increasing options for effective disease management. However, the high cost of biologic therapies and the need for lifelong treatment raise economic concerns. Payer satisfaction with current therapies and uncertainty about added value of new therapies will create challenges for new medications coming to market.

heumatoid arthritis (RA) is a chronic systemic autoimmune disorder and the most common form of inflammatory arthritis.1 RA affects 1% of the population, most often adults aged 40 to 70 years.2 Recent epidemiologic data indicate that the incidence of RA in women has risen in the past 10 years.3 Because RA affects many individuals who are of working age and remains a major cause of disability, the economic burden Ms Greenapple is President, Reimbursement Intelligence, LLC, Madison, NJ.

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March/April 2012

Stakeholder Perspective, page 91

Am Health Drug Benefits. 2012;5(2):83-92 www.AHDBonline.com Disclosures are at end of text

of RA adds a significant cost not only to patients and their families, but also to society as a whole.1,4 In addition, reduced quality of life, loss of work productivity, and substantial healthcare utilization are factors that must be considered in RA management.4,5 Because complications of RA may begin to develop within months of disease onset, early and aggressive treatment is considered clinically necessary to manage immediate symptoms of pain associated with inflammation, but also to slow disease progression to prevent longterm disability.1,6,7 Historically, estimates of work disabili-

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KEY POINTS ➤

➤

Advances in RA medications, particularly biologics, have transformed the treatment paradigm for RA; however, the associated costs of these therapies result in a significant economic burden on the healthcare system. With a chronic disease requiring lifelong treatment, most health plans are positioning RA drugs as a high-priority therapeutic category. This survey of 100 rheumatologists and 50 payers representing >80 million lives revealed that provider experience and satisfaction with older RA agents remains the underlying driver for choice of biologics. Payers and providers alike reported that they did not anticipate a change in the way their plans would manage biologics over the next 2 to 4 years. Payers were uncertain about the therapeutic positioning for newer, small-molecule drugs at price parity to biologics. Survey responses also suggest that an indication for a biologic to treat early RA will likely not change current prescribing and reimbursement patterns.

ty rates for RA have been high, with higher rates associated with longer disease duration; work disability estimates have been shown to reach 30% within 2 to 3 years of diagnosis.4,5 Recent estimates suggest that RA-related work disability rates remain high, although potentially lower than in earlier estimates.8 This 2008 longitudinal analysis showed estimates of 23% work disability at 1 to 3 years of disease onset and of 35% within 10 years.8 Clinical studies have shown better clinical outcomes when aggressive treatment is initiated early, including treatment with a wide range of disease-modifying antirheumatic drugs (DMARDs) and non-DMARD combination therapies.7-9 A recent joint collaboration of the American College of Rheumatology (ACR) and the European League Against Rheumatism has led to the development of an updated classification system of RA, to shift the focus from late-stage disease features—such as structural changes and joint damage that can be determined from various imaging techniques—to early-stage disease features that are associated with persistent disease.6 Given the advances in treatment for RA, including nonbiologic and biologic options, along with the associated improved outcomes, this classification system update to include early-disease features marked a major shift in the RA disease construct.6 The ACR guidelines outline clinical treatment pathways by first defining disease duration and activity.7 Disease duration is divided into 3 major categories: <6

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months (equivalent to early disease), 6 to 24 months (equivalent to intermediate disease duration), and >24 months (equivalent to longer disease duration).7 Disease activity measurements are often qualitative in early-stage disease, and measures are subject to clinical judgment.7 Pharmacotherapy for RA often includes a nonsteroidal antiinflammatory drug, selected use of glucocorticoids, and initiation of a DMARD early in the disease course.1,7 Biologic therapies may be added when adequate disease control has not been met by previously initiated drug therapies, which may occur within the first year of diagnosis.1,7 With regard to biologic therapies, the ACR further subdivides “early disease” by disease duration of <3 months or 3 to 6 months, to accommodate the needs for early advancement of the patient to biologic therapies when disease activity is high.7 Despite positive clinical outcomes from treatment advances, healthcare costs associated with the treatment of a prevalent and lifelong disease such as RA are a considerable issue for health plans. The ACR estimates that per-patient treatment with biologic therapies is typically in excess of $12,000 annually.10 The Agency for Healthcare Research and Quality estimates the annual costs for RA medications from as low as a few hundred dollars for oral, nonbiologic DMARDs to a high of more than $16,000 for injectable biologic DMARDs.11 As new therapeutic options for RA become available, provider practices and payer strategies to support evidence-based care within the confines of cost management demand close examination. This study was conducted to identify provider and payer practices and perceptions regarding therapeutic options and reimbursement for RA. To this end, Reimbursement Intelligence, a healthcare research company, conducted parallel online surveys with health plan payers and rheumatologists. Payers were asked to also consider market trends and potential for formulary coverage of RA therapies currently in development.

Methods Online parallel-structure surveys were conducted in November 2011 and were completed by 2 groups: 100 rheumatologists and 50 payers identified as advisors to Pharmacy & Therapeutics Committees who are formulary decision makers for RA coverage. The payer group survey respondents included 50 pharmacy and medical directors from national and regional health plans who had held their positions for more than 2 years. The payer group of health plans represented 80 million covered lives. The distribution of plan types among payer respondents included Medicare Part D, commercial plans, Medicare Advantage, freestanding prescription drug

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Vol 5, No 2

Trends in Biologic Therapies for RA

Figure 1 Payer Formulary Tier Placement for RA Biologics

Question to payers (N = 50): For the following agents covered under your pharmacy benefit, please select the corresponding tier positioning. 100% 90% 80% 70% 60% 50% 40% 30%

Tier 2 Tier 3 Tier 4 N/A

20% 10% 0% Enbrel

Humira

Remicade

Cimzia

Simponi

Rituxan

Orencia

Actemra

N/A indicates not applicable; RA, rheumatoid arthritis.

plans, Managed Medicaid, and dual-eligible populations. More than two thirds (69%) of payers represented commercial plans with 3- or 4-tier formularies. The rheumatologist group represented providers from large and small group practices, and ones with and without in-office infusion capabilities. Rheumatologists were screened as to whether their practice offered in-office biologic infusions, the practice volume of in-office infusions weekly, and the number of rheumatologists in the practice. The sample was weighted toward rheumatology and multispecialty group practices seeing more than 80 patients with RA monthly. The parallel-structure payer and rheumatologist surveys were comprised of approximately 150 questions, and the survey instrument required answers to all questions. Survey questions included specific probes about 8 biologic therapies currently indicated for RA (Table 1); existing medications that may receive an RA indication; and new, small-molecule oral agents still in development. All respondents received an honorarium for their participation.

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March/April 2012

Biologic Medications Indicated for Table 1 Rheumatoid Arthritis Brand name

Generic name

Actemra

Tocilizumab

Cimzia

Certolizumab

Enbrel

Etanercept

Humira

Adalimumab

Orencia

Abatacept

Simponi

Golimumab

Rituxan

Rituximab

Remicade

Infliximab

Results Tier Placement Tiered cost-sharing is a common strategy for therapies covered under a pharmacy benefit. Payers reported that

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Figure 2 Approval Rates for Prior Authorization/Step Edits

Question: What is the approval rate for prior authorizations and step edits for your patients with RA? Providers, 85% Payers, 72%

55%

Rheumatologists (N = 100) Payers (N = 50) 50 46%

Respondents, %

29%

26%

20 12% 9%

6% 2%

0 1%-20%

21%-40%

41%-60%

61%-80%

81%-100%

N/A

N/A indicates not applicable; RA, rheumatoid arthritis.

none of the current 8 biologic medications (Table 1, page 85) covered under the pharmacy benefit is placed on tier 1. Tier 2 status was given most frequently to etanercept (Enbrel; 36%) and adalimumab (Humira; 34%), whereas the remaining products were distributed across tiers 3 and 4 (Figure 1, page 85).

Prior Authorizations and Step Edits To target medications to appropriate patients, health plans may require patients to meet predetermined clinical criteria and receive prior authorization before reimbursement is approved. Similarly, health plans may use step edits, or a “fail-first” requirement, where payment for a therapy will be made only after certain therapies have been used first. If the patient does not respond appropriately (ie, considered a “step” or “failure”), then the provider will likely recommend a second-line therapy.12 Payers were asked about approval rates when prior authorizations or step edits are required. Survey results show that most health plans use prior authorizations to manage utilization of RA therapies; 80% to 88% reported they require prior authorizations for the 8 bio-

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logic options presented in the survey. More than half (55%) of the providers reported approval rates between 81% and 100% of the time, whereas 29% reported approval rates from 61% to 80% of the time (Figure 2).

Distribution Strategy and Use of Specialty Pharmacies Most (80%) payers in the survey reported they use specialty pharmacies for distribution of biologic therapies for RA. Among those who use specialty pharmacies, 65% reported using closed networks, whereas 83% reported they do not mandate the use of specialty pharmacies for distribution of office-infused biologic agents. Specialty pharmacy services often offer services beyond product dispensing. Payers reported that the most valuable add-on services are patient education (60%), compliance programs (54%), compliance/adherence data reported back to payers (46%), and reimbursement assistance (28%). Perceptions of Management Approach Payer respondents characterized their general approach

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March/April 2012

Vol 5, No 2

Trends in Biologic Therapies for RA

to RA management in terms of level of stringency of drug approval requirements for providers. Specifically, payers were asked, “How would you characterize your plan’s general approach toward the management of rheumatoid arthritis?” Respondents were asked to choose from 5 categories—“open access,” “somewhat regimented,” “regimented approach,” and “other.” Regimented was defined as “patients must have documented failure on a DMARD and a preferred biologic.” Open access was defined as “physician decides patient therapy and no documentation needed.” Overall, 40% of payers characterized their plan’s approach as regimented. In contrast, only 33% of providers characterized their plans as regimented. A little more than one third (36%) of payers characterized their management approach as somewhat regimented, in which patients must have a documented failure while using a DMARD before a biologic drug will be approved. Conversely, 57% of providers characterized their health plans as somewhat regimented. Of the payers, 10% reported that they offer open access, in which the physician decides on the patient’s therapy and no documentation is needed for treatment initiation or changes. More payers (16%) than providers (10%) reported open access in this survey.

Provider-Reported Number of RA Biologics Prescribed Figure 3 per Patient during the Course of Disease

Impact of Reimbursement Process on Access to Biologics Providers reported that oral methotrexate (Trexall, Rheumatrex) is initiated within the first 3 months of RA diagnosis: 74% reported immediate initiation of the drug; 22% reported initiating methotrexate within 1 to 3 months. In addition, 21% of providers also reported initiating biologics within 1 to 3 months after initiation of methotrexate; 61% reported initiating biologics between 3 to 6 months; and 8% reported initiation of biologics between 6 months and 1 year. With regard to the number of biologics used for each patient, only 7% of providers reported that patients remained using the first biologic throughout the duration of their disease; 48% and 43% of providers indicated that patients typically cycle through 2 or 3 biologics, respectively, in the course of the disease (Figure 3). Payers and providers were asked to rank, in order of importance (from highest to lowest), the reasons for choice of preferred biologic (Figure 4). For both respondent groups, efficacy ranked the highest in influence on choice of biologics. Payers ranked etanercept, adalimumab, and infliximab (Remicade)—the 3 most established of the 8 biologics studied—as the most frequent first- and second-line drug choices. Payers reported that contracting/rebating is the second most frequent influence in determining a preferred biologic for patients

Figure 4 Ranked Order of Importance for Choosing Preferred Biologics

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March/April 2012

Question to rheumatologists (N = 100): How many biologics do your patients with RA typically cycle through during the course of their disease? 100 90 80

Providers, %

70 60 48%

43%

40 30 20 10

7% 2%

0 1

≥4

Biologics prescribed

RA indicates rheumatoid arthritis.

Question: Please rank in order of importance (from highest to lowest) the reasons for your choice of preferred biologic(s). Rheumatologists (N = 53)

Payers (N = 28)

Efficacy profile

Safety profile

Contracting/rebating

My personal experience

Safety profile

Mode of administration

Frequency of dosing

Market share

Reimbursement easier to obtain on most health plans

Utilization rate among plan’s in-network physicians

with commercial coverage. For the Medicare population, payers ranked safety as more important than contracting/rebating.

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Provider-Reported Staff Success Rate in Obtaining Figure 5 Reimbursement Approval

Question to rheumatologists (N = 100): How successful is your staff in obtaining reimbursement approval for your patients? 0%-20% 21%-40% 1%

41%-60%

2% 81%-100%

12%

51% 34%

61%-80%

Disease-Modifying Rheumatoid Arthritis Agents in Table 2 Development Generic name/drug type

Development phase

Fostamatinib, oral, spleen tyrosine kinase inhibitor

Phase 2 clinical trial

Tofacitinib, oral, Janus kinase inhibitor

NDA submitted to the FDA on December 21, 2011

Tabalumab, IV, human immunoglobulin G4 monoclonal antibody

Phase 3 clinical trial

FDA indicates US Food and Drug Administration; IV, intravenous; NDA, New Drug Application.

Payers and providers were asked about the main reason for low utilization of newer tumor necrosis factor (TNF) inhibitors, such as certolizumab (Cimzia) and golimumab (Simponi), and asked to rank in order from highest to lowest the reason for low utilization. Although contracting/price had some impact on product choice, ranking third, provider comfort with older agents was the first-ranked reason given by both providers and payers. More than three fourths (79%) of providers

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reported that some documentation of medical need for a biologic is always required. However, providers, like payers, stated that approval is granted more than two thirds of the time (Figure 2). Only 15% of providers reported that plans require quantitative measurements (ie, x-ray) of active disease to allow the initiation or change of biologics. One third (34%) of providers and 40% of payers reported ACR 20% criteria for improvement (ACR20) achievement as a requirement for approval of a biologic therapy, and 42% of providers and 44% of payers reported that demonstrated safety and tolerability are required to initiate biologic drug therapy. Providers were asked, “Under what circumstances would you be willing to take steps to dispute a payer decision?” More than two thirds (68%) agreed with the statement, “To appeal a denied prior authorization of one autoimmune biologic because payer requires failure of a different autoimmune biologic agent (eg, step edit).” Similarly, 60% chose the statement, “To counter onerous administrative or documentation requirements (eg, to eliminate burdens some request for additional documentation beyond reasonable medical notes),” with 68% choosing the statement, “to secure reimbursement following a claim denial for an on-label diagnosis.” In a follow-up question, providers were asked how many times they would dispute a denial before accepting the denial as a defined payer policy. Nearly one third (32%) of providers reported 1 time, 38% reported 2 times, and 17% reported 3 times. In this survey, providers reported that their support staff was generally successful at overcoming prior authorization and stepedit requirements (Figure 5). Overall, payers and providers were consistent in their responses in regard to changes in the way RA will be managed over the next 2 to 4 years, with 54% of rheumatologists and 68% of payers reporting no change. Payers were asked if changes in reimbursement for office-infused products influenced the treatment selection rheumatologists currently make. More than 6 of 10 (62%) payers said that these changes would not influence treatment selection. Regarding sites of care, 82% of the rheumatologists reported providing in-office infusion, although 62% of these providers also reported using an alternate site of care at least part of the time. When asked does “site of care affect your choice of therapy,” 72% of providers agreed with the statement, “It does not affect my choice of biologic.”

Potential Impact of Expanding Therapeutic Options for RA Payers and providers were asked to assess the potential impact of several emerging trends in RA therapies,

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March/April 2012

Vol 5, No 2

Trends in Biologic Therapies for RA

Figure 6 Impact of Early RA Indication on Prescribing Patterns

Question for rheumatologists: If an early RA indication were FDA approved, how do you think this will impact your biologic prescribing? Question for payers: If an early RA indication were FDA approved, how do you think this will impact the biologic prescribing patterns of rheumatologists in your network? 50 46% 45 40

38%

Rheumatologists (N = 100) Payers (N = 50)

Respondents, %

35 31% 30 25

23% 20%

20 15 10 4%

5 0% 0 Will prescribe a biologic at the time methotrexate or another DMARD is initiated

Will add a biologic to therapy within 1 year of initiating methotrexate

Would not change prescribing, because biologics are already initiated within 3 years of diagnosis

Other

DMARD indicates disease-modifying antirheumatic drug; FDA, US Food and Drug Administration; RA, rheumatoid arthritis.

including new, small-molecule oral disease-modifying agents (Table 2, page 88). Respondents were asked, â&#x20AC;&#x153;Once FDA [US Food and Drug Administration] approved, how will they change your treatment strategy? Assume efficacy and safety are similar to current TNF inhibitors. Assume price parity to current biologics.â&#x20AC;? One third (36%) of providers and one fifth (20%) of payers reported these agents will be used after methotrexate but before TNF inhibitors. One third (33%) of providers and 16% of payers reported these agents will be used after TNF inhibitor failure. Smaller numbers, 15% of providers and 18% of payers, reported these agents will be used after TNF inhibitors fail. Only 11% of providers and 34% of payers say they are not sure. If small-molecule drugs are priced at a 15% to 20% discount to biologics, a little more than half (52%) of payers reported they would position them before TNF inhibitors. However, if small-molecule drugs were priced at a 15% to 20% premium to biologics in product costs,

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March/April 2012

they would position them after TNF inhibitors. If the price of these compounds were discounted relative to TNF inhibitors, an expedited review would be expected by 46% of payer respondents. Most payers (88%) and more than half (57%) of providers reported they believe small-molecule therapies to be in the same therapeutic class as biologics. More than two thirds (68%) of payers noted that approval of the first small-molecule therapy would likely trigger a class review of the biologics. Regarding compliance potential of orals, which will be dosed 2 or 3 times daily,13,14 58% of payers and 44% of providers reported that oral dosing would improve patient compliance; 25% of providers and 8% of payers reported they believe it will reduce compliance as a result of the 2- or 3-timesdaily dosing regimen, and 29% of providers and 28% of payers reported that compliance will not be an issue. Consideration of adoption of new therapies at launch was reported by only 27% of providers. However, 46% of

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providers reported they would require <1 year of experience with a new therapy to regularly prescribe it, with the balance of respondents (27%) reporting a 1- to 3year time frame to adoption. In addition, payers and providers were asked if they were aware of any ongoing head-to-head trials in RA; affirmative responses were given by 12% of payers and 26% of providers. Payers and providers were then asked, “How significant would the results of a head-to-head trial be in selecting your preferred biologic, if the trial design is for superiority?” On a scale of 1 to 7, with 1 representing “not significant at all” and 7 representing “most significant,” 40% of both payers and providers selected 6, whereas 34% and 33%, respectively, selected 7. Payers and providers in this survey were asked if there would be an impact on prescribing patterns if an early RA indication was approved by the FDA. Among rheumatologists, 46% reported they would not change prescribing of biologics, with 23% reporting they will add a biologic within 1 year of initiating methotrexate. Nearly one third (31%) of rheumatologists reported they would prescribe a biologic at the time methotrexate or another DMARD is initiated (Figure 6, page 89).

Drugs covered under the medical benefit lack the scrutiny of drug utilization review and coverage management protocols used in pharmacy benefit structures. The entry of new oral and self-injectable products will generate greater scrutiny, which may result in an impact on cost. Discussion Cost Burden RA represents a significant burden to payers and is positioned as the highest priority therapeutic category for most health plans.15 Specialty pharmacy costs for RA therapies account for more than 25% of total spending for specialty drugs.16 Although nonspecialty drug costs in many categories are expected to grow more slowly over the next 3 years (because of increased availability of generics), costs for specialty therapies are expected to grow between 15% and 17% annually.16 Between 2011 and 2013, the costs for RA biologics are expected to be the single largest contributor to increases in specialty drug spending and are predicted to represent approximately one fifth (21%) of all health plan drug spending by 2014.16 Payers continue to implement and refine a variety of reimbursement strategies to balance quality of care in

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light of the economic burden of RA biologics, with varying effects.

Payer Reimbursement Management The high costs associated with RA therapies have led payers to look for strategies to manage immediate costs, while weighing the potential for long-term costs of delayed treatment (eg, disability). Health plans have historically covered biologic therapies with subcutaneous delivery under a pharmacy benefit, because patients can self-administer these therapies.15 Intravenous and infusion therapies have been covered largely under a medical benefit, because drug administration needs to be delivered by a healthcare professional.15 Drugs covered under the medical benefit lack the scrutiny of drug utilization review and coverage management protocols used in pharmacy benefit structures. The entry of new oral and self-injectable products will generate greater scrutiny, which may result in an impact on cost.16 As new biologics enter the market, health plans will need to consider how coverage channels, including rebates or other discounts offered under a pharmacy benefit structure, will impact future costs. Currently, there is no biologic therapy on the market that is specifically indicated for “early” RA. Because early stages of RA are diagnosed by clinical presentation rather than a definitive test, diagnostic parameters of early RA remain unclear.1 The survey findings highlight emerging trends in RA cost-management strategies, including payers’ efforts to follow evidence-based guidelines for use of RA biologics, and the trend toward shifting a greater proportion of the cost to patients; the resulting framework can inform the coordination of cost and clinical management of RA. Results from this survey also show that payers and providers were generally aligned in terms of perceptions of current and future treatments for RA. Because provider experience and satisfaction with older RA agents were reported as the underlying driver for using current therapies, uptake of newer agents may also follow a similar pattern. Of note were responses that having an indication for early RA would not influence prescribing patterns, because biologics generally are already being used within 1 year of diagnosis, which is still considered early in the course of the disease. Limitations The limitations of this study include those inherent to all surveys. Survey questions must be developed broadly to be appropriate to as many respondents as possible. Surveys in general are inflexible to adaptation to individuals or subsets of respondents, so captured data may not reveal the richer context of the questions posed.

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Trends in Biologic Therapies for RA

In addition, this survey was administered online and was formatted with forced-answer questions. Although there is a benefit to capturing responses for all questions and all respondents, question saliency may not be uniform for all respondents, thereby impacting the weight of each question in relation to others. Furthermore, the sample size of the provider group was twice that of the payer group, which could skew intergroup comparisons.

Conclusion Although the availability of highly effective biologic therapies for RA has greatly improved patient care, the cost of these therapies remains a priority concern for patients, providers, and payers alike. Provider and payer satisfaction with older RA agents, and skepticism about the incremental value of new therapies, will continue to raise the hurdles for new RA therapies coming to market. ■ Author Disclosure Statement Ms Greenapple reported no conflicts of interest.

References 1. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005;72:1037-1047. 2. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358:903-911. 3. Myasoedova E, Crowson CS, Kremers HM, et al. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62:1576-1582.

4. Sokka T. Work disability in early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21(5 suppl 31):S71-S74. 5. Verstappen SM, Bijlsma JW, Verkleij H, et al; Utrecht Rheumatoid Arthritis Cohort Study Group. Overview of work disability in rheumatoid arthritis patients as observed in cross-sectional and longitudinal surveys. Arthritis Rheum. 2004;51:488-497. 6. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580-1588. 7. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784. 8. Allaire S, Wolfe F, Niu J, LaValley MP. Contemporary prevalence and incidence of work disability associated with rheumatoid arthritis in the US. Arthritis Rheum. 2008;59:474-480. 9. Resman-Targoff BH, Cicero MP. Aggressive treatment of early rheumatoid arthritis: recognizing the window of opportunity and treating to target goals. Am J Manag Care. 2010;16(9 suppl):S249-S258. 10. Cush JJ. American College of Rheumatology. Biologic treatments for rheumatoid arthritis. 2010. www.rheumatology.org/practice/clinical/patients/medications/biologics. pdf. Accessed January 26, 2012. 11. Effective Health Care, Agency for Healthcare Research and Quality. Rheumatoid arthritis medicines: a guide for adults. AHRQ Publication Number 08-EHC004-2A; April 2008. www.effectivehealthcare.ahrq.gov/repFiles/Rheum ArthritisConsumerGuide_Singlepage.pdf. Accessed March 1, 2012. 12. Hoadley J, Henry J. Kaiser Foundation. Cost containment strategies for prescription drugs: assessing the evidence in the literature. March 2005. www.kff.org/ rxdrugs/upload/Cost-Containment-Strategies-for-Precription-Drugs-Assessing-TheEvidence-in-the-Literature-Report.pdf. Accessed March 1, 2012. 13. Rigel Pharmaceuticals, Inc. Rigel’s R788 significantly improves rheumatoid arthritis in phase 2b clinical trial: expected and manageable safety profile demonstrated in TASKi2. Media release. July 9, 2009. www.drugs.com/clinical_trials/rigels-r788-significantly-improves-rheumatoid-arthritis-phase-2b-clinical-trial-7714. html. Accessed March 2, 2012. 14. van Vollenhoven RF, Fleischmann RM, Cohen SB, et al. Tofacitinib (CP690,550), an oral Janus kinase inhibitor, or adalimumab versus placebo in patients with rheumatoid arthritis on background methotrexate: a phase 3 study. Arthritis Rheum. 2011;63(suppl 10):408. 15. EMD Serono. Managed care strategies for management of specialty injectable drugs. EMD Serono Injectables Digest. 4th ed. 2008. www. amcp.org/WorkArea/ DownloadAsset.aspx?id=12974. Accessed January 26, 2012. 16. Medco. 2011 Drug Trend Report: Healthcare 2020. Franklin Lakes, NJ: Medco; 2011. www.drugtrendreport.com/Medco-2011-Drug-Trend-Report-Executive-Summary.pdf. Accessed March 1, 2012.

STAKEHOLDER PERSPECTIVE Biologic Therapies for Rheumatoid Arthritis: It’s All about Value Value has been defined as the relationship between benefits and costs. Using mathematical concepts, value has been described as “value = benefits/cost” or the units of benefit derived from a given number of units of costs. Applying this definition, if we wish to maximize the value of a therapy, there are only 2 ways to achieve it: either by increasing the benefits obtained from the therapy, or by decreasing the cost paid for that therapy. Value in healthcare is also a function of perspective. What may be considered valuable to an individual patient undergoing treatment or to a physician prescribing that treatment to a similar group of patients

may not necessarily be considered valuable to the same extent by a payer, who must not only pay for that individual’s treatment but who also has to manage the needs of multiple groups of patients and/or members with equally compelling medical conditions and priorities. Optimizing value within the healthcare system means that physicians and payers must be aligned in the way they view the various benefits and costs of a given treatment. Achieving such optimization is where the article by Ms Greenapple in this issue of American Health & Drug Benefits fits in. In her article, Ms Greenapple shows Continued

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STAKEHOLDER PERSPECTIVE (Continued) that providers and payers, at least when it comes to the use of biologics for the treatment of rheumatoid arthritis, have much more in common than not when looking at value within this drug class. The findings from this survey have several important implications to providers, payers, and patients/plan members. PROVIDERS: Providers can practice more autonomously in addressing the needs of the patient with rheumatoid arthritis. They can do this by following evidence-based guidelines as they initiate treatment with disease-modifying antirheumatic drugs, and only progress to more costly biologic therapies when they need to improve treatment benefits, thereby optimizing the value of treatment. Such staged management is aligned with payer coverage policies. PAYERS: For payers, this issue is a matter of expectation. Knowing that providers practice using the same specialty guidelines that payers follow will allow payers to expect that their contracted providers will “do the right thing” when it comes to promoting evidencebased medicine when treating patients with rheumatoid arthritis. PATIENTS/PLAN MEMBERS: When provider practice is aligned with plan policy, patients or plan

members are the ultimate winners. As is described in this article, with 84% of providers reporting approval rates of at least 61% of requests for rheumatoid arthritis biologics (and 55% reporting approvals of at least 81% of such requests), patients who need more intensive treatment for their arthritis can receive it in a more timely and coordinated manner. MEDICAL DIRECTORS: Does this mean that payers should stop enforcing step therapies or other such strategies? Regretfully, not yet; complete buy-in to evidence-based medicine has not yet been achieved, and we continue to see treatment irregularities for certain disease states. Perhaps one day soon, with the advancement of meaningful use parameters by providers, along with electronic medical records and decision support systems promoting evidencebased medicine, we will be able to get there. After all, reaching such a goal for rheumatoid arthritis, or any other significant condition, would not only be admirable, but more important, it would provide great value in healthcare. Albert Tzeel, MD, MHSA, FACPE National Medical Director, HumanaOne

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ORIGINAL RESEARCH

Stakeholder Perspective, page 101

Am Health Drug Benefits. 2012;5(2):94-101 www.AHDBonline.com Disclosures are at end of text

Background: The management of patients with pulmonary arterial hypertension (PAH) requires extensive coordination between patients, their support system, third-party payers, and healthcare professionals. For patients with PAH who are receiving endothelin receptor antagonists (ERAs), such cross-stakeholder coordination was needed to ensure compliance with a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) requirement for monthly liver function tests (LFTs). In March 2011, the FDA removed this requirement for ambrisentan (Letairis) in conjunction with a change to the product label. Objective: This study sought to explore the impact of the ambrisentan label change on payers, providers who treat PAH, and specialty pharmacies. Methods: This study, conducted in June and July 2011, involved telephone interviews with 5 medical/pharmacy directors in commercial health plans (representing 78,345,000 covered lives collectively); written surveys and telephone interviews with 6 nurses managing patients with PAH; and written surveys and telephone interviews with 4 staff members from specialty pharmacies to determine direct and indirect cost-savings associated with the removal of the monthly LFT requirement for ambrisentan. Qualitative telephone interviews with payer decision makers informed the cost-savings for payers. Direct cost-savings were calculated from the responses of the nurses managing PAH regarding the prescribing trends of their practices and the frequency of LFTs. Indirect cost-savings were calculated using time-savings data collected from the PAH-managing nurses and the specialty pharmacy staff, as well as from the US Bureau of Labor Statistics data regarding national wage averages for the respective staff. Results: Payers reported that REMS requirements did not play a large role in their planâ&#x20AC;&#x2122;s coverage or management of ERAs; although direct cost-savings resulting from the label change were an estimated $28 per patient per month, this amount is relatively small compared with the overall cost of PAH treatment for payers. The impact of the ambrisentan label change was more significant for providers and specialty pharmacies. The label change resulted in a significant, average 69% reduction in the frequency of LFTs for patients using ambrisentan. The average monthly time-savings realized by providers as a result of the label change was 12 minutes per patient receiving ambrisentan, and the average monthly direct and indirect cost-savings totaled $10.75 and $29.75, respectively, per patient taking ambrisentan. Telephone interviews with specialty pharmacies indicated that the average monthly time-savings for the 4 specialty pharmacies surveyed was 14 minutes per patient using ambrisentan, representing an 86.7% decrease in the amount of time specialty pharmacies spent on LFT-related administrative tasks for patients using ambrisentan. Conclusion: Findings from this study indicate that the ambrisentan label change significantly reduced the number of LFTs for patients with PAH, resulting in time-savings or cost-savings for payers, providers, and specialty pharmacies.

Ms Durst is Registered Nurse Research Study Coordinator, Mayo Clinic, Rochester, MN; Mr Carlsen is Vice President, Ms Kuchinski is Director, Ms Harner is Associate, and Mr Neves is Associate, Covance Market Access Services Inc, Gaithersburg, MD; Ms Harris is Nurse Coordinator, Pulmonary Vascular Disease Program, University of Washington Medical Center, Seattle; Ms Traiger is Pulmonary Hypertension CNS, Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA.

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March/April 2012

Vol 5, No 2

Impact of Removal of Monthly Liver Test Requirement

ulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally high blood pressure (ie, hypertension) in the pulmonary artery, with 1000 new cases being diagnosed annually in the United States, based on a 2009 report.1 Because of the complex nature of PAH and its treatments, healthcare providers must closely follow patients with PAH; depending on the stage of the illness, patients should generally be seen by a physician every 3 to 6 months according to the 2009 American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association.1 One treatment regimen for PAH includes the use of endothelin receptor antagonists (ERAs), namely ambrisentan (Letairis) and bosentan (Tracleer). Ambrisentan is a nonsulfonamide, propanoic-class ERA, whereas bosentan is a sulfonamide-class ERA and was the first US Food and Drug Administration (FDA)-approved ERA for the treatment of PAH. Because of the small number of patients and complexity of the disease, payers generally do not manage the treatment of PAH and leave the clinical treatment decisions to providers who manage patients with PAH. By contrast, providers are heavily involved in the treatment of patients with PAH, particularly nurses. Because of concerns regarding the connection between ERAs and liver damage, ERAs were subject to Risk Evaluation and Mitigation Strategy (REMS) requirements imposed by the FDA. For example, the REMS requirements for ERAs involved monthly liver function tests (LFTs) to ensure patient safety; before refilling a patient’s ERA prescription each month, a representative from the specialty pharmacy was required to verify that the patient completed his or her monthly LFT. More recently, based on clinical trial data and postmarketing safety information, the FDA concluded that the risk of liver injury in patients treated with ambrisentan is low.2 On March 4, 2011, the FDA approved a change to ambrisentan’s prescribing information, removing language concerning the potential risk of liver injury from the product label. As a result, patients taking ambrisentan are no longer required to obtain monthly LFTs as part of the REMS program.2 This change to ambrisentan’s label did not affect the REMS program for bosentan; the FDA’s monthly LFT requirement for bosentan remains in place. The present study explored the impact of the removal of the REMS monthly LFT requirement for payers, providers who treat PAH, and specialty pharmacies.

Methods In June and July 2011, primary research was con-

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KEY POINTS ➤

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The management of patients with pulmonary arterial hypertension population requires extensive coordination between patients, providers, and payers. Until recently, the use of endothelin receptor antagonists (ERAs) for this patient population was associated with a REMS program requiring monthly liver function tests (LFTs). In 2011, the FDA removed the monthly LFT requirement for ambrisentan; this study evaluated the impact of removing this requirement for ambrisentan on payers, providers, and specialty pharmacies. The label change resulted in a significant, average 69% reduction in LFTs for patients taking ambrisentan. Payers reported that REMS requirements were not a major factor in their plan’s coverage or management of ERAs, and therefore they did not realize significant cost-savings or time-savings relative to the overall costs of this condition. Providers, however, reported an average monthly time-savings of 12 minutes and an average monthly direct and indirect cost-savings of $10.75 and $29.75, respectively, per patient using ambrisentan. Specialty pharmacies reported an 86.7% decrease in the amount of time they spent on LFT-related administrative tasks per patient using this medication.

ducted with 5 commercial payer decision makers (medical and pharmacy directors whose health plans represent 78,345,000 covered lives collectively), 6 nurses managing patients with PAH, and staff from 4 specialty pharmacies to understand the impact of the removal of the monthly LFT requirement for patients taking ambrisentan. Telephone interviews with payers focused on their plans’ management of ERA therapies and the direct cost-savings and time-savings associated with the removal of the monthly LFT requirement. Each nurse who treats patients with PAH completed a written survey and telephone interview that included questions designed to quantify resource requirements for activities related to LFTs, as well as time-savings and cost-savings resulting from the change in LFT requirements. Similarly, 4 specialty pharmacy representatives were surveyed and interviewed by telephone to obtain costsavings and time-savings associated with activities related to LFTs.

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Table 1 25 LFT-Related Activities Performed by Providers Completing LFT orders Scheduling LFT appointments Rescheduling missed LFT appointments Coordinating LFT visits (eg, finding a laboratory for a patient) Performing blood draw for LFTs Performing LFT laboratory test Tracking/obtaining LFT results Evaluating LFT results Logging LFT results Enrolling new patients in LabSync Reenrolling patients in LabSync Communicating with LabSync (not including enrollment of new patients) Communicating with REMS program (ie, LEAP or T.A.P.) Communicating with laboratories Communicating with other (nonlaboratory) providers (eg, PCP, rheumatologist) Counseling patients LFT-related follow-up visits (other than patient counseling described above) Phone calls from patients about LFTs (eg, answering patient questions) Phone calls to patients about LFTs (eg, placing reminder calls, relaying test results) Communicating with patient about LabSync paperwork Other time spent communicating/interacting with patients about LFTs (if applicable) Communicating/interacting with payers about insurance issues specific to LFTs Communicating/interacting with other providers (eg, laboratories) about insurance issues specific to LFTs Communicating/interacting with patients about insurance issues specific to LFTs Communicating/interacting with specialty pharmacies about LFTs LEAP indicates Letairis Education and Access Program; LFT, liver function test; PCP, primary care provider; REMS, Risk Evaluation and Mitigation Strategy; T.A.P., Tracleer Access Program.

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Definitions For the purpose of this study, “direct cost-savings,” “time-savings,” and “indirect cost-savings” are defined as follows: • Direct cost-savings. Savings derived from a reduction in the number of laboratory tests ordered or medical services performed (eg, a reduction in LFTs ordered); these savings are referred to as direct cost-savings because they translate into fewer tests and services billed to payers • Time-savings. Savings that result from reduced time spent on LFT-related activities (eg, ordering tests, evaluating results, following up with patients) • Indirect cost-savings. The monetary value associated with the time-savings; indirect cost-savings were derived using US Bureau of Labor Statistics wage data to convert the time-savings (as measured in minutes) to labor-related cost-savings. Data Collection Payers. To assess the impact of the change in LFT requirements for ambrisentan, payers were asked a series of questions on topics such as their plan’s coverage and management of PAH and ERAs, as well as the total direct cost-savings and time-savings that the plan would realize from the change in LFT requirements. Providers. Provider research focused on the reductions in LFTs ordered and the reduced time spent on LFT-related activities, as well as changes in the frequency of other tests and services associated with LFTs. To capture direct cost data, participants were asked to report each of the following for patients taking ambrisentan before and after the label change: • Number of patients prescribed ambrisentan • Frequency and type of LFT ordered • Frequency and type of additional laboratory tests ordered in conjunction with LFTs • Frequency and type of services performed in conjunction with LFTs (eg, office visit). To capture the time-savings and resulting indirect cost-savings realized by providers treating PAH, the nurse participants were asked to estimate the amount of time each type of staff member (ie, physicians, nurses, and administrative staff) spent monthly on 25 LFTrelated activities (Table 1) for their patients taking ambrisentan before and after the label change. Participants reported the time requirements for each activity using a scale ranging from 0 to 7 (Table 2). To calculate the time saved, the midpoint value of each time range was used, except for the highest range (81+ minutes), which had no end point; the lowest possible value (81 minutes) was used for this range to be conservative. The participants were also asked to rate the over-

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Impact of Removal of Monthly Liver Test Requirement

all administrative burden of LFTs on their practice using a scale of 0 to 5, where 0 indicated no burden and 5 indicated significant burden. Specialty pharmacies. Specialty pharmacy research focused on the time-savings associated with the removal of the monthly LFT requirement for patients taking ambrisentan. Participants were not asked about direct cost-savings, because specialty pharmacies do not order tests or provide medical services. Instead, 4 specialty pharmacy participants were asked to estimate the total time that staff members (ie, pharmacists and pharmacy technicians) spent monthly on 3 LFT-related activities for patients taking ambrisentan before and after the label change. These 3 activities involved: 1. Communicating with patients regarding LFTs 2. Communicating with providers (eg, physician practices) regarding LFTs 3. Communicating with payers regarding LFTs. Interviewees reported the time requirements using a scale ranging from 0 to 5 (Table 3). To calculate the time saved, the midpoint value of each time range was used, except for the highest range (46+ minutes), which had no end point; the lowest possible value (46 minutes) was used for this range to be conservative. In addition, participants were asked to provide the number of patients who were prescribed ambrisentan. Like the providers, specialty pharmacy participants were asked to rate the administrative burden of LFTs on their pharmacy using the same scale of 0 to 5.

Data Analysis Payers. Because of the qualitative nature of the payer interviews, formal data analysis was not required. Interview responses were assessed to tabulate payers’ estimates of overall cost-savings and time-savings attributable to changes in the monthly LFT requirement as a result of the label change, and to identify payers’ coverage and management practices and implications for ERA access. Providers. Providers completed surveys intended to assess the overall direct cost-savings and time-savings associated with the monthly LFT requirement. Direct cost-savings were calculated by comparing the frequency with which LFTs and other associated tests were performed before and after the label change. Each test included in the survey was identified by a Current Procedural Terminology (CPT®) code (Table 4, page 98); the cost associated with each test was based on the Medicare payment rate for 2011.3 Monthly time-savings were reported for physicians, a

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Time Scale for LFT-Related Activities Performed by Table 2 Providers Scale

Time, min 0

1-10 11-20 21-30 31-45 46-60 61-80 81+

LFT indicates liver function test.

Time Scale for LFT-Related Activities Performed by Table 3 Specialty Pharmacies Scale

Time, min

1-10

11-20

21-30

31-45

46+

LFT indicates liver function test.

nurses, and administrative staff for 25 LFT-related activities. The time-savings for each activity were summed to illustrate the overall monthly time-savings realized by the facility. As an extension of the time-savings analysis, the savings in labor costs were calculated based on national wage averages for the respective staff types. Referred to as indirect cost-savings, these figures were calculated using the 2010 US Bureau of Labor Statistics average national hourly wage for office-based physicians ($100.97), administrative staff ($14.31), and specialty nurses ($35.23).4,5 Using the methodology described in a 2010 study,6 a 27% adjustment was added to hourly wages to account for fringe benefits, and opportunity costs were calculated by multiplying each 30-minute increment of time saved by physicians and nurses by $68.97, the 2011 national unadjusted payment rate for a level 3 office visit for an established patient (CPT® code 99213a) under the Medicare physician fee schedule.7 Data on the burden associated with LFTs in the form of direct and indirect cost-savings, as well as timesavings, were calculated on a per-patient per-month (PPPM) basis using the facility’s ambrisentan patient population data reported in the surveys and interviews. Specialty pharmacies. Because the objectives of the provider and the specialty pharmacy surveys and interviews were closely aligned, the analysis of the timesavings and indirect cost-savings was conducted in a similar fashion. Monthly time spent on the 3 LFT-related activities before and after the label change was reported for pharmacists and pharmacy technicians. The timesavings for each activity were summed to illustrate the overall monthly time-savings realized by the pharmacy. Indirect cost-savings were calculated using the US Bureau of Labor Statistics average national wage for

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2011 Medicare Payment Rates for LFTs and Other Table 4 Associated Tests CPT® code

2011 Medicare payment rate, $a

Description

36415

Collection of venous blood by venipuncture

3.00

80053

Comprehensive metabolic panel

14.87

80076

Hepatic function panel

11.49

81025

Urine pregnancy test, by visual color comparison methods

8.90

84450

Transferase; aspartate amino (AST) (SGOT)

7.28

84460

Transferase; alanine amino (ALT) (SGPT)

7.44

84702

Gonadotropin, chorionic (hCG); quantitative (pregnancy test)

21.19

84703

Gonadotropin, chorionic (hCG); qualitative (pregnancy test)

10.57

85025

Blood count; complete (CBC), automated (Hgb, Hct, RBC, WBC, and platelet count) and automated differential WBC count

10.94

85027

Blood count; complete (CBC), automated (Hgb, Hct, RBC, WBC, and platelet count)

9.11

a Medicare payment rates reflect national limit or midpoint amounts listed in the clinical laboratory fee schedule, March 2011. CBC indicates complete blood count; CPT®, Current Procedural Terminology; Hct, human chorionic thyrotropin; Hgb, hemoglobin; LFTs, liver function tests; RBC, red blood cell; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamate pyruvate transaminase; WBC, white blood cell. CPT® copyright 2011 American Medical Association. All rights reserved. CPT® is a registered trademark of the American Medical Association.

pharmacists ($52.59) and pharmacy technicians ($14.10), as reported in 2010.8 Fringe benefits and opportunity costs were included in the indirect costs, as described earlier. Data on the overall burden associated with LFTs were assessed in the form of indirect cost-savings and timesavings on a PPPM basis.

Results Payers Although the total impact of PAH on their plans is limited, all payer decision makers interviewed acknowl-

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edged the high cost of PAH treatment and management on a per-patient basis. Most payers were also aware of the REMS requirements for ERAs, as well as the ambrisentan label change; however, payers indicated that they generally leave decisions regarding ERA selection and other aspects of PAH treatment to physicians. The total estimated direct cost-savings averaged $28 PPPM, yet given the high overall PAH treatment costs for payers, the savings PPPM are relatively small. All participating payers indicated that no time-savings would result from the change in LFT requirements, considering that claims processing for LFTs is automated. In addition, the payers reported that REMS requirements did not play a role in their plans’ coverage or management of either ambrisentan or bosentan.

Providers The responses from participating providers who manage patients with PAH indicate that the majority of the savings associated with the ambrisentan label change was driven by an average 69% reduction in LFTs for patients taking ambrisentan. Most of this reduction can be attributed to a decrease in the frequency of administering LFTs for patients taking ambrisentan from once monthly (which was required by the REMS before the label change) to once every 3 months. The reduced frequency of administering LFTs reflects the revised REMS language for ambrisentan, which states that LFTs should be performed at the physician’s discretion; interviewees stated that most patients using ambrisentan now undergo LFTs at their regularly scheduled clinic appointments for PAH—once every 3 months on average. The reduction in LFTs was responsible for direct cost-savings in the form of fewer tests billed to payers, and time-savings in the form of reduced time spent by providers on LFT-related activities. The average time-savings realized by providers was 12.0 minutes PPPM, representing a 76% average reduction in time spent on LFT-related activities; 1 clinic reported time-savings of 91%. Savings were realized by each provider type (ie, physicians, nurses, and administrative staff), and were most pronounced for nurses, because they are most intensely involved in the daily management of PAH. Results of this study show that nurses saved an average of 8.2 minutes PPPM as a result of the label change for ambrisentan. Table 5 (page 99) lists the 5 activities for which nurses realized the greatest monthly time-savings, based on 431 patients. These activities represent only 20% of the 25 activities for which nurses were asked to estimate time-savings (Table 1); the wide range of activities in which nurses are involved demonstrates their important role in the management of patients with PAH.

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Impact of Removal of Monthly Liver Test Requirement

The average direct cost-savings PPPM for the providers interviewed was $10.75; the average PPPM time-savings was 12 minutes, resulting in an indirect cost-savings of $29.75 PPPM. Direct cost-savings were calculated using 2011 Medicare reimbursement rates, as described above. Fringe benefits and opportunity cost adjustments, as described above,6 were included in the indirect cost-savings. Using the rating scale of 0 to 5, providers rated the overall administrative burden of LFTs on nurses an average of 1.3 after the label change compared with 3.9 before the label change, which supported the significant reduction in time spent on LFT-related activities. The changes in ratings for physicians and administrative staff were comparatively smaller, illustrating that the administrative burden of LFTs is felt largely by nurses.

Specialty Pharmacies The results of the interviews with specialty pharmacies indicated that the average time-savings for all specialty pharmacies surveyed was 14.0 minutes PPPM, representing an 86.7% decrease in the amount of time specialty pharmacies spent on LFT-related administrative tasks for patients using ambrisentan. This average time-savings translates to an average indirect cost-savings of $11.97 PPPM among patients using ambrisentan. The total indirect cost-savings for specialty pharmacies was greater than the time-savings alone, because in some instances the pharmacies were able to shift responsibilities for LFT-related activities from higher-cost staff members, such as pharmacists, to lower-cost staff members, such as pharmacy technicians. Before the label change, the REMS requirement around LFTs mandated that a pharmacist perform patient counseling; some participants reported that with the removal of this requirement for ambrisentan, patient counseling can now be provided by other staff members at a lower cost to the specialty pharmacy. Using the scale of 0 to 5, participants rated the administrative burden associated with performing LFTrelated tasks on their pharmacy an average of 0.5 after the label change compared with 2.5 before the label change, again illustrating that the label change has reduced the burden of LFTs on specialty pharmacies. Discussion With the removal of the monthly LFT requirement for ambrisentan, providers who treat PAH, specialty pharmacies, and payers have all reported that they realized savings in direct costs or in time spent performing LFT-related activities. Further research could explore the time-savings and cost-savings realized by patients on activities directly and indirectly related to LFTs.

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Table 5 Activities Resulting in Greatest Monthly Time-Savings for Nurses, Based on 431 Patients Average time saved, min/mo

Activity Time spent with specialty pharmacies

45.3

Reenrolling patients in laboratory scheduling/management service

42.2

Evaluating LFT results

41.5

Tracking/obtaining LFT results

41.4

Completing LFT orders

26.8

LFT indicates liver function test.

The results of this study may underestimate potential time-savings and cost-savings. All the providers who treat PAH and were surveyed have elected to use LabSync, an optional laboratory scheduling and management service offered by Gilead Sciences (the manufacturer of ambrisentan) to help coordinate required laboratory tests for patients taking ambrisentan. Providers who do not participate in LabSync might have seen greater savings than those reported in this study, because nonparticipating providers likely spend more time coordinating their patientsâ&#x20AC;&#x2122; LFTs. In addition, this particular analysis provides a snapshot of data based on the number of patients taking ambrisentan that each practice was following at the time the research was conducted. The analysis does not take into account practice growth, or patients who have been switched from bosentan to ambrisentan since the label change. For example, multiple providers indicated that they have switched several patients who were using bosentan to ambrisentan since the label change and will continue to prescribe ambrisentan more frequently for their patients as a result of the reduced burden of LFTs associated with the label change. The analysis also does not forecast additional savings that may result from future changes in practice patterns for patients using ambrisentanâ&#x20AC;&#x201D;several practices indicated that they would consider further reducing LFT frequency for patients taking ambrisentan (eg, to once every 6 months or once annually) in the future. Future research would be needed to quantify the impact of changes in ERA prescribing and LFT ordering practices attributable to the label change. The management of patients with PAH requires extensive coordination between patients, their support system, third-party payers, and healthcare professionals.9 The reductions in time spent on LFT-related activities as reported in this study may enable both providers and

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specialty pharmacies to devote more of their resources to patient management, education, and counseling. This potential impact is especially significant for nurses, who typically spend the most time managing patients with PAH. For example, a reduction in time spent on administrative tasks related to LFTs may allow nurses of patients with PAH to spend more time counseling and educating their patients via telephone, as recommended by McLaughlin and colleagues.1 Although further research is needed in this area, several nurses managing PAH surveyed for this study saw a significant reduction in time-consuming activities, including completing standing LFT orders and tracking and obtaining LFT results.

The management of patients with PAH requires extensive coordination between patients, their support system, third-party payers, and healthcare professionals. The financial benefits associated with the ambrisentan label change become even greater when the patient’s perspective is taken into account; a separate study conducted with patients indicates that before the label change, the average patient using ambrisentan spent $40 monthly on LFT-related costs, including insurance copayments and costs for transportation to and from testing locations.10 The current study conducted with payers, providers treating PAH, and specialty pharmacies indicates that the ambrisentan label change has resulted in a significant reduction (69% on average) in the frequency of LFTs, and that this has produced time-savings and indirect cost-savings across providers treating PAH and specialty pharmacies surveyed, as well as direct costsavings for payers. The label change for ambrisentan reflects a unique FDA position; the removal of the monthly LFT monitoring requirement is a reflection of ambrisentan’s safety profile,10 and also has led to decreased administrative and cost burden for providers.

Limitations It is important to note the limitations of this study. First, the sample size for each stakeholder group involved in this study was small; as a result, the impact of the ambrisentan label change may not be fully reflected in this study’s findings. Second, as discussed above, prescribing trends were not systematically tracked in this study; therefore, the findings reflect only the immediate impact of the removal of the monthly LFT requirement for ambrisen-

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tan and do not address long-term implications. Third, savings realized by patients were not captured in the study. Finally, this study focused only on the time-savings and cost-savings associated with patients taking ambrisentan; it did not address how the resources required for these patients compare with the resources required for patients who are prescribed bosentan. The exact impact of the label change likely will vary based on each stakeholder’s mix of patients taking ambrisentan and bosentan. The limitations of this study potentially could be addressed by expanding the scope of future research efforts in this area—for example, by including a more robust sample of all relevant stakeholders (patients, payers, providers, and specialty pharmacies), by conducting a longitudinal analysis that tracks savings over time, or by examining differences in resources for patients taking ambrisentan versus those taking other ERAs.

Conclusion The FDA’s removal of the REMS requirements for monthly LFTs for patients using the ERA ambrisentan has resulted in considerable cost-savings and time-savings for providers and specialty pharmacies, and modest cost-savings for payers. Nurses in particular realized significant time-savings resulting from the reduction in LFTs for patients receiving ambrisentan. Further research could explore the cost-savings and time-savings realized by patients on activities directly and indirectly related to the reduced requirement for LFTs associated with the use of ambrisentan. ■ Study Funding This study was supported by funding from Gilead Sciences, Inc. Author Disclosure Statement Ms Durst has reported no conflict of interest related to this study. Mr Carlsen, Ms Kuchinski, Ms Harner, Mr Neves, Ms Harris, and Ms Traiger have served as Consultants to Gilead Sciences, Inc.

References 1. McLaughlin VV, Archer SL, Badesch DB, et al, for the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension developed in collaboration with the American College of Chest Physicians, American Thoracic Society, and the Pulmonary Hypertension Association. Circulation. 2009;119:2250-2294. 2. US Food and Drug Administration. FDA Drug Safety Communication: Liver injury warning to be removed from Letairis (ambrisentan) tablets. March 4, 2011. www.fda.gov/Drugs/DrugSafety/ucm245852.htm. Accessed August 4, 2011. 3. Centers for Medicare & Medicaid Services. Clinical Laboratory Fee Schedule: 11CLABMAR. March 2011. www.cms.gov/ClinicalLabFeeSched/02_clinlab.asp. Accessed August 4, 2011. 4. US Bureau of Labor Statistics. May 2010 national industry-specific occupational employment and wage estimates NAICS 621100-offices of physicians. May 17, 2011.

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Impact of Removal of Monthly Liver Test Requirement

www.bls.gov/oes/current/naics4_621100.htm. Accessed March 16, 2012. 5. US Bureau of Labor Statistics. May 2010 national industry-specific occupational employment and wage estimates, NAICS 622300-specialty (except psychiatric and substance abuse) hospitals. May 17, 2011. www.bls.gov/oes/current/naics4_622300. htm. Accessed March 16, 2012. 6. Raper JL, Willig JH, Lin HY, et al. Uncompensated medical provider costs associated with prior authorization for prescription medications in an HIV clinic. Clin Infect Dis. 2010;51:718-724. 7. Centers for Medicare & Medicaid Services. Physician fee schedule, relative value files-RVU11C. July 2011. www.cms.gov/PhysicianFeeSched/PFSRVF/itemdetail.asp?

filterType=none&filterByDID=-99&sortByDID=1&sortOrder=descending &itemID=CMS1247894&intNumPerPage=10. Accessed August 4, 2011. 8. US Bureau of Labor Statistics. May 2010 national occupational employment and wage estimates, United States, April 6, 2011. www.bls.gov/oes/current/oes_nat.htm# 29-0000. Accessed August 4, 2011. 9. Housten-Harris T. The nurse specialist and practical issues in the care of pulmonary arterial hypertension patients. Int J Clin Pract Suppl. 2007;(158):10-18. 10. Gilead Sciences. US FDA removes warning about potential liver injury from boxed warning of prescribing information for Gileadâ&#x20AC;&#x2122;s Letairis. Press release, March 4, 2011. www.gilead.com/pr_1535940. Accessed August 10, 2011.

STAKEHOLDER PERSPECTIVE The Challenges of Pulmonary Arterial Hypertension Management: Potential Benefits of Removing Monthly Testing PAYERS/PROVIDERS: The patient population with pulmonary arterial hypertension (PAH) is a challenging group to manage, because of varying levels of disease severity and progression and the need to add additional therapies to the patient treatment protocols to achieve positive outcomes. The complex regimens place a burden on the practice and the patients. The additional drugs add clinical value and potential side effects and may include required laboratory monitoring for specific therapies. The Risk Evaluation and Mitigation Strategies (REMS) requirements for medications have an impact on the physician, patient, and pharmacy; however, health plans are usually not impacted directly by REMS programs. The formulary review process may acknowledge a REMS program for a particular product, but the true value of the drug resides in its associated clinical benefits, combined with the cost of treating the average patient. It is challenging for medical practices to effectively manage patients and provide examinations, treatments, and mandatory or optional screenings for complex diseases. Any program that will reduce the use of medical resources benefits the practice, the patient, and the health plan. When a drug provides savings on the medical side, this is a positive attribute for the product from a formulary management perspective. The requirement to test patients for safety concerns adds a burden on the healthcare system and stretches already scarce resources at the physician practice level. The removal of the monthly testing requirement for ambrisentan that is discussed in this article by Durst and colleagues offers an advantage to the health plan, by providing direct cost-savings through the elimination of the associated laboratory testing expense. The authors suggest that from the providerâ&#x20AC;&#x2122;s point of view, the lack of testing may lead to a more favorable consid-

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eration for the use of ambrisentan in new patients with PAH. The clinical value of the drugs will likely be the key decision point for providers, and the convenience of less testing will be an added advantage when all other considerations are equal. The conservative approach, as suggested by the nurses in this study, is to decrease the testing interval to every 3 months to coincide with the regular 3-month check-ups in this patient population. Health plans would look to see if the testing frequency could decrease even further, offering additional resource savings to the practice and cost-savings to the health plans. PATIENTS: Patient adherence presents a unique challenge to managed care pharmacy programs across virtually all disease states. The distribution of products through a specialty pharmacy has demonstrated improvements in patient adherence across a number of disease areas, including rheumatoid arthritis and multiple sclerosis. Although it is not clear where the additional time saved as a result of the lack of testing requirements, as shown in this study, will be used, perhaps specialty pharmacies will provide additional adherence counseling for patients with PAH. Physicians and nurses may use the additional time for coordination of care for these or other patients. In addition, time could be spent counseling patients on the importance of adherence to therapies for PAH, or identifying risks for disease complications or progression that could be avoided. Health plans are very supportive of any programs that will improve patient adherence to therapy, and manufacturers and specialty pharmacies should strive to help providers and pharmacies improve outcomes through effective adherence programs.

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James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care, MA

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NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

SC (n=148) IV (n=74)

ORR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. †

Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

VELCADE IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness ▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/ postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been

isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. (continued)

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/ prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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OPINION

No, You Can’t Keep Your Health Plan: Think the Contraception Decision Was Bad? Wait Until Bureaucrats Start Telling Your Insurer Which Cancer Screenings to Cover By Scott Gottlieb, MD

ffended by President Obama’s decision to force health insurers to pay for contraception and surgical sterilization? It gets worse: In the future, thanks to ObamaCare, the government will issue such health edicts on a routine basis—and largely insulated from public view. This goes beyond contraception to cancer screenings, the use of common drugs like aspirin, and much more. Under ObamaCare, a single committee—the United States Preventative Services Task Force—is empowered to evaluate preventative health services and decide which will be covered by health-insurance plans. The task force already rates services with letter grades “A” through “D” (or “I” if it has “insufficient evidence” to make a rating). But under ObamaCare, services “A” or “B”—such as colon cancer screening for adults aged 50-75—must be covered by health plans in full, without any copays. Many services that get “Cs” and “Ds”—such as screenings for ovarian or testicular cancer—could get nixes from coverage entirely. That is because mandating coverage for all the “A” and “B” services will be very costly. In 2000, the Congressional Budget Office estimated that the marginal cost of similar state insurance mandates was 5%-10% of total claims. Other estimates put the cost of mandates as high as 20% of premiums. Health plans will inevitably choose to drop coverage for many services that do not get a passing grade from the task force and therefore aren’t mandated. Insurance companies will need to conserve their premium money, which the government regulates, in order to spend it subsidizing those services that the task force requires them to cover in full. Americans first became familiar with the task force in November 2009, when it made the controversial deci-

Dr Gottlieb, former Deputy Commissioner of the US Food and Drug Administration, is a fellow at the American Enterprise Institute and a practicing internist. He is partner to a firm that invests in healthcare companies. Reprinted from the Wall Street Journal. Used with permission.

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sion to recommend that women ages 40-49 should not get routine mammograms. More recently, it rebuffed routine prostate-cancer screening and the use of tests that detect the viruses that can cause cervical cancer. The task force relishes setting a very high bar. Like the Food and Drug Administration in approving new drugs, it usually requires a randomized, prospective trial to “prove” that a diagnostic test or other intervention improves clinical outcome and therefore deserves a high grade of “A” or “B.” This means its advice is often out of sync with conventional medical practice. For example, it recommended against wider screening for HIV long after such screening was accepted practice. As a result, many of its verdicts are widely ignored by practicing doctors. The task force is a part-time board of volunteer advisers that works slowly and is often late to incorporate new science into its recommendations. Only in 2009 did it finally recommend aspirin for the prevention of stroke and heart attack among those at risk—decades after this practice was demonstrated to save lives and become part of standard medical practice. The task force is also the only federal health agency to have the explicit legal authority to consider cost as one criterion in recommending whether patients should use a medical test or treatment. Over time, the task force will surely recommend against many services that patients now take for granted, while mandating full insurance coverage for things that they would be just as happy paying for. Among the interventions that it plans to consider in 2012 are screening for hepatitis C in adults, for osteoporosis in men and for depression in children; counseling for obesity in adults and for alcohol use in adolescents; and daily aspirin for heart-attack and stroke prevention in people over 80. The task force’s problems are compounded by the fact that it is deliberately exempted from the rules that govern other government advisory boards and regulatory agencies. Thus it has no obligation to hold its meetings in public, announce decisions in draft form or even consider public comments. Consumers have no way to

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OPINION

directly appeal its decisions. And health providers or product developers affected by its decisions cannot sue it for recourse. To begin addressing these problems, Congress should make the task force subject to the Federal Advisory Committee Act, which would at least require it to hold its deliberations in public. Congress could also make it a full-fledged part of the Agency for Healthcare Research and Quality, which already convenes its meetings. That would make the task force subject to the Administrative Procedures Act and all the rules that bind other regula-

tory bodies, including the legal requirement to consider public comments and provide avenues for appeal. Better still, Congress could let private health plans— and their members—decide on their own how preventive tests and treatments should be covered. If not, Americans will soon be surprised by all the important tests and treatments that become costly, and all the less relevant stuff that is suddenly free. It is all a reminder that President Obama’s decision on contraception is not a one-off political intervention but the initial exploit of an elaborate new system. ■

CALL FOR PAPERS Cardiometabolic Health Theme Issue American Health & Drug Benefits will be publishing a Theme Issue on Cardiometabolic Health later this year. Readers are invited to submit articles on topics relevant to the clinical, business, and policy aspects of cardiometabolic health. Original research studies, white papers, evidence-based comprehensive reviews, and case studies are of particular interest. All healthcare stakeholders are invited to present their data, best practices, innovations, and initiatives to facilitate management strategies and benefit design to improve cardiometabolic outcomes and prevent common risk factors while reducing costs for those at risk for cardiovascular disease, diabetes, or obesity.

Readers are invited to submit original, outcomes-based research, white papers, evidence-based comprehensive reviews, and case studies on topics such as:

• Benefit designs to improve cardiometabolic outcomes • Best practices in diabetes management and prevention • Best practices in insulin control, lipid management, or blood pressure control • Comparative effectiveness analyses of best therapies for cardiovascular health • Cost-effectiveness comparisons • Employers’ strategies to enhance cardiometabolic wellness • New and emerging therapies • Health plan initiatives in cardiometabolic health and wellness

• Hot topics in diabetes obesity, or cardiovascular disease • Lifestyle strategies and cardiometabolic health • Lipid management in patients with diabetes • Medication adherence and diabetes progression • New biomarkers for assessing cardiometabolic risk • Prevention strategies for diabetes risk reduction • Prevention programs for cardiometabolic comorbidities

Submission deadline for this issue is June 20, 2012. Articles submitted by June 1 will be given priority. All articles will undergo the Journal’s standard peer-review process. Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) Submit articles to editorial@engagehc.com, or call 732-992-1889

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RJ Health Systems The Creators of ReimbursementCodes.com

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CALL FOR PAPERS American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid • Patient Advocacy/Patient Care

• Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

• Pharmacoeconomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Social Media and Health • Survey Results • Value-Based Healthcare • Wellness Programs

Clinical Topics of High Interest: AGING/DEMENTIA—With the aging of the US population there is a growing need for early implementation of outcomesbased preventive and therapeutic strategies for older people. ALLERGIES—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles to patient management. ARTHRITIS—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated. Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs. CANCER CARE—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management. CARDIOVASCULAR DISEASE—Original, outcomesbased research on appropriate therapies, cost comparisons, emerging prevention strategies, and comparative effectiveness of best practices will enhance readers’ decision-making.

DIABETES, OBESITY—The increasing comorbid epidemics of these twin conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies. We invite articles that will address how to improve patient outcomes and best patient care. GASTROINTESTINAL CONDITIONS—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge. INFECTIOUS DISEASES—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance. MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, best practices, and reimbursement.

PAIN MANAGEMENT—Chronic pain is associated with a slew of complicated medical disorders and an enormous economic burden, yet pain medications are still underused.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com). Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

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REVIEW ARTICLE

Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis after Total Hip or Knee Arthroplasty Richard J. Friedman, MD, FRCSC Background: The incidence of venous thromboembolism (VTE) after total hip arthroplasty (THA) or total knee arthroplasty (TKA) is reduced by the use of thromboprophylactics, such as vitamin K antagonists, low-molecular-weight heparin (LMWH), or fondaparinux. However, these agents have a number of limitations that constrain their use and increase the clinical and economic burden on patients, caregivers, and healthcare resources. Effective prophylaxis may also be complicated by poor adherence to guideline recommendations. Objective: This article reviews the potential of newly developed oral anticoagulants to address many of the management challenges associated with vitamin K antagonists, LMWHs, and fondaparinux. Discussion: The 3 oral anticoagulants rivaroxaban, apixaban, and dabigatran have been evaluated in large phase 3 trials, and all 3 represent promising alternatives to the current standard of care. Currently, rivaroxaban is the only new oral agent to have received US Food and Drug Administration approval in the United States for prophylaxis of deep-vein thrombosis, which may lead to pulmonary embolism in patients undergoing THA or TKA. The simplified management of the new oral agents may encourage adherence with published guidelines for VTE prophylaxis and help to reduce the economic burden of VTE. Pharmacoeconomic data suggest that rivaroxaban and dabigatran may result in cost-savings when compared with enoxaparin after THA or TKA. Conclusions: The numbers of THA and TKA surgeries are expected to increase significantly in coming years, and safer and more effective thromboprophylaxis is essential to mitigate the morbidity and mortality associated with VTE. Newly developed oral anticoagulants have the potential to address many of the limitations of current thromboprophylaxis and may reduce the cost burden associated with the management of VTE after THA or TKA.

otal hip arthroplasty (THA) and total knee arthroplasty (TKA) are among the most common orthopedic procedures performed in the United States, with almost 300,000 THA surgeries and more than 500,000 TKA surgeries performed annually.1 This number is projected to rise to approximately 572,000 annual THA surgeries and 3.5 million annual TKA surgeries by 2030.1 THA and TKA procedures improve mobility and quality of life, but patients undergoing these surgeries are at a significantly increased risk for developing postoper-

Dr Friedman is Chairman, Department of Orthopaedic Surgery, Roper Hospital; Clinical Professor of Orthopaedic Surgery, Medical University of South Carolina, Charleston; and Medical Director of Charleston Orthopaedic Associates.

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Am Health Drug Benefits. 2012;5(2):115-122 www.AHDBonline.com Disclosures are at end of text

ative venous thromboembolism (VTE).2-4 VTE comprises both deep-vein thrombosis (DVT) and pulmonary embolism (PE). In the absence of thromboprophylaxis, proximal DVT occurs in approximately 5% to 36% of patients who have THA and TKA.5 PE occurs in 50% of patients with proximal DVT,4 and proves fatal in approximately 15% of these patients.6 VTE is also associated with significant long-term complications, such as postthrombotic syndrome, chronic thromboembolic pulmonary hypertension, and an increased risk of recurrent events.7 Postthrombotic syndrome develops in 23% to 60% of patients, often in the 2 years after a DVT, and approximately 10% of cases are considered to be severe.8 Approximately 4% of patients with PE are diagnosed with chronic thromboembolic pulmonary hypertension within 2 years9; approximately

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KEY POINTS ➤

➤

THA and TKA are common orthopedic procedures that improve a patient’s quality of life but are associated with a significant risk for postoperative VTE and long-term complications. The incidence of VTE can be effectively reduced with thromboprophylactics, including vitamin K antagonists, LMWHs, or fondaparinux. However, these agents are associated with management challenges that limit their use and increase the clinical and economic burden on patients, caregivers, and the US healthcare overall. Currently, 3 new oral anticoagulants are in different stages of development—rivaroxaban, apixaban, and dabigatran—with the first agent recently receiving FDA approval in the United States. The new oral anticoagulants offer several benefits over current thromboprophylactics, including fixed dosing thanks to their predictable pharmacokinetics, no requirement for coagulation monitoring, few drug–drug and drug–food interactions, and once-daily or twice-daily oral administration. When considering the best thromboprophylactic agent, the associated costs related to anticoagulation need to be taken into account, including costs for drug acquisition, mode of administration, and routine coagulation monitoring.

10% of patients who experience VTE after THA or TKA are readmitted to the hospital within 3 months after discharge.10 The incidence of VTE can be effectively reduced with the use of thromboprophylactics, including vitamin K antagonists, low-molecular-weight heparins (LMWHs), or fondaparinux (Arixtra). Thromboprophylaxis reduces the cumulative incidence of symptomatic VTE to 1.7% within 3 months of THA and to 2.3% within 3 months of TKA.11 However, these agents pose a number of management challenges that limit their use and increase the clinical and economic burden on patients, caregivers, and healthcare resources. Effective prophylaxis may also be complicated by poor adherence to guideline recommendations, possibly resulting from physicians’ concern about the risk for bleeding or the difficulties of maintaining prophylaxis in an outpatient setting. Newly developed oral anticoagulants have the potential to address many of the limitations associated with vitamin K antagonists, LMWHs, and fondaparinux. They may also simplify treatment strategies for these patients, encourage compliance with therapy, and reduce the economic burden of VTE.

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The Economic Burden of VTE The costs of managing acute and chronic VTE are considerable, particularly those associated with hospitalization, long-term therapy, and monitoring.12,13 In the United States, management of VTE costs almost $500 million annually.13 A study using data from a large healthcare claims database showed that for patients with in-hospital VTE, mean billed charges were $18,834 higher than for matched controls (ie, individuals of the same age who underwent the same procedure but had no claim for DVT or PE); the increment was $7351 in TKA patients and $27,034 in THA patients.10 Another analysis of the economic burden of VTE in hospitalized patients estimated the cost of managing an initial episode of DVT to be between $7712 and $10,804, and between $9566 and $16,644 for an initial PE event.14 Long-term complications of VTE, such as recurrent VTE, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension, add to the cost of treatment.15-17 The cost of hospital readmission for a recurrent DVT is estimated to be 21% greater than the cost for the initial DVT event, mainly because of the longer hospital stay.16 The long-term costs of treating postthrombotic syndrome are estimated to add 75% to the cost of treating the initial DVT.17 The considerable morbidity associated with chronic thromboembolic pulmonary hypertension also adds to costs. The direct cost of managing patients with chronic thromboembolic pulmonary hypertension has been estimated to be $4782 per patient per month (PPPM) versus $511 PPPM for controls, with circulatoryrespiratory–related costs accounting for 55% of the excess costs.18 Although thromboprophylaxis reduces the incidence of VTE and its associated costs, the costs associated with anticoagulation need to be considered, including those for drug acquisition, administration, and routine coagulation monitoring. In addition, because the use of anticoagulants may increase the risk for bleeding, the cost of bleeding management should be taken into consideration. A recent analysis of insurance healthcare claims found that the monthly incremental costs per patient are similar for the management of VTE and bleeding events ($2729 and $2696, respectively) in patients with major orthopedic surgery.19 However, the overall 3month risk for bleeding was substantially lower than the risk for VTE.19 Barriers to Optimal Thromboprophylaxis Although thromboprophylaxis can effectively reduce the incidence of VTE in patients undergoing THA or TKA, barriers to optimal thromboprophylaxis exist.

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Oral Anticoagulants after Total Hip or Knee Arthroplasty

These barriers include: • Poor implementation of guidelines • Bleeding concerns • Limitations of existing agents.

Poor Implementation of Guidelines for the Prevention of VTE Clinical practice guidelines for the prevention of VTE have been published by the American College of Chest Physicians (ACCP) every 3 years for more than 20 years.3,20 The most up-to-date version of these guidelines recommends the routine use of traditional anticoagulants—LMWHs, fondaparinux, vitamin K antagonists (ie, warfarin)—aspirin, or one of the new oral anticoagulants—rivaroxaban (Xarelto), dabigatran (Pradaxa), or apixaban (Eliquis)—for pharmacologic thromboprophylaxis in individuals who have undergone THA or TKA surgery.3 The American Academy of Orthopaedic Surgeons (AAOS) recently published updated guidelines for the prevention of VTE in patients undergoing THA or TKA.21 The AAOS recommends the use of mechanical compression devices in appropriate patients, in addition to pharmacologic agents.21 Retrospective analyses of data collected by the Global Orthopaedic Registry (GLORY) between June 2001 and December 2004 have demonstrated limited adherence to guidelines for VTE prophylaxis in the United States, with room for much improvement.22,23 One barrier to the implementation of guidelines in the United States may be the considerably shorter period of time that patients undergoing THA or TKA spend in the hospital compared with other countries. In the United States, median lengths of hospital stay are only 3 and 4 days for THA or TKA, respectively, and it is likely that the duration of prophylaxis recommended by the ACCP (10-35 days) is difficult to achieve in an outpatient setting.3,22 A retrospective cohort study has also showed that physicians often use lower-than-recommended doses of LMWH, inadequate bridging protocols when switching from injectable agents to warfarin (which takes 3-5 days to reach effective levels), and insufficient or no therapy after hospital discharge.24 Concerns about Bleeding Although the major complication of all anticoagulant therapy is bleeding, when thromboprophylaxis is administered postsurgically to patients undergoing THA or TKA, the rates of major bleeding events are low. Major bleeding with LMWH prophylaxis after THA or TKA is estimated to be between 3% and 5%.25 Major bleeding with warfarin use is also low (approximately 4% at a target international normalized ratio of 2.0) and is heavily

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dependent on the patient’s predisposing risk factors, such as comorbid conditions (eg, cancer, hypertension, heart disease, cerebrovascular disease, renal insufficiency, and paraplegia).25 Patient characteristics (eg, age and a history of bleeding), concomitant medications, and incorrect timing and/or dosing of the anticoagulant also contribute to bleeding risk.25 For example, a patient aged >75 years who weighs >50 kg and has compromised renal function is at an increased risk for a major bleeding event. Complications may be avoided by taking a highly conservative approach to anticoagulation in these individuals; therefore, the risk for bleeding with appropriate use of thromboprophylactics may be overestimated.26,27

Limitations of Current Agents Existing anticoagulants carry a number of limitations that contribute to suboptimal thromboprophylaxis in patients undergoing THA or TKA. LMWHs and fondaparinux are inconvenient, particularly in the outpatient setting, because they are administered parenterally, and their use may accrue significant costs related to home administration by nurses, patient training, and monitoring. In addition, all heparins, including LMWHs, carry the risk for heparin-induced thrombocytopenia, and long-term therapy is associated with osteoporosis.28 Orally administered warfarin has complex pharmacokinetic and pharmacodynamic properties and a narrow therapeutic window, making routine coagulation monitoring and dose adjustments essential.28,29 Warfarin also has a slow onset and offset of action, which means that patients already receiving warfarin may need to adhere to complicated perioperative bridging protocols. In addition, warfarin has multiple food and drug interactions, and its metabolism is susceptible to numerous genetic polymorphisms.28,29 The New Oral Anticoagulants Three new oral anticoagulants have undergone phase 3 clinical studies in patients undergoing THA or TKA in the United States (Table).30-40 Two of these agents— rivaroxaban and apixaban—are factor Xa inhibitors, whereas dabigatran is a direct thrombin inhibitor. The beneficial characteristics of these 3 new anticoagulants include41: • Fixed dosing as a result of their predictable pharmacokinetics • No requirement for coagulation monitoring • Few drug–drug and drug–food interactions • Once- or twice-daily oral administration. Rivaroxaban Rivaroxaban selectively blocks the active site of factor

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Table Phase 3 Clinical Trials of Rivaroxaban, Apixaban, and Dabigatran Prophylaxis after Total Hip or Knee Arthroplasty

Drug

Surgery

Study

Subcutaneous enoxaparin dose

Oral drug dose

RECORD1 (2008)30 RECORD2 (2008)31

40 mg once daily

Rivaroxaban

TKA Apixaban THA

RECORD4 (2009)33

30 mg twice daily

ADVANCE-1 (2009)34

30 mg twice daily

40 mg once daily

ADVANCE-3 (2010)36

2.5 mg twice daily 32-38 150 mg or 220 mg once daily

40 mg once daily

RE-NOVATE II (2011)38 RE-MODEL (2007)39 RE-MOBILIZE (2009)40

Efficacy of study drug vs enoxaparin

30 mg twice daily

Composite of any DVT, nonfatal PE, and death

Superior

10-14

ADVANCE-2 (2010)35

THA

TKA

10 mg once daily

Rivaroxaban: 31-39 Enoxaparin: 10-14

RECORD3 (2008)32

RE-NOVATE (2007)37

Dabigatran

Primary efficacy outcome

31-39

THA

TKA

Duration, days

Superior Superior

28-35

220 mg once daily 150 mg or 220 mg once daily

Composite of symptomatic or asymptomatic DVT, nonfatal PE, and death

Did not meet noninferiority

Composite of total VTE events and death

Noninferior a

6-10 12-15

Did not meet noninferiority

Dabigatran was superior to enoxaparin for reducing the risk of major VTE (secondary end point) in the RE-NOVATE II study. DVT indicates deep-vein thrombosis; PE, pulmonary embolism; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism.

Xa and does not require a cofactor (such as antithrombin) for activity. Because rivaroxaban has predictable pharmacokinetic and pharmacodynamic properties and a low potential for interactions with food or other drugs, it can be administered as a fixed dose, without the requirement for routine coagulation monitoring.42 A large phase 3 investigative program composed of 4 clinical trials that compared rivaroxaban with enoxaparin (Lovenox) in patients undergoing THA or TKA— Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism (RECORD)—has been completed.42 The pri-

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mary efficacy end point of the 4 RECORD studies was total VTE—the composite of any DVT, nonfatal PE, and all-cause mortality (Table).30-33 The RECORD1 trial demonstrated that rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily for 30 to 35 days after THA,30 whereas the RECORD2 study demonstrated the superiority of longterm thromboprophylaxis with rivaroxaban 10 mg once daily (31-39 days) versus short-term thromboprophylaxis with enoxaparin 40 mg once daily (10-14 days) in patients undergoing THA.31 The RECORD3 and RECORD4 studies demonstrated the superior efficacy

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of rivaroxaban 10 mg once daily versus enoxaparin 40 mg once daily and 30 mg twice daily (a regimen approved in North America after TKA), respectively, for 10 to 14 days after TKA.32,33 In a pooled analysis of the RECORD studies, rivaroxaban significantly reduced the composite of symptomatic VTE and all-cause mortality versus enoxaparin and was associated with a similar safety profile.43 In July 2011, rivaroxaban became the first new oral agent to be approved by the US Food and Drug Administration (FDA) in the United States for prophylaxis of DVT (which may lead to PE) in patients undergoing THA or TKA, based on results from the RECORD1, 2, and 3 trials. The Centers for Medicare & Medicaid Services has issued a memo that rivaroxaban administration after THA and TKA is Surgical Care Improvement Project–compliant as of July 2, 2011.

Apixaban Another oral, direct factor Xa inhibitor, apixaban, has also been studied in phase 3 trials in patients undergoing THA or TKA (Table).34-36 Apixaban is currently approved for the prevention of VTE after THA or TKA in the European Union. In the Apixaban Versus Enoxaparin for Thromboprophylaxis After Knee Replacement (ADVANCE)-1 trial, apixaban 2.5 mg twice daily was compared with enoxaparin 30 mg twice daily in patients post-TKA. However, apixaban did not meet the prespecified statistical criteria for noninferiority for the composite primary efficacy end point of asymptomatic and symptomatic DVT, nonfatal PE, and death from any cause during treatment.34 In the ADVANCE-2 and ADVANCE-3 trials, apixaban 2.5 mg twice daily was compared with enoxaparin 40 mg once daily and demonstrated superior efficacy in patients who had undergone TKA (ADVANCE-2) and THA (ADVANCE-3).35,36 Apixaban compared with enoxaparin was not associated with an increase in bleeding events in any of the 3 ADVANCE studies.34-36 Dabigatran Dabigatran etexilate is an oral direct thrombin inhibitor that has a low potential for drug–drug interactions and a predictable anticoagulant effect.44 Dabigatran is approved for VTE prophylaxis after THA/TKA surgery in Canada and the European Union, but not currently in the United States. Dabigatran 150 mg or 220 mg once daily demonstrated noninferiority to enoxaparin 40 mg once daily for 28 to 35 days after THA in the RE-NOVATE and RENOVATE II studies, and for 6 to 10 days after TKA in the RE-MODEL study (Table).37-39 In the RE-MOBILIZE study (TKA), dabigatran failed to meet the noninferior-

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ity criteria when compared with enoxaparin 30 mg twice daily.40 Dabigatran had a similar safety profile versus enoxaparin in all 4 studies.37-40

Limitations of the New Oral Anticoagulants Despite their important advantages―oral administration, a rapid onset and offset of action, predictable pharmacokinetics that allow fixed dosing, no requirement for coagulation monitoring, and significantly fewer food–drug and drug–drug interactions than warfarin―the new oral anticoagulants also have some limitations. Although to date rivaroxaban is the only anticoagulant approved in the United States for use in orthopedic patients, efficacy and safety data from phase 3 clinical trials facilitate assessment of the limitations of dabigatran and apixaban as well. Renal function is very important for dabigatran; 80% is renally excreted, with the remainder excreted via the bile.44,45 There has been recent concern regarding excess bleeding in patients receiving dabigatran. These reports are currently being investigated by the FDA. The rivaroxaban dose must be adjusted in patients with renal insufficiency, and its use should be avoided in patients with severe renal impairment (creatinine clearance <30 mL/min).42 Dabigatran requires a dose adjustment if creatinine clearance is <50 mL/min.45 Caution should be used when any of these agents is administered concomitantly with either a P-glycoprotein inhibitor or inducer, or a strong cytochrome P-450 3A4 inhibitor or inducer.42,45,46 Rivaroxaban should be used with caution in patients receiving neuraxial anesthesia, because epidural or spinal hematomas have occurred in that setting.42 Reversal None of the new oral agents has a specific antidote that will completely reverse its anticoagulant effects. Data regarding the potential reversibility of these drugs are primarily derived from animal studies. Nevertheless, for patients who experience mild bleeding while taking these agents, discontinuation of therapy may be considered a reasonable strategy because of their relatively short half-lives. For patients who experience moderateto-severe bleeding, supportive measures include fluid replacement, hemodynamic support, and blood products, including fresh frozen plasma.47,48 For those patients whose bleeding is considered life-threatening, prothrombin complex concentrate or recombinant activated factor VIIa (rVIIa) have been used with some success in healthy volunteers receiving dabigatran or rivaroxaban.48 Administration of rVIIa significantly reduced bleeding times in rats receiving high doses of dabigatran in one study,47 but did not reduce hematoma

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size in mice with dabigatran-induced intracranial hemorrhage in another study.49

Cost and Cost-Effectiveness of the New Oral Anticoagulants Because no routine coagulation monitoring is required with the new oral anticoagulants—unlike with warfarin—the costs associated with the administration and monitoring of these medications are eliminated. These costs were found to be $51.25 PPPM in a 2004 study,50 which would be at least $10 more in 2012 dollars. Although enoxaparin has been shown to be more costeffective than warfarin,51 enoxaparin’s subcutaneous route of administration adds to its costs. In 2002, home nursing visits for outpatient administration of enoxaparin amounted to approximately $100 for 1 course of therapy.52 These additional costs are eliminated with the new oral anticoagulants. Although pharmacoeconomic data are currently sparse for these new agents, the few pharmacoeconomic models that have been developed in this setting show these drugs to be more cost-effective than enoxaparin. In one study, it was found that for THA patients in the UK National Health Service, the use of dabigatran was associated with substantial cost-savings compared with enoxaparin, primarily because it was not necessary to train patients in the use of an injectable agent.53 Avoidance of expenses associated with heparin-induced thrombocytopenia, needlestick injuries, and needle disposal also played an important role in reducing costs.53 In cost-effectiveness analyses of the RECORD1 and RECORD2 trials of patients undergoing THA, rivaroxaban was found to be more cost-effective than enoxaparin, because of the lower costs of hospitalization and administration associated with rivaroxaban as a result of reduced rates of VTE.54,55 Similar results were seen in RECORD3 in patients undergoing TKA; in this trial, the need for either home nurse time or training in selfadministration of the injectable agent enoxaparin resulted in higher costs.56 In another study using data from RECORD1, 2, and 3, rivaroxaban was found to reduce total costs to payers in both populations of patients undergoing either THA or TKA compared with enoxaparin.57 Conclusion Over the past 20 years, the incidence of VTE in patients who undergo THA or TKA has decreased markedly. This decline is explained, in part, by the uptake of new prophylactic agents, such as enoxaparin and fondaparinux. However, other improvements in patient care (eg, shorter surgery times, quicker and more intense rehabilitation programs, and multimodal

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approaches to pain management) may also have contributed to better patient outcomes. A quick review of clinical trial data suggests that among patients who received enoxaparin after THA as part of a clinical trial, VTE rates fell from 12% in the late 1980s58 to approximately 8% in the late 1990s,59 approximately 4.6% in the first years of the new century,60 and >4% in clinical trials of new oral anticoagulants.30,36 Despite this improvement, thromboprophylaxis remains suboptimal for the reasons discussed in this article. It is encouraging that new oral anticoagulants have demonstrated superior efficacy versus enoxaparin, while exhibiting safety profiles similar to established agents, and the simplified management associated with these new agents should encourage compliance with published guidelines for VTE prophylaxis. With the number of THA and TKA surgeries increasing, safe and effective thromboprophylaxis is essential to mitigate the morbidity and mortality associated with VTE. The limitations of current agents, such as LMWHs and warfarin, further suggest a need for new therapies that can improve patient outcomes and reduce the clinical and cost burden associated with TKA/THA. The new oral anticoagulants have the potential to reduce the incidence of VTE after THA and TKA. In addition, compared with established agents, the new oral anticoagulants may produce significant cost-savings through reduced rates of VTE, improved safety, and reduced administration and monitoring costs. ■ Acknowledgment The author would like to acknowledge Richard Dobson, PhD, who provided editorial support. Study Funding This study was funded by Janssen Scientific Affairs, LLC. Author Disclosure Statement Dr Friedman is a Consultant to Janssen and Exactech, is on the Speaker’s Bureau of Janssen, and has received research grants from Tournier.

References 1. Iorio R, Robb WJ, Healy WL, et al. Orthopaedic surgeon workforce and volume assessment for total hip and knee replacement in the United States: preparing for an epidemic. J Bone Joint Surg Am. 2008;90:1598-1605. 2. Baser O, Supina D, Sengupta N, et al. Clinical and cost outcomes of venous thromboembolism in Medicare patients undergoing total hip replacement or total knee replacement surgery. Curr Med Res Opin. 2011;27:423-429. 3. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e278S-e325S. 4. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358:1037-1052. 5. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. 6. Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107(23 suppl 1):I22-I30. 7. Heit JA. The epidemiology of venous thromboembolism in the community: impli-

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cations for prevention and management. J Thromb Thrombolysis. 2006;21:23-29. 8. Ashrani AA, Heit JA. Incidence and cost burden of post-thrombotic syndrome. J Thromb Thrombolysis. 2009;28:465-476. 9. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264. 10. Oster G, Ollendorf DA, Vera-Llonch M, et al. Economic consequences of venous thromboembolism following major orthopedic surgery. Ann Pharmacother. 2004;38: 377-382. 11. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br. 2007;89:799-807. 12. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med. 1999;159:445-453. 13. Nutescu E. Characteristics of novel anticoagulants and potential economic implications. Am J Manag Care. 2011;17(1 suppl):S27-S32. 14. Dobesh PP. Economic burden of venous thromboembolism in hospitalized patients. Pharmacotherapy. 2009;29:943-953. 15. MacDougall DA, Feliu AL, Boccuzzi SJ, Lin J. Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome. Am J Health Syst Pharm. 2006;63(20 suppl 6):S5-S15. 16. Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm. 2007;13:475-486. 17. Sullivan SD, Kahn SR, Davidson BL, et al. Measuring the outcomes and pharmacoeconomic consequences of venous thromboembolism prophylaxis in major orthopaedic surgery. Pharmacoeconomics. 2003;21:477-496. 18. Kirson NY, Birnbaum HG, Ivanova JI, et al. Excess costs associated with patients with chronic thromboembolic pulmonary hypertension in a US privately insured population. Appl Health Econ Health Policy. 2011;9:377-387. 19. Vekeman F, Lamori JC, Laliberte F, et al. Risks and cost burden of venous thromboembolism and bleeding for patients undergoing total hip or knee replacement in a managed-care population. J Med Econ. 2011;14:324-334. 20. Hirsh J, Guyatt G, Lewis SZ. Reflecting on eight editions of the American College of Chest Physicians antithrombotic guidelines. Chest. 2008;133:1293-1295. 21. American Academy of Orthopaedic Surgeons. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty: evidencebased guidelines and evidence report. 2011. www.aaos.org/research/guidelines/VTE/ VTE_full_guideline.pdf. Accessed March 19, 2012. 22. Friedman RJ, Gallus AS, Cushner FD, et al. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin. 2008;24:87-97. 23. Friedman RJ, Gallus A, Gil-Garay E, et al. Practice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty—insights from the Multinational Global Orthopaedic Registry (GLORY). Am J Orthop (Belle Mead NJ). 2010;39(9 suppl):14-21. 24. Caprini JA, Tapson VF, Hyers TM, et al. Treatment of venous thromboembolism: adherence to guidelines and impact of physician knowledge, attitudes, and beliefs. J Vasc Surg. 2005;42:726-733. 25. Levine MN, Raskob G, Landefeld S, Hirsh J. Hemorrhagic complications of anticoagulant treatment. Chest. 1995;108(4 suppl):276S-290S. 26. Kakkar AK, Davidson BL, Haas SK. Compliance with recommended prophylaxis for venous thromboembolism: improving the use and rate of uptake of clinical practice guidelines. J Thromb Haemost. 2004;2:221-227. 27. Caprini JA, Hyers TM. Compliance with antithrombotic guidelines. Manag Care. 2006;15:49-60, 66. 28. Tufano A, Coppola A, Cerbone AM, et al. Preventing postsurgical venous thromboembolism: pharmacological approaches. Semin Thromb Hemost. 2011;37:252-266. 29. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):160S-198S. 30. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775. 31. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31-39. 32. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786. 33. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673-1680. 34. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604. 35. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for throm-

boprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815. 36. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498. 37. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. 38. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721-729. 39. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185. 40. Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9. 41. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):234S-256S. 42. Xarelto (rivaroxaban) prescribing information. December 2011; Titusville, NJ: Janssen. 43. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105:444-453. 44. Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15(suppl 1):9S-16S. 45. Pradaxa (dabigatran) package insert. 2011; Ridgefield, CT: Boehringer Ingelheim. 46. Eliquis (apixaban) summary of product characteristics. 2011; Middlesex, England: Bristol-Myers Squibb. 47. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127. 48. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579. 49. Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594-3599. 50. Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm. 2004;10:159-165. 51. Botteman MF, Caprini J, Stephens JM, et al. Results of an economic model to assess the cost-effectiveness of enoxaparin, a low-molecular-weight heparin, versus warfarin for the prophylaxis of deep vein thrombosis and associated long-term complications in total hip replacement surgery in the United States. Clin Ther. 2002;24: 1960-1986. 52. de Lissovoy G, Subedi P. Economic evaluation of enoxaparin as prophylaxis against venous thromboembolism in seriously ill medical patients: a US perspective. Am J Manag Care. 2002;8:1082-1088. 53. Wolowacz SE, Roskell NS, Maciver F, et al. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery. Clin Ther. 2009;31:194-212. 54. Friedman RJ, Lees M, Sengupta N, Haas S. Rivaroxaban for prevention of venous thromboembolism after total hip replacement: impact on healthcare costs based on the RECORD1 study. J Bone Joint Surg Br. 2008;92-B(suppl II):289. 55. Kakkar A, Lees M, Sengupta N, Muntz J. Prevention of venous thromboembolism with rivaroxaban after total hip replacement: economic impact of extended thromboprophylaxis (abstract). J Bone Joint Surg Br. 2008;92-B(suppl II):273. 56. Kwong LM, Lees M, Sengupta N. Rivaroxaban for prevention of venous thromboembolism after total knee arthroplasty: impact on healthcare costs based on the RECORD3 study. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 1874. 57. Duran A, Sengupta N, Diamantopoulos A, et al. Cost and outcomes associated with rivaroxaban vs enoxaparin for the prevention of postsurgical venous thromboembolism from a US payer’s perspective. J Med Econ. 2011;14:824-834. 58. Turpie AG, Levine MN, Hirsh J, et al. A randomized controlled trial of a lowmolecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med. 1986;315:925-929. 59. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet. 2002;359: 1721-1726. 60. Colwell CW Jr, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study. J Thromb Haemost. 2003;1:2119-2130.

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STAKEHOLDER PERSPECTIVE A Paradigm Shift in Anticoagulation? MEDICAL/PHARMACY DIRECTORS: We have made significant progress since the 1940s, when a group of chemists at the University of Wisconsin synthesized dicoumarol. This initial discovery of a synthetic anticoagulant led to the development and marketing of warfarin in 1954, the first oral anticoagulant available for human use.1 Or was it? If you consider that aspirin was developed in 1897, then it is clear that aspirin was the first oral anticoagulant available for human use. In fact, another anticoagulant was available even before warfarin, although it was not available in an oral dosage form. Heparin was first made available for intravenous (IV) administration in the 1930s.2 We have had decades of experience with aspirin, warfarin, and heparin, and they have all served us well for preventing and treating conditions associated with thromboembolism. All of these medications are also associated with significant adverse effects and, in some cases, have risks that outweigh their benefits. The ideal anticoagulant should be highly effective in preventing and treating thromboembolism; should be safe for use, with minimal to no monitoring requirements; and should be affordable. A major advance in the development of anticoagulants occurred when enoxaparin was made available for human use 25 years ago. Enoxaparin, a low-molecularweight heparin, provided the efficacy of IV heparin, without the same level of bleeding risk and monitoring associated with IV heparin. Available as a generic drug since 2010, enoxaparin is an effective, safe, and affordable medication. The challenge with enoxaparin is that it has to be injected by the patient. Today, we are observing a paradigm shift in the pharmaceutical marketplace from injectable to oral therapies. Although warfarin can be an alternative to injectable anticoagulants, the newer oral anticoagulants definitely offer some advantages. In this issue of American Health & Drug Benefits, Dr Friedman provides a comprehensive review of this paradigm shift we are observing in the prevention and treatment of venous thromboembolism (VTE) after total hip arthroplasty (THA) or total knee arthroplasty (TKA). This shift is characterized by the availability of new anticoagulants, such as rivaroxaban, apixaban, and dabigatran. These therapies have been found to be either superior to or noninferior to enoxaparin,

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the gold standard in the prevention of VTE after THA or TKA.3-13 In addition, similar to enoxaparin, these new therapies have the advantage of not requiring extensive monitoring. Although not compared in head-to-head trials with warfarin, the new oral anticoagulants offer safety and monitoring advantages over warfarin that make them appealing for the prevention of VTE. The question that most payers are asking about these new anticoagulants is, â&#x20AC;&#x153;Are these new medications affordable?â&#x20AC;? This depends on how affordability is measured. Based on drug costs alone, it is clear that these new agents are more expensive than enoxaparin or warfarin. But if we take into account monitoring costs, efficacy, safety, and reduction in hospital readmissions, the higher drug cost can be justified. There are still significant restrictions placed on the use of the newer oral anticoagulants; however, I believe that this is entirely based on cost rather than on safety and efficacy concerns. 1. Hirsh J. Heparin. N Engl J Med. 1991;324:1565-1574. 2. Hirsh J. Oral anticoagulant drugs. N Engl J Med. 1991;324:1865-1875. 3. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775. 4. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31-39. 5. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786. 6. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673-1680. 7. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604. 8. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815. 9. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498. 10. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956. 11. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721-729. 12. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5: 2178-2185. 13. Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.

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Constipation Dyspepsia

5.3 0.9 1.7 5.2 0.9 2.6 Add-on to Metformin + Glimepiride Placebo + Metformin + Glargine + Metformin Victoza® 1.8 + + Glimepiride Glimepiride Metformin + N = 232 N = 114 Glimepiride N = 230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 Diarrhea 10.0 5.3 1.3 Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone All Victoza® + Metformin + Placebo + Metformin Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 Vomiting 12.4 2.9 Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency ≥5% and occurring more frequently with Victoza® compared to exenatide are listed) Exenatide 10 mcg twice Victoza® 1.8 mg once daily + metformin and/or daily + metformin and/or sulfonylurea N = 232 sulfonylurea N = 235 (%) (%) Preferred Term Diarrhea 12.3 12.1 Dyspepsia 8.9 4.7 Constipation 5.1 2.6 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/ or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/ or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Crossreacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibodynegative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks

duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake). Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator Monotherapy Victoza® Glimepiride None (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — Placebo + Glimepiride + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 121) (N = 242) (N = 724) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Add-on to Glimepiride Victoza® + Placebo + Rosiglitazone + Glimepiride Glimepiride Glimepiride (N = 114) (N = 231) (N = 695) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Victoza® + Placebo + Add-on to None Metformin + Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 175) (N = 355) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Placebo + Add-on to Victoza® + Insulin glargine Metformin + Metformin + Glimepiride + Metformin + Metformin + Glimepiride Glimepiride Glimepiride (N = 114) (N = 232) (N = 230) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Post-Marketing Experience: The following additional adverse reactions have been reported during post-approval use of Victoza®. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: nausea, vomiting and diarrhea sometimes resulting in dehydration [see Warnings and Precautions]. Renal and Urinary Disorders: increased serum creatinine, acute renal failure or worsening of chronic renal failure, which may sometimes require hemodialysis [see Warnings and Precautions]. OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. More detailed information is available upon request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: May 18, 2011 Version: 3 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2011 Novo Nordisk 140586-R3 6/2011

Help adult patients with type 2 diabetes gain greater access

Get to know Victoza® on a deeper level. Powerful reductions in A1C from -0.8% to -1.5%*

Low rate of hypoglycemia

Flexible dosing any time of day, independent of meals

May reduce weight

VictozaCare™ helps patients stay on track with ongoing support

—Victoza® is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials

—Patients enrolled in VictozaCare™ were more adherent to Victoza® than those not enrolled†

To see how Victoza® works for your patients, visit VictozaPro.com/GLP1.

Indications and usage Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. ®

The concurrent use of Victoza and insulin has not been studied.

Important safety information Liraglutide causes dose-dependent and treatment-durationdependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors. If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed. When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza® in patients with renal impairment. There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients. Victoza® should be used with caution in patients with hepatic impairment. Please see brief summary of Prescribing Information on adjacent page. *Victoza® 1.2 mg and 1.8 mg when used alone or in combination with OADs. † Crossix ScoreBoard™ Report, September 2011. Adherence measured by number of actual Victoza® prescriptions filled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through first 8 months of enrollment.

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January 2012