May/June 2012, Vol 5, No 3

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MAY/JUNE 2012

VOLUME 5, NUMBER 3

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

“SCOTUS”: Will They or Won’t They?

David B. Nash, MD, MBA CLINICAL

Managing Hypertension in the Elderly: A Common Chronic Disease with Increasing Age ™

Quang T. Nguyen, DO, FACE; Scott R. Anderson, MS IV; Lindsay Sanders, DO, MPH; Loida D. Nguyen, PharmD, BCPS Stakeholder Perspective by Katrina Moore, PharmD BUSINESS

Utilization of Anticoagulation Therapy in Medicare Patients with Nonvalvular Atrial Fibrillation Kate Fitch, RN, MEd; Jonah Broulette; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Winghan Jacqueline Kwong, PharmD, PhD Stakeholder Perspective by Michael F. Murphy, MD, PhD

Recent Developments, Utilization, and Spending Trends for Pompe Disease Therapies Jing Guo, BPharm; Christina M.L. Kelton, PhD; Jeff J. Guo, PhD Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

AMCP 2012 HIGHLIGHTS

©2012 Engage Healthcare Communications, LLC www.AHDBonline.com

Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the Jakafi® (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment

Myelofibrosis (MF) is a life-threatening, progressive disease

benefits in clinical trials.2,3 Use of a PRO instrument can

characterized by splenomegaly, debilitating symptoms and

evaluate symptoms best judged by the patient, whether

cytopenias.5-7 Measures to assess both the splenomegaly

caused by the disease or treatment toxicity. Assessment

and core symptoms of MF were incorporated into the phase III,

of symptom burden is important because it can be a major

double-blind placebo-controlled study, COMFORT-I, for Jakafi.

indicator of disease severity, progression or improvement.

Spleen reduction, as measured by imaging (MRI or CT), was the

Incorporating PROs into a clinical trial program provides a

primary and biologic endpoint, and a reduction in total symptom

means for evaluating the impact of therapy from the patient’s

score (TSS), the PRO measure, was a key secondary endpoint.8,9

perspective and helps patients and clinicians make better-

The TSS encompassed the following symptoms: abdominal

informed decisions.4

discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

-20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

Placebo (n = 153)

Each bar represents an individual patient’s response.

50 0 -50

-100

WORSENING

0

100

IMPROVEMENT

20

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit.

The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials.

3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.

6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011.

10. Data on File, Incyte Corporation.

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III

study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a registered trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved.

RUX-1130 05/12

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). a Reactions Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved.

Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

MAY/JUNE 2012

VOLUME 5, NUMBER 3 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS 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

EDITORIAL

141 “SCOTUS”: Will They or Won’t They?

David B. Nash, MD, MBA CLINICAL

146 Managing Hypertension in the Elderly: A Common Chronic Disease with Increasing Age Quang T. Nguyen, DO, FACE; Scott R. Anderson, MS IV; Lindsay Sanders, DO, MPH; Loida D. Nguyen, PharmD, BCPS 153 Stakeholder Perspective by Katrina Moore, PharmD

BUSINESS

157 Utilization of Anticoagulation Therapy in Medicare Patients with Nonvalvular Atrial Fibrillation Kate Fitch, RN, MEd; Jonah Broulette; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Winghan Jacqueline Kwong, PharmD, PhD

Founding Editor-in-Chief Robert E. Henry

Mission Statement

167 Stakeholder Perspective by Michael F. Murphy, MD, PhD

Continued on page 136

This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

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Vol 5, No 3

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May/June 2011

American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare.

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133

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.

100 90

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

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

4

• 200,000 hospitalizations *

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

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VOLUME 5, NUMBER 3 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

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FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

BUSINESS

182 Recent Developments, Utilization, and Spending Trends for Pompe Disease Therapies Jing Guo, BPharm; Christina M.L. Kelton, PhD; Jeff J. Guo, PhD 188 Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE DEPARTMENTS

168 Correction 175 AMCP Highlights Electronic Service Alerts Providers of Low-Cost Drugs, Shows Significant Cost-Savings Consumer-Directed Health Plans’ Impact on Medication Adherence in Chronic Conditions High-Deductible Health Plans: Mixed Results in Clinical Outcomes, Associated Costs Pharmacists’ Knowledge Gap about Oncology Genetic Testing, Benefit Design

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher.

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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, LLC Washington, DC

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

HEALTH INFORMATION TECHNOLOGY

DEPUTY EDITORS

J. B. Jones, PhD, MBA Research Investigator, 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, CMD 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 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

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

CARDIOLOGY RESEARCH

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

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

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

Leslie S. Fish, PharmD Senior Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh Vice President National Accounts Truveris, Inc., New York, NY 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, Adjunct Scientist, RAND Health Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research consultancy J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

Charles E. Collins, Jr, MS, MBA Executive Vice President, Managing Director RESEARCH & DEVELOPMENT Engage Managed Markets Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD Worldwide Clinical Trials Faculty, Center for Experimental Professor of Pharmacy Law & Ethics Pharmacology and Therapeutics, HarvardVice Chair, Dept. of Pharmacotherapy MIT Division of Health Sciences and College of Pharmacy, Washington State Technology, Cambridge, MA University, Spokane, WA PERSONALIZED MEDICINE

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation PHARMACOECONOMICS

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

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SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President, Managed Markets/Clinical Serivces Diplomat Specialty Pharmacy Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

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R D IV O F AN D E US ION V O EO AT R P AN STR P A UT INI BC DM U S A

VELCADEHCP.COM

If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.

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 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 the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection 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.

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.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. 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 (bortezomib) 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 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.

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EDITORIAL

“SCOTUS”: Will They or Won’t They?

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

F

or the political junkies among us, the acronym SCOTUS (otherwise known as the Supreme Court of the United States) has practically become a household word. By now, oceans of ink have been devoted to media coverage of the Affordable Care Act (ACA), the 3 days of unprecedented legal hearings and speculation about the potential outcome to be announced sometime in June. My colleagues in health policy circles have been making friendly wagers, not just about what the ultimate decision will be, but how the actual vote count will fall. Democrats and Republicans have flooded the airways, and the expert “talking heads” have impressed us with their punditry. By March 29, 2012, major national newspapers, such as the Wall Street Journal and the New York Times had already lined up the faithful on their respective editorial pages.

The tenor and tone of the exchange between the Justices and the attorneys arguing for and against the legislation were eye opening. It seemed as if the justices were asking the same questions as everyday people, “Do you really want us to read all 2700 pages?” and, “Are we doing a wrecking project or a salvage project?” Some political commentators framed the arguments in terms of social class, maligning the “punditocracy,” and calling the legislation itself a “masterpiece of mandarin abstraction.”1 I became more than a casual observer once I was invited to serve as a panelist on a local national public radio (NPR) program devoted to the topic. In a few paragraphs, I would like to quickly reframe some of the issues from this past spring, reflect on my own personal experience in the eye of the storm, and attempt to answer the rhetorical question, “Will they or won’t they?”

As best as I can tell, the Supreme Court is going to address 4 questions.2 First, the Court will determine whether the Tax Anti-Injunction Act (AIA), an archaic law from the late 1800s, precludes a review of the ACA until 2014, when any financial penalties would be assessed on individuals who do not purchase health insurance. Some experts contend that this penalty would, in effect, be a tax and therefore fall under the AIA. The AIA provides that the legality of a tax cannot be challenged until the tax has actually been assessed.

Because no penalty (tax) will be assessed until 2014, the whole conversation is premature.

The second question that the Court will review

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remains the “hot button” issue—whether the federal government can compel citizens to purchase health insurance (otherwise known as the “individual mandate”). The government attorneys argued strenuously that the federal government has this authority under the Constitution’s Commerce Clause; previously, the Supreme Court has interpreted the section as providing Congress with wide latitude in this arena. The challengers argued that the mandate to purchase a product from a private entity is unprecedented and an intrusion on individual liberty.

If the Court rules the mandate unconstitutional, the third question they must consider is whether the mandate is “severable” from the rest of the law. Opponents of the ACA argue that the entire law must be overturned if the Court invalidates any part of it, and that the mandate is inextricably entangled with the other elements.

On the other hand, the government argues that only 2 other portions of the law would fall if the mandate were struck down. These other conditions are the requirements that ensure coverage for people with preexisting conditions (the “guaranteed issue”), while not charging them higher premiums (the “community rate”).

The fourth and final question is regarding the constitutionality of the ACA’s Medicaid expansion, and whether states must comply with it to remain eligible to receive any federal Medicaid funds.

We all need to take a collective step backward and reexamine the core issues that the bill is attempting to address. The easiest way to frame this argument is the recognition that the ACA is really like 2 laws in 1. One aspect deals with insurance reform; in my view, the questions to be considered by the Court fall into this category.

The other aspect of the law deals with delivery reform.

The healthcare industry has been working diligently on healthcare delivery reform for more than 2 years. Our Jefferson School of Population Health has been educating leaders to be active participants in the conversation regarding delivery reform. We embrace the now-famous Triple Aim, which was articulated by Donald M. Berwick, MD, several years ago.3 We recognize that we must improve the health of the population, enhance the experience of care, and decrease cost by reducing waste.

We support payment reform that accelerates the move from “volume to value.” We certainly support inte-

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gration via bundled payment and coordination of chronic care, because these are the critical underpinnings of the population health model. In my columns and in my speaking engagements around the country, I have attempted to summarize the entire delivery reform aspect of the bill in 4 simple words: “no outcome, no income.”4 In my view, the 4 questions being considered by the Court essentially ignore these central issues. They also ignore the fact that stakeholders within the healthcare system have made substantive progress toward these critically important delivery system goals in the past 2 years.

On the third and final day of the hearings, I was privileged to appear on Radio Times with Marty Moss-Coane, a popular radio program produced by WHYY, the Philadelphia public broadcasting station. I thought I had prepared well for this important opportunity to help clarify what I perceived were some of the missing issues in the public debate about the ACA.

Cooler heads will prevail, and we will make progress in our unique American journey to improve the health of the population and reduce waste in our system. Somehow we must find a way to achieve value for the $8000 per person that we spend annually.

Of course, I sadly recognize that these complex concepts cannot be distilled into a 15-second sound bite— especially on the radio. When the program was open to questions from listeners, I was truly depressed by the questions, because they focused on a narrow interpretation of the individual mandate.

A December 2011 tracking poll from the Kaiser Family Foundation found that support for the mandate varied from 17% to 61%, depending on which messages or information opponents or supporters of the mandate hear on the issue.5 One thing all of the experts agree on, regardless of where their opinions lie, is that the administration has done a poor job of communicating how the various components of the ACA would play out once it is fully implemented.

“Perhaps, surprisingly, the most effective information on changing people’s minds is the basic reminder that, ‘under the reform law, most Americans would still get coverage through their employers and so would automatically satisfy the requirement without having

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to buy any new insurance.’ After hearing that message, favorable reviews of the mandate went up 28 percentage points to 61%.”5 Although the 1 hour flew by quickly, I was happy to have expert colleagues sitting on either side of me in the studio. I thought we handled the live phone-in portion of the program with relaxed camaraderie and ease. Later that same day, most of my e-mails and text messages were positive, although a few people took issue with my position that the discussion should center on delivery reform and not these narrow constitutional issues.

Where does all of this public attention on the healthcare system over the past several months leave us? That is the question of the hour for our industry. Does the notion of the Triple Aim mean anything to our citizenry?

Is the public so afraid of “government intervention” in their lives that they lose sight of the fact that the bill itself represents a colossal compromise, wherein most stakeholders put future economic rewards aside so that a historic bill could be fashioned and approved? Walking back from the local NPR studio to my office, I asked myself these same questions and found no ready answers.

Will they or won’t they? There’s no future in predicting the future, but I will add my voice to the cacophony attempting to answer this important health policy question. I tend to believe that the court will strike down the individual mandate and uphold its severability. In such a case, the insurance industry will respond with a flurry of activity. There is no doubt that premiums will continue their inexorable rise.

But there is some good news—those much-needed delivery system reforms will continue to transform.

Cooler heads will prevail, and we will make progress in our unique American journey to improve the health of the population and reduce waste in our system.

Somehow we must find a way to achieve value for the $8000 per person that we spend annually. Of course, I am interested to hear your views, and you can reach me at david.nash@jefferson.edu. ■

References 1. Henninger D. We’re not France yet. Wall Street Journal. May 29, 2012:A17.

2. Curfman GD, Abel BS, Landers RM. Supreme Court review of the health care reform law. N Engl J Med. 2012;366:977-979.

3. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health and cost.

Health Aff (Millwood). 2008;27:759-769.

4. Jacoby R, Berman B, Nash DB. No outcome, no income CMS’s “meaningful use” initiative. Health Policy Newsl. 2011;24:1-2. http://jdc.jefferson.edu/hpn/vol24/iss1/12/.

Accessed May 31, 2012.

5. The Henry J. Kaiser Family Foundation. Kaiser Public Opinion. March 2012. www.kff.org/healthreform/upload/8296.pdf. Accessed May 31, 2012.

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Review ARticle

Managing Hypertension in the Elderly: A Common Chronic Disease with Increasing Age Quang t. Nguyen, DO, FAce; Scott R. Anderson, MS iv; lindsay Sanders, DO, MPH; loida D. Nguyen, PharmD, BcPS

Quang T. Nguyen

Stakeholder Perspective, page 153

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2012;5(3):146-153 www.AHDBonline.com Disclosures are at end of text

Background: Hypertension increases with age, affecting approximately 66% of the elderly population (aged ≥65 years). By the year 2030, 1 of 5 Americans will be aged ≥65 years. A number of placebo-controlled clinical trials have demonstrated that blood pressure (BP) control reduces cardiovascular events in elderly patients, even in those aged >80 years. Despite advances in medical care, hypertension control rates remain low, especially in the elderly population.

Objective: The goal of this article is to review the information that addresses hypertension in the elderly and current strategies that can facilitate improvement in the management of this common, chronic, and life-threatening condition, which is often undertreated or inappropriately managed.

Discussion: The goals and strategies of treating hypertension in the elderly population are different from, and more challenging than, those in younger patients. Lifestyle modification is effective in this population, but it is difficult to maintain. Many antihypertensive medications are available, with thiazide diuretics being the preferred first-line treatment. Beta-blockers and alpha-blockers are generally not recommended in this population. A majority of older patients will require 2 or 3 antihypertensive medications to reach BP goal. This article reviews current data on hypertensive treatment in the elderly and summarizes the strategies and challenges healthcare providers face when dealing with this population.

Conclusion: Understanding the strategies and challenges that apply to the management of hypertension in the US elderly population can help providers and payers better address the growing need for improving the management of this condition in the elderly, because their numbers are expected to increase dramatically in the coming decades.

H

ypertension, defined as systolic blood pressure (BP) ≥140 mm Hg, diastolic BP ≥90 mm Hg, increases with age, affecting more than 50% of patients aged ≥60 years, and approximately 66% of those aged ≥65 years.1-3 It is well known that by 2030, 1 of 5 Americans is expected to be 65 years or older.

Hypertension is the number one diagnosis in the ambulatory setting, and is one of the top diagnoses in the nursing home.4 Data from the Framingham Heart Study suggest that patients who are normotensive at age 55 years

Dr QT Nguyen is an Endocrinologist, Carson Tahoe Physicians Clinic-Carson City, Adjunct Associate Professor Endocrinology and Internal Medicine, Touro University Nevada, College of Osteopathic Medicine; Mr Anderson is Senior Medical Student, University of Nevada School of Medicine, Reno; Dr Sanders is Senior Medical Resident, Internal Medicine Program, University of Nevada; Dr LD Nguyen is Clinical Pharmacy Specialist, VA Sierra Nevada Health Care System, Reno.

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have a 90% lifetime risk of developing hypertension.5 Between 1988-1994 and 2005-2008, the prevalence of hypertension increased among patients aged ≥65 years.6 The use of antihypertensive medications also increased during that period.6 As life expectancy continues to rise, approaching 75 years for men and 80 years for women, the use of antihypertensive medications in the elderly will intensify.6 Approximately 10% of the current US total annual drug expenditure is spent on antihypertensive medications.7 In 2009, the total direct and indirect costs attributable to hypertension in the United States were estimated to be $73.4 billion.8

Special Considerations in the Elderly Population In the United States, the prevalence of elderly patients with adequately treated hypertension (defined as BP <140/90 mm Hg) is quite low, estimated to be only 30% (range, 23%-38%).9 Elderly patients are more prone to having isolated systolic hypertension (ISH)—systolic BP ≥140 mm Hg; diastolic BP <90 mm Hg—which is

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likely a result of an increase in arterial stiffness from arteriosclerosis or impairment of nitric oxide–mediated vasodilation.10-12 ISH occurs in the majority of elderly patients with hypertension: more than 65% of hypertensive patients aged ≥60 years and more than 90% of those aged >70 years have ISH.1,13 ISH is associated with a 2- to 4-fold increase in the risk for stroke, myocardial infarction (MI), or cardiovascular (CV) mortality.14,15 Elderly persons are more sensitive to salt intake compared with a younger population, leading to higher systolic BP and higher pulse pressure (ie, the difference between systolic BP and diastolic BP) when more salt is consumed by elderly individuals.16 Finally, elderly persons are at increased risk for developing orthostatic hypotension, a potentially dangerous drop in BP during positional change from supine to standing position, increasing the risk for syncope, falls, and injuries.

These characteristics must be taken into account and considered carefully when choosing an appropriate treatment protocol for this patient population.

Treatment Considerations The goals and strategies for treating hypertension in the elderly population are different from, and more challenging than, in younger patients. Lifestyle modification is effective in this population, but it is difficult to maintain.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends treating all patients, including the elderly population from the age of 65 through 79 years who have uncomplicated hypertension, to a target BP of <140/90 mm Hg.17 JNC 8 is anticipated to be released at the end of 2012, but it is unclear whether the report will have specific recommendations regarding hypertension management in the elderly population.

The American College of Cardiology (ACC) and the American Heart Association (AHA) recently released the first expert consensus statement to help clinicians effectively manage hypertension in the elderly population.18 Like JNC 7, the ACC/AHA document recommends BP measurement of <140/90 mm Hg for those aged 65 to 79 years. For patients aged ≥80 years, most experts, including the ACC/AHA statement, recommend a less-stringent systolic BP goal of 140 to 145 mm Hg, to minimize side effects.18 This ACC/AHA document further recommends starting the evaluation of the elderly patient with known or suspected hypertension with 3 measurements of BP, including in the standing position, to obtain an accurate BP value. If BP is elevated, the cause should be iso-

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Approximately 10% of the US total annual drug expenditure is spent on antihypertensive medications.

It is estimated that only 30% (range, 23%-38%) of elderly patients with hypertension are adequately managed in the United States, leaving considerable room for improvement.

JNC 7 recommends treating all patients with uncomplicated hypertension, including those aged 65 to 79 years, to a target blood pressure (BP) of <140/90 mm Hg. For patients aged ≥80 years, most experts recommend a systolic BP goal of 140-145 mm Hg, to minimize medication side effects.

A recent ACC/AHA statement suggests that lifestyle modifications may be all that is needed to treat milder forms of hypertension in elderly patients; in those with resistant hypertension, drug treatment is recommended.

First-line drug therapy with diuretics, angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers should be started at the lowest dose, and titrated as tolerated.

The unique characteristics responsible for the increased risk for hypertension in the elderly population must be taken into account and considered carefully when choosing a treatment protocol.

lated. Any organ damage should be assessed. Other CV disease (CVD) risk factors or comorbid conditions should be identified, along with any potential barriers to treatment adherence.18 According to this ACC/AHA statement, lifestyle modifications may be all that is necessary to treat milder forms of hypertension in elderly patients. In patients with resistant hypertension, drug therapy is recommended and should be started at the lowest dose possible, with gradual increases depending on response.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) are effective in lowering BP and reducing CV outcomes in the elderly.

Beta-blockers are inferior in benefits compared with these drug classes, but they may be used in selected cases in the elderly population.18

Nonpharmacologic Treatment Lifestyle modification is recommended as the firstline treatment for all patients with hypertension, especially in the elderly population, where polypharmacy, potential drug interactions, and nonadherence to treat-

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Table Lifestyle Modifications and Benefitsa Approximate SBP reductionb

Modification

Recommendation

Weight reduction

Maintain normal body weight (BMI, 18.5-24.9 kg/m2)

5-20 mm Hg/ 10-kg weight loss

Adopt DASH diet

Consume diet rich in fruits/vegetables, and low-fat dairy products with a reduced content of saturated and total fat

8-14 mm Hg

Dietary sodium reduction

Reduce intake to ≤2.4 g sodium or ≤6 g sodium chloride/day

2-8 mm Hg

Engage in physical activity

≥30 minutes aerobic activity per day, most days of the week

4-9 mm Hg

Moderate alcohol intake

≤2 drinks per day for men and ≤1 drink per day for women

2-4 mm Hg

a

For overall cardiovascular risk reduction, stop smoking.

The effects of implementing these modifications are dose- and time-dependent and could be greater for some individuals.

BMI indicates body mass index; DASH, Dietary Approaches to Stop Hypertension; SBP, systolic blood pressure.

Source: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National High Blood Pressure Education Program. Bethesda, MD: National Heart, Lung, and Blood Institute (US); August 2004. Report No. 04-5230. b

ment regimens are serious concerns. Weight control, adoption of the Dietary Approaches to Stop Hypertension (DASH), dietary sodium restriction, increasing activity level, and limiting alcohol intake are effective tools in the treatment of hypertension (Table).17,19-23 One landmark study that proved that nonpharmacologic intervention is effective in treating older patients is the Trial of Nonpharmacologic Interventions in the Elderly (TONE).21 In this trial, 975 men and women with hypertension (aged 60-80 years; BP <145/85 mm Hg on 1 antihypertensive drug) were recruited. Obese and normal-weight subjects were separated and randomly assigned to the following groups: usual care, salt restriction (≤1800 mg per 24 hours), weight loss (obese patients, ≥10-lb goal), or salt restriction and weight loss.

Withdrawal of the drug being taken for hypertension was attempted after 3 months of intervention. The primary outcome end point was a diagnosis of high BP at 1 or more follow-up appointments, treatment with antihy-

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pertensive drugs, or a CV event. The study yielded positive results, with significant reductions in BP seen in all intervention groups compared with the usual-care group.

The primary end point at 30 months occurred significantly less in the intervention groups compared with the usual-care group, illustrating that “reduced sodium intake and weight loss constitute a feasible, effective, and safe nonpharmacologic therapy of hypertension in older persons.”21 The beneficial effects of exercise on hypertension control in the elderly population have been illustrated in a number of studies24-26 and in a meta-analysis.27 These studies solidify the concept that it is never too late to implement lifestyle changes in the control of hypertension.

One study explored the effect of moderate and intense aerobic exercise on the BP of sedentary patients aged ≥75 years.28 The subjects were randomized into 1 of 3 groups: a control group (no exercise), a moderateintensity group (3 days per week for a total of 30 exercise sessions of 40-minute duration each) at 65% to 70% of maximal heart rate), and a high-intensity group (85%90% of maximal heart rate).

After only 10 weeks of exercise, significant reductions in systolic BP (–7.8 mm Hg) and diastolic BP (–9.6 mm Hg) were seen in the high-intensity group compared with the control group (+2.6 mm Hg). The effects were seen independent of weight changes. The editorial accompanying the study agreed that “these data support the contention that pharmacologic intervention should be coupled with exercise and other lifestyle modification even in our more elderly patients.”29

Pharmacologic Therapy Many placebo-controlled trials, as well as meta-analyses, have demonstrated the benefits of antihypertensive therapy in the elderly population.17,30-47 There is no age limit at which antihypertensive drugs should not be used. Initiation of antihypertensive drugs should be started at the lowest dose, with gradual incremental increase as tolerated. If the first agent fails to lower BP to goal at full dose, a second and third medication should be added as tolerated. When BP is >20/10 mm Hg above goal, consideration toward initiating 2 antihypertensives or a combination drug therapy is warranted. The risks and benefits of treatment should be continuously reevaluated. In the elderly population, especially those aged >80 years, a systolic BP of 140 to 145 mm Hg is acceptable in individual cases.

Diuretics Thiazide diuretics are inexpensive, are generally well tolerated, and are recommended as a first-line therapy in the treatment of hypertension in the elderly population.17

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One landmark study that supports the use of thiazide diuretics in the treatment of ISH in older patients is the Systolic Hypertension in the Elderly Program (SHEP).30 In this trial, 4736 older individuals with systolic BP levels ≥160 mm Hg and diastolic BP levels <90 mm Hg (mean BP, 170/77 mm Hg) were randomized to treatment with the thiazide diuretic chlorthalidone or with placebo. Significant improvement in BP was accomplished in the treatment group compared with the group receiving placebo (systolic BP, 143 mm Hg vs 155 mm Hg, respectively), leading to significant reduction in stroke (36%), coronary artery disease (CAD; 27%), chronic heart failure (HF; 55%, 81% in those with previous MI), and all-cause CVD (32%).30 Another landmark trial demonstrating that thiazide diuretics are as effective as any drug for first-line treatment of hypertension in the elderly population is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study.31 This trial included 42,418 patients (mean age, 67 years) with hypertension and at least 1 other risk factor for CAD. The patients were randomized to a treatment group with a thiazide-type diuretic (chlorthalidone), a beta-blocker (atenolol), a CCB (amlodipine), an ACE inhibitor (lisinopril), or an alpha-blocker (doxazosin). Other than the group receiving doxazosin, which was stopped early because of higher rates of adverse events, final data showed no differences in the primary outcome of fatal or nonfatal coronary events and no mortality difference between the CCB, ACE inhibitor, and diuretic groups.

Patients who received the diuretic had a lower incidence of CV events (secondary outcomes) compared with the other groups. The diuretic treatment group had lower HF rates compared with the CCB group (relative risk [RR], 1.33; 95% confidence interval [CI], 1.18-1.49) and lower combined CV outcomes (RR, 1.13; 95% CI, 1.061.20), and HF (RR, 1.20; 95% CI, 1.09-1.34) compared with the ACE inhibitor group.31 Indapamide, a nonthiazide diuretic, was featured in the Hypertension in the Very Elderly Trial (HYVET).33 In this highly anticipated study published in 2008, more than 3800 elderly patients (patients aged ≥80 years; mean, 83.6 years) with systolic hypertension, diastolic hypertension, or ISH were randomly assigned to take indapamide or placebo. The primary end point was fatal or nonfatal stroke. Significant reduction in mean BP was achieved in the treatment group (143/78 mm Hg vs 158/84 mm Hg). The study was stopped early as a result of significant reductions in fatal stroke (6.5% in the active group vs 10.7% in the placebo group) and allcause mortality (47.2% in the active group, 59.6% in the placebo group). This is the first trial that provided evidence that treatment of hypertension in the very elderly

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(aged >80 years) is beneficial and should be pursued.33 Other diuretics, such as loop diuretics, mineralocorticoid antagonists, or sodium transport channel antagonists, can also be used in the elderly as adjunct treatments when appropriate.18

Calcium Channel Blockers CCBs can be used as first-line hypertension treatment in the elderly if a diuretic is contraindicated or if the patient has angina or heart rhythm/conduction problems. In general, CCBs are well tolerated in the elderly.

The most common adverse events for the dihydropyridine CCBs are symptoms of vasodilation, such as ankle edema, headache, or postural hypotension. Common adverse events for the nondihydropyridine CCBs include constipation, bradycardia, and potential for heart block; as such, this subclass should be avoided in elderly patients with underlying cardiac conduction defects or with left-ventricular systolic dysfunction.18 Several clinical trials have shown that CCBs are effective and safe in the elderly population.31,34-36 One landmark study involving this drug class includes Systolic Hypertension in Europe (Syst-Eur).34,35 In this study, more than 4600 elderly patients (mean age, 76 years) with ISH were randomized to receive dihydropyridine nitrendipine or placebo. The trial was stopped earlier than anticipated as a result of a significant reduction in stroke (42% reduction; P = .003) and all fatal and nonfatal cardiac end points, including sudden death (26% reduction; P = .03) in the treatment group.34 The authors calculated that treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major CV end points. The prevalence of vascular dementia was significantly lowered in the group receiving antihypertensives compared with those receiving placebo (3.8 vs 7.7 cases per 1000 patient-years, respectively).35 The efficacy and safety of CCBs in combination with other medications for the elderly patients were illustrated in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial.36 More than 11,500 elderly patients with hypertension (mean age, 68 years; mean BP, 145/88 mm Hg) were randomized to receive the ACE inhibitors (benazepril) with a CCB (amlodipine) or a diuretic (hydrochlorothiazide).

The primary end point was the composite of death from CV causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. The trial was terminated early after a mean follow-up of 36 months when significantly fewer primary end points were seen in the group receiving benazepril/amlodipine—552 (9.6%) primary-outcome events in the group receiving

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benazepril/amlodipine versus 679 (11.8%) in the group receiving benazepril/hydrochlorothiazide.36

ACE Inhibitors ACE inhibitors lower BP by inhibiting the conversion of angiotensin I to angiotensin II, thereby preventing vasoconstriction (by angiotensin II) and aldosterone production. ACE inhibitors are considered alternative first-line hypertension treatments in the elderly population if a diuretic is contraindicated.18 ACE inhibitors have been shown to decrease morbidity and mortality in patients with MI, with HF (systolic dysfunction), or in those with diabetic renal disease.37-39 The main side effects of ACE inhibitors are dry cough and hypotension.18 Hyperkalemia can occur with ACE inhibitor use. Close monitoring and extreme caution are recommended if they are going to be used in elderly patients with renal impairment.18 One important clinical trial that illustrated the effectiveness and beneficial effects of ACE inhibitors in the elderly population with hypertension is the Second Australian National Blood Pressure Study (ANBP2).40 This study randomized 6083 patients with hypertension (aged 65-84 years) to receive either enalapril or hydrochlorothiazide. At study end, BP reduction was found to be similar in both groups. The ACE inhibitor group was found to have fewer CV events/all-cause death (695 vs 736, respectively) and fewer cerebrovascular events (152 vs 163, respectively) compared with the diuretic group. In addition, males receiving an ACE inhibitor achieved a 17% reduction in all CV events.40 Two landmark trials involving ACE inhibitors and high-risk elderly patients with hypertension are the Heart Outcomes Prevention Evaluation (HOPE)41 and Perindopril Protection Against Recurrent Stroke Study (PROGRESS).42 In the HOPE trial, 9297 high-risk patients (aged ≥55 years) who had evidence of vascular disease or diabetes plus 1 other CV risk factor and who were not known to have a low ejection fraction or HF were randomly assigned to receive oral ramipril (10 mg once daily) or matching placebo for a mean of 5 years.

Significant reductions in CV death (26%), all-cause mortality (16%), stroke (32%), and HF (23%) were seen in the ramipril group at the end of the study.41 In the PROGRESS trial, 6105 patients (mean age, 64 years) who had suffered a stroke or transient ischemic attack were assigned to perindopril (4 mg daily) with the addition of the diuretic indapamide at the discretion of treating physicians or placebo.42 At the end of the study, combination therapy with perindopril plus indapamide reduced BP by 12/5 mm Hg and stroke risk by 43%.

Single-drug therapy reduced BP by 5/3 mm Hg and produced no reduction in stroke risk.42

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Angiotensin Receptor Blockers ARBs work by blocking the effects of angiotensin II on vascular smooth muscle, thus causing vasodilation.

ARBs also decrease the production of aldosterone, thereby lowering sodium reabsorption and fluid retention.

ARBs are considered the alternative first-line treatment for hypertension in the elderly population when a diuretic is contraindicated. In elderly hypertensive patients with diabetes or HF, ARBs are considered first-line treatment and an alternative to ACE inhibitors.

Some landmark trials involving ARBs in the treatment of hypertension in elderly patients are the Losartan Intervention for End point Reduction in Hypertension (LIFE),43 the Study on Cognition and Prognosis in the Elderly (SCOPE),44 and the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study.45 The LIFE trial randomized 9193 patients aged 55 to 80 years with hypertension and left-ventricular hypertrophy on electrocardiogram to losartan or atenolol.43 Although reductions in BP were similar in both groups, CV death, stroke, and MI were reduced by >13% in those participants receiving losartan compared with atenolol (508 vs 588, respectively). In addition, significant reduction in fatal or nonfatal stroke was seen in the group receiving losartan (25%; 232 vs 309 actual events, respectively). In the subgroup with diabetes (n = 1195), there was a greater reduction in CV and all-cause mortality for losartan versus atenolol.43 The SCOPE trial involved 4964 patients aged 70 to 89 years, with systolic BP 160 mm Hg to 179 mm Hg and/or diastolic BP 90 mm Hg to 99 mm Hg and a Mini-Mental State Examination test score ≥24.44 Patients were assigned randomly to receive the ARB candesartan or placebo, with open-label active antihypertensive therapy added as needed. Mean follow-up was 3.7 years. Reduction in BP for the group receiving candesartan was 21.7/10.8 mm Hg. Significant reduction in nonfatal stroke was seen (27.8%; 95% CI, 1.347.2; P = .04) with a trend for reduction in fatal stroke (23.6%; 95% CI, –0.7-42.1; P = .056).44 The ACCESS trial was designed to assess the safety of modest BP reduction by candesartan cilexetil in the early treatment of stroke.45 The study was stopped early as a result of significant reductions in deaths, CV events, or cerebrovascular events in the candesartan group compared with placebo (odds ratio, 0.475; 95% CI, 0.252-0.895).45 Direct Renin Inhibitors Renin inhibitors bind the active site of renin, such that it cannot act to cleave angiotensinogen to angiotensin I, preventing the conversion of angiotensin I to angiotensin II. This prevents the vasoconstriction of arterial smooth muscle that angiotensin II is responsible

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for. In addition, angiotensin II would not be available to stimulate the production of aldosterone and decrease fluid retention.48 Renin inhibitors are as effective as ACE inhibitors or ARBs for the treatment of hypertension, and they are well tolerated in the elderly population.49 There are few clinical trials involving aliskiren and elderly patients. The Aliskiren for Geriatric Lowering of Systolic Hypertension (AGELESS) trial compared aliskiren with ramipril for treatment of essential systolic hypertension in elderly patients.46 A total of 901 elderly patients (aged ≥65 years) with systolic BP ≥140 mm Hg were randomized to receive aliskiren or ramipril. The primary end point was noninferiority of aliskiren versus ramipril monotherapy for change from baseline in mean sitting systolic BP at week 12. At week 36, fewer patients receiving aliskiren-based therapy required add-on treatment with hydrochlorothiazide or amlodipine (P = .01 and P = .048, respectively). The authors concluded that “in elderly patients with systolic hypertension, aliskiren proved to be more effective and better overall antihypertensive therapy compared to ramipril.”46 The Aliskiren Observation of Heart Failure Treatment (ALOFT) trial studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in elderly patients (mean age, 68 years) with HF.47 The authors found that the “addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and betablocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated.”47

Beta-Blockers Beta-blockers are not the optimal first-line treatment for elderly patients with hypertension.18 They are associated with more adverse events, and their evidence of benefits is weaker compared with other drug classes (ie, diuretics, ACE inhibitors, ARBs, CCBs).18,30,43 A recent meta-analysis comparing beta-blockers and diuretics showed that diuretics are more effective as monotherapy and are superior to beta-blockers in all clinical outcomes.50 Beta-blockers have been shown to provide less protection from stroke in the elderly patient with hypertension according to the International Verapamil SRTrandolapril Study (INVEST).51 This randomized, blinded, prospective trial was aimed to understand the differences in outcomes of newer antihypertensive medications compared with the traditional treatment with beta-blockers and diuretics. The study recruited 22,576 elderly patients with hypertension who were randomized to receive either verapamil or atenolol, and followed outcomes for at least 2 years.

The results of the study showed similar control in BP between the 2 treatment groups. However, there was a

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higher incidence of new-onset diabetes, stroke, and mortality in the atenolol group. Of interest, beta-blockers showed more protection from MIs but were also associated with a higher incidence of persistent depressive mood, which is a rising problem among the elderly population. Although beta-blockers may lower the rate of stroke in patients with hypertension compared with placebo, they have been shown to be inadequate compared with newer antihypertensive medications in the aging population.51 Beta-blockers can be added in combination therapy and have a proven role in the treatment of elderly patients with hypertension complicated by CAD, HF, or arrhythmias.52

Other Drugs Alpha-adrenergic blocking agents are used primarily for urinary symptoms related to benign prostate hypertrophy and should not be considered a first-line hypertensive drug in the elderly.18,31 They can induce orthostatic hypotension and increase the risk of falls and injuries.

Minoxidil and hydralazine can cause fluid retention, reflex tachycardia, and atrial arrhythmia, and they should not be used as first-line therapy or monotherapy in the treatment of hypertension in the elderly. Centrally acting agents such as clonidine can cause sedation, bradycardia, and rebound hypertension if stopped abruptly, and they should not be used as monotherapy in the elderly or in those patients who are noncompliant. Nitrates have no role in the long-term treatment of hypertension in the elderly because of tolerance. They can be used as an antianginal agent as needed.18 Conclusions JNC 7 recommends a treatment BP target of <140/90 mm Hg for all patients with hypertension, including the elderly population. Clinical trials that included patients aged >65 years have shown that patients who receive treatment for their elevated BP have fewer strokes, fewer heart attacks, and less congestive HF compared with those with untreated hypertension. In patients aged 40 to 89 years, each 20-mm Hg increase in systolic BP or 10mm Hg increase in diastolic BP is associated with a 2-fold increase in mortality from ischemic heart disease and a more than 2-fold increase in mortality from stroke.53 There is great benefit in the successful treatment of hypertension in the elderly population. Encouraging lifestyle changes is the first-line treatment. Medications should be started as appropriate. Diuretics, ACE inhibitors, ARBs, and CCBs have all been proved as firstline treatment agents, and should be started with the lowest dose and titrated as tolerated. Vigilance is needed to avoid treatment-related adverse events. For very eld-

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erly patients (aged >80 years), the risks and benefits of tight control need to be frequently reevaluated. ■ Author Disclosure Statement Dr QT Nguyen, Mr Anderson, Dr Sanders, and Dr LD Nguyen reported no conflicts of interest.

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2. Ostchega Y, Dillon CF, Hughes JP, et al. Trends in hypertension prevalence, awareness, treatment, and control in older U.S. adults: data from the National Health and Nutrition Examination Survey 1988 to 2004. J Am Geriatr Soc. 2007;55:1056-1065.

3. Vasan RS, Larson MG, Leip EP, et al. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001;358:1682-1686.

4. Centers for Disease Control and Prevention. FastStats: hypertension. www.cdc. gov/nchs/hyprtens.htm. Accessed April 18, 2012.

5. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA. 2002;287:1003-1010.

6. Centers for Disease Control and Prevention. Health, United States, 2010: In Brief.

Hyattsville, MD: National Center for Health Statistics; 2011:33-53. www.cdc.gov/ nchs/data/hus/hus10.pdf. Accessed May 21, 2012.

7. Spurgeon D. NIH promotes use of lower cost drugs for hypertension. BMJ. 2004;328:539.

8. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics— 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21-181.

9. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA. 2005;294:466-472.

10. Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension.

2001;37:869-874.

11. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275:1571-1576.

12. O’Rourke MF, Nichols WW. Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension. 2005;45:652-658.

13. Franklin SS, Gustin W 4th, Wong ND, et al. Hemodynamic patterns of agerelated changes in blood pressure. The Framingham Heart Study. Circulation. 1997; 96:308-315.

14. Izzo JL Jr, Levy D, Black HR. Clinical Advisory Statement. Importance of systolic blood pressure in older Americans. Hypertension. 2000;35:1021-1024.

15. Young JH, Klag MJ, Muntner P, et al. Blood pressure and decline in kidney function: findings from the Systolic Hypertension in the Elderly Program (SHEP). J Am Soc Nephrol. 2002;13:2776-2782.

16. Weinberger MH, Miller JZ, Luft FC, et al. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(suppl II): II127-II134.

17. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

18. Aronow WA, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.

Circulation. 2011;123:2434-2506.

19. He J, Whelton PK, Appel LJ, et al. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension. 2000;35:544-549.

20. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.

DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:3-10.

21. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group. JAMA. 1998;279:839-846.

22. Kelley GA, Kelley KS. Progressive resistance exercise and resting blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2000;35:838-843.

23. Xin X, He J, Frontini MG, et al. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized control trials. Hypertension. 2001;38:1112-1117.

24. Hagberg JM, Park JJ, Brown MD. The role of exercise training in the treatment of hypertension: an update. Sports Med. 2000;30:193-206.

25. Hamdorf PA, Penhall RK. Walking with its training effects on the fitness and activity patterns of 79-91 year old females. Aust N Z J Med. 1999;29:22-28.

26. Brandão Rondon MU, Alves MJ, Braga AM, et al. Postexercise blood pressure

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reduction in elderly hypertensive patients. J Am Coll Cardiol. 2002;39:676-682.

27. Kelley GA, Sharpe Kelley K. Aerobic exercise and resting blood pressure in older adults: a meta-analysis review of randomized controlled trials. J Gerontol A Biol Med Sci. 2001;56:M298-M303.

28. Huang G, Thompson CJ, Osness WH. Influence of a 10-week controlled exercise program on resting blood pressure in sedentary older adults. J Appl Res. 2006;6:188-195.

29. Toth PP. Short-term aerobic exercise in the elderly promotes blood pressure reduction. J Appl Res. 2006;6:186-187.

30. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265: 3255-3264.

31. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997.

32. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000; 355:865-872.

33. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-1898.

34. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.

The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997; 350:757-764.

35. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.

Lancet. 1998;352:1347-1351.

36. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 359:2417-2428.

37. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325:293-302.

38. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435.

39. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcome Prevention Evaluation Study Investigators. Lancet. 2000;355:253-259.

40. Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348:583-592.

41. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.

42. PROGRESS Collaborative Group. Randomized trial of a perindopril-based blood pressure–lowering regimen among 6105 individuals with previous stroke or transient ischemic attack. Lancet. 2001;358:1033-1041.

43. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359: 1004-1010.

44. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875-886.

45. Schrader J, Lüders S, Kulschewski A, et al. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke. 2003;34:1699-1703.

46. Duprez DA, Munger MA, Botha J, et al. Aliskiren for geriatric lowering of systolic hypertension: a randomized controlled trial. J Hum Hypertens. 2010;24:600-608.

47. McMurray JJ, Pitt B, Latini R, et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail. 2008;1:17-24.

48. Volpe M, Pontremoli R, Borghi C. Direct renin inhibition: from pharmacological innovation to novel therapeutic opportunities. High Blood Press Cardiovasc Prev.

2011;18:93-105.

49. Verdecchia P, Calvo C, Möckel V, et al. Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension. Blood Press. 2007;16: 381-391.

50. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systemic review. JAMA.1998;279:1903-1907.

51. Cooper-DeHoff RM, Handberg EM, Mancia G, et al. INVEST revisited: review of findings from the International Verapamil SR-Trandolapril Study. Expert Rev Cardiovasc Ther. 2009;7:1329-1340.

52. Fleg JL, Aronow WS, Frishman WH. Cardiovascular drug therapy in the elderly: benefits and challenges. Nat Rev Cardiol. 2011;8:13-28.

53. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-1913.

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STAKEHOLDER PERSPECTIVE Improving Hypertension Management in the Elderly a Core Clinical Goal PATIENTS: According to the National Health and Nutrition Examination Survey 2007-2008, approximately 20% of patients with hypertension aged >60 years are unaware that they have the condition.1 The symptoms of hypertension are generally silent, and patients often do not understand the importance of blood pressure (BP) control to reduce the risk of stroke, coronary artery disease, and chronic kidney disease.

Patients need to be educated about the disease state and the importance of medication compliance. In addition, patients need to understand the impact they can personally have in reaching their BP goals through lifestyle modifications such as those described in the article by Nguyen and colleagues. Patients should also be encouraged to record home BP readings, which can help them understand how certain behaviors affect BP and to give their providers an idea of BP trends outside of office visits.

PAYERS: Payers have several reasons for improving hypertension control in their patient populations.

Antihypertensive therapy can reduce the risk of congestive heart failure by approximately 40%, stroke by 30%, coronary heart disease by 15%, and all-cause mortality by 10%.2 The cost-savings for preventing these long-term complications far outweigh the price of antihypertensive therapy. Furthermore, with the wide variety of generic antihypertensive medications now available, payers have greater flexibility to reduce the cost of hypertension management. Utilization management strategies, such as step therapy through a generic medication and quantity limits to promote dose optimization, can encourage cost-effective options.

An additional reason to improve BP control is the National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set (HEDIS), which evaluates health plans with regard to certain outcomes to facilitate comparison of health plans. The

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HEDIS measure for hypertension is the percentage of patients (aged 18-85 years) with a diagnosis of hypertension whose most recent BP was adequately controlled (<140/90 mm Hg).3 Hypertension management is also included in the HEDIS measure that focuses on comprehensive diabetes care.

Payers need to be proactive to ensure that patients have adequate BP control to perform well in these HEDIS measures. Methods that payers can use to assist with BP control include education for providers and for patients, low-priced cost-sharing, and direct incentives if certain BP goals are met.

In addition to HEDIS measures, hypertension has also been chosen as one of the 9 core chronic conditions to qualify patients for Medicare Part D Medication Therapy Management (MTM).4 Pharmacists and other qualified providers involved in MTM programs will be able to help providers optimize antihypertensive therapy and will be in a position to counsel patients about their medication therapy. Cooperation between patients, providers, and payers is imperative to improve outcomes in elderly patients with hypertension.

Katrina Moore, PharmD Clinical Pharmacy Coordinator SelectHealth, Salt Lake City, UT 1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303:2043-2050.

2. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis.

JAMA. 2003;289:2534-2544.

3. National Committee for Quality Assurance. The State of Health Care Quality: Reform, The Quality Agenda and Resource Use. 2010. www.ncqa.org/portals/0/ state%20of%20health%20care/2010/sohc%202010%20-%20full2.pdf. Accessed June 13, 2012.

4. Centers for Medicare & Medicaid Services. Prescription drug coverage-general information. Memorandum: CY 2013 Medication Therapy Management Program Guidance and Submission Instructions. April 10, 2012. www.cms.gov/Medicare/ Prescription-Drug-Coverage/PrescriptionDrugCovGenIn/Downloads/MemoContract-Year-2013-Medication-Therapy-Management-MTM-ProgramSubmission-v041012.pdf. Accessed June 13, 2012.

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Original research

Utilization of Anticoagulation Therapy in Medicare Patients with Nonvalvular Atrial Fibrillation Kate Fitch, rn, Med; Jonah Broulette; Bruce Pyenson, Fsa, Maaa; Kosuke iwasaki, FiaJ, Maaa; Winghan Jacqueline Kwong, PharmD, PhD Background: Clinical guidelines recommend oral anticoagulation for stroke prevention in patients with atrial fibrillation (AF) at moderate or high risk for stroke but not at high risk for bleeding; however, studies consistently report suboptimal use of such therapy. This study used Medicare Part D claims data to assess the use of warfarin in the Medicare population.

Objectives: To compare real-world warfarin utilization with current treatment guideline recommendations, and to assess the effect of warfarin exposure level on patient outcomes in Medicare beneficiaries with nonvalvular AF (NVAF).

Methods: Patients who were recently diagnosed with NVAF were identified using a random 5% sample of Research Identifiable Files of Medicare beneficiaries in 2006 or 2007. Individuals with moderate-to-high stroke risk per CHADS2 but not at high bleeding risk per ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score were evaluated for warfarin use, as identified by the presence of ≥1 warfarin prescription claims within 12 months after the index diagnosis. Warfarin exposure level was assessed by the proportion of days covered during the 12-month follow-up period. The effect of warfarin exposure on ischemic stroke and major bleeding event rates during the 12-month follow-up period were assessed using multivariate logistic regression.

Results: Data from 14,149 newly diagnosed patients with NVAF (mean age, 79 years; 58.7% female) were analyzed, and of these, 7524 (53.2%) patients were identified as having moderate-to-high stroke risk and not being at high bleeding risk. Of these patients, 3110 (41.3%) did not receive warfarin within 12 months of the index diagnosis. The risk for ischemic stroke was significantly lower in those with warfarin exposure versus no warfarin exposure (adjusted odds ratio [OR], 0.51; confidence interval [CI], 0.43-0.61; P <.001) and in patients with warfarin proportion of days covered ≥80% versus those with proportion of days covered <80% (adjusted OR, 0.59; 95% CI, 0.48-0.72; P<.001). Warfarin exposure was associated with a significantly higher major bleeding rate (adjusted OR, 1.19; 95% CI, 1.04-1.36; P = .013), with this significant difference being driven by patients aged >65 years.

Conclusions: Based on a risk-stratification scheme composed of previously published tools, such as CHADS2 and the ATRIA bleeding risk index, a significant proportion of Medicare beneficiaries with AF are not receiving guideline-recommended anticoagulation therapy, which leads to an excess rate of ischemic stroke in this patient population. These findings highlight quality-of-care issues for patients with AF and the need to improve compliance with anticoagulation guidelines in the Medicare population.

A

trial fibrillation (AF) is a significant health and cost concern for the Medicare population (age ≥65 years), because of its association with an increased risk for stroke and all-cause mortality.1 The risk

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2012;5(3):157-168 www.AHDBonline.com Disclosures are at end of text

for stroke in patients with AF is almost 5-fold higher than in patients without AF.2 One of every 6 strokes in the United States is associated with AF,3 and strokes in patients with AF are more severe and disabling than in

Ms Fitch is a Principal and Healthcare Management Consultant, Mr Broulette is an Actuarial Analyst, Mr Pyenson is a Principal and Consulting Actuary, Mr Iwasaki is a Consulting Actuary, all at Milliman, Inc, New York, NY; Dr Kwong is Senior Director, Health Economics and Outcomes Research, Daiichi Sankyo, Inc, Parsippany, NJ. Part of the study findings was presented at the Academy of Managed Care Pharmacy 24th Annual Meeting and Exposition, April 20, 2012, San Francisco, CA.

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patients without AF.4 The prevalence of AF in the Medicare population increased from 3.2% in 1992 to 6.0% in 2002.5 Recent estimates indicate the prevalence rate is rising.6 The prevalence of AF increases with age, currently affecting approximately 3.8% of persons aged ≥60 years and 9.0% of persons aged ≥80 years.7 It is expected that by 2050 the prevalence of AF will double from current estimates, when 88% (4.9 million) of those with AF will be aged ≥65 years and 53% (2.9 million) will be aged ≥80 years.7 Oral anticoagulation therapy is the cornerstone of stroke prevention for patients with AF. Warfarin reduces the risk for ischemic stroke by 67% compared with placebo and by 38% compared with aspirin.8 Recent clinical trials of newer oral anticoagulation agents report a similar or a greater rate of stroke risk reduction with these agents than with warfarin in patients with AF.9-11 Antithrombotic treatment guidelines from the American College of Cardiology/American Heart Association recommend oral anticoagulation therapy for patients with AF and moderate-to-high stroke risk, assuming that patients are not at high bleeding risk.12,13 Several evaluation schemes are available to estimate a stroke risk, including CHADS214 and CHA2DS2VASc.15 Similarly, several bleeding risk schemes are available to assess the risk of bleeding, including HEMORR2HAGES,16 HAS-BLED,17 and, more recently, the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk scheme.18 Despite well-established guideline recommendations, however, oral anticoagulation therapy is underutilized.19-24 Underutilization has been linked to healthcare system, physician, and patient factors.25 A major factor cited for underutilization involves physician concern with hemorrhage associated with oral anticoagulation.26 For patients who receive warfarin, optimizing anticoagulation and maintaining anticoagulation within the recommended international normalized ratio (INR) therapeutic range can also be a challenge. A large, nationwide study of electronic medical records reported that patients spent only 48% of study days within the recommended INR range.23 Another study showed that approximately 33% of patients were within the INR therapeutic range less than 20% of the time, and only 19% of patients were within the therapeutic range all or almost all of the time.27 Physician surveys suggest that healthcare system barriers to optimizing anticoagulation include delays in laboratory reports for INR levels, the general inconvenience of INR monitoring, and the lack of consultant services for anticoagulation management.28 Without careful monitoring of INR levels, supratherapeutic INR levels can and do lead to major bleeding events. Bleedings associated with oral anticoagulation

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KEY POINTS ➤

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Patients with atrial fibrillation (AF) are at a significant, 5-fold increased risk for stroke and allcause mortality compared with those without AF. Oral anticoagulation therapy is recommended by national guidelines as the cornerstone for stroke prevention in patients with AF. Warfarin significantly reduces the risk for ischemic stroke; newer anticoagulant agents have shown even greater reduction of stroke risk in patients who are not at risk for bleeding.

Although AF risk increases with age, this present study shows that anticoagulation therapy is underutilized in Medicare beneficiaries who have nonvalvular AF (NVAF), resulting in an increase in ischemic strokes.

These findings suggest the need to follow guidelinebased anticoagulation recommendations in patients with NVAF to prevent strokes and the associated excess in healthcare costs, reduced quality of life, and even death.

These findings also raise the need to investigate provider compliance with clinical guidelines regarding oral anticoagulation therapy for stroke prevention in older patients (aged >65 years) with NVAF.

therapy are reported as a significant portion of emergency department visits for drug-related adverse events among older adults.29 The objective of this study was to compare actual warfarin utilization with current treatment guideline recommendations, and to assess the effect of warfarin exposure level on ischemic stroke and bleeding rates in Medicare beneficiaries (ie, age ≥65 years) with AF. This analysis used the 5% Sample Medicare Research Identifiable File (RIF) dataset with Medicare Part A and Part B claims data linked to Part D prescription drug claims, unlike previous analyses that were based on 5% Sample Medicare Limited Dataset (LDS), which uses INR monitoring and prothrombin time claims as a proxy for warfarin use.30 This current approach provides a more precise estimate of warfarin use in the Medicare population.

Methods Study Population and Characteristics Study participants were patients in the Medicare 5% Sample RIF who were designated as having AF by the Centers for Medicare & Medicaid Services (CMS) Chronic Condition Data Warehouse (CCW) in the years 2006 or 2007. For each patient with AF, the Medicare RIF data included all Medicare Part A and

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Part B claims incurred between 2005 and 2008, monthly eligibility data for each patient with AF from 2005 to 2008, and all Medicare Part D claims incurred from 2006 to 2008. Unlike LDS data, the actual date of service for each claim was provided in the RIF data.

Patients included in this analysis were required to have ≥2 medical claims (inpatient, emergency department, observation unit, physician evaluation and management [E/M] office visit) coded with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code of 427.31 between January 1, 2006, and December 31, 2007. At least 2 of the claims were required to occur at least 30 days apart, with 1 of the claims incurred in an outpatient setting. To ensure that eligible beneficiaries were patients with newly diagnosed AF, patients with ≥1 claim associated with AF in the 12month period before the index AF diagnosis (first claim associated with the ICD-9 code 427.31 between January 1, 2006, and December 31, 2007) were excluded from the analysis.

The sample was further limited to patients with nonvalvular AF (NVAF), by excluding AF patients with claims identified by ICD-9 codes for mitral and/or aortic valvular disease, repair or replacement, transient preoperative AF, or hyperthyroidism in the 12 months before and after the index AF diagnosis date (Appendix 1, page 166).

Eligible patients were further required to have continuous enrollment in Medicare Part A and Part B benefits for 12 months before the index AF diagnosis date and for the lesser of 12 months after the AF index diagnosis date or the date of mortality, and Part D enrollment for the lesser of 12 months after the AF index date or the date of mortality. Patients who had an ischemic stroke within 7 days before or after the AF index diagnosis date were excluded from the analysis.

CHADS2 stroke risk14 and ATRIA bleeding risk18 scores were calculated using claim data 12 months before the index AF diagnosis for each eligible patient. The CHADS2 and ATRIA risk factors (Table 1) of congestive heart failure, hypertension, diabetes, anemia, severe renal disease, prior bleeding, and history of stroke or transient ischemic attack were identified by ≥1 inpatient, emergency department, hospital observation unit, or physician E/M office visit claims associated with specific ICD-9 diagnosis codes (Appendix 2, page 166).

Newly diagnosed patients with NVAF and moderate or high CHADS2 stroke risk (CHADS2 score ≥2) and low-to-moderate ATRIA bleeding risk (score ≤4) were identified.

warfarin prescription claim within 12 months after the index AF diagnosis. Patients who had a warfarin prescription claim within 12 months after the index AF diagnosis but not until after an ischemic stroke claim, and those who had no warfarin prescription claims during the 12-month period after the index AF diagnosis, were considered in this analysis to have not received warfarin.

Warfarin claims were identified using a comprehensive National Drug Code list, which was obtained from the Medi-Span Master Drug Database from Wolters Kluwer Health in May 2011. The algorithm by Go and colleagues31 was adopted to determine the duration of warfarin therapy. The duration of warfarin therapy was calculated based on the number of days of supply associated with each prescription claim; continuous warfarin use was assumed for periods of ≤60 days between any 2 consecutive warfarin prescriptions.

For gaps lasting longer than 60 days, continuous warfarin use was assumed if there were intervening outpatient INR measurements at least every 42 days.

Otherwise, the patient was considered not to be taking warfarin from day 31 after the end date of the first prescription until the start date of the next prescription.

Warfarin exposure level was assessed by the proportion of days covered, by dividing the total duration of warfarin therapy during the 12-month follow-up period by the length of follow-up.

Outcome Measures Warfarin Use Warfarin use was determined by the presence of ≥1

Stroke and Major Hemorrhage Events The rate of ischemic strokes and major hemorrhage were identified based on claims data in the 12 months

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Table 1 CHADS2 Stroke Risk and ATRIA Bleeding Risk Variables and Scoring Schemes ATRIA scoring

CHADS2 scoring Variable

Points

Variable

Points

Prior stroke or TIA

2

Anemia

3

Age ≥75 years at index diagnosis year

1

Age ≥75 years at index diagnosis year

2

Hypertension

1

Severe renal disease

3

Diabetes

1

Prior bleeding

1

Heart failure

1

Hypertension

1

CHADS2 scoring: 0-1 point, low risk; 2 points, moderate risk; ≥3 points, high risk.

ATRIA scoring: 0-3 points, low risk; 4 points, moderate risk; 5-10 points, high risk.

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; TIA, transient ischemic attack.

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Figure 1 Sample Selection Criteria

Medicare beneficiaries identified as patients with AF in 2006-2007 N = 189,835

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Patients with ≥1 claims associated with AF in the 12 months before the index AF diagnosis N = 99,682

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AF patients with claims associated with ICD-9 codes for mitral and/or aortic valvular disease, repair, or replacement; transient AF; or hyperthyroidism N = 10,501

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Patients not eligible for Parts A and B for 12 mo before the index AF and Parts A, B, and D for 12 mo after the index AF or date of death N = 40,382

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Patients who had a stroke on or within 7 days before or after AF index date N = 406

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AF patients with <2 medical claims associated with ICD-9 code of 427.31 during 1/1/06-12/31/07 N = 24,715

AF patients with ≥2 medical claims associated with an ICD-9 diagnosis code of 427.31 during 1/1/06-12/31/07 N = 165,120

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Patients with newly diagnosed AF N = 65,438

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Patients with NVAF N = 54,937

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Patients eligible for Parts A and B for 12 mo before the index AF and eligible for Parts A, B, and D for the lesser of 12 mo after the index AF or date of death N = 14,555

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Patients who did not have a stroke on or within 7 days before or after the AF index date N = 14,149

AF indicates atrial fibrillation; ICD-9, International Classification of Diseases, Ninth Revision; NVAF, nonvalvular atrial fibrillation.

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after the index AF diagnosis. Ischemic strokes were defined as an inpatient or emergency department claim associated with a primary ICD-9 diagnosis of 433.xx, 434.xx, or 436.xx. A major hemorrhage was defined as an inpatient admission with an ICD-9 diagnosis code for either an extracranial hemorrhage in the primary diagnosis position or an ICD-9 code for intracranial hemorrhage in any position of the claim (Appendix 3, page 166).

Statistical Analysis The proportion of patients receiving warfarin within 12 months after the index AF diagnosis was evaluated and compared with guideline recommendations by CHADS2 stroke risk and ATRIA bleeding risk levels.

Specifically, this was the cohort of patients with moderate-to-high stroke risk who were not at high risk for bleeding and filled at least 1 warfarin prescription during the 12 months after the index AF diagnosis.

To assess the effect of warfarin exposure level on the rates of ischemic stroke and major bleeding events for those receiving and not receiving warfarin within 12 months of the index AF diagnosis, incidence rates for ischemic stroke and major bleeding events were separately analyzed, using multivariate logistic regression by controlling for differences in baseline characteristics.

Ischemic stroke rates were also compared in patients with any exposure to warfarin (proportion of days covered >0%), in those with warfarin proportion of days covered exposure ≥80%, and in patients who did not receive warfarin during the 12-month follow-up period.

Covariates included in the ischemic stroke model were age, dual-eligibility (Medicare and Medicaid eligibility) status, and CHADS2 score. Major bleeding event rates were compared for patients who had any exposure to warfarin versus those who did not receive warfarin during the 12-month follow-up period. Covariates included in the major bleeding event model were age, dual-eligibility status (Medicare and Medicaid eligibility), and ATRIA score.

Results A total of 189,835 Medicare beneficiaries with AF were identified by CMS CCW as having AF in 2006 and in 2007. Limiting the sample to AF patients with ≥2 medical claims associated with an ICD-9 diagnosis code of 427.31 from January 1, 2006, to December 31, 2007, reduced the initial cohort to 165,120 beneficiaries with AF. Limiting this sample to patients with newly diagnosed AF reduced the sample size to 65,438, and further limiting the sample to patients with NVAF reduced the sample size to 54,937.

Requiring Medicare Parts A and B eligibility for the 12 months before the AF index and requiring Medicare

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Parts A, B, and D eligibility for the lesser of 12 months after the AF index date or date of death reduced the sample size to 14,555 patients with newly diagnosed NVAF. Removing patients with a stroke on or within 7 days before or after the AF index date reduced the sample size to a final total of 14,149 patients with newly diagnosed NVAF (Figure 1).

Baseline characteristics for patients who received warfarin were generally similar to those who did not receive warfarin within 12 months after the index NVAF diagnosis, with a few noteworthy exceptions.

There was a higher proportion of patients who had dual eligibility for Medicare and Medicaid (12.6% vs 7.6%, respectively), as well as a higher proportion of patients aged ≥85 years (37.1% vs 21.1%, respectively) among those who did not receive warfarin.

The mean CHADS2 score was significantly lower in patients receiving warfarin, and patients not receiving warfarin had a higher mean ATRIA bleeding risk score (3.7 vs 3.2, respectively; Table 2, page 162).

Of the 14,149 patients with newly diagnosed NVAF, 75.8% had moderate or high stroke risk (CHADS2 score ≥2), and 24.5% had high bleeding risk (ATRIA score ≥5). The proportion of patients with high bleeding risk increased from 8% of those with low stroke risk to 43% in the group with high stroke risk (Figure 2, page 163).

Warfarin Use Overall, 6981 (49.3%) patients received warfarin within 12 months of the index AF diagnosis. Figure 3 (page 163) presents the number and proportion of patients who received warfarin within 12 months of the index AF date at each stroke and bleeding risk level.

Warfarin use was lower in the group with a high bleeding risk than in the groups with low/moderate bleeding risk across all stroke risk levels.

Among patients recommended for oral anticoagulation therapy, 41.3% did not receive warfarin within 12 months of the index NVAF diagnosis.

However, warfarin use did not seem to differ across stroke risk levels. Of the 14,149 patients with NVAF included in the study, 10,725 patients (75.8%) had moderate (CHADS2, 2 or 3) or high (CHADS2 ≥4) stroke risk; of these, 7524 patients did not have high bleeding risk (ATRIA ≥5) and would meet the recommendations for oral anticoagulation therapy. Those recommended for oral anticoagulation therapy (moderate-to-high stroke risk and low-to-moderate bleeding risk) comprised 53.2% (7524/14,149) of the study sample of

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Table 2 Baseline Characteristics for Patients with NVAF, by Patient Population

Patients, N Dual-eligible patients, %

Study population of patients with NVAF

Patients not receiving warfarin within 12 moa

Patients receiving warfarin within 12 mo

14,149

6248

7901

12.6

7.6b

79.3 (8.3)

80.9 (8.6)

78.1 (7.9)b

80 (38-106)

82 (38-106)

78 (38-104)

9.8

Age, yr Mean (SD) Median (min-max) Age, % 2.6

2.2

2.9b

65-74 yr

25.7

21.4

29.0b

75-84 yr

43.6

39.3

47.0b

≥85 yr

28.1

37.1

21.1b

Male

41.3

41.5

41.1

Female

58.7

58.5

58.9

2.31 (1.18)

2.35 (1.17)

2.27 (1.18)b

2 (0-6)

2 (0-6)

2 (0-6)

Prior stroke or TIA (2 pt)

10.8

10.6

11.0

Hypertension (1 pt)

79.1

79.2

79.0

Diabetes (1 pt)

26.6

25.4

27.5b

Heart failure (1 pt)

31.5

32.7

30.6b

Age ≥75 yr (1 pt)

71.7

76.4

68.1b

3.43 (2.23)

3.75 (2.32)

3.17 (2.13)b

3 (0-10)

3 (0-10)

3 (0-10)

Anemia (3 pt)

22.0

26.6

18.5b

Severe renal disease (3 pt)

13.4

15.6

11.6b

Prior bleeding (1 pt)

14.0

16.6

12.0b

Hypertension (1 pt)

79.1

79.2

79.0

Age ≥75 yr (2 pt)

71.7

76.4

68.1b

<65 yr

Sex, %

CHADS2 score Mean (SD) Median (min-max) Risk conditions, %

ATRIA score Mean (SD) Median (min-max) Risk conditions, %

a

Includes patients who received warfarin within 12 months, but only after having had a stroke.

P <.05 versus patients not receiving warfarin within 12 months.

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; NVAF, nonvalvular atrial fibrillation; SD, standard deviation; TIA, transient ischemic attack.

b

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Figure 2 Distribution of ATRIA Bleeding Risk Score by CHADS2 Stroke Risk Level (N = 14,149) patients with newly diagnosed NVAF. Among patients recommended for oral anticoagulation therapy, 41.3% (3110/7524) did not receive warfarin within 12 months of the index NVAF diagnosis (Table 3).

High bleeding risk (5-10) Moderate bleeding risk (4) Low bleeding risk (0-3) 100

270 184

90

Stroke and Bleeding Events The unadjusted rate of ischemic stroke during the 12month period after the index NVAF diagnosis was 2.6% for those receiving warfarin within 12 months of the index NVAF versus 5.5% for those not receiving warfarin within 12 months of the index NVAF. After adjusting for age, dual-eligibility status, and CHADS2 score, the risk for ischemic stroke was 49% lower (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.43-0.61; P <.001) for patients receiving warfarin compared with those not receiving warfarin within 12 months.

Among patients who received warfarin within 12 months after the index AF date, 66.74% had warfarin exposure proportion of days covered â&#x2030;Ľ80% during the follow-up period. After adjusting for age, dual-eligibility status, and CHADS2 score using regression, the risk of ischemic stroke for patients with warfarin exposure pro-

900

2301

80

Patients, %

70

773

60 157

50 40

2970

5559

1035

Low stroke risk (0-1)

Moderate stroke risk (2-3)

High stroke risk (4-6)

30 20 10 0

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation.

Figure 3 Actual Warfarin Use, by CHADS2 and ATRIA Risk Level (N = 14,149) Receiving warfarin within 12 months Not receiving warfarin within 12 monthsa 100 90

1779

110

111

3301

414

1051

601

98

436

1191

74

159

2258

359

1250

434

59

464

Low bleeding risk (21% of study sample)

Moderate bleeding risk (1% of study sample)

High bleeding risk (2% of study sample)

Low bleeding risk (39% of study sample)

Moderate bleeding risk (5% of study sample)

Moderate bleeding risk (1% of study sample)

High bleeding risk (6% of study sample)

80

Patients, %

70 60 50 40 30 20 10 0

Low stroke risk

High Low bleeding risk bleeding risk (16% of study (7% of study sample) sample)

Moderate stroke risk

High stroke risk

a Patients who received warfarin within 12 months but only after having had a stroke are not considered to be receiving warfarin within 12 months.

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation.

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Percent of Patients with NVAF Not Receiving Warfarin Table 3 within 12 Months, by CHADS and ATRIA Scores 2 Patient population, % (study sample, %) Low bleeding risk

Moderate bleeding risk

High bleeding risk

Low

40.1 (21.0)

40.2 (1.3)

58.9 (1.9)

Moderate

40.6 (39.3)

46.4 (5.5)

54.3 (16.3)

High

41.9 (7.3)

37.6 (1.1)

51.6 (6.4)

Stroke risk

NOTE: Patients who received warfarin within 12 months but only after having a stroke are not considered to be receiving warfarin within 12 months.

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; NVAF, nonvalvular atrial fibrillation.

portion of days covered â&#x2030;Ľ80% was significantly lower (unadjusted stroke rate of 2.9% vs 4.8%; adjusted OR, 0.586; 95% CI, 0.48-0.72; P <.001) compared with those who had proportion of days covered <80% (including patients who did not receive any warfarin) during the 12-month postindex AF date. However, among warfarin users, no significant difference was seen in ischemic stroke risk between patients with warfarin exposure proportion of days covered â&#x2030;Ľ80% (unadjusted stroke rate, 2.9%) and patients with warfarin exposure proportion of days covered <80% (unadjusted stroke rate, 1.7%; adjusted OR, 0.95; 95% CI, 0.71-1.27).

These findings highlight quality-of-care issues for patients with AF and the need to improve compliance with anticoagulation guidelines in the Medicare population.

The unadjusted major bleeding event rate during the 12-month period after the index AF diagnosis was 6.8% for those receiving warfarin within 12 months of index NVAF versus 6.5% for those not receiving warfarin within 12 months of the index NVAF. After adjusting for age, dual-eligibility status, and ATRIA score using logistic regression, the major bleeding rate for patients who received warfarin was statistically higher (adjusted OR, 1.19; 95% CI, 1.04-1.36; P = .013) than patients who did not receive warfarin within 12 months of the index NVAF. Subgroup analysis found that warfarin exposure was significantly associated with increased bleeding risk in patients aged â&#x2030;Ľ65 years (OR, 1.17; 95% CI, 1.02-1.35; P = .024) but not for patients aged <65 years (OR, 1.32; 95% CI, 0.45-3.91; P = .613).

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Discussion Our results confirm previous studies regarding the underuse of warfarin for patients with NVAF, and the lower rate of stroke for those receiving warfarin. Using INR monitoring claims as a proxy for warfarin use, Mercaldi and colleagues found that 58.5% of patients with NVAF were receiving warfarin, and the incidence of ischemic stroke was 27% lower in patients taking warfarin than in those not taking warfarin.30 Using a similar methodology, Lakshminarayan and colleagues reported a 26% lower risk of ischemic stroke in patients with NVAF taking warfarin.5 We found that 41.3% of patients at moderate-to-high stroke risk and not at high risk of bleeding were not receiving warfarin within 12 months of the index diagnosis, which amounts to 22% of the total patients with AF study sample. For those taking warfarin within 12 months of the index diagnosis, the relative risk of ischemic stroke was 49% lower than for those not taking warfarin within 12 months. The level of ischemic stroke reduction observed in our study fell within similar ranges reported in previous clinical trials,9 where the relative risk reductions of stroke for adjusted-dose warfarin versus aspirin and placebo were 38% and 67%, respectively.

Similar to previous clinical trials, we found that absolute increases in major hemorrhage were less than the absolute reductions in stroke.

These findings highlight quality-of-care issues for patients with AF and the need to improve compliance with anticoagulation guidelines in the Medicare population, which would be associated with fewer stroke-related deaths and lower stroke-related healthcare costs for Medicare. Several studies have emphasized the overestimation of bleeding risk and underestimation of stroke risk as reasons for underprescribing anticoagulants in patients with AF,28,32,33 and our study results corroborate these reports.

We further found that warfarin use was sensitive to bleeding risk, but it did not vary across stroke risk levels.

Although the CHADS2 score has been available and validated for stroke risk stratification for the past decade, and was cited by national treatment guidelines as a tool to determine when oral anticoagulation is warranted, it remains unclear to what extent it has been routinely used in clinical practice to guide decisions on anticoagulation therapy.34 It has been suggested that the CHADS2 score may not be sensitive in stratifying patients clearly into low-, intermediate-, and high-risk groups in clinical practice.34 The more recently developed stroke stratification scheme, CHA2DS2-VASc,15 which was endorsed by European guidelines,35 may provide more specificity on anticoagulation decision, especially in patients with

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moderate stroke risk based on CHADS2. However, the performance of this new scheme in predicting strokes in clinical practice remains to be confirmed.36 These results suggest the need for action by health insurers and policymakers to develop programs to aid clinicians to overcome the clinical decision challenges in prescribing oral anticoagulation therapy for the population with NVAF. The strength of this study is the use of Medicare Part D data to evaluate warfarin use among patients with NVAF who are recommended for oral anticoagulation therapy and, in particular, the identification of patients with newly diagnosed NVAF and their use of warfarin after the index diagnosis. Past studies have used a proxy of INR testing to establish warfarin use, and dates of service have been unavailable to precisely identify an index diagnosis date and stroke incidence date after the diagnosis of NVAF. Studies that do not have precise start dates of warfarin and stroke incidence dates may inadvertently assign individuals to the group receiving warfarin when in fact they were prescribed warfarin after their stroke occurred.

This will understate the outcomes differences between the groups taking and not taking warfarin. We have tried to control for this by identifying patients who are newly diagnosed with NVAF and excluding strokes that occur 7 days before or after the index diagnosis, and by excluding from the cohort receiving warfarin within 12 months, those receiving warfarin within 12 months but only after a stroke.

Novel oral anticoagulants, including dabigatran and rivaroxaban, have recently been approved for stroke prevention in US patients with AF. Clinical studies have shown that these new agents have either similar or better efficacy in preventing stroke while having a lower risk for intracranial bleeding than warfarin. Future studies are needed to determine whether these newer agents would reduce underutilization of anticoagulation therapy for stroke prevention in patients with AF. Additional studies to assess compliance of warfarin and novel oral anticoagulants and their implications on patient outcomes are also warranted.

Limitations The present study has several limitations. First, it shares the limitations associated with all administrative claims studies, and it depends on accurate and complete coding practices by providers. Because of data availability, we were limited to a 12-month period preceding the index AF diagnosis to determine whether a patient was newly diagnosed with AF. This methodology cannot rule out the exclusion of all existing patients with AF, because it is possible that a patient with AF may not get coded with AF during a 12-month preindex period, especially if other

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conditions become more prominent in the patientâ&#x20AC;&#x2122;s care.

An insufficient preindex period may also underestimate the prevalence of the risk factors for the CHADS2 stroke and ATRIA bleeding risk schemes, leading to lower than actual stroke and bleeding risk levels. In addition, clinical information not available in claims data and inaccurate coding practice may introduce bias when determining stroke and bleeding risk levels in this study.

Studies that do not have precise start dates of warfarin and stroke incidence dates may inadvertently assign individuals to the group receiving warfarin when in fact they were prescribed warfarin after their stroke occurred.

Because we required Medicare patients to have 12 months of eligibility before the index diagnosis, we inadvertently excluded 65-year-old Medicare beneficiaries who are new to Medicare through aging. Therefore, our patient selection methodology may have resulted in a slightly older population, which can impact risk factor prevalence. Warfarin use and level of warfarin exposure were identified by filled warfarin prescription claims, which may not accurately represent patient adherence to warfarin therapy.

In this study, we used the ATRIA bleeding risk scheme as a tool to stratify patients into different bleeding risk levels. Different bleeding risk assessment schemes have been developed for the past decade.

Current treatment guidelines for anticoagulation do not specify a standard instrument that should be used for bleeding risk assessment. We arbitrarily chose to use the ATRIA bleeding risk scheme because it was developed and validated based on administrative claims data of patients receiving warfarin. The ATRIA bleeding risk scheme has been shown to identify a higher proportion of patients at high bleeding risk and higher major bleeding rates than other bleeding risk schemes.18 Therefore, our estimate that 53.2% of patients with NVAF are eligible for oral anticoagulation therapy (ie, at moderateto-high stroke risk and not at high bleeding risk) is a conservative estimate, because using other bleeding risk schemes may lead to a higher proportion of patients with NVAF being eligible for oral anticoagulation therapy.

Further studies are needed to confirm our study findings.

Conclusion AF is a prevalent disease in the Medicare population, with patients with AF having a 5-fold higher risk of

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Appendix 1 ICD-9/CPT Codes for Exclusion Criteria ICD-9/CPT codes Type of 1 inpatient, emergency department, observacondition/event tion stay, or physician E/M claim with ICD-9 code in any position of the claim Valvular AF exclusions

Valvular AF exclusions

35.00-35.04, 35.10-35.14, 35.2-35.28, 35.335.35, 35.39, 35.4-35.42, 35.5-35.54, 35.6-35.63, 35.7-35.73, 36.1-36.17, 36.19, 37.1-37.12, 37.3-37.33, 37.4

Appendix 3 Diagnosis Codes Used to Identify Major Hemorrhage ICD-9 codes 423.0, 430.**, 431.**, 432.**, 852.0*, Major hemorrhage 852.2*, 852.4*, 853.0*, 455.2, 455.5, 455.8, 456.0, 456.20, 459.0, 530.7, 530.82, 531.00, 531.01, 531.20, 531.21, 531.40, 531.41, 531.60, 531.61, 533.01, 533.20, 533.21, 533.40, 533.41, 533.60, 533.61, 534.00, 534.01, 534.20, 534.21, 534.40, 534.41, 534.60, 534.61, 535.11, 535.21, 535.31, 535.41, 535.51, 535.61, 537.83, 562.02, 562.03, 562.12, 562.13, 568.81, 569.3, 569.85, 578, 578.0, 578.1, 578.9, 593.81, 599.7, 719.10, 719.11, 719.12, 719.13, 719.14, 719.15, 719.16, 719.17, 719.18, 719.19, 784.7, 784.8, 786.3

394.0, 394.2, 396.0, 396.1, 396.8, V42.2, V43.3, 242

AF indicates atrial fibrillation; CPT, Current Procedural Terminology; E/M, evaluation and management; ICD-9, International Classification of Diseases, Ninth Revision.

CPT copyright 2012 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

Diagnosis Codes Used to Identify CHADS Stroke Appendix 2 Risk and ATRIA Bleeding Risk Factors 2 Risk factor

1 inpatient claim with ICD-9 code 430.**, 431.**, 432.**, 852.0*, 852.2*, 852.4*, 853.0* in any position of the

ICD-9 codes

claim and the remaining ICD-9 codes in the primary position of the claim

Prior stroke/TIA 433.xx, 434.xx, 435.0, 435.1, 435.2, 435.3, 435.8, 435.9

ICD-9 indicates International Classification of Diseases, Ninth Revision.

Hypertension

401.xx-405.x

Diabetes

250.xx

Heart failure

398.91, 402.01, 402.11, 425.1, 425.4, 425.7, 428.xx

Anemia

285.1, 282.41, 282.42, 282.5, 282.60-282.64, 282.68, 282.69, 280.1, 280.8, 280.9, 281.0, 281.1, 281.2, 281.3, 281.4, 281.8, 281.9, 284.0, 284.01, 284.09, 284.1, 284.8, 284.81, 284.89, 284.9, 280, 283.0, 283.1, 283.11, 283.19, 283.2, 283.9, 282.0, 282.1, 282.2, 282.3, 282.4, 282.49, 282.7, 282.8, 282.9, 284.2, 285.0, 285.21, 285.22, 285.29, 285.8, 285.9

Severe renal disease

584, 584.5, 584.6, 584.7, 584.8, 584.9, 585, 585.3, 585.4, 585.5, 585.6, 585.9, 586, 792.5, V420, V451, V4511, V4512, V560, V561, V562, V5631, V5632, V568

Bleeding

423.0, 430.**, 431.**, 432.**, 852.0*, 852.2*, 852.4*, 853.0*, 455.2, 455.5, 455.8, 456.0, 456.20, 459.0, 530.7, 530.82, 531.00, 531.01, 531.20, 531.21, 531.40, 531.41, 531.60, 531.61, 533.01, 533.20, 533.21, 533.40, 533.41, 533.60, 533.61, 534.00, 534.01, 534.20, 534.21, 534.40, 534.41, 534.60, 534.61, 535.11, 535.21, 535.31, 535.41, 535.51, 535.61, 537.83, 562.02, 562.03, 562.12, 562.13, 568.81, 569.3, 569.85, 578, 578.0, 578.1, 578.9, 593.81, 599.7, 719.10, 719.11, 719.12, 719.13, 719.14, 719.15, 719.16, 719.17, 719.18, 719.19, 784.7, 784.8, 786.3

ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; ICD-9, International Classification of Diseases, Ninth Revision; TIA, transient ischemic attack.

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stroke than those without AF. Strokes in the AF population are more severe and disabling than in patients without AF. Oral anticoagulation significantly reduces the risk of stroke for patients with AF, yet there is continued underuse of anticoagulation therapy for this population.

Notwithstanding its limitation, this study corroborates results from the previous literature and highlights the need for quality improvement initiatives to reduce underuse of oral anticoagulation in patients with clinically indicated AF to reduce stroke-related mortality and healthcare resource use.

Funding Source The study and the preparation of this manuscript were funded by Daiichi Sankyo, Inc. Author Disclosure Statement Ms Fitch, Mr Broulette, Mr Pyenson, and Mr Iwasaki have reported no conflicts of interest. Dr Kwong is an employee of Daiichi Sankyo, Inc.

References 1. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the longterm risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med. 2002;113:359-364.

2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.

3. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention. Ann Intern Med. 1999;131:688-695.

4. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27:1760-1764.

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5. Lakshminarayan K, Solid CA, Collins AJ, et al. Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002). Stroke.

2006;37:1969-1974.

6. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;104:1534-1539.

7. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001;285:2370-2375.

8. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.

9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

10. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817.

11. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

12. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.

13. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123:1144-1150.

14. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.

JAMA. 2001;285:2864-2870.

15. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest. 2010;137:263-272.

16. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151:713-719.

17. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-1100.

18. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58:395-401.

19. Fang MC, Stafford RS, Ruskin JN, Singer DE. National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation. Arch Intern Med. 2004;164: 55-60.

20. Waldo AL, Becker RC, Tapson VF, et al. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation.

J Am Coll Cardiol. 2005;46:1729-1736.

21. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med. 2000;160:967-973.

22. Glazer N, Dublin S, Smith NL, et al. Newly detected atrial fibrillation and compliance with antithrombotic guidelines. Arch Intern Med. 2007;167:246-252.

23. Boulanger L, Kim J, Friedman M, et al. Patterns of use of antithrombotic therapy and quality of anticoagulation among patients with non-valvular atrial fibrillation in clinical practice. Int J Clin Pract. 2006;60:258-264.

24. Harley CR, Riedel AA, Hauch O, et al. Anticoagulation therapy in patients with chronic atrial fibrillation: a retrospective claims data analysis. Curr Med Res Opin.

2005;21:215-222.

25. Kneeland PP, Fang MC. Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism.

Patient Prefer Adherence. 2010;4:51-60.

26. Gross CP, Vogel EW, Dhond AJ, et al. Factors influencing physicians’ reported use of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional survey. Clin Ther. 2003;25:1750-1764.

27. Walker AM, Bennett D. Epidemiology and outcomes in patients with atrial fibrillation in the United States. Heart Rhythm. 2008;5:1365-1372.

28. Bungard TJ, Ghali WA, Teo KK, et al. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med. 2000;160:41-46.

29. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765.

30. Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulation with warfarin to prevent stroke in medicare beneficiaries with nonvalvular atrial fibrillation. Stroke. 2011;42:112-118.

31. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA. 2003;290:2685-2692.

32. Bungard TJ, Ghali WA, McAlister FA, et al. The relative importance of barriers to the prescription of warfarin for nonvalvular atrial fibrillation. Can J Cardiol. 2003; 19:280-284.

33. Beyth RJ, Antani MR, Covinsky KE, et al. Why isn’t warfarin prescribed to patients with nonrheumatic atrial fibrillation? J Gen Intern Med. 1996;11:721-728.

34. Klein D, Levine M. Are family physicians using the CHADS2 score? Is it useful for assessing risk of stroke in patients with atrial fibrillation? Can Fam Physician.

2011;57:e305-e309.

35. Camm AJ, Kirchhof P, Lip GY, et al, for the European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.

36. Singer DE, Fang MC, Go AS. CHA2DS2-VASc risk scheme not ready for clinical use. Chest. 2010;138:1020; author reply 1020-1021.

STAKEHOLDER PERSPECTIVE Warfarin Utilization in Medicare Patients with Nonvalvular Atrial Fibrillation: Sentinel Data from an Administrative Claims Database PROVIDERS/PATIENTS: Warfarin is the primary therapy for reducing the risk of thromboembolic events in patients with atrial fibrillation (AF).

Treatment guidelines recommend oral anticoagulation in patients with AF who are at moderate-to-high risk for stroke but with no high bleeding risk.1 Underutilization of warfarin in clinical practice in patients with AF appears to stem from intrinsic limitations

that include food and drug interactions, the need for regular blood monitoring, and dose adjustments to maintain anticoagulation levels within the recommended international normalized ratio (INR).2 Newer anticoagulant agents, such as apixaban, dabigatran, and rivaroxaban, are also effective in reducing the risk for stroke in patients with AF, while having a lower risk of intracranial bleeding compared with warfarin.3,4 (Continued)

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STAKEHOLDER PERSPECTIVE (Continued) However, compliance with guidance also may be dictated by nonpharmacologic variables within the system, the physician, and the patient. The need to understand the underlying causes of deviation from guidelines in the use of anticoagulation therapy in clinical practice has implications that transcend therapeutic class.

RESEARCHERS: Warfarin underutilization in the Medicare population with nonvalvular AF (NVAF) is confirmed in this new research by Fitch and colleagues: 41% of patients with NVAF with moderate-high stroke and low bleeding risk did not receive warfarin within 12 months of the index NVAF diagnosis, which is approximately 22% of the total AF data set. In contrast with previous studies, where warfarin use was inferred using INR ratios and prothrombin time as proxies,5 the approach in the current study uses Medicare Parts A and B claims data linked to Part D claims information to provide a precise estimate of warfarin use, including date of service for each claim.

The methodology in this study illustrates a “state-ofthe-art” approach to the use of administrative claims data for estimating utilization in a naturalistic setting, yielding estimates for risk reductions for stroke versus increases in major hemorrhage, which nevertheless were congruent with randomized trials. Selection criteria and the impact on sample size at each decision point are described, eligibility criteria that are associated with stroke and major hemorrhage events parallel the care taken in the characterization of warfarin usage, and statistical analyses adjust for prognostically important confounders. The discussion of research methodology is a model of an objective exposé of strengths and limitations of this method.

PAYERS/POLICYMAKERS: This study corroborates previous findings that have demonstrated the clinical value of anticoagulation therapy for prevention of

stroke in patients with AF with appropriate risk stratification. Although no information on the cost burden of AF with or without antithrombotic prophylaxis is provided, previous research has estimated the healthcare cost burden in patients with AF in a privately insured population6 and the US population,7 with significant cost-savings for Medicare patients with NVAF taking warfarin based on multivariate modeling.5 Clinical decision barriers that limit warfarin utilization provide a catalyst for quality control interventions, because available algorithms for risk stratification, such as CHADS2, may poorly stratify patients or incompletely penetrate the practice environment. In addition, evaluating the interaction of pharmacotherapy and system attributes with physician and patient perception of benefit versus risk for oral anticoagulation in NVAF is needed to provide a 3-dimensional characterization of the significant gap in critical prophylactic care.

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials 1. European Heart Rhythm Association; European Association for CardioThoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.

2. Bungard TJ, Ghali WA, Teo KK, et al. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med. 2000;160:41-46.

3. Mega JL. A new era for anticoagulation in atrial fibrillation. N Engl J Med. 2011; 365:1052-1054.

4. Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012 Apr 24. [Epub ahead of print].

5. Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation. Stroke. 2011;42:112-118.

6. Wu EQ, Birnbaum HG, Mareva M, et al. Economic burden and comorbidities of atrial fibrillation in a privately insured population. Curr Med Res Opin. 2005;21: 1693-1699.

7. Bajpai A, Savelieva I, Camm AJ. Epidemiology and economic burden of atrial fibrillation. US Cardiovascular Dis. 2007;4:14-17.

Correction In the March/April issue of the journal, the article titled, “Benefits of novel oral anticoagulant agents for thromboprophylaxis after total hip or knee arthroplasty” (2012;3[4]:115-122) contained 2 errors.

On page 117, the following statement is incorrect: “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.” The correct sentence should have read: “For example, a patient aged >75

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years who weighs <50 kg and has compromised renal function is at increased risk for having a major bleeding event.”

On page 119, the following statement is incorrect: “Dabigatran requires a dose adjustment if creatinine clearance is <50 mL/min.” The correct statement should have read: “Dabigatran requires a dose adjustment if creatinine clearance is <30 mL/min.”

This article has been corrected online at www.AHDBonline.com.

www.AHDBonline.com

May/June 2012

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Vol 5, No 3

Help manage

MANY THREATS: Rheumatoid Arthritis.

Psoriatic Arthritis.

Ankylosing Spondylitis.

Indications1 Moderate to severe rheumatoid arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

Psoriatic arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.

Ankylosing spondylitis: HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Please see Brieff Summa Summary ary y of full Prescribing Information on last pages off this advertisement.

ONE

40 mg every other week. Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Safety Considerations1 Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Malignancies: Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA. Other Serious Adverse Reactions: Patients treated with HUMIRA also may be at risk for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

Please see Importantt Safety Information, including BOXED WARNING on Serious Infections and Malignancy, on the following page.

IMPORTANT SAFETY INFORMATION1 SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

HUMIRA should be discontinued if a patient develops a serious infection or sepsis.

Reported infections include: s !CTIVE TUBERCULOSIS 4" INCLUDING REACTIVATION OF LATENT 4" 0ATIENTS WITH 4" HAVE FREQUENTLY PRESENTED WITH DISSEMINATED OR EXTRAPULMONARY DISEASE 0ATIENTS SHOULD BE TESTED FOR LATENT 4" BEFORE (5-)2! USE AND DURING THERAPY 4REATMENT FOR LATENT 4" SHOULD BE INITIATED PRIOR TO (5-)2! USE s )NVASIVE FUNGAL INFECTIONS INCLUDING HISTOPLASMOSIS

COCCIDIOIDOMYCOSIS CANDIDIASIS ASPERGILLOSIS BLASTOMYCOSIS AND PNEUMOCYSTOSIS 0ATIENTS WITH HISTOPLASMOSIS OR OTHER INVASIVE FUNGAL INFECTIONS MAY PRESENT WITH DISSEMINATED

RATHER THAN LOCALIZED DISEASE !NTIGEN AND ANTIBODY TESTING FOR HISTOPLASMOSIS MAY BE NEGATIVE IN SOME PATIENTS WITH ACTIVE INFECTION %MPIRIC ANTI FUNGAL THERAPY SHOULD BE CONSIDERED IN PATIENTS AT RISK FOR INVASIVE FUNGAL INFECTIONS WHO DEVELOP SEVERE SYSTEMIC ILLNESS s "ACTERIAL VIRAL AND OTHER INFECTIONS DUE TO OPPORTUNISTIC PATHOGENS INCLUDING ,EGIONELLA AND ,ISTERIA 4HE RISKS AND BENElTS OF TREATMENT WITH (5-)2! SHOULD BE CAREFULLY CONSIDERED PRIOR TO INITIATING THERAPY IN PATIENTS WITH CHRONIC OR RECURRENT INFECTION 0ATIENTS SHOULD BE CLOSELY MONITORED FOR THE DEVELOPMENT OF SIGNS AND SYMPTOMS OF INFECTION DURING AND AFTER TREATMENT WITH (5-)2!

INCLUDING THE POSSIBLE DEVELOPMENT OF 4" IN PATIENTS WHO TESTED NEGATIVE FOR LATENT 4" INFECTION PRIOR TO INITIATING THERAPY s $O NOT START (5-)2! IN PATIENTS WITH AN ACTIVE INFECTION INCLUDING LOCALIZED INFECTIONS s 0ATIENTS OLDER THAN YEARS PATIENTS WITH CO MORBID CONDITIONS AND OR PATIENTS TAKING CONCOMITANT IMMUNOSUPPRESSANTS MAY BE AT GREATER RISK OF INFECTION s %XERCISE CAUTION IN PATIENTS WITH CHRONIC OR RECURRENT INFECTION OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE THEM TO INFECTION PATIENTS WHO HAVE BEEN EXPOSED TO 4" PATIENTS WITH A HISTORY OF OPPORTUNISTIC INFECTION OR PATIENTS WHO HAVE RESIDED OR TRAVELED IN REGIONS WHERE 4" OR MYCOSES ARE ENDEMIC s 0ATIENTS WHO DEVELOP A NEW INFECTION SHOULD UNDERGO A PROMPT AND COMPLETE DIAGNOSTIC WORKUP AND APPROPRIATE ANTIMICROBIAL THERAPY SHOULD BE INITIATED s $RUG INTERACTIONS WITH BIOLOGIC PRODUCTS #ONCURRENT USE OF ANAKINRA OR ABATACEPT WITH (5-)2! IS NOT RECOMMENDED AS THE COMBINATION OF ANAKINRA OR ABATACEPT WITH 4.& BLOCKERS HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF SERIOUS INFECTIONS 4HIS RISK HAS ALSO BEEN OBSERVED WITH RHEUMATOID ARTHRITIS PATIENTS TREATED WITH RITUXIMAB WHO RECEIVED SUBSEQUENT TREATMENT WITH A 4.& BLOCKER -!,)'.!.#9 ,YMPHOMA AND OTHER MALIGNANCIES SOME FATAL HAVE BEEN REPORTED IN CHILDREN AND ADOLESCENT PATIENTS TREATED WITH 4.& BLOCKERS OF WHICH (5-)2! IS A MEMBER 0OSTMARKETING CASES OF HEPATOSPLENIC 4 CELL LYMPHOMA (34#, A RARE TYPE OF 4 CELL LYMPHOMA HAVE BEEN REPORTED IN PATIENTS TREATED WITH 4.& BLOCKERS INCLUDING (5-)2!

4HESE CASES HAVE HAD A VERY AGGRESSIVE DISEASE COURSE AND HAVE BEEN FATAL 4HE MAJORITY OF REPORTED 4.& BLOCKER CASES HAS OCCURRED IN PATIENTS WITH #ROHN S DISEASE OR ULCERATIVE COLITIS AND THE MAJORITY WERE IN ADOLESCENT AND YOUNG ADULT MALES !LMOST ALL THESE PATIENTS HAD RECEIVED TREATMENT WITH AZATHIOPRINE OR MERCAPTOPURINE CONCOMITANTLY WITH A 4.& BLOCKER AT OR PRIOR TO DIAGNOSIS )T IS UNCERTAIN WHETHER THE OCCURRENCE OF (34#, IS RELATED TO USE OF A 4.& BLOCKER OR A 4.& BLOCKER IN COMBINATION WITH THESE OTHER IMMUNOSUPPRESSANTS s 4HE RISKS AND BENElTS OF (5-)2! TREATMENT SHOULD BE CONSIDERED PRIOR TO INITIATING OR CONTINUING THERAPY IN A PATIENT WITH KNOWN MALIGNANCY s -ORE CASES OF MALIGNANCIES WERE OBSERVED AMONG (5-)2! TREATED PATIENTS COMPARED TO CONTROL PATIENTS IN CLINICAL TRIALS

s .ON MELANOMA SKIN CANCER .-3# HAS BEEN REPORTED DURING CLINICAL TRIALS FOR (5-)2! TREATED PATIENTS !LL PATIENTS PARTICULARLY THOSE WITH HISTORY OF PROLONGED IMMUNOSUPPRESSANT OR 056! THERAPY SHOULD BE EXAMINED FOR THE PRESENCE OF .-3# PRIOR TO AND DURING TREATMENT WITH (5-)2! s )N (5-)2! CLINICAL TRIALS THERE WAS AN APPROXIMATE FOLD HIGHER RATE OF LYMPHOMA THAN EXPECTED IN THE GENERAL 5 3 POPULATION 0ATIENTS WITH CHRONIC INmAMMATORY DISEASES PARTICULARLY WITH HIGHLY ACTIVE DISEASE AND OR CHRONIC EXPOSURE TO IMMUNOSUPPRESSANT THERAPIES MAY BE AT HIGHER RISK OF LYMPHOMA THAN THE GENERAL POPULATION EVEN IN THE ABSENCE OF 4.& BLOCKERS s 0OSTMARKETING CASES OF ACUTE AND CHRONIC LEUKEMIA WERE REPORTED WITH 4.& BLOCKER USE s !PPROXIMATELY HALF OF THE POSTMARKETING CASES OF MALIGNANCIES IN CHILDREN ADOLESCENTS AND YOUNG ADULTS RECEIVING 4.& BLOCKERS WERE LYMPHOMAS OTHER CASES INCLUDED RARE MALIGNANCIES ASSOCIATED WITH IMMUNOSUPPRESSION AND MALIGNANCIES NOT USUALLY OBSERVED IN CHILDREN AND ADOLESCENTS HYPERSENSITIVITY s !NAPHYLAXIS AND ANGIONEUROTIC EDEMA HAVE BEEN REPORTED RARELY FOLLOWING (5-)2! ADMINISTRATION s )F A SERIOUS ALLERGIC REACTION OCCURS STOP (5-)2! AND INSTITUTE APPROPRIATE THERAPY (%0!4)4)3 " 6)253 2%!#4)6!4)/. s 5SE OF 4.& BLOCKERS INCLUDING (5-)2!

MAY INCREASE THE RISK OF REACTIVATION OF HEPATITIS " VIRUS ("6 IN PATIENTS WHO ARE CHRONIC CARRIERS 3OME CASES HAVE BEEN FATAL s 0ATIENTS AT RISK FOR ("6 INFECTION SHOULD BE EVALUATED FOR PRIOR EVIDENCE OF ("6 INFECTION BEFORE INITIATING 4.& BLOCKER THERAPY s %XERCISE CAUTION IN PATIENTS WHO ARE CARRIERS OF ("6 AND MONITOR THEM DURING AND AFTER TREATMENT WITH (5-)2! s $ISCONTINUE (5-)2! AND BEGIN ANTIVIRAL THERAPY IN PATIENTS WHO DEVELOP ("6 REACTIVATION s %XERCISE CAUTION WHEN CONSIDERING RESUMPTION OF (5-)2! THERAPY AFTER APPROPRIATE TREATMENT FOR ("6 .%52/,/')# 2%!#4)/.3 s 4.& BLOCKERS INCLUDING (5-)2!

HAVE BEEN ASSOCIATED IN RARE CASES WITH NEW ONSET OR EXACERBATION OF CENTRAL NERVOUS SYSTEM AND PERIPHERAL DEMYELINATING DISEASES INCLUDING MULTIPLE SCLEROSIS OPTIC NEURITIS AND 'UILLAIN "ARRÏ

SYNDROME s %XERCISE CAUTION WHEN CONSIDERING (5-)2! FOR PATIENTS WITH THESE DISORDERS (%-!4/,/')# 2%!#4)/.3 s 2ARE REPORTS OF PANCYTOPENIA INCLUDING APLASTIC ANEMIA HAVE BEEN REPORTED WITH 4.& BLOCKERS -EDICALLY SIGNIlCANT CYTOPENIA E G THROMBOCYTOPENIA LEUKOPENIA HAS BEEN INFREQUENTLY REPORTED WITH (5-)2! s #ONSIDER STOPPING (5-)2! IN PATIENTS WITH SIGNIlCANT HEMATOLOGIC ABNORMALITIES #/.'%34)6% (%!24 &!),52% s 7ORSENING OR NEW ONSET CONGESTIVE HEART FAILURE #(& MAY OCCUR s %XERCISE CAUTION IN PATIENTS WITH #(& AND MONITOR THEM CAREFULLY !54/)--5.)49 s 4REATMENT WITH (5-)2! MAY RESULT IN THE FORMATION OF AUTOANTIBODIES AND RARELY IN DEVELOPMENT OF A LUPUS LIKE SYNDROME s $ISCONTINUE TREATMENT IF SYMPTOMS OF A LUPUS LIKE SYNDROME DEVELOP )--5.):!4)/.3 s 0ATIENTS ON (5-)2! SHOULD NOT RECEIVE LIVE VACCINES s )T IS RECOMMENDED THAT JUVENILE IDIOPATHIC ARTHRITIS PATIENTS IF POSSIBLE

BE BROUGHT UP TO DATE WITH ALL IMMUNIZATIONS IN AGREEMENT WITH CURRENT IMMUNIZATION GUIDELINES PRIOR TO INITIATING (5-)2! THERAPY !$6%23% 2%!#4)/.3 s 4HE MOST COMMON ADVERSE REACTIONS IN (5-)2! CLINICAL TRIALS INCIDENCE WERE INFECTIONS E G UPPER RESPIRATORY SINUSITIS

INJECTION SITE REACTIONS HEADACHE AND RASH

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

Please see Brief Summary of full Prescribing Information on the following pages of this advertisement. ©2012 Abbott Laboratories Abbott Park, IL 60064 64C-758606 January 2012 Printed in U.S.A.

HUMIRA® (adalimumab) WARNINGS: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

HUMIRA should be discontinued if a patient develops a serious infection or sepsis.

Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before HUMIRA use and during therapy. Treatment for latent TB should be initiated prior to HUMIRA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with HUMIRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. [See Warnings and Precautions and Adverse Reactions] MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member. [See Warnings and Precautions] Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males.

Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate.

Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warnings and Warnings and Precautions].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS (see also Boxed WARNINGS) Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions].

Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection.

Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating HUMIRA and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy.

Anti-tuberculosis therapy should also be considered prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating antituberculosis therapy is appropriate for an individual patient.

Tuberculosis should be strongly considered in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with HUMIRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.

Invasive Fungal Infections For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Malignancies The risks and benefits of TNF-blocker treatment including HUMIRA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.

Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNFblocker-treated adult patients compared to control-treated adult patients.

During the controlled portions of 32 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.93) per 100 patientyears among 6694 HUMIRA-treated patients versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 control-treated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).

In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.

Non-Melanoma Skin Cancer During the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.50, 1.11) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.06, 0.56) per 100 patient-years among control-treated patients. All patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF blocker-treated patients compared to control-treated patients. In the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, 3 lymphomas occurred among 6694 HUMIRA-treated patients versus 1 among 3749 control-treated patients. In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps with a median duration of approximately 0.6 years, including 22,026 patients and over 32,000 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development

of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNFblocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy Ū 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months).

Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

Hypersensitivity Reactions In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients.

Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus.

In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known.

Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities.

Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNFblocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions].

Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully.

Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions].

Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines.

Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions].

ADVERSE REACTIONS Clinical Studies Experience The most serious adverse reactions were: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] The most common adverse reaction with HUMIRA was injection site reactions.

In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Infections In the controlled portions of the 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions].

Tuberculosis and Opportunistic Infections In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions].

Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown.

Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ū 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ū 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of controltreated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ū 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients.

Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibodypositive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy.

In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.

Other Adverse Reactions The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebocontrolled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week.

Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

Table 1. Adverse Reactions Reported by Ű5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis Studies HUMIRA 40 mg subcutaneous Placebo Every Other Week (N=690) (N=705) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests* Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction ** 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3% * Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs.

HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.

A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers.

Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment.

In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.

Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment.

In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment.

No patient developed clinical signs of autoimmunity during the clinical trial.

Approximately 15% of children treated with HUMIRA developed mild-tomoderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.

Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV. Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 patients with Crohn’s disease in four placebo-controlled and two open-label extension studies. The safety profile for patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 patients with plaque psoriasis in placebocontrolled and open-label extension studies. The safety profile for patients with plaque psoriasis treated with HUMIRA was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).

Postmarketing Experience Adverse reactions have been reported during post-approval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar) Vascular disorders: Systemic vasculitis

DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biologic Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker.

There is insufficient information to provide recommendations regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, Crohn’s Disease, and plaque psoriasis.

Live Vaccines Live vaccines should not be given concurrently with HUMIRA [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed.

Pregnancy Registry: To monitor outcomes of pregnant women exposed to HUMIRA, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-877-311-8972.

Nursing Mothers It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HUMIRA, 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 efficacy of HUMIRA in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established.

Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age.

HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg.

The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions [see Adverse Reactions].

Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNFblockers including HUMIRA [see Warnings and Precautions].

Geriatric Use A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 ye ars of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of HUMIRA were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.

PATIENT COUNSELING INFORMATION Patients or their caregivers should be provided the HUMIRA “Medication Guide” and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.

Patient Counseling Patients should be advised of the potential benefits and risks of HUMIRA. Physicians should instruct their patients to read the Medication Guide before starting HUMIRA therapy and to reread each time the prescription is renewed.

• Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.

• Malignancies Patients should be counseled about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Patients should be advised to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex.

• Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

Revised: December, 2011 Ref: 03-A569-R27 Abbott Laboratories North Chicago, IL 60064, U.S.A. Master # 64C-758202 64C-758606

AMCP HIGHLIGHTS

The following summaries of posters presented at the 2012 Annual Meeting of the Academy of Managed Care Pharmacy (AMCP), April 18-20, 2012, in San Francisco, represent areas of direct relevance to payers, employers, providers, and other healthcare stakeholders.

Electronic Service Alerts Providers of Low-Cost Drugs, Shows Significant Cost-Savings Identifying low-cost medication alternatives can be time-consuming and is often therefore not followed by clinicians. A group of pharmacists led by Nicole Allie, PharmD, CGP, at Atrius Health, Watertown, MA, instituted the Chart Flag Service, a program designed to alert prescribing providers, in real time, on appropriate, lowcost medication alternatives.

This service involves a monthly list of patients with upcoming appointments who are prescribed nonpreferred medications. If the pharmacist determines an alternate preferred medication is appropriate for the patient, the clinician is notified by e-mail the day before an appointment and via notations in the clinician’s electronic schedule.

To evaluate the effectiveness of the Chart Flag Service at Atrius Health—an alliance of 5 multispecialty groups serving approximately 700,000 patients at 24 eastern Massachusetts sites—a survey was sent to 178 clinicians and 12 clinical pharmacists.

Overall, a 2-week analysis showed significant cost-savings, with an average cost-saving of $78.33 per lower-cost medication recommendation. The total annual savings for the group of patients included in this analysis was estimated at $51,014. A conservative estimate of the total savings for the program for 1 year is approximately $850,000.

Of the 25% of clinicians who responded to the survey, 80% found that a recommended medication switch could be completed in ≤5 minutes. Clinicians followed 31.1% of the medication-switching recommendations, and the program was considered useful by 84% of the responding clinicians.

Alternate medications were considered appropriate for 30.6% of the 849 patient appointments. The service was considered useful or very useful by 83% of clinical pharmacist respondents. [Allie N, Lubelczyk E, Robin S. Success with electronic chart flags to alert clinicians about medication cost-savings opportunities at the time of patient visits.] ■

Consumer-Directed Health Plans’ Impact on Medication Adherence in Chronic Conditions Enrollment in consumer-directed health plans (CDHPs) has evolved as a strategy to control healthcare costs and improve member satisfaction. According to the Mercer National Survey of Employer-Sponsored Health Plans, in 2010, 10% of employers offered their employees CDHPs; in 2011, that grew to 13%; and by June 8, 2012, 10% of employers offered CDHPs to their employees.

Including a preventive therapy option—which excludes drugs for chronic conditions from the member’s deductible and typically offers a lower cost-sharing to members—may contribute to better value by increasing member access to medications for chronic diseases, according to Shalini Thuppal Prakash, BPharm, MS, of CVS Caremark, Northbrook, IL. Mr Prakash compared adherence outcomes among CDHPs that offered a preventive therapy option, those that did not, and traditional health plans. Previous studies have shown that medication adherence can result in cost-savings to members, in addition to improving outcomes.

Using an integrated database of administrative pharmacy claims, Mr Prakash analyzed quarterly data (spanning the year 2010) from 47 clients with more than 1.2 million members in voluntary CDHPs and 1.8 million members in

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traditional health plans. Approximately 305,000 CDHP members had a preventive therapy option.

Adherence to medications for chronic diseases was significantly greater in CDHPs that offered a preventive therapy option than CDHPs without such an option— 65% versus 60%, respectively, for antidiabetes drugs; 69% versus 63%, respectively, for antihypertensive medications; and 67% versus 61%, respectively, for cholesterol-lowering drugs. However, the differences were not significant compared with traditional plans.

In addition, fewer members stopped taking their antihypertensive agents in CDHPs with a preventive therapy option compared with plans with no preventive therapy option (26% vs 30%, respectively) or cholesterol-lowering drugs (26% vs 29%, respectively); the one exception was for antidiabetes medications (33% vs 24%, respectively).

Finally, cost-sharing for prescription drugs was significantly greater in CDHPs than in the traditional plans— 34% versus 19%, respectively, for CDHP with a preventive therapy option (and 39% for CDHPs with no preventive therapy option). [Prakash TS. Consumer directed health plans (CDH plans): impact on member adherence to chronic condition medications.] ■ Continued

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High-Deductible Health Plans: Mixed Results in Clinical Outcomes, Associated Costs The use of high-deductible health plans (HDHPs) is a growing strategy by employers to control costs, who claim that they encourage member responsibility and reduce unnecessary care utilization. Opponents of HDHPs suggest that this may result in some members going without necessary care. Katrina Moore, PharmD, and colleagues at SelectHealth, Murray, UT, conducted a retrospective database analysis to compare medical and pharmacy costs, as well as clinical outcomes, between members in traditional health plans (N = 21,480) or in an HDHP (N = 971). They also compared outcomes for those choosing an HDHP compared with members offered only an HDHP option by their employer.

There were no significant differences in median changes in glycated hemoglobin values or in low-density lipoprotein levels among the different plan options.

However, there was a small, but significant, difference in

the median number of asthma exacerbations among members enrolled in an HDHP compared with those in a traditional plan, with fewer exacerbations seen in the latter (P = .011). These results were not affected by whether a member had the ability to choose an HDHP, although more data are needed.

In addition, members switching to an HDHP had higher out-of-pocket pharmacy costs, but lower medical costs, in the year after switching from a traditional plan.

Furthermore, the health plan had significantly lower medical and pharmacy costs associated with members switching to an HDHP during that year.

The investigators noted that these results suggest that more studies are needed to evaluate the true impact of HDHP on healthcare costs and utilizations.

[Moore K, Dunn J, Mitchell M, et al. Clinical outcomes in high-deductible health plans.] ■

Pharmacists’ Knowledge Gap about Oncology Genetic Testing, Benefit Design Knowledge of pharmacogenomics—a collection of genomic factors contributing to individual variability in response to drug therapy—enhances the ability to diagnose, prevent, and treat disease. Although understanding the correct application of pharmacogenomics may be essential to providing cost-effective care, barriers include the absence of provider knowledge and inappropriate reimbursement strategies. Angela Luong, PharmD, and colleagues at OPTUMInsight conducted a survey of pharmacists regarding their knowledge of genetic testing and utilization strategies.

A total of 19 pharmacists at 4 different managed care organizations responded to the survey, revealing a basic lack of knowledge of pharmacogenomics (or personalized medicine). The majority of respondents (84%) agreed or strongly agreed that pharmacogenomics will have an impact on healthcare expenditures and that pharmacists should have a good knowledge base of pharmacogenomicsrelated drug therapies and tests; however, the majority (84%) did not routinely have much education in this area.

Overall, 95% of participants scored <60% on a pharmacogenomics knowledge test.

In addition, knowledge of pharmacogenomics does not necessarily have a direct impact on patient care or

benefit design. Only 47% (n = 9) of respondents said their plan requires prior authorization (PA) for the use of the US Food and Drug Administration–approved companion diagnostic test for vemurafenib compared with 58% (n = 11) of respondents whose plans require a PA for the companion test for crizotinib. By contrast, only 16% (n = 3) of respondents said their plans require testing for HER2 mutation before prescribing trastuzumab compared with 58% (n = 11) of respondents whose plans do not require testing and 26% (n = 5) who did not know whether their plans require such testing.

Furthermore, the majority of respondents did not know whether their plans had reimbursement policies related to pharmacogenomics. Overall, this survey reveals gaps in pharmacists’ knowledge of pharmacogenomics utility and its related benefit design strategies. As a result of the growing impact of personalized medicine and tests for pharmacogenomics, understanding and designing appropriate benefit policies are essential; the group at OPTUMInsight plans on continuing this research with a larger pharmacist population. [Luong A, Lal L, King K, et al. Assessment for clinical utility of currently available oncology genetic tests and assessment of pharmacogenomics knowledge of pharmacists.] ■

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For your patients with type 2 diabetes who need more than A1C control, choose Levemir ® (insulin detemir [rDNA origin] injection)

24/7 GLUCOSE CONTROL MORE

Karen’s doctor said taking Levemir ® (insulin detemir [rDNA origin] injection) once-daily may get her the control she needs & more Low rates of hypoglycemia In 1 study, approximately 45% of patients in each treatment arm achieved A1C <7% with no hypoglycemic events within the last 4 weeks of observation.1 t A single major hypoglycemic event was reported in the 70-90 mg/dL group; no major hypoglycemic events in the 80-110 mg/dL group t Minor hypoglycemia rates were 5.09 (70-90 mg/dL) and 3.16 (80-110 mg/dL) per patient-year*

From a 20-week, randomized, controlled, multicenter, open-label, parallel-group, treat-to-target trial using a self-titration algorithm in insulin-naïve patients with type 2 diabetes, A1C ≥7% and ≤9% on OAD therapy randomized to Levemir® and OAD (1:1) to 2 different fasting plasma glucose (FPG) titration targets (70-90 mg/dL [n=121] or 80-110 mg/dL [n=122]). At study end, in the 80-110 mg/dL group, 55% of patients achieved goal (A1C <7%) with A1C decrease of 0.9%. The mean A1C was 7%.1

Covered on more than 90% of managed care plans2† hypoglycemia usually reflects the time action profile of the administered insulin formulations. Glucose monitoring is essential for all patients receiving insulin therapy. Any changes to an insulin regimen should be made cautiously and only under medical supervision.

Needles and Levemir ® FlexPen® must not be shared.

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Levemir ®. Adverse reactions associated with Levemir ® include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus. Careful glucose monitoring and dose adjustments of insulin, including Levemir ®, may be necessary in patients with renal or hepatic impairment.

Levemir ® has not been studied in children with type 2 diabetes, and in children with type 1 diabetes under the age of six.

Indications and Usage Levemir ® (insulin detemir [rDNA origin] injection) is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use: Levemir ®isnotrecommendedforthetreatmentof diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.

Important Safety Information Levemir ® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.

Do not dilute or mix Levemir® with any other insulin solution, or use in insulin infusion pumps. Do not administer Levemir® intravenously or intramuscularly because severe hypoglycemia can occur.

Hypoglycemia is the most common adverse reaction of insulin therapy, including Levemir®. The timing of

Please see brief summary of Prescribing Information on adjacent page.

Needles are sold separately and may require a prescription in some states. *Minor=SMPG <56 mg/dL and not requiring third-party assistance.

On your iPhone®

Scan the QR code to download the NovoDose™ app to know how to optimally dose Levemir®

†

Intended as a guide. Lower acquisition costs alone do not necessarily reflect a cost advantage in the outcome of the condition treated because other variables affect relative costs. Formulary status is subject to change.

References: 1. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE™ Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE™ study. Diabetes Obes Metab. 2009;11(6):623-631. 2. Data on file. Novo Nordisk Inc, Princeton, NJ. iPhone ® is a registered trademark of Apple, Inc. FlexPen® and Levemir ® are registered trademarks and NovoDose™ is a trademark of Novo Nordisk A/S. © 2012 Novo Nordisk Printed in the U.S.A. 0911-00005042-1 April 2012

LEVEMIR® (insulin detemir [rDNA origin] injection) Rx ONLY BRIEF SUMMARY. Please consult package insert for full prescribing information.

INDICATIONS AND USAGE: LEVEMIR® is indicated to improve glycemic control in adults and children with diabetes mellitus. Important Limitations of Use: LEVEMIR® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.

CONTRAINDICATIONS: LEVEMIR® is contraindicated in patients with hypersensitivity to LEVEMIR® or any of its excipients. Reactions have included anaphylaxis.

WARNINGS AND PRECAUTIONS: Dosage adjustment and monitoring: Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.

Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment. As with all insulin preparations, the time course of action for LEVEMIR® may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity. Administration: LEVEMIR® should only be administered subcutaneously. Do not administer LEVEMIR® intravenously or intramuscularly. The intended duration of activity of LEVEMIR® is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia. Do not use LEVEMIR® in insulin infusion pumps. Do not dilute or mix LEVEMIR® with any other insulin or solution. If LEVEMIR® is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR® and the mixed insulin may be altered in an unpredictable manner. Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR®. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia. The prolonged effect of subcutaneous LEVEMIR® may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Hypersensitivity and allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR®. Renal Impairment: No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment.

Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with renal impairment. Hepatic Impairment: Nondiabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with hepatic impairment. Drug interactions: Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia.

ADVERSE REACTIONS: The following adverse reactions are discussed elsewhere: Hypoglycemia; Hypersensitivity and allergic reactions. Clinical trial experience: Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR® clinical trials in patients with type 1 diabetes mellitus and

type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings.

Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Pharyngitis Influenza-like illness Abdominal Pain

LEVEMIR®, % (n = 767) 26.1 22.6 9.5 7.8 6.0

NPH, % (n = 388) 21.4 22.7 8.0 7.0 2.6

Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Back pain Influenza-like illness Gastroenteritis Bronchitis

LEVEMIR®, % (n = 161) 26.7 14.3 8.1 6.2 5.6 5.0

Glargine, % (n = 159) 32.1 19.5 6.3 8.2 4.4 1.9

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache

LEVEMIR®, % (n = 432) 12.5 6.5

NPH, % (n = 437) 11.2 5.3

Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Pharyngitis Gastroenteritis Influenza-like illness Abdominal pain Pyrexia Cough Viral infection Nausea Rhinitis Vomiting

LEVEMIR®, % (n = 232) 35.8 31.0 17.2 16.8 13.8 13.4 10.3 8.2 7.3 6.5 6.5 6.5

NPH, % (n = 115) 42.6 32.2 20.9 11.3 20.9 13.0 6.1 4.3 7.8 7.0 3.5 10.4

Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR®. Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR® clinical trials. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a blood glucose below 50 mg/ dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose < 56 mg/dL (<50 mg/dL in Study A and C) that was self-treated by the patient. The rates of hypoglycemia in the LEVEMIR® clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR®-treated patients and non-LEVEMIR ®-treated patients (see Tables 5 and 6).

Table 5: Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 16 weeks In combination with insulin aspart Twice-Daily Twice-Daily NPH LEVEMIR® Severe hypo- Percent of patients 10.6 8.7 with at least 1 event glycemia (14/132) (24/276) (n/total N) Event/patient/year 0.52 0.43 Non-severe Percent of patients 88.0 89.4 hypoglycemia (n/total N) (243/276) (118/132) Event/patient/year 26.4 37.5

Study B Type 1 Diabetes Adults 26 weeks In combination with insulin aspart Twice-Daily Once-Daily LEVEMIR® Glargine

Study C Type 1 Diabetes Adults 24 weeks In combination with regular insulin Once-Daily Once-Daily NPH LEVEMIR®

Study D Type 1 Diabetes Pediatrics 26 weeks In combination with insulin aspart Once- or Twice Once- or Twice Daily LEVEMIR® Daily NPH

5.0 (8/161)

10.1 (16/159)

7.5 (37/491)

10.2 (26/256)

15.9 (37/232)

20.0 (23/115)

0.13 82.0 (132/161) 20.2

0.31 77.4 (123/159) 21.8

0.35 88.4 (434/491) 31.1

0.32 87.9 (225/256) 33.4

0.91 93.1 (216/232) 31.6

0.99 95.7 (110/115) 37.0

Table 6: Hypoglycemia in Patients with Type 2 Diabetes

Severe hypo- Percent of patients with at least 1 event glycemia (n/total N) Event/patient/year Non-severe Percent of patients hypoglycemia (n/total N) Event/patient/year

Study E Type 2 Diabetes Adults 24 weeks In combination with oral agents Twice-Daily NPH Twice-Daily LEVEMIR® 0.4 2.5 (1/237) (6/238) 0.01 0.08 40.5 64.3 (96/237) (153/238) 3.5 6.9

Insulin Initiation and Intensification of Glucose Control: Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy: Long-term use of insulin, including LEVEMIR®, can cause lipodystrophy at the site of repeated insulin injections.

Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy. Weight Gain: Weight gain can occur with insulin therapy, including LEVEMIR®, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema: Insulin, including LEVEMIR®, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Allergic Reactions: Local Allergy: As with any insulin therapy, patients taking LEVEMIR ® may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR® reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy. Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks. Systemic Allergy: Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR®, and may be life-threatening. Antibody Production: All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LEVEMIR®, antibody development has been observed with no apparent impact on glycemic control. Postmarketing experience: The following adverse reactions have been identified during post approval use of LEVEMIR®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported during post-approval use of LEVEMIR® in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR®. To avoid medication errors between LEVEMIR® and other insulins, patients should be instructed always to verify the insulin label before each injection.

Study F Type 2 Diabetes Adults 22 weeks In combination with insulin aspart Once- or Twice Daily LEVEMIR® Once- or Twice Daily NPH 1.5 4.0 (3/195) (8/199) 0.04 0.13 32.3 32.2 (63/195) (64/199) 1.6 2.0

More detailed information is available upon request.

For information about LEVEMIR® contact: Novo Nordisk Inc., 100 College Road West Princeton, NJ 08540 1-800-727-6500 www.novonordisk-us.com Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark Revised: 1/2012 Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo Nordisk A/S. LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents pending.

FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending. © 2005-2012 Novo Nordisk 0212-00007333-1 2/2012

JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other healthcare experts who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal.

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewersâ&#x20AC;&#x2122; names will be published online at the end of the year.

Please indicate at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted to AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to) those listed below.

Please mark the categories that apply to your expertise: Administration/management Benefit design Disease management/state (eg, asthma, diabetes, heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@engagehc.com Your Information _______________________________________________________________________________________ First Name

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Tell your patients about NovoTwist®, the first and only single-twist needle attachment on the market.

GOOD DESIGN

The benefits of NovoTwist® are:

Winner of the US Good Design™ award1

• Less time consuming for patients to attach • Features an audible and tactile confirmatory click for correct attachment • Available in 30G (8mm) and 32G Tip (5mm) needles Available for use with FlexPen® and other compatible Novo Nordisk devices.*

For more information, visit myflexpen.com or call 1-800-727-6500

* Designed to be used with Levemir® FlexPen®, NovoLog® FlexPen®, NovoLog® Mix 70/30 FlexPen®, and other compatible Novo Nordisk delivery devices. Please refer to the delivery device user manual to see if NovoTwist® can be used with your device.

Also refer to the user manual for information on assembly and injection.

Needles are sold separately and may require a prescription in some states.

Reference: 1. http://www.chi-athenaeum.org/gdesign/2010/medical/index.html

FlexPen®, Levemir®, NovoLog®, and NovoTwist® are registered trademarks of Novo Nordisk A/S. © 2011 Novo Nordisk

Printed in the U.S.A.

0311-00002127-1

April 2011

BUSINESS

Original research

Recent Developments, Utilization, and Spending Trends for Pompe Disease Therapies Jing guo, BPharm; christina M.l. Kelton, PhD; Jeff J. guo, PhD

Jing Guo

Stakeholder Perspective, page 188

Am Health Drug Benefits.

2012;5(3):182-189 www.AHDBonline.com Disclosures are at end of text

Background: Pompe disease is a rare condition, with an incidence rate estimated to be between 1 in 40,000 and 1 in 300,000 live births worldwide. For an infant who contracts the disease, which is an inherited metabolic myopathy caused by deficiency of the acid alphaglucosidase (GAA) enzyme in lysosomal cells, the survival rate to age 1 year is estimated to be 25.7%. Before 2006, no therapies were available for this disease.

Objectives: The goals of this study were to review recent developments in therapies for Pompe disease, including the US Food and Drug Administration (FDA) approval of 2 biologic drugs, and to describe the associated drug utilization and spending trends in the US Medicaid program for patients with this disease.

Methods: We reviewed 2 recently approved therapies for Pompe disease and compared their indications, as well as their efficacy and safety profiles. A retrospective analysis was performed using the national Medicaid pharmacy claims database. Quarterly prescriptions and reimbursement amounts were calculated for each drug from 2006 quarter 2 through 2011 quarter 2.

Average per-prescription spending was calculated by dividing the drug reimbursement by the number of prescriptions written for that drug.

Results: Myozyme (alglucosidase alfa, recombinant human GAA) and Lumizyme (alglucosidase alfa), the first 2 enzyme replacement therapies available for Pompe disease, were approved as orphan drugs by the FDA in 2006 and in 2010, respectively. Myozyme is indicated for infantile-onset Pompe disease; Lumizyme is indicated for patients aged â&#x2030;Ľ8 years. Although both drugs have been shown to improve patient survival rates, they both also have a boxed warning, because of the possibility of life-threatening allergic reactions. Moreover, Lumizyme has a restricted distribution system to ensure it is used by the correct patient population. In 2010, Medicaid spending for Myozyme was $3.6 million. In the first 2 quarters of 2011, Medicaid spending for Lumizyme was $1.8 million. Prescriptions for Myozyme increased from 1 in 2006 quarter 2 to 127 in 2011 quarter 2, whereas prescriptions for Lumizyme increased from 6 in 2010 quarter 3 to 60 in 2011 quarter 2. During the same period, expenditures rose from $9450 to $930,459 for Myozyme and from $119,691 to $1.16 million for Lumizyme. The average price per prescription was approximately $10,000 for Myozyme and approximately $20,000 for Lumizyme over the study period.

Conclusion: As can be expected after the FDAâ&#x20AC;&#x2122;s approval of Myozyme and Lumizyme, Medicaid beneficiaries have experienced rising utilization of the 2 therapies. Spending by Medicaid has increased proportionately, implying a steady per-prescription average price for both drugs where if both numerator and denominator increase at the same rate, the ratio (price) should remain the same. New promising therapies for Pompe disease are currently being studied.

Miss Jing Guo is a PhD student at James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center; Dr Kelton is Professor, College of Business, University of Cincinnati; and Dr Jeff J. Guo is Professor, James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, OH. A version of this work was presented at the 17th Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research in Washington, DC, June 4-6, 2012.

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Recent Developments in Pompe Disease

P

ompe disease is a rare condition, with a global incidence rate estimated to be between 1 in 40,000 (0.0025%) and 1 in 300,000 (0.0003%) live births.1 According to a study published in 1998, the annual incidence of Pompe disease in New York City was estimated to be approximately 1 in 40,000 births, and approximately 90 babies are assumed born with Pompe disease in the United States annually.2 A similar incidence rate was found in the Dutch population (1 in 40,000 births), a relatively lower rate was found among the Chinese (1 in 50,000 births; 0.0020%), and a higher rate was seen among African Americans (1 in 31,000 births; 0.0032%).2-4 In 1998, the total number of patients with Pompe disease was estimated to be between 1900 and 3000 in the United States.2 By 2004, the estimated number of patients with Pompe disease was between 5000 and 10,000 worldwide.5 Pompe disease is named after Johannes Cassianus Pompe, the physician who was first to identify it as a glycogen storage disease in 1932. Pompe disease is also referred to as glycogen storage disease (GSD) type II (GSD II) or acid maltase deficiency.6 For an infant who contracts the disease, the survival rate to age 12 months is estimated to be 25.7%.7 As an autosomal recessive disease, Pompe disease is caused by an acid alpha-glucosidase (GAA) gene disorder that leads to the GAA deficiency in this disease.

GAA is the only enzyme that is active in the acidic milieu of the lysosomes for degradation of glycogen.8 Because the glycogen cannot be broken down effectively into a simpler sugar (glucose), which is the main source of body energy, the accumulation of the glycogen in organs and tissues causes myopathy, with progressive muscle weakness. The heart, liver, respiratory system, and nervous system are all affected.

The goals of this study were to review recent developments in Pompe disease therapies and describe drug utilization and spending trends associated with this disease in the US Medicaid program.

The 2 Forms of Pompe Disease Depending on whether symptoms occur within the first 6 months after birth or, alternatively, later in life, Pompe disease is classified as infantile-onset or lateonset illness, respectively.3 The late-onset form of the disease progresses more slowly than the infantile-onset and can present in patients as old as age 60 years.

Common signs and symptoms of infantile-onset disease include cardiomegaly, hypotonia (ie, muscle weakness), hepatomegaly, cardiomyopathy, respiratory distress, enlarged tongue (ie, macroglossia), feeding difficulties, and failure to thrive.7 Heart failure and respi-

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KEY POINTS ➤

➤

➤

➤

➤

Pompe disease is a rare inherited metabolic myopathy caused by deficiency of the acid alphaglucosidase enzyme in lysosomal cells, which causes progressive muscle weakness.

With a global incidence rate estimated to be between 1 in 40,000 and 1 in 300,000 live births, infants who contract the disease have an approximate 25.7% survival rate to age 1 year.

Before 2006, no effective treatments were available for Pompe disease.

Like most biologics, Myozyme and Lumizyme, the 2 recently approved enzyme replacement therapies for Pompe disease, are costly; the cost of Lumizyme is approximately double that of Myozyme.

Because these new drugs can have serious lifethreatening adverse events, their use should be carefully monitored by Medicaid and by other payers.

ratory weakness are the most common causes of death among infants with Pompe disease.3 The primary clinical manifestations of late-onset disease include progressive proximal muscle weakness (especially in the body and legs), exercise intolerance, exertional dyspnea, sleep apnea, and joint contractures.

For those who contract the disease in childhood or adolescence, additional symptoms include scoliosis, hepatomegaly, macroglossia, and cardiac hypertrophy.9 The main cause of death for patients with late-onset Pompe disease is respiratory failure.9

Current Treatments Before 2006, there was no effective treatment for Pompe disease, despite several decades of studying potential treatments in clinical trials. Unsuccessful trials involved altering the synthesis of glycogen, bone-marrow transplantation, and administration of unphosphorylated enzyme isolated from Aspergillus niger or from human placenta.10 Myozyme On April 28, 2006, under priority review, the US Food and Drug Administration (FDA) approved a Biologic License Application for the orphan drug Myozyme (alglucosidase alfa, recombinant human [rh]GAA) for patients with Pompe disease.11 Myozyme received marketing authorization in the European Union slightly earlier, in March 2006.12 Myozyme is an enzyme replacement therapy (ERT) drug, which uses recombinant DNA technology to produce the enzyme from Chinese hamster ovary cells.12 Clinical studies have

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shown that Myozyme can improve ventilator-free survival in patients with infantile-onset Pompe disease.13 This therapy has several adverse reactions, including pneumonia, respiratory failure and distress, infections, and fever. Myozyme may also be involved in life-threatening allergic reactions, heart or lung failure, and immune-mediated reactions.13 A boxed warning is included in the Myozyme label to caution about possible life-threatening allergic reactions.11

Lumizyme On May 25, 2010, the FDA approved Lumizyme (alglucosidase alfa), the first treatment for late-onset Pompe disease, which is indicated for patients aged ≥8 years (younger children may experience more rapid disease progression while receiving Lumizyme).1 Also using the ERT principle, Lumizyme is believed to work by replacing the deficient GAA enzyme, thereby allowing

the breakdown of glycogen in the heart and skeletal muscle cells. However, although both Myozyme and Lumizyme have the same generic ingredient and work by enzyme replacement, the FDA considers the 2 treatments as different drugs, with distinct manufacturing processes, as well as some biologic differences.

Lumizyme cannot be used in patients who have cardiac hypertrophy (enlarged heart), because it may cause life-threatening allergic reactions, heart or lung failure, and immune-mediated reactions—the same serious side effects as those associated with Myozyme. Moreover, according to postmarketing experience with Lumizyme therapy, the drug may be involved in cardiorespiratory arrest, respiratory failure, hemothorax, pneumothorax, cardiac failure, sepsis, aortic dissection, cerebrovascular accident, and skin necrosis.14 Lumizyme is available only through a restricted distribution system called the Lumizyme Alglucosidase Alfa

Table Comparing Myozyme and Lumizyme for Pompe Disease Variable

Myozyme (alglucosidase alfa, rhGAA)

Lumizyme (alglucosidase alfa)

Source of biologics

Derived from CHO cells

Derived from CHO cells

Mechanism

Enzyme replacement therapy

Enzyme replacement therapy

Manufacturing process

160-L bioreactor

4000-L bioreactor

Dosage

20 mg/kg body weight, administered every 2 weeks

20 mg/kg body weight, administered every 2 weeks

Formulation

50 mg/vial

50 mg/vial

Route of administration

Intravenous infusion

Intravenous infusion

Indications

Only for infantile-onset Pompe disease

Only for patients aged ≥8 years

Efficacy profile

Improve ventilator-free survival (based on 39 patients with infantileonset Pompe disease, aged 1 month-3.5 years)

Reduce the accumulated glycogen in heart and skeletal muscle cells (based on 90 patients aged 10-70 years with lateonset Pompe disease)

Safety profile

Serious AEs include life-threatening allergic reactions, heart and lung failure, and immune-mediated reactions; boxed warning

Serious AEs include life-threatening allergic reactions, anaphylaxis, and immune-mediated reactions; boxed warning; only available through a restricted distribution system for patients aged ≥8 years; the Lumizyme Alglucosidase Alfa Control and Education program is approved by the FDA

FDA approval date

April 28, 2006

May 25, 2010

Manufacturer

Genzyme

Genzyme

AEs indicates adverse events; CHO, Chinese hamster ovary; FDA, US Food and Drug Administration; rhGAA, recombinant human acid alpha-glucosidase.

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Recent Developments in Pompe Disease

Control and Education (ACE) program,1 one of the FDAâ&#x20AC;&#x2122;s approved risk evaluation and mitigation strategy programs. The primary goal of the ACE program is to ensure that known risks of anaphylaxis and severe allergic reactions associated with Lumizyme are communicated to patients, caregivers, and prescribers.

ERT has been tried for some lysosomal storage diseases, such as Gaucher disease, Fabry disease, and mucopolysaccharidoses (MPS I, MPS II, MPS VI).15 With these first-approved ERTs for Pompe disease (GSD II) comes the hope that ERT may also prove effective for other GSDs as well. The current primary treatment for other GSDs involves control of hypoglycemia.16 The Table summarizes the basic characteristics of Myozyme and Lumizyme therapies.

Methods A retrospective analysis was conducted for the period between the second quarter of 2006 (first approval of Myozyme) and the second quarter of 2011 (the most current data available). The primary data source is the publicly available National Summary Files for the Medicaid State Drug Utilization Data, which are maintained by the Centers for Medicare & Medicaid Services (CMS). The database covers Medicaid beneficiaries in 49 states (all states except Arizona) and the District of Columbia, and it is restricted to outpatient pharmaceuticals.17 The National Summary Files were compiled by aggregating state databases. Because the data are collected as part of the Medicaid Rebate Program, they include fee for service but not managed Medicaid pharmacy claims.

Each data record included the National Drug Code (NDC), drug name, year and quarter of Medicaid expenditure, number of pharmacy claims, number of units, and total pharmacy reimbursement amount, including costs of the drug and its administration. We searched the database for Myozyme and for Lumizyme.

For each drug, quarterly prescription counts and reimbursement amounts were calculated by summing data across individual NDCs for the 2 drugs. Quarterly perclaim pharmacy reimbursement, as a proxy for drug price, was computed for the 2 drugs. Reimbursements are inclusive of the costs for the drug ingredients and administration, but they do not include manufacturer rebates.

All of the data analyses were conducted using the SAS software package for Windows (Version 9.1.3; SAS Institute, Inc; Cary, NC).

Results Prescriptions for Myozyme increased from 1 in 2006 quarter 2 to 127 in 2011 quarter 2, whereas prescriptions for Lumizyme increased from 6 in 2010 quarter 3 to 60 in

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2011 quarter 2. During the same period, expenditures rose from $9450 to $930,459 for Myozyme and from $119,691 to $1.16 million for Lumizyme. The average price per prescription was approximately $10,000 for Myozyme and approximately $20,000 for Lumizyme over the study period.

Figure 1 depicts the quarterly trends of utilization for Myozyme and Lumizyme, and Figure 2 describes the quarterly trends of reimbursement (or Medicaid spending) for Myozyme and Lumizyme. As seen in Figure 3, average reimbursement per prescription (or spending per prescription) as a proxy for drug price remained high and stable over time.

Discussion Because Myozyme and Lumizyme are the first 2 therapies to be approved by the FDA for Pompe disease, the increase in their utilization is not surprising. Moreover, because of the higher proportion of infants and children among Medicaid beneficiaries than among the population as a whole, some incidence of Pompe disease is certainly expected. The price per prescription for Lumizyme was essentially double the price for Myozyme. This difference is likely a result of the higher dosages required for older/larger patients with late-onset Pompe disease compared with small infants with Pompe disease (see Table).

The price for both medications is high and is expected to remain so. The 2 therapies were approved as orphan drugs, which are usually priced higher than drugs with a large target market.

The high cost of the medication, and the potential for off-label use and serious adverse events related to heart or lung failure, argue for careful monitoring of these medications by Medicaid, as well as by other payers.

Given patent protection, coupled with the complexity of production procedures for biologic therapies, it is unlikely that another company will compete anytime soon with Genzyme, the manufacturer of both drugs.

The high cost of the medication, and the potential for off-label use and serious adverse events related to heart or lung failure, argue for careful monitoring of these medications by Medicaid, as well as by other payers.

Potential Future Treatments In the United States, currently 18 clinical trials are studying Pompe disease and its treatment and are recruiting patients.18 Among them is a study about the

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Figure 1 Quarterly Utilization of Myozyme and Lumizyme in Medicaid, from 2006 Quarter 2 to 2011 Quarter 2 Myozyme Lumizyme 160 140

Number of prescriptions

120 100 80 60 40 20 0 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 2006 2006 2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009 2009 2010 2010 2010 2010 2011 2011

Period

Figure 2 Quarterly Reimbursement (or Spending) on Myozyme and Lumizyme in Medicaid, from 2006 Quarter 2 to 2011 Quarter 2 Myozyme Lumizyme 1,600,000

Amount of spending, current $

1,400,000 1,200,000 1,000,000 800,000 600,000 400,000 200,000 0 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 2006 2006 2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009 2009 2010 2010 2010 2010 2011 2011

Period

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Figure 3 Average Reimbursement (or Spending) per Prescription for Myozyme and Lumizyme in Medicaid, from 2006 Quarter 2 to 2011 Quarter 2 Myozyme Lumizyme 22,000

Spending per perscription, current $

20,000 18,000 16,000 14,000 12,000 10,000 8000 6000 4000 2000 0 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 2006 2006 2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009 2009 2010 2010 2010 2010 2011 2011

Period

safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BMN-701 (GILT-tagged rhGAA) in patients with late-onset Pompe disease. BMN-701, which is manufactured by BioMarin, is an rhGAA. It can increase the number of mannose-6-phosphates that provide better delivery of GAA to the lysosome, where it causes Pompe disease, thereby improving efficacy, with less enzyme.19 Because the enzyme for Pompe disease needs life-long infusions, a limitation of ERT is the high cost of the recombinant enzyme and the extremely high doses of the drug.8 BMN-701 may solve this problem by requiring lower enzyme doses, at a lower cost, which is a big improvement over ERT. Gene therapy is another possibility for the treatment of Pompe disease. The idea is to create a permanent GAA source through the use of adenoviral (Ad), adenoassociated (AAV), or hybrid Ad-AAV vectors to introduce a correct sequence coding gene for the deficient enzyme into cells. The first clinical trial for recombinant AAV-mediated gene-based therapy for Pompe disease achieved some success.20 Nutrition and exercise therapy may help patients with late-onset Pompe disease to increase muscle protein synthesis and muscle fibers.21According to Schoser and colleagues, nutrition and exercise therapy includes a combination of a high-protein, low-carbohydrate diet

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and daily conditioning aerobic exercise.8 Among all known treatments for Pompe disease, it is the only therapy that can slow the progressive deterioration in muscle function.22

Nutrition and exercise therapy may help patients with late-onset Pompe disease to increase muscle protein synthesis and muscle fibers.

Limitations This study has a number of limitations. First, patientspecific information was not available in the national Medicaid pharmacy file provided by CMS. Therefore, it was not possible to determine the cost per patient and/or indication for medication use.

In addition, adherence to medication therapy could not be assessed. As with all database studies, misclassification bias may be present if the CMS data contain reporting errors. All data are prerebate; hence, to some degree (that we cannot measure), they overstate the actual acquisition cost to the US Medicaid program.

Moreover, the results of this study are specific to the Medicaid population, which is heavily comprised of low-

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income women and children. Hence, they do not necessarily represent utilization and expenditure trends in other populations.

Finally, comparing the pricing data among states, as well as exploring data regarding utilization trends in the commercial population, are beyond the scope of this article.

Conclusion Medicaid spent $3.6 million in 2010 on Myozyme and $1.8 million in 2011 on Lumizyme, the only 2 FDAapproved therapies (both ERTs) for the treatment of Pompe disease. ERT has been a major breakthrough in the treatment of patients with Pompe disease. It can change the course of the disease and can prolong a patient’s survival, although there are still many challenges. Other promising treatments for Pompe disease that are currently under study may expand the treatment options in the near future. ■ Author Disclosure Statement The authors have no conflict of interest concerning this research. They did not receive any consulting fees, grants, honoraria, patents, royalties, stocks, or other financial or material gain that may involve the subject matter of the article. Dr Jeff J. Guo and Dr Kelton have received research grants from Novartis, Johnson & Johnson, and Eli Lilly.

Miss Jing Guo has nothing to disclose.

References 1. FDA approves new treatment for late-onset Pompe disease [news release]. Silver Spring, MD: US Food and Drug Administration; May 25, 2010. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2010/ucm213282.htm. Accessed

May 9, 2012.

2. Martiniuk F, Chen A, Mack A, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79:69-72.

3. Di Rocco M, Buzzi D, Tarò M. Glycogen storage disease type II: clinical overview.

Acta Myologica. 2007;26:42-44.

4. Ausems MG, ten Berg K, Kroos MA, et al. Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency. Community Genet. 1999;2:91-96.

5. Werber Y. Lysosomal storage diseases market. Nat Rev Drug Discov. 2004;3:9-10.

6. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267-288.

7. Kishnani PS, Hwu WL, Mandel H, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148: 671-676.

8. Schoser B, Hill V, Raben N. Therapeutic approaches in Glycogen Storage Disease type II (GSDII)/Pompe disease. Neurotherapeutics. 2008;5:569-578.

9. Winkel LP, Hagemans ML, van Doorn PA, et al. The natural course of non-classic Pompe’s disease; a review of 225 published cases. J Neurol. 2005;252:875-884.

10. Kishnani PS, Howell RR. Pompe disease in infants and children. J Pediatr. 2004; 144(5 suppl):S35-S43.

11. FDA approves first treatment for Pompe disease [news release]. Silver Spring, MD: US Food and Drug Administration; April 28, 2006. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/2006/ucm108645.htm. Accessed May 9, 2012.

12. Erasmus MC Pompe Center. Treatment. www.erasmusmc.nl/klinische_genetica/ research/pompe_center/behandeling/?lang=en. Accessed May 9, 2012.

13. Myozyme [prescribing information]. Cambridge, MA: Genzyme Corporation; 2006.

14. Lumizyme [prescribing information]. Cambridge, MA: Genzyme Corporation; 2010.

15. Neufeld EF. Enzyme replacement therapy—a brief history. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, England: Oxford PharmaGenesis; 2006.

16. Hendriksz CJ, Gissen P. Glycogen storage disease. Paediatr Child Health. 2011;21:84-89.

17. Centers for Medicare & Medicaid Services. State Drug Utilization Data. www.cms. hhs.gov/MedicaidDrugRebateProgram/SDUD/list.asp#TopOfPage. Accessed December 9, 2011.

18. ClinicalTrials.gov. Pompe trials. www.clinicaltrials.gov/ct2/results?term=pompe.

Accessed May 23, 2012.

19. BioMarin Company. BMN-701: IFG2-GAA for Pompe. www.bmrn.com/ patients-physicians/pompe-disease.php. Accessed May 9, 2012.

20. Byrne BJ, Falk DJ, Pacak CA, et al. Pompe disease gene therapy. Hum Mol Genet.

2011;20(R1):R61-R68.

21. Slonim AE, Bulone L, Minikes J, et al. Benign course of glycogen storage disease type IIb in two brothers: nature or nurture? Muscle Nerve. 2006;33:571-574.

22. Slonim AE, Bulone L, Goldberg T, et al. Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy. Muscle Nerve.

2007;35:70-77.

STAKEHOLDER PERSPECTIVE Beyond “Patient Amusement”: New Treatments and Genetic Disease Voltaire once remarked that “the role of the doctor is to amuse the patient whilst nature takes its course.”

Until recently, this comment would seem especially appropriate for how physicians addressed the needs of patients with certain rare genetic diseases. In most instances, these diseases—which result from the combination of recessive genes and are more common than those resulting from spontaneous mutations— had no effective therapies or interventions.

Individuals with genetic diseases, whether from inborn errors of metabolism, sickle-cell anemia, or other conditions, suffered greatly.

More recently, the role of the physician has evolved

from “amusing the patient” to being able to offer some alleviation to the patient’s suffering. This “holistic healing,” as Egnew calls it, involves transcending suffering.1 This transcendence involves shifting the patient’s relationship to the illness. Although some of this shift involves helping the patient accept his or her fate, the rest involves providing treatment when it is available.

The provision of said treatment, in this case for Pompe disease, is aptly discussed in the article by Guo and colleagues in this issue of American Health & Drug Benefits. The authors provide a review of Pompe disease and of current treatment options for this rare condition.

Most important, this article shows that because (Continued)

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STAKEHOLDER PERSPECTIVE (Continued) Myozyme and Lumizyme define the only treatment options for Pompe disease, one can infer several things.

PROVIDERS: Providers want to treat their patients holistically and effectively. The availability of new options to mitigate the patient’s suffering helps physicians do what they were meant to do—to help a “fellow creature in pain.”2 Physicians should be expected to use therapies at their disposal to treat specific conditions.

PAYERS: Payers should expect that costly biologic therapies will be used not only for Pompe disease but for other genetic conditions for which treatment options are limited. Some may even argue that health insurance, in its purest form, requires that health plans provide coverage for biologics, such as those used to treat Pompe disease. “Real insurance” pays for treatments that are unavoidable, prohibitively expensive, and appropriate for rare illnesses.3 If the evidence shows that the treatment meets the need, payers have

shown themselves amenable to stepping up and providing coverage.

Ultimately, why are these inferences important?

They become important because providers and payers want to do right by their patients/members, and, in doing so, they develop processes of assessing value for treatments that result in improved health and/or decreased suffering. Doing so becomes paramount and is beyond mere amusement.

Albert Tzeel, MD, MHSA, FACPE National Medical Director, HumanaOne & KMG Clinical Leadership & Policy Development 1. Egnew TR. Suffering, meaning and healing: challenges of contemporary medicine. Ann Fam Med. 2009;7:170-175.

2. Fordham University. Oath of Maimonides. www.fordham.edu/halsall/source/ rambam-oath.asp. Accessed June 10, 2012.

3. Kling A. Insulation versus insurance. Cato Unbound. January 8, 2007. www.cato-unbound.org/2007/01/08/arnold-kling/insulation-vs-insurance/.

Accessed June 10, 2012.

CALL FOR PAPERS Value-Based Care in Cardiometabolic Health American Health & Drug Benefits will be publishing a Theme Issue on Cardiometabolic Health 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.

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

Benefit designs and cardiometabolic outcomes Best practices in insulin control, lipid management, or blood pressure control Comparative effectiveness analyses of best therapies for cardiovascular health Cost-effectiveness comparisons New and emerging therapies Health plan initiatives in cardiometabolic health and wellness

• • • • • •

Hot topics in diabetes, obesity, or CVD Lifestyle strategies and cardiometabolic health Lipid management Medication adherence and diabetes progression New biomarkers for assessing cardiometabolic risk Prevention strategies for cardiometabolic risk reduction

Submission deadline for this issue is July 5, 2012. 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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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.

© 2012 Novo Nordisk

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